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 9,220,631
`
`__________
`
`
`DECLARATION OF DR. KIMBERLY CAMERON IN SUPPORT OF
`PATENT OWNERS’ CONTINGENT MOTION TO AMEND
`
`
`
`
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`
`
`Introduction .......................................................................................................... 1
`I.
`II. Qualifications and Compensation ........................................................................ 2
`III. Summary of Opinions ....................................................................................... 3
`IV. Relevant Legal Standards ................................................................................. 4
`A. Prior Art ............................................................................................................ 4
`B. Obviousness ...................................................................................................... 5
`V. Person of Skill in the Art (“POSA”) .................................................................... 7
`VI. Claim Construction ........................................................................................... 8
`VII. U.S. Patent NO. 9,220,631 ............................................................................... 9
`A. Specification ..................................................................................................... 9
`B. Substitute Claims ............................................................................................11
`C. IPR Proceedings .............................................................................................15
`VIII. Background On the Technology .....................................................................18
`A. Syringe Components and Use ........................................................................18
`B. Siliconization ..................................................................................................20
`C. Sterilization .....................................................................................................22
`D. VEGF Antagonists and Intravitreal Injections ...............................................24
`IX. Key Prior Art References Identified by Petitioner .........................................25
`A. Boulange .........................................................................................................25
`B. Sigg .................................................................................................................34
`C. Lam .................................................................................................................38
`X. Opinions .............................................................................................................40
`A. The Prior Art Does Not Disclose Each Element of the Claims .....................40
`1. The prior art does not teach a syringe barrel comprising from about 1 μg to
`less than about 25 μg silicone oil ......................................................................40
`2. The prior art does not teach a syringe having at least a 12 month shelf life
`
`44
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`
`
`i
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.002
`Regeneron v. Novartis, IPR2021-00816
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`

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`B. A POSA Would Not Have Been Motivated to Combine the Teachings of the
`Prior Art to Arrive at the Claimed Syringe ...........................................................50
`C. A POSA Would Not Have Expected to Arrive at the Claimed Syringe by
`Combining the Teachings of the Prior Art ...........................................................58
`D. Opinions Relating to Secondary Considerations ............................................61
`1. The Lucentis® pre-filled syringe meets the additional limitations reflected
`in the substitute claims .......................................................................................61
`2. It was surprising and unexpected that a syringe having less than about 25
`μg of silicone oil could achieve a stopper break loose force of less than 11 N
`over a 12-month shelf life ..................................................................................65
`XI. Declaration ......................................................................................................68
`
`
`
`
`ii
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.003
`Regeneron v. Novartis, IPR2021-00816
`
`

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`I.
`
`INTRODUCTION
`
`1.
`
`I, Kimberly Cameron Ph.D., submit this declaration on behalf of
`
`Novartis Pharma AG, Novartis Technology LLC, Novartis Pharmaceuticals
`
`Corporation, (collectively, “Patent Owners” or “Novartis”), as an expert witness
`
`regarding the proposed substitute claims of U.S. Patent No. 9,220,631 (“the ’631
`
`patent”).
`
`2.
`
`I understand that Regeneron Pharmaceuticals, Inc. (“Petitioner” or
`
`“Regeneron”) filed a petition for inter partes review (“IPR”) in Regeneron
`
`Pharmaceuticals, Inc. v. Novartis Pharma AG, IPR2021-00816 seeking
`
`cancellation of all claims of the ’631 patent. I further understand that the Patent
`
`Trial and Appeal Board (“Board”) of the U.S. Patent and Trademark Office
`
`(“PTO”) issued a decision on October 26, 2021, granting institution of inter partes
`
`review of the ’631 patent (“Institution Decision”).
`
`3.
`
`I understand that Novartis is submitting claim amendments in the
`
`alternative, if the current claims are found unpatentable. I have reviewed the
`
`proposed claim amendments submitted by Novartis in the substitute claims. I have
`
`been asked by Novartis to offer opinions on the obviousness of the substitute
`
`claims. This declaration sets forth my analysis and opinions based on my
`
`knowledge, experience, and the materials I have considered.
`
`
`
`1
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.004
`Regeneron v. Novartis, IPR2021-00816
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`4.
`
`In reaching my opinions, I have reviewed the Institution Decision, the
`
`petition for IPR, the Patent Owner’s preliminary response, and subsequent replies
`
`filed by the parties. I have also reviewed the supporting materials filed in the IPR
`
`proceeding, including the expert declarations, the prior art identified by the
`
`petitioner, particularly those cited by the PTAB in its decision granting institution,
`
`as well as literature cited herein.
`
`5.
`
`In my opinion, the substitute claims are not obvious in view of the
`
`prior art, including the prior art relied upon by Petitioner and considered by the
`
`Board in its October 26, 2021 decision.
`
`II. QUALIFICATIONS AND COMPENSATION
`
`6.
`
`I earned a B.S.in Mechanical Engineering from Princeton University
`
`in 1999. I then earned a M.S. in Mechanical Engineering from Stanford University
`
`in 2000, and a Ph.D. in Mechanical Engineering from Stanford University in 2004.
`
`7.
`
`I am a Principal for Engineering Systems Inc. (“ESi”), an engineering
`
`and scientific investigation and analysis firm, in the Mechanics and Materials
`
`practice. I specialize in design, failure analysis, and risk assessments of
`
`engineering structures and components. I have conducted hundreds of
`
`investigations on a wide range of engineering structures, and I have extensive
`
`experience in the area of biomedical devices and drug delivery devices. I have
`
`designed microneedles for drug delivery, syringes for wound irrigation and fluid
`2
`
`
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.005
`Regeneron v. Novartis, IPR2021-00816
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`

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`removal. I have also worked on injector pens and basic syringes with no
`
`mechanical advantage.
`
`8.
`
`Additional information regarding my background, professional
`
`experience, and published works are listed on my curriculum vitae, attached as Ex.
`
`2210.
`
`9.
`
`I am being compensated at my standard rate of $700/hour. My
`
`compensation is in no way contingent upon my opinions or the outcome of this
`
`proceeding.
`
`III. SUMMARY OF OPINIONS
`
`10. The substitute claims of the ’631 patent, are not obvious over the prior
`
`art, including that previously identified by the Petitioner in IPR2021-00816, at
`
`least because:
`
`(cid:120) The prior art does not teach a syringe barrel comprising from about 1 μg to
`
`about 25 μg silicone oil;
`
`(cid:120) A person of skill in the art (“POSA”) would not have been motivated to use
`
`from about 1 μg to about 25 μg of silicone oil in a syringe for intravitreal
`
`injection;
`
`(cid:120) A POSA would not have expected that a syringe barrel comprising from
`
`about 1 μg to about 25 μg of silicone oil and containing a VEGF antagonist
`
`would have a stopper break loose force of less than about 11 N, including, or
`3
`
`
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.006
`Regeneron v. Novartis, IPR2021-00816
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`

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`that such a syringe could maintain a break loose force less than 11N over a
`
`shelf life of twelve months;
`
`(cid:120) The Lucentis® pre-filled syringe is an embodiment of the substitute claims;
`
`and
`
`(cid:120) It was surprising and unexpected for a pre-filled syringe containing an
`
`ophthalmic solution comprising a VEGF antagonist and having from about 1
`
`μg to about 25 μg of silicone oil to achieve a stopper break loose force of
`
`less than 11 N and maintain it over a shelf life of twelve months.
`
`IV. RELEVANT LEGAL STANDARDS
`
`11.
`
`I have been retained by Patent Owner as an expert witness regarding
`
`the proposed substitute claims of the ’631 patent. This section provides my
`
`understanding of the appropriate legal standards as I understand them and have
`
`been informed by counsel.
`
`A.
`
`12.
`
`Prior Art
`
`I understand that, in this IPR proceeding, the prior art to the substitute
`
`claims of the ’631 patent includes patents and printed publications in the relevant
`
`field(s) that predate the ’631 patent’s priority date. I provide my opinions herein
`
`from the perspective of a POSA as of July 3, 2012, which I understand is the date
`
`of the earliest application to which the ’631 patent claims priority, and the date
`
`Petitioner and their expert, Mr. Koller, rely on for their obviousness analysis. Ex.
`
`
`
`4
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.007
`Regeneron v. Novartis, IPR2021-00816
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`2001 ¶ 30; IPR2021-0816, Paper 1, Petition for Inter Partes Review (Apr. 16,
`
`2021) at 24; Ex. 1003 ¶ 20. Mr. Koller admits that the ’631 patent is entitled to a
`
`priority date of October 23, 2012 at the earliest, and my opinions would not change
`
`if I consider this date in my analysis instead. Ex. 1003 ¶ 95.
`
`B. Obviousness
`
`13.
`
`I understand that a claim of a patent may be obvious to a person of
`
`ordinary skill in the art if the differences between the subject matter claimed in the
`
`patent and disclosed in the prior art are such that the claimed subject matter as a
`
`whole would have been obvious as of the priority date.
`
`14.
`
`I understand that obviousness is a determination of law based on
`
`various underlying determinations of fact. These determinations of fact include (1)
`
`the scope and content of the prior art; (2) the level of the ordinary skill in the art at
`
`the time the claimed invention was made; (3) the differences between the claimed
`
`invention and the prior art; and (4) the extent of any proffered objective “indicia”
`
`of non-obviousness.
`
`15. To understand the scope and content of the prior art, I understand that
`
`it is necessary to examine the field of the invention and the particular problem the
`
`invention was made to solve. The relevant prior art includes patents and printed
`
`publications in the field of the invention, and those from other fields that a person
`
`of ordinary skill would look to when attempting to solve the problem.
`5
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`
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.008
`Regeneron v. Novartis, IPR2021-00816
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`16.
`
`It is my understanding that in order to find a claim invalid as obvious,
`
`each element in each limitation of the claim must be disclosed, taught, or suggested
`
`by the relevant prior art in view of the knowledge of a POSA.
`
`17. Furthermore, I understand that, to render a patent claim invalid as
`
`obvious from a combination of references, there must be some evidence within the
`
`prior art as a whole to suggest the desirability, and thus the obviousness, of making
`
`the combination in a way that would produce the patented invention. In other
`
`words, there needs to be a motivation or reason to combine the known elements in
`
`the way claimed by the patent at issue. I also understand that, in addition to having
`
`a reason to combine the teachings of the prior art references, the POSA must have
`
`a reasonable expectation of success.
`
`18.
`
`It is my understanding that “objective indicia” of non-obviousness,
`
`also called secondary considerations, may be considered as part of a determination
`
`of obviousness. I understand that these factors may include, among others: the
`
`commercial success of the patented invention; the existence of a long-felt, unmet
`
`need in the field satisfied by the invention; failure of others to achieve the patented
`
`invention; unexpected or surprising results; initial skepticism of the invention by
`
`others in the field; the extent to which the inventors proceeded in a direction
`
`contrary to the accepted wisdom of those of ordinary skill in the art; and licensing
`
`of the patent.
`
`
`
`6
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.009
`Regeneron v. Novartis, IPR2021-00816
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`V.
`
`PERSON OF SKILL IN THE ART (“POSA”)
`
`19.
`
`I understand Patent Owner Novartis has proposed the following
`
`definition of the POSA:
`
`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.
`20.
`I understand that Petitioner has proposed two different standards for
`
`the person of ordinary skill in the art for the ’631 patent: one level of skill for the
`
`apparatus claims, and another level of skill for the method claims. With respect to
`
`the apparatus claims, I understand that Petitioner has proposed as follows:
`
`[a] person having ordinary skill in the art (“POSITA”) relevant to the
`’631 Patent as of July 3, 2012 would have had at least an advanced
`degree (Dipl.Ing, M.S., or Ph.D.), with research experience in
`mechanical engineering, biomedical engineering, materials science,
`chemistry, or a related field, or at least 2-3 years of professional
`experience in one or more of those fields. Furthermore, a POSITA
`would have had experience with (i) the design of pre-filled syringes;
`7
`
`
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.010
`Regeneron v. Novartis, IPR2021-00816
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`

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`and (ii) sterilization of drug delivery devices, including those
`containing sterilization-sensitive therapeutics. Sterilization
`experience would include experience with microbiology.
`
`Paper 1 (Petition) at 24.
`21. For the purposes of my analysis and opinions, I have applied Patent
`
`Owner’s definition of a POSA, but my opinions would not change if the Board
`
`were to adopt Petitioner’s definition. I had qualifications consistent with that of a
`
`POSA, under either definition, during the relevant time period.
`
`VI. CLAIM CONSTRUCTION
`
`22.
`
`I understand that the Board put forward constructions for certain terms
`
`from the ’631 patent. I utilize those constructions, which are recited below, in
`
`performing my analysis and opinions:
`
`(cid:120) “Stopper Break Loose Force” is construed to mean “the force required
`
`to make the plunger/stopper move from its resting position in the syringe
`
`barrel.”
`
`(cid:120) “Stopper Slide Force” is construed to mean “the force required to
`
`sustain movement of the stopper after movement has already begun.”
`
`(cid:120) “Terminally Sterilized” is construed to mean the “process whereby the
`
`outside of a pre-filled syringe is sterilized, while contact between the
`
`sterilizing agent and the drug product within the syringe is minimized.”
`
`
`
`8
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.011
`Regeneron v. Novartis, IPR2021-00816
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`

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`VII. U.S. PATENT NO. 9,220,631
`
`23. The ’631 patent relates to a small volume terminally sterilized pre-
`
`filled syringe (“PFS”) for intravitreal injection containing a VEGF antagonist and
`
`comprising low levels of silicone oil, and having low stopper break loose forces.
`
`Specification
`
`A.
`24. The ’631 patent specification explains that it is important for patient
`
`safety and drug integrity that a syringe and its contents are sufficiently sterile to
`
`avoid risks for patients, such as infection. Ex. 1001 at 1:14–18. The ’631 patent
`
`identifies terminal sterilization techniques, noting that sterilization can pose unique
`
`difficulties for small volume syringes, such as those use for injections into the eye.
`
`Id. at 1:22-30. The ’631 patent further explains that biologic molecules are
`
`particularly sensitive to sterilization, such as cold gas sterilization, thermal
`
`sterilization, or irradiation. Therefore, a syringe containing biologic therapeutics
`
`must be suitably sealed such that the therapeutic is not compromised during
`
`sterilization, but also maintain its ease of use. In other words, the force required to
`
`depress the plunger during administration must remain low. Id. at 1:31-39.
`
`25. Additionally, although silicone oil is typically applied to the inside of
`
`the syringe barrel to allow ease of use by decreasing the force required to move the
`
`stopper, “it is desirable to decrease the likelihood of silicone oil droplets being
`
`injected into the eye.” Id. at 4:48-52. Thus, one aspect of the invention of the ’631
`
`
`
`9
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.012
`Regeneron v. Novartis, IPR2021-00816
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`

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`patent seeks to limit the amount of silicone oil typically applied to the syringe
`
`barrel (i.e., 100-800 (cid:541)g silicone oil in a 1 mL syringe), including to amounts less
`
`than about 25 (cid:541)g silicone oil in the barrel. Id. at 4:56-66.
`
`26. The ’631 patent explains that the break loose and sliding forces for
`
`standard pre-filled syringes known in the art, containing about 100 (cid:541)g to about 800
`
`(cid:541)g silicone oil, are typically less than 20 N. Id. at 5:34-38. However, with respect
`
`to the pre-filled syringe that is claimed by the ’631 patent, the break loose and/or
`
`gliding/sliding forces are less than 11 N, even with a reduced amount of silicone
`
`oil. Id. at 5:38-50. The ’631 patent further discloses the typical experimental
`
`parameters for measuring break loose and glide forces in the claimed syringes.
`
`Specifically, the ’631 patent states that the forces are measured in syringes having
`
`0.5 mL to 1 mL nominal maximal fill with a 30 G x 0.5 inch needle attached,
`
`containing less than 100 (cid:541)g silicone oil, and with the stopper travelling at a speed
`
`of 190 mm/min. Id. at 5:44-50.
`
`27. The ’631 patent provides a specific example of measuring stopper
`
`movement forces. Specifically, the ’631 patent describes measuring the break
`
`loose and sliding force of a 0.5 mL syringe attached with a 30 G x 0.5 inch needle
`
`
`
`10
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.013
`Regeneron v. Novartis, IPR2021-00816
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`

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`and containing about 0.2 mL of Lucentis1 and less than 100 (cid:541)g silicone oil. Using
`
`a stopper speed of 190 mm/minute, the average and maximum break loose forces
`
`were measured to be less than 3 N. Id. at 12:27-45
`
`28. The ’631 patent also discloses that the sterility and shelf life of the
`
`prefilled syringe may be at least 12 months after sterilization using a sterilizing
`
`gas. Id. at 9:55-63.
`
`B.
`
`29.
`
`Substitute Claims
`
`I understand that Patent Owner is proposing amendments to claim 1,
`
`which are carried forth in the dependent claims. These amendments are reflected
`
`in the substitute claims below, and my opinions address these proposed substitute
`
`claims.
`
`
`1 The ’631 patent provides an example of a 0.5 mL syringe having an internal
`
`diameter of about between 4.5 mm and 4.8 mm, a length of between about 45 mm
`
`and 50 mm that is filled with between about 0.1 and 0.3 mL of an injectable
`
`medicament. Id. at 11:41-46. The example explains that the travel length of the
`
`stopper is 10.9 mm. Id. at 12:27. This travel length would result in about
`
`(cid:4673)(cid:2870)(1.09 (cid:1855)(cid:1865))=0.17 (cid:1855)(cid:1865)(cid:2871)=(cid:2777).(cid:2778)(cid:2784) (cid:2195)(cid:2168) to about
`(cid:4673)(cid:2870)(1.09 (cid:1855)(cid:1865))=0.20 (cid:1855)(cid:1865)(cid:2871)=(cid:2777).(cid:2779)(cid:2777) (cid:2195)(cid:2168) of Lucentis expelled.
`
`(cid:2024)(cid:4672)(cid:2868).(cid:2872)(cid:2873) (cid:3030)(cid:3040)(cid:2870)
`(cid:2024)(cid:4672)(cid:2868).(cid:2872)(cid:2876) (cid:3030)(cid:3040)(cid:2870)
`
`
`
`11
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`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
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`Novartis Exhibit 2208.014
`Regeneron v. Novartis, IPR2021-00816
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`27. A pre-filled, terminally sterilized syringe for
`intravitreal injection, the syringe comprising a glass
`body forming a barrel, a stopper and a plunger and
`containing an ophthalmic solution which comprises a
`VEGF-antagonist, wherein:
`
`(a) the syringe has a nominal maximum fill volume of
`between about 0.5 ml and about 1 ml,
`
`(b) the syringe barrel comprises from about 1 μg to 100
`ug about 25 μg silicone oil,
`
`(c) the VEGF antagonist solution comprises no more
`than 2 particles >50 μm in diameter per ml and wherein
`the syringe has a stopper break loose force of less than
`about 11N and has a shelf life of at least twelve months
`after terminal sterilization.
`
`28. A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating of
`silicone oil that has an average thickness of about 450
`nm or less.
`
`29. A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating of
`from about 3 μg to about 100 ug 25 μg silicone oil.
`
`30. A pre-filled syringe according to claim [[1]] 27,
`wherein the silicone oil is DC365 emulsion.
`
`31. A pre-filled syringe according to claim [[1]] 27,
`wherein the VEGF antagonist solution further comprises
`(cid:82)(cid:81)(cid:72)(cid:3)(cid:82)(cid:85)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:11)(cid:76)(cid:12)(cid:3)(cid:81)(cid:82)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:24)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:149)(cid:21)(cid:24)(cid:3)(cid:151)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)
`(cid:71)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:80)(cid:79)(cid:15)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:11)(cid:76)(cid:76)(cid:12)(cid:3)(cid:81)(cid:82)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:24)(cid:19)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:149)(cid:20)(cid:19)(cid:3)
`μm in diameter per ml.
`
`32. A pre-filled syringe according to claim [[1]] 27,
`wherein the VEGF antagonist solution meets USP789.
`
`
`
`12
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.015
`Regeneron v. Novartis, IPR2021-00816
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`

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`33. A pre-filled syringe according to claim [[1]] 27,
`wherein the VEGF antagonist is an anti-VEGF antibody.
`
`34. A pre-filled syringe according to claim [[7]] 33,
`wherein the anti-VEGF antibody is ranibizumab.
`
`35. A pre-filled syringe according to claim [[8]] 34,
`wherein the ranibizumab is at a concentration of 10
`mg/ml.
`
`36. A pre-filled syringe according to claim [[8]] 34,
`wherein the silicone oil has a viscosity of about 350 cP,
`and the VEGF antagonist solution further comprises one
`(cid:82)(cid:85)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:11)(cid:76)(cid:12)(cid:3)(cid:81)(cid:82)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:24)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:149)(cid:21)(cid:24)(cid:3)(cid:151)(cid:80)(cid:3)(cid:76)(cid:81)(cid:3)
`(cid:71)(cid:76)(cid:68)(cid:80)(cid:72)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:72)(cid:85)(cid:3)(cid:80)(cid:79)(cid:15)(cid:3)(cid:68)(cid:81)(cid:71)(cid:3)(cid:11)(cid:76)(cid:76)(cid:12)(cid:3)(cid:81)(cid:82)(cid:3)(cid:80)(cid:82)(cid:85)(cid:72)(cid:3)(cid:87)(cid:75)(cid:68)(cid:81)(cid:3)(cid:24)(cid:19)(cid:3)(cid:83)(cid:68)(cid:85)(cid:87)(cid:76)(cid:70)(cid:79)(cid:72)(cid:86)(cid:3)(cid:149)(cid:20)(cid:19)(cid:3)
`μm in diameter per ml.
`
`37. A pre-filled syringe according to claim [[1]] 27
`wherein the VEGF antagonist is a non-antibody VEGF
`antagonist.
`
`38. A pre-filled syringe according to claim [[11]] 37,
`wherein the non-antibody VEGF antagonist is
`aflibercept or conbercept.
`
`39. A pre-filled syringe according to claim [[12]] 38,
`wherein the non-antibody VEGF antagonist is
`aflibercept at a concentration of 40 mg/ml.
`
`40. A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe has a stopper break loose force of
`less than about 5N, and wherein the syringe has a
`stopper slide force of less than about 5N.
`
`41. A pre-filled syringe according to claim [[14]] 40,
`wherein the stopper break loose force or stopper slide
`force is measured using a filled syringe, at a stopper
`travelling speed of 190 mm/min, with a 30 Gx0.5 inch
`needle attached to the syringe.
`13
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`42. A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe has a stopper slide force of less than
`about 11N.
`
`43. A blister pack comprising a pre-filled syringe
`according to claim [[8]] 27, wherein the syringe has
`been sterilised using H2O2 or EtO.
`
`44. A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, wherein the outer surface
`(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:86)(cid:92)(cid:85)(cid:76)(cid:81)(cid:74)(cid:72)(cid:3)(cid:75)(cid:68)(cid:86)(cid:3)(cid:148)(cid:20)(cid:3)(cid:83)(cid:83)(cid:80)(cid:3)(cid:40)(cid:87)(cid:50)(cid:3)(cid:82)(cid:85)(cid:3)(cid:43)2O2 residue.
`
`45. A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, wherein the syringe has
`been sterilised using EtO or H2O2 and the total EtO or
`H2O2 residue found on the outside of the syringe and
`(cid:76)(cid:81)(cid:86)(cid:76)(cid:71)(cid:72)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:69)(cid:79)(cid:76)(cid:86)(cid:87)(cid:72)(cid:85)(cid:3)(cid:83)(cid:68)(cid:70)(cid:78)(cid:3)(cid:76)(cid:86)(cid:3)(cid:148)(cid:19)(cid:17)(cid:20)(cid:3)(cid:80)(cid:74)(cid:17)
`
`46. A blister pack comprising a pre-filled syringe
`according to claim [[18]] 44(cid:15)(cid:3)(cid:90)(cid:75)(cid:72)(cid:85)(cid:72)(cid:76)(cid:81)(cid:3)(cid:148)(cid:24)(cid:8)(cid:3)(cid:82)(cid:73)(cid:3)(cid:87)(cid:75)(cid:72)(cid:3)(cid:57)(cid:40)(cid:42)(cid:41)(cid:3)
`antagonist is alkylated.
`
`47. A blister pack comprising a pre-filled syringe
`according to claim [[17]] 43, wherein the syringe has
`been sterilised using EtO or H2O2 with a Sterility
`Assurance Level of at least 10-6.
`
`48. A pre-filled syringe according to claim [[1]] 27,
`wherein the syringe barrel has an internal coating of
`from about 1-50 to about 25 μg silicone oil.
`
`49. A pre-filled syringe according to claim [[1]] 27,
`wherein the silicone oil has a viscosity of about 350 cP.
`
`50. A method of treating a patient suffering from of
`an ocular disease selected from choroidal
`neovascularisation, wet age-related macular
`degeneration, macular edema secondary to retinal vein
`occlusion (RVO) including both branch RVO (bRVO)
`14
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`and central RVO (cRVO), choroidal neovascularisation
`secondary to pathologic myopia (PM), diabetic macular
`edema (DME), diabetic retinopathy, and proliferative
`retinopathy, comprising the step of administering an
`ophthalmic solution to the patient using a pre-filled
`syringe according to claim [[1]] 27.
`
`51. The method of claim [[24]] 50, further comprising
`an initial priming step in which the physician depresses
`the plunger of the pre-filled syringe to align the pre-
`determined part of the stopper with the priming mark.
`
`52. A method according to claim [[24]] 50, wherein
`the VEGF antagonist administered is a non-antibody
`VEGF antagonist and wherein the patient has previously
`received treatment with an antibody VEGF antagonist.
`
`
`
`C.
`30.
`
`IPR Proceedings
`
`I understand Regeneron has filed this inter partes review (IPR2021-
`
`00816), challenging all claims of the ’631 patent, and asserting the following
`
`grounds:
`
`Claim(s) Challenged
`
`35 U.S.C. §
`
`Reference(s)/Basis
`
`1-3, 5-9, 14-22, 24
`
`1-3, 5-9, 14-22, 24
`
`103(a)
`
`103(a)
`
`Sigg, Boulange, “and if necessary
`USP 789”
`Lam and Boulange
`
`
`
`15
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`4, 10, 23
`
`4, 10, 23
`
`11-13
`
`11-13
`
`25
`
`25
`
`26
`
`26
`
`
`
`103(a)
`
`Sigg, Boulange, Fries2
`
`103(a)
`
`Lam, Boulange, Fries
`
`103(a)
`
`Sigg, Boulange, Furfine3
`
`103(a)
`
`Lam, Boulange, Furfine
`
`103(a)
`
`Sigg, Boulange, 2008 Macugen
`
`Label4
`
`103(a)
`
`Lam, Boulange, 2008 Macugen Label
`
`103(a)
`
`Sigg, Boulange, Dixon5
`
`103(a)
`
`Lam, Boulange, Dixon
`
`31.
`
`I have reviewed Petitioner Regeneron’s declaration from Horst Koller
`
`(Ex. 1003) to support its Petition.
`
`
`2 Arno Fries, Drug Delivery of Sensitive Biopharmaceuticals With Prefilled
`
`Syringes, 9(5) DRUG DELIVERY TECH. 22 (2009) (Ex. 1012).
`
`3 PCT Patent Publication No. WO 2007/149334 (Ex. 1021).
`4 Ex. 1009.
`5 James A. Dixon, et al. "VEGF Trap-Eye for the treatment of neovascular age-
`
`related macular degeneration." Expert opinion on investigational drugs 18.10
`
`(2009): 1573-1580 (Ex. 1030).
`
`16
`
`
`
`CONTAINS CONFIDENTIAL BUSINESS INFORMATION, SUBJECT TO PROTECTIVE ORDER
`
`Novartis Exhibit 2208.019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`32.
`
`I understand that the Board granted institution on all of the challenged
`
`claims on all grounds asserted in Regeneron’s petition. I understand that the Board
`
`preliminarily determined that the combination of Sigg6, Boulange7, and USP 7898
`
`teaches each element of original claim 1.
`
`33.
`
`In particular, I understand the Board found that although “Sigg does
`
`not disclose any particular break loose force, [] Boulange discloses several tests of
`
`‘friction force B’ of various syringes.” IPR2021-00816, Paper 13 at 60. The
`
`Board further determined that syringes A, B1, and C described in Table 7 of
`
`Boulange were each siliconized with 40 (cid:541)g of silicone oil, and Table 7 shows that
`
`each syringe type was measured to have a break loose force below 11 N at time
`
`zero.
`
`34.
`
`I further understand that the Board preliminarily determined that there
`
`is a reasonable likelihood that a POSA “would have been motivated to combine
`
`Sigg’s terminally sterilized PFS comprising a VEGF-antagonist with Boulange’s
`
`
`6 PCT Patent Publicat