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. JEREMY WOLFE, IN SUPPORT OF
`PATENT OWNERS' CONTINGENT MOTION TO AMEND
`
`-i-
`
`Novartis Exhibit 2209.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`__________
`
`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. JEREMY WOLFE, IN SUPPORT OF
`PATENT OWNERS' CONTINGENT MOTION TO AMEND
`
`-i-
`
`Novartis Exhibit 2209.001
`Regeneron v. Novartis, IPR2021-00816
`
`
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`TABLE OF CONTENTS
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`Page
`
`Introduction ..................................................................................................... 1
`I.
`Qualifications and Compensation ................................................................... 2
`II.
`III. Relevant Legal Standards ............................................................................... 4
`A.
`Obviousness .......................................................................................... 4
`B.
`Secondary Considerations .................................................................... 6
`Person of Ordinary Skill in the Art (“POSA”) ............................................... 6
`IV.
`Claim Construction ......................................................................................... 7
`V.
`Patent Owner’s Substitute Claims .................................................................. 8
`VI.
`VII. Background Regarding the Treatment of Retinal Vascular Diseases
`With Intravitreal Injections of VEGF Antagonist .......................................... 9
`A.
`Storage of VEGF Therapeutics .......................................................... 10
`B.
`Clinical Use ........................................................................................ 12
`C.
`Benefits of a PFS with a VEGF Antagonist ....................................... 13
`VIII. Declaration .................................................................................................... 17
`
`ii
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`Novartis Exhibit 2209.002
`Regeneron v. Novartis, IPR2021-00816
`
`
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`I.
`
`Introduction
`I, Jeremy Wolfe M.D., submit this declaration on behalf of Novartis
`
`1.
`
`Pharma AG, Novartis Technology LLC, Novartis Pharmaceuticals
`
`Corporation, (collectively, “Patent Owners” or “Novartis”), as an independent
`
`expert witness regarding the proposed amended 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 (“PTAB”) 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. I understand that Novartis is submitting claim
`
`amendments in the alternative, if the current claims are found unpatentable.
`
`3.
`
`I have been asked to opine on certain issues relating to the non-
`
`obviousness of the proposed substitute claims of the ’631 patent. This
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`declaration provides my opinions and an explanation of certain practices and
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`subject matter related to ophthalmology and intravitreal injections. My
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`opinions and analyses are based on my knowledge and experience, in addition
`
`1
`
`Novartis Exhibit 2209.003
`Regeneron v. Novartis, IPR2021-00816
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`
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`
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`to the materials I have considered from this IPR proceeding including the prior
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`art referenced by Petitioner in its IPR petition.
`
`II. Qualifications and Compensation
`4.
`I attended Case Western Reserve University and graduated with my
`
`B.A. in biochemistry in 1999, magna cum laude. I earned my M.D. and a M.S.
`
`in Biomedical Science from the Medical College of Ohio in 2004. While in
`
`medical school, I was selected to be a Howard Hughes research scholar at the
`
`National Eye Institute in Bethesda, Maryland, where I conducted research on
`
`macular degeneration. I completed my internship and medical residency in
`
`Ophthalmology at Emory University, and then completed a two-year fellowship
`
`in Vitreoretinal Surgery at the Wills Eye Institute in Philadelphia, Pennsylvania.
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`5.
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`I am a board certified ophthalmologist specializing in all aspects of
`
`vitreoretinal disease. I obtained my Board Certification in 2009. I have
`
`extensive experience in the medical and surgical treatment of all retinal
`
`diseases, and I regularly perform advanced retinal surgery for many
`
`vitreoretinal diseases. I completed my ophthalmology residency in 2008 and
`
`my vitreoretinal fellowship in 2010 and have been practicing continuously in
`
`this field since then. As an experienced ophthalmologist with an established
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`practice, I treat more than 5,000 patients per year, and I conduct on average 25
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`injections/day to treat patients with retinal diseases such as Neovascular Age-
`
`2
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`
`
`Novartis Exhibit 2209.004
`Regeneron v. Novartis, IPR2021-00816
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`
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`
`
`
`
`
`
`Related Macular Degeneration, Macular Edema Following Retinal Vein
`
`Occlusion, Diabetic Macular Edema, Myopic Choroidal Neovascularization,
`
`and Diabetic Retinopathy.
`
`6.
`
`I have been a partner at my practice, Associated Retinal Consultants,
`
`since August 2010. I also have served as the co-Director of the Vitreoretinal
`
`Surgery Fellowship Program at the practice since September 2019. In
`
`September 2021, I became the co-President of the practice. In addition to
`
`working at my practice, I treat patients through medical staff appointments at
`
`William Beaumont Hospital, Truvista Surgery Center.
`
`7.
`
`In addition to my medical practice, I am an Associate Professor of
`
`Ophthalmology at Oakland University William Beaumont School of Medicine
`
`in Rochester, Michigan, where I have taught since December 2010.
`
`8.
`
`Additional information regarding my background, professional and
`
`research experience, and published works are listed on my curriculum vitae,
`
`attached as Ex. 2211.
`
`9.
`
`I am being compensated at my standard rate of $750/hour. My
`
`compensation is in no way contingent upon my opinions or the outcome of this
`
`proceeding.
`
`3
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`
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`Novartis Exhibit 2209.005
`Regeneron v. Novartis, IPR2021-00816
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`
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`III. Relevant Legal Standards
`10.
`In formulating my opinions and conclusions with regard to the
`
`amended claims, I have been provided with an understanding of the relevant
`
`legal principles of U.S. patent law that govern the issues of patent validity, as
`
`outlined below.
`A. Obviousness
`11.
`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.
`
`12.
`
`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.
`
`13. 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
`
`4
`
`
`
`Novartis Exhibit 2209.006
`Regeneron v. Novartis, IPR2021-00816
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`
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`
`
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`
`
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`that a person of ordinary skill would look to when attempting to solve the
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`problem.
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`14.
`
`I understand that, in this IPR proceeding, the prior art to the amended
`
`claims of the ’631 patent includes patents and printed publications in the
`
`relevant field(s) that predate the ’631 patent’s priority date. I have been
`
`informed that the ’631 patent claims an earliest priority date of July 3, 2012. I
`
`therefore have considered the state of the art as of and before July 3, 2012.
`
`15.
`
`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 intention.
`
`16. Furthermore, 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.
`
`17.
`
`I also understand that the prior art used to invalidate a claim must
`
`enable the invention. A claim cannot be obvious if the prior art as a whole does
`
`not enable a POSA to make and use the claimed invention even if every
`
`separate element of the invention can be found somewhere in the prior art. I
`
`further understand that a reference used in an obviousness analysis must enable
`
`5
`
`
`
`Novartis Exhibit 2209.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
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`the portions of its disclosure being relied upon, particularly in the absence of
`
`supporting evidence to enable a POSA to make the claimed invention.
`B.
`Secondary Considerations
`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,
`
`amongst others: the commercial success of the patented invention, including
`
`evidence of industry recognition; the existence of a long-felt but unmet need in
`
`the field satisfied by the invention; 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.
`
`IV. Person of Ordinary Skill in the Art (“POSA”)
`19.
`I understand that obviousness is evaluated from the perspective of a
`
`person of ordinary skill in the art (“POSA”). I also 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. IPR2021-00816, Paper 13, Decision Granting
`
`Institution of Inter Partes Review, at 29-30. Specifically for the method claims
`
`24-26, Petitioner contends that “a POSITA would have an M.D. with a specialty
`
`in ophthalmology.” Pet. 24 (citing Ex. 1003 ¶¶ 30-32).
`6
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`
`
`
`
`Novartis Exhibit 2209.008
`Regeneron v. Novartis, IPR2021-00816
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`
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`20.
`
`I understand Patent Owner has proposed the following definition for
`
`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. (Ex. 2201 ¶ 16.)
`
`21. While I have applied Patent Owner’s definition of a POSA for
`
`purposes of my analysis and opinions in this declaration, my opinions would
`
`not differ had I used Petitioner’s definition. I also understand that obviousness
`
`is evaluated as of the priority date of a patent. I have utilized the knowledge
`
`and skill of a POSA in 2012 in forming and offering my opinions in this
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`declaration.
`
`V.
`
`Claim Construction
`I understand that the PTAB proposed constructions for certain claim
`
`22.
`
`terms of the ’631 patent. In my analysis, I utilize those constructions as
`
`follows:
`
`7
`
`Novartis Exhibit 2209.009
`Regeneron v. Novartis, IPR2021-00816
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`
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`(cid:120) “Stopper Break Loose Force” is construed to mean “the force
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`required to make the plunger/stopper move from its resting
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`position in the syringe barrel.”
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`(cid:120) “Stopper Slide Force” is construed to mean “the force required to
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`sustain movement of the stopper after movement has already
`
`begun.”
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`(cid:120) “Terminally Sterilized” is construed to mean the “process
`
`whereby the outside of a pre-filled syringe is sterilized, while
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`contact between the sterilizing agent and the drug product within
`
`the syringe is minimized.”
`
`VI. Patent Owner’s Substitute Claims
`23.
`I understand that the Patent Owner has proposed that claim 1 of the
`
`’631 be substituted with the following claim:
`
`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 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.
`8
`
`
`Novartis Exhibit 2209.010
`Regeneron v. Novartis, IPR2021-00816
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`
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`I also understand that Patent Owner has made related changes to other claims to
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`make them consistent with the upper limit of silicone oil in its substitute claim 27:
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`28. A pre-filled syringe according to claim 1, wherein the syringe
`barrel has an internal coating of from about 3 μg to about 25 μg
`silicone oil.
`
`29. A pre-filled syringe according to claim 1, wherein the syringe
`barrel has an internal coating of from about 1 to about 25 μg silicone
`oil.
`
`I further understand that the remaining claims of the ’631 patent have
`
`
`24.
`
`been amended to refer to their counterpart substitute claims.
`
`25. My opinions are focused on Patent Owner’s substitute claims
`
`(substitute claims 27-52).
`
`VII. Background Regarding the Treatment of Retinal Vascular Diseases
`With Intravitreal Injections of VEGF Antagonist
`26.
`“VEGF” or vascular endothelial growth factor, is a protein within the
`
`human body. VEGF antagonists are compounds that disrupt the function of
`
`VEGF, and have been used for the treatment of certain retinal conditions, such
`
`as Neovascular Age-Related Macular Degeneration, Macular Edema Following
`
`Retinal Vein Occlusion, Diabetic Macular Edema, Myopic Choroidal
`
`Neovascularization, and Diabetic Retinopathy, since the early 2000s.
`
`Ophthalmologists administer VEGF antagonist drugs by injecting them into the
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`eye in a procedure called an intravitreal injection. VEGF antagonist drugs for
`
`
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`
`
`9
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`
`
`Novartis Exhibit 2209.011
`Regeneron v. Novartis, IPR2021-00816
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`
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`intravitreal injection are available as a sterile liquid solution in vials or pre-
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`filled syringes.
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`27. Most patients who are treated with VEGF antagonists for retinal
`
`diseases will require periodic injections on an ongoing basis. In my practice I
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`commonly prescribe intravitreal injections (or, injections directly into a
`
`patient’s eye) of a VEGF antagonist solution using pre-filled syringes (“PFS”),
`
`such as LUCENTIS® (ranibizumab) and EYLEA® (aflibercept). I personally
`
`perform approximately 4,000-6,000 such intravitreal injections each year.
`A.
`Storage of VEGF Therapeutics
`28. Because VEGF-antagonists are biological products, they are typically
`
`stored and required to be stored at cold temperatures, such as in a refrigerator.
`
`When my clinic receives VEGF-antagonists, we store them at refrigerated
`
`temperatures until their use. That was true with all VEGF-antagonist drugs we
`
`used prior to 2012, such as vial formulations of ranibizumab and bevacizumab,
`
`and PFS of pegaptanib.
`
`29. A POSA in 2012 would have known that pre-filled syringes of a
`
`VEGF-antagonist solution would need to be stored in a refrigerator and in
`
`accordance with the packaging of the product label. For example, the labels for
`
`both LUCENTIS® and EYLEA® specify that the products should be
`
`refrigerated at a temperature of 2 to 8 degrees Celsius, which is common for
`
`10
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`
`
`Novartis Exhibit 2209.012
`Regeneron v. Novartis, IPR2021-00816
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`
`
`
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`biologics. Ex. 1027.0061; Ex. 1040.0142. Neither product label directs that the
`
`syringe be brought to a certain temperature before use. In the absence of any
`
`such instruction, a clinician would understand that they are able to inject the
`
`solution immediately upon removal from refrigeration, or shortly thereafter.
`
`Typically, a VEGF-antagonist solution is administered to a patient promptly
`
`(within minutes) after removal of the PFS from refrigeration, and that is often
`
`what happens in my own practice. This is consistent with how I administered
`
`ranibizumab and aflibercept in their vial presentations prior to 2012.
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`30. A POSA would also have desired that a PFS of a VEGF antagonist
`
`solution for intravitreal injection would function as intended throughout the
`
`course of its shelf-life, as indicated by the expiration date of the product, and
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`when stored in accordance with the product label. Typically, my practice uses
`
`our stock of PFS within 4-6 months of delivery, but I understand that the shelf-
`
`life of a product can be longer and is often more than one year following
`
`product manufacture. A clinician in 2012 (and to this day) would have desired
`
`that the force needed to utilize a pre-filled syringe with a VEGF-antagonist
`
`should not materially differ depending on when the product was used, i.e., early
`
`1 Lucentis Label 2010.
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`
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`2 Eylea Label 2011.
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`11
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`
`
`Novartis Exhibit 2209.013
`Regeneron v. Novartis, IPR2021-00816
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`
`
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`or late in its shelf-life, or immediately following removal from refrigeration or
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`at room temperature for a prolonged period of time.
`B. Clinical Use
`31. Pre-filled syringes of VEGF-antagonist solution for intravitreal
`
`injection have significant advantages that make them preferable to drugs
`
`administered from vials in non-pre-filled syringes. The PFS are filled with a
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`standard amount of medication and are terminally sterilized by the
`
`manufacturer before being distributed to a physician for use on a patient. PFS
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`are therefore significantly more convenient, save physician time, minimize risk
`
`of physician error, and decrease the risk of infection.
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`32. When used from a vial (as opposed to a PFS), the typical ranibizumab
`
`injection preparation required the clinician to (1) open package and remove
`
`vial, (2) remove the vial cap, (3) disinfect the drug vial top with an alcohol
`
`swab, (4) attach a fill needle to a sterile syringe, (5) draw up medicine, (6)
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`remove the fill needle, (7) attach a smaller gauge injection needle, (8) prime and
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`purge the syringe, and (9) perform the intravitreal injection. A PFS simplifies
`
`this process significantly, as the medication comes packaged in a single-use,
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`sealed sterile package. The clinician attaches the injection needle directly to the
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`sterile syringe, primes the syringe while adjusting to the proper dose, and
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`administers the medication.
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`12
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`
`
`Novartis Exhibit 2209.014
`Regeneron v. Novartis, IPR2021-00816
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`
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`
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`33. When using a PFS of VEGF antagonist solution for intravitreal
`
`injection, I attach a needle to the injection end of the syringe at the time of
`
`administering to the patient. Physicians typically administer the VEGF
`
`antagonist within an intravitreal PFS using a needle size of 30 G (diameter) and
`
`0.5 inches (length), as is evidenced by the product labels. Ex. 2212.0023; Ex.
`
`2213.0024.5 This was also the needle size we would prefer to use when we
`
`administered the VEGF antagonist in vial presentations.
`C. Benefits of a PFS with a VEGF Antagonist
`34. Since their commercial introduction, pre-filled syringes of VEGF
`
`antagonist solution for intravitreal injection have become the accepted standard
`
`in the field. In my experience, very few (if any) physicians currently prefer to
`
`use vials of VEGF antagonists. They have all, or nearly all, switched to PFS
`
`versions of VEGF antagonists. As I mentioned earlier, one of the primary
`
`benefits of pre-filled syringes is the reduced risk of infection.
`
`
`
`3 Eylea Label 2021.
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`4 Lucentis Label 2017.
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`5 While a narrower needle, such as a 31 or 32 G could also be used, this is atypical
`
`in the field. See, e.g., Ex. 2214.012.
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`13
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`
`
`Novartis Exhibit 2209.015
`Regeneron v. Novartis, IPR2021-00816
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`35. As of 2012, ophthalmologists were very much aware of the adverse
`
`risks associated with intravitreal injection, especially endophthalmitis (an
`
`infection of the eye). Although rare, the development of endophthalmitis
`
`following injection is the greatest risk associated with intravitreal injection. Ex.
`
`2214.0026; Ex. 2215.0027. I recently co-authored a study evaluating the use of
`
`PFS and their impact on rates of endophthalmitis following intravitreal
`
`injections. Our findings indicated a decreased risk of developing
`
`endophthalmitis following an intravitreal injection when the clinician uses a
`
`PFS rather than a conventional preparation. Ex. 2215.003. (Compared to a
`
`conventional preparation, use of a PFS was associated with “a statistically
`
`significant decreased risk of culture-positive endophthalmitis,” with rates
`
`dropping from 1 in 7,516 to 1 in 39,204 injections. Id.) This is likely due in
`
`part to the elimination of several steps in the process required to transfer the
`
`
`6 Rahul Chaturvedi et al., “Real World Trends in Intravitreal Injection Practices
`
`Among American Retina Specialists,” Ophthalmology Retina, Vol. 3 Issue 8: 656-
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`662, August 2019.
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`7 Phillip P. Storey et al., “The Impact of Prefilled Syringes on Endophthalmitis
`
`Following Intravitreal Injection of Ranibizumab,” American Journal of
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`Ophthalmology, 199: 200-208, March 1, 2019.
`
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`14
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`
`
`Novartis Exhibit 2209.016
`Regeneron v. Novartis, IPR2021-00816
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`
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`medication from the vial to the syringe. Reducing the steps required to prepare
`
`the medication in a non-sterile environment reduces the risk of introducing
`
`contaminants such as skin flora or aerosolized droplets containing oral bacteria.
`
`Id. at .007.
`
`36. PFS products such as LUCENTIS® and EYLEA® also reduce the
`
`risk of damaging a patient’s eye by inadvertently injecting silicone. It is my
`
`understanding that silicone oil is commonly used to lubricate the inner syringe
`
`wall to allow for a smoother and less forceful injection. In the past, certain
`
`ophthalmic syringes were known to inadvertently inject small amounts of this
`
`silicone oil along with the medication into the patient’s eye. Ex. 1067.002.8
`
`When excessive silicone oil gets into the eye, it often causes a dark spot that
`
`obstructs the patient’s vision, sometimes permanently. Since the mid-2000s,
`
`ophthalmologists have been aware of the desirability of minimizing the problem
`
`of inadvertent injection of silicone, while maintaining sufficiently low
`
`operations forces in a PFS. Ex. 2232.011.9 In my experience, the PFS of
`
`
`8 S. Bakri et al., “Intravitreal Silicone Oil Droplets After Intravitreal Drug
`
`Injections,” RETINA, 28:996-1001, 2008.
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`9 K. Bailey Freund et al., “Silicone Oil Droplets Following Intravitreal Injection,”
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`RETINA, 26:701-703, 2006.
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`15
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`
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`Novartis Exhibit 2209.017
`Regeneron v. Novartis, IPR2021-00816
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`LUCENTIS® and EYLEA® carry very low risk of silicone being injected into
`
`the eye during use. I understand this is likely due to the use of an optimized
`
`application process of the silicone oil to the syringe wall in pre-filled syringes,
`
`and to a reduction in the amount of silicone oil used in this new application
`
`process. Ex. 2018.003.10 (Citing a recent study demonstrating “1.73% of
`
`patients receiving bevacizumab prepared with insulin syringes to have a
`
`complication of silicone oil drops,” whereas the “‘baked silicone’ process [of
`
`the PFS design] is thought to reduce the incidence of silicone-related
`
`complications from repeated intravitreal injections.”). This is an important
`
`consideration in light of the large number of repeating anti VEGF intravitreal
`
`injections performed on a particular patient, and given that treatment of retinal
`
`pathologies can require years of repeated injections. Ex. 2215.001, .008.
`
`37. PFS also significantly increase physician efficiency while decreasing
`
`the risk of physician error. Published research shows “a 27%-39% reduction in
`
`syringe preparation time when using the PFS” rather than a conventional
`
`preparation, and some researchers have “postulated that the accuracy of anti-
`
`VEGF injection volume was better achieved using a PFS compared to their
`
`
`10 Thérèse M Sassalos and Yannis M Paulus, “Prefilled syringes for intravitreal
`
`drug delivery,” CLINICAL OPHTHALMOLOGY, 13:701-06 (2019).
`
`
`
`
`
`16
`
`
`
`Novartis Exhibit 2209.018
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`
`
`
`conventional counterparts.” Ex. 2018.002, .004. This is particularly important
`
`in a field like ophthalmology, in which busy practices conduct many such
`
`intravitreal injections on a daily basis.
`
`38. Because of the sensitive nature of the eye, the amount of stopper
`
`break-loose force and glide-force required to inject a VEGF antagonist solution
`
`is of particular importance in pre-filled syringes for intravitreal injection. A
`
`PFS that requires less break-loose and glide forces increases the physician’s
`
`control in administering a drug thereby reducing the risk of injury due to drug
`
`administration, and increasing patient comfort. Similarly, a syringe for
`
`intravitreal injection that requires a consistent level of glide force over the
`
`course of the injection allows for a smoother injection and is superior to a
`
`syringe that requires inconsistent levels of glide force during injection. A PFS
`
`with a VEGF antagonist that has consistent break loose and glide forces over
`
`the shelf life of the product are important to clinicians and provide significant
`
`benefits in clinical practice.
`
`VIII. Declaration
`39.
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`believed to be true; and further that these statements were made with the
`
`17
`
`
`
`Novartis Exhibit 2209.019
`Regeneron v. Novartis, IPR2021-00816
`
`
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`knowledge that willful false statements and the like so madeare punishable by
`
`fine or imprisonment, or both, under Section 1001 of Title 18 of the United
`
`States Code.
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`Dated:___
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`01/18/2022
`
`
`
`By DWet
`Jeremy Wolfe, M.D.
`
`18
`
`Novartis Exhibit 2209.020
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2209.020
`Regeneron v. Novartis, IPR2021-00816
`
`
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