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 Owner
`
`__________
`
`
`Case IPR2021-00816
`Patent 9,220,631
`
`__________
`
`
`DECLARATION OF ANDREW F. CALMAN, M.D., PH.D., IN SUPPORT
`OF PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`Novartis Exhibit 2204.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1 
`I. 
`Qualifications and Compensation .................................................................... 1 
`II. 
`III.  Legal Principles ............................................................................................... 7 
`A.  Obviousness ........................................................................................... 7 
`B. 
`Secondary Considerations of Nonobviousness ..................................... 8 
`C. 
`Coverage of a Product or Its Use by a Patent’s Claims ........................ 9 
`D. 
`Person of Ordinary Skill in the Art ....................................................... 9 
`IV.  Summary of Opinions ................................................................................... 9 
`A. 
`Person of Ordinary Skill in the Art ....................................................... 9 
`B. 
`Clinical Requirements for a Prefilled Syringe for Intravitreal Injection
` ............................................................................................................. 10 
`Long-Felt Need .................................................................................... 11 
`C. 
`Coverage of Lucentis® PFS by Claims 24 and 25 of the ’631 Patent 13 
`D. 
`Nonobviousness of Claims 24–26 of the ʼ631 Patent ......................... 13 
`E. 
`Person of Ordinary Skill in the Art ................................................................ 15 
`V. 
`VI.  Background Regarding Retinal Vascular Diseases and their Treatments ..... 17 
`A.  VEGF as a therapeutic target for retinal vascular diseases ................. 17 
`B. 
`FDA-approved VEGF antagonists for use in treating retinal vascular
`conditions ............................................................................................ 18 
`VII.  Clinical Considerations for Prefilled Syringes for Intravitreal Injection ...... 24 
`A. 
`Importance of Using Only Components Compatible with The Eye in
`Pre-Filled Syringes for Intravitreal Injection ...................................... 24 
`Importance of Low, Predictable Operation Forces ............................. 30 
`B. 
`Importance of Potency and Stability Over Time ................................ 34 
`C. 
`VIII.  Long-Felt Need .............................................................................................. 36 
`A. 
`By the Mid-2000s, there Were Recognized, Unsolved Problems with
`Respect to the Lack of a PFS with Low Levels of Silicone Oil while
`Maintaining Low, Predictable Operation Forces for Sterile Intravitreal
`Injection of VEGF Antagonists ........................................................... 36 
`i. 
`Sterile Administration of Intravitreal Injections of a VEGF
`Antagonist ................................................................................. 38 
`i
`
`
`
`Novartis Exhibit 2204.002
`Regeneron v. Novartis, IPR2021-00816
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`

`

`B. 
`
`C. 
`
`Low Silicone Oil and Low, Predictable Operation Forces ....... 43 
`ii. 
`iii.  Response to Mr. Koller’s Opinion Regarding Long-Felt Need 51 
`The Lucentis® PFS Solved These Unmet Problems By Providing a
`PFS with Low, Predictable Operation Forces and Low Levels of
`Silicone Oil for Sterile Intravitreal Injection of VEGF Antagonists .. 53 
`Ophthalmologists Have Used the Lucentis® PFS Because, as a Result
`of the Features Claimed as the Invention of the ’631 Patent, the
`Lucentis® PFS is a Convenient and Safe Alternative to Lucentis®
`Vials ..................................................................................................... 55 
`IX.  A Physician Administering the Lucentis PFS Practices the Methods of
`Claims 24 and 25 of the ʼ631 Patent ............................................................. 57 
`A.  Dependent Claim 24 of the ’631 Patent Covers a Method of Using the
`Lucentis® PFS to Treat Patients ......................................................... 57 
`Dependent Claim 25 of the ’631 Patent Covers Use of the Lucentis®
`PFS ...................................................................................................... 59 
`X.  Nonobviousness of Claims 24, 25, and 26 of The ʼ631 Patent ..................... 61 
`XI.  Declaration ....................................................................................................... 1 
`
`B. 
`
`
`
`ii
`
`Novartis Exhibit 2204.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`I.
`
`INTRODUCTION
`1.
`I, Andrew F. Calman, M.D., Ph.D., have been retained by Novartis
`
`Pharma AG, Novartis Technology LLC, and Novartis Pharmaceuticals Corp.
`
`(collectively, “Patent Owner” or “Novartis”) as an independent expert witness in
`
`the above-captioned inter partes review (“IPR”), in which Petitioner Regeneron
`
`Pharmaceuticals, Inc. (“Petitioner” or “Regeneron”) has requested that the U.S.
`
`Patent and Trademark Office cancel as unpatentable all claims of U.S. Patent No.
`
`9,220,631 (“the ’631 patent”). This declaration sets forth my opinions based on
`
`the materials I have considered and my knowledge, education, skills, training, and
`
`experience.
`
`2.
`
`I provide this declaration to provide medical and ophthalmological
`
`context for the ʼ631 patent and the claims contained therein, including a
`
`description of age-related macular degeneration and its treatments, injection of
`
`drugs directed against vascular endothelial growth factor (VEGF), and the factors
`
`and considerations that a clinician would have found important as of the priority
`
`date of the ʼ631 patent with regard to drug injection devices, particularly pre-filled
`
`syringes (PFS).
`
`II. QUALIFICATIONS AND COMPENSATION
`3.
`I graduated in 1982 from Yale University, having earned both my B.S.
`
`(summa cum laude, with Distinction in the Major) and my M.S. in Molecular
`
`
`
`1
`
`Novartis Exhibit 2204.004
`Regeneron v. Novartis, IPR2021-00816
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`

`

`Biophysics and Biochemistry in four years. I then spent seven years at the
`
`University of California, San Francisco (“UCSF”), earning an M.D. and a Ph.D. in
`
`Microbiology and Immunology. While in medical and graduate school, I earned
`
`the Dean’s Prize for Student Research, the Chancellor’s Fellowship, and received
`
`the E.E. Osgood Award from the American Federation for Clinical Research,
`
`awarded for the best student research in the Western United States. My published
`
`research (including two papers in Nature and two in the Proceedings of the
`
`National Academy of Sciences) included identification of a human T-cell antigen
`
`receptor gene, an in vitro model of immune deficiency, and mechanisms of HIV
`
`gene activation.
`
`4.
`
`I went on to pursue a year of medical internship, during which time I
`
`oversaw a UCSF laboratory team responsible for isolating a human galactokinase
`
`gene, followed by ophthalmology residency training at UCSF. During the eleven
`
`years that I spent working in research laboratories, from undergraduate to
`
`internship, I was exposed to a variety of methods in biochemistry, microbiology,
`
`immunology, and molecular genetics, including gene splicing, manipulation of
`
`DNA, RNA, and proteins, production and use of antibodies including monoclonal
`
`antibodies, growth of bacterial and viral cultures, and various types of sterilization.
`
`5.
`
`Since completing my ophthalmology residency training in 1993, I
`
`have served on the UCSF clinical faculty, currently as Associate Clinical Professor
`
`
`
`2
`
`Novartis Exhibit 2204.005
`Regeneron v. Novartis, IPR2021-00816
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`

`

`of Ophthalmology, while maintaining a private comprehensive ophthalmology
`
`practice in San Francisco’s Mission District. I have taught the diagnosis and
`
`treatment, including surgical treatment, of ophthalmic disease to resident
`
`physicians and medical students at UCSF and at California Pacific Medical Center,
`
`where I also serve on the clinical faculty. I have also taught medical students and
`
`physicians who have come from around the world to train at my practice, Premier
`
`Eyecare of San Francisco. From 2005 to 2014, I held a joint appointment as
`
`Associate Clinical Professor of Family and Community Medicine at UCSF, where
`
`I directed the ophthalmology training of UCSF Family and Community Medicine
`
`residents.
`
`6.
`
`I have held a number of leadership and policy positions in my
`
`profession at the state and national level. From 1996 to 2004, I served as the
`
`ophthalmology representative on the Medicare Carrier Advisory Committee for
`
`California and several other Western states, helping to set (and in some cases
`
`write) policies for diagnosis and treatment of ophthalmic diseases. From 2004 to
`
`2008, I served on the Health Policy Committee of the American Academy of
`
`Ophthalmology, performing essentially the same function at the national level. I
`
`also served for five years on the Executive Council of the American Academy of
`
`Ophthalmology, and in 2010 was the President of the California Academy of Eye
`
`Physicians and Surgeons, the official ophthalmology professional association for
`
`
`
`3
`
`Novartis Exhibit 2204.006
`Regeneron v. Novartis, IPR2021-00816
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`

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`California. I have held other leadership positions with these organizations, as well
`
`as the California Medical Association and the San Francisco Medical Society, as
`
`detailed in my Curriculum Vitae, attached as Exhibit 1 to this Declaration.
`
`7.
`
`In addition to these leadership positions in medical professional
`
`societies, I served for 15 years on the Board of Directors, and for three years as
`
`President, of Prevent Blindness Northern California, a non-profit organization
`
`dedicated to the prevention and treatment of blinding diseases in children and
`
`adults. I have served as an ophthalmology expert for the Medical Board of
`
`California in discipline and quality of care cases. Since 1997, I have been an
`
`Associate Examiner for the American Board of Ophthalmology, administering the
`
`examination for board certification in ophthalmology.
`
`8.
`
`I hold a valid and unrestricted medical license from the Medical
`
`Board of California. I am board certified by the American Board of
`
`Ophthalmology, and my Maintenance of Certification is current. I have an active
`
`clinical practice in ophthalmology, including the treatment of age-related macular
`
`degeneration (“AMD”) and other retinal vascular diseases, as detailed below. I
`
`
`
`4
`
`Novartis Exhibit 2204.007
`Regeneron v. Novartis, IPR2021-00816
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`

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`have testified as an expert in state and federal courts, and the German
`
`Oberlandesgericht Frankfurt am Main.1
`
`9.
`
`In my ophthalmology practice at Premier Eyecare of San Francisco, I
`
`regularly diagnose and treat adult patients with a variety of ophthalmic disorders,
`
`including nAMD, MEfRVO, DME, DR,2 and other retinal vascular diseases,
`
`cataracts, glaucoma, various infectious and inflammatory conditions, neuro-
`
`ophthalmic disorders, and ocular manifestations of injuries and systemic diseases.
`
`The majority of my patients are immigrants from around the world, who have one
`
`or more serious and potentially blinding diseases.
`
`10. Over the course of my clinical practice, I have participated as a
`
`Clinical Investigator in fifteen clinical trials involving ophthalmic drugs and
`
`devices. Six of these concerned retinal vascular disease (diabetic retinopathy, age-
`
`related macular degeneration, retinal vascular occlusions, and other macular
`
`
`1 This is the high court for the German state (“Land”) of Hesse, roughly equivalent
`
`to the Supreme Court of an American state.
`
`2 These abbreviations refer to neovascular age-related macular degeneration,
`
`macular edema following retinal vein occlusion, diabetic macular edema, and
`
`diabetic retinopathy, respectively.
`
`
`
`5
`
`Novartis Exhibit 2204.008
`Regeneron v. Novartis, IPR2021-00816
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`

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`diseases), eight pertained to glaucoma drugs, and one was a monitoring study for
`
`ophthalmic side effects of a systemic drug.
`
`11. For the past fifteen years, approximately half of my practice has
`
`consisted of the diagnosis and treatment of retinal vascular diseases including
`
`nAMD, MEfRVO, DME, and DR. In my office, I routinely interpret diagnostic
`
`tests for retinal vascular disease such as optical coherence tomography (“OCT”)
`
`and OCT angiography, fluorescein angiography, fundus autofluorescence,
`
`ultrasonography, and fundus photography. I perform focal and panretinal laser
`
`treatments, and inject medications including anti-vascular endothelial growth
`
`factor (“anti-VEGF”) agents such as Avastin® (bevacizumab), Lucentis®
`
`(ranibizumab), Eylea® (aflibercept), and Beovu® (brolucizumab), as well as
`
`corticosteroids such as Triescence® (triamcinolone) and Iluvien® (fluocinolone
`
`acetonide intravitreal implant) for various retinal vascular diseases. I also train and
`
`oversee California Pacific Medical Center ophthalmology residents who perform
`
`these treatments upon their patients. In the course of my practice, I have
`
`administered approximately 5,500 intravitreal injections of VEGF antagonists,
`
`both before and after 2012. These injections have included VEGF antagonists
`
`contained in vials and VEGF antagonists contained in pre-filled syringes.
`
`12.
`
`I am familiar with other ophthalmologists’ practices from my regular
`
`review of clinical literature in the field, including regarding usage patterns and best
`
`
`
`6
`
`Novartis Exhibit 2204.009
`Regeneron v. Novartis, IPR2021-00816
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`

`

`practices, my attendance at relevant conferences, personal discussions and
`
`interactions with other ophthalmologists in the context of my professional
`
`experience including shared care of various patients, and surveys such as the
`
`“Preferences and Trends” surveys performed by the American Society of Retina
`
`Specialists.
`
`13.
`
`I am billing my work in this matter at $750 per hour, with
`
`reimbursement for actual expenses. My payment is not contingent upon my
`
`testimony or outcome of this investigation. I have no personal interest in the
`
`outcome of this investigation.
`
`III. LEGAL PRINCIPLES
`14.
`I am not an attorney and I will offer no opinions on the law. I have,
`
`however, been instructed by Counsel regarding the following legal principles
`
`related to my opinions. Based on these instructions, I have developed and applied
`
`the following understandings in arriving at the opinions and conclusions in this
`
`Declaration. The legal principles I have employed are set out below.
`
`A. Obviousness
`15.
`I understand that a claimed invention is obvious if the claimed subject
`
`matter as a whole would have been obvious to a person of ordinary skill in the art
`
`at the time the invention was made.
`
`
`
`7
`
`Novartis Exhibit 2204.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`16.
`
`I understand that when a POSA combines pieces of prior art to arrive
`
`at the claimed subject matter, there must have existed a motivation for the POSA to
`
`combine the references.
`
`17.
`
`I further understand that when a POSA combines references to arrive
`
`at the claimed subject matter, he or she must have had a reasonable expectation of
`
`success in achieving the desired result in order to demonstrate obviousness. I
`
`understand that, although absolute predictability is not required, a showing of
`
`obviousness requires some degree of predictability in achieving the subject matter
`
`claimed in the patent.
`
`B.
`18.
`
`Secondary Considerations of Nonobviousness
`I understand that it is not permissible to use hindsight in determining
`
`whether or not a patent was obvious as of the relevant date, and the existence of
`
`certain factors, referred to as secondary considerations of nonobviousness, are
`
`considered to mitigate the possible impact of hindsight in an obviousness analysis.
`
`I understand that secondary considerations of non-obviousness include, among
`
`others, a “long-felt need.”
`
`19.
`
`I understand that “long-felt need” refers to the recognition in the
`
`relevant industry or field of an unsolved problem and a desire for a solution to that
`
`problem. I understand that this secondary consideration is analyzed as of the date
`
`of an articulated, identified problem and evidence of efforts to solve that problem.
`
`
`
`8
`
`Novartis Exhibit 2204.0011
`Regeneron v. Novartis, IPR2021-00816
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`

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`20.
`
`I also understand that, to qualify as a “long-felt need,” the problem
`
`must have remained unsolved as of the effective filing date for the relevant patent,
`
`and that it can also be relevant if the problem continued to be unsolved even after
`
`that time.
`
`C. Coverage of a Product or Its Use by a Patent’s Claims
`21.
`I understand that an analysis of whether a product or its use is covered
`
`by a patent claim requires two steps. First, the language of the patent claim must
`
`be properly construed. Second, to be covered by a patent claim, a product or its
`
`use must include elements or steps that correspond to each and every limitation in
`
`the claim as it has been properly construed.
`
`22.
`
`It is my understanding that to be covered by a dependent claim, a
`
`product or its use must also include each and every limitation of all claims from
`
`which the claim depends.
`
`D.
`23.
`
`Person of Ordinary Skill in the Art
`I understand that the contents of patents and prior art should be
`
`interpreted the way a person of ordinary skill in the art (“POSA”) would have
`
`interpreted the information at the time of invention.
`
`IV. SUMMARY OF OPINIONS
`A.
`Person of Ordinary Skill in the Art
`24.
`I have been informed that Novartis’s expert, Karl Leinsing, has
`
`offered a definition of a POSA involving a product development team.
`9
`
`
`
`Novartis Exhibit 2204.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`25. Under this proposed definition of a POSA, in my opinion, the product
`
`development team would have included someone who would have had an M.D.
`
`with a specialty in clinical ophthalmology and some experience administering
`
`VEGF-antagonist intravitreal injections.
`
`26.
`
`I understand Regeneron has proposed that a POSA for claims 24–26 is
`
`“an ophthalmologist with some experience administering VEGF-antagonist drugs
`
`to patients via the intravitreal route.”3
`
`27. My opinions herein are unchanged if either POSA definition is
`
`adopted.
`
`B. Clinical Requirements for a Prefilled Syringe for Intravitreal
`Injection
`In my opinion, in 2012 ophthalmologists4 would have found it
`
`28.
`
`unacceptable to administer an intravitreal injection using a PFS containing a
`
`
`3 Ex. 1003 ¶ 32 (Declaration of Horst Koller); Ex. 1031 ¶ 23 (Declaration of
`
`Slizard Kiss).
`
`4 The term “ophthalmologist” in my Declaration refers to an ordinary
`
`ophthalmologist referenced in the parties’ POSA definitions—the ophthalmologist
`
`who is the member of the POSA team proposed by Novartis (see infra, ¶¶ 37–40)
`
`and the ophthalmologist who Regeneron has proposed is a POSA for claims 24–26
`
`of the ʼ631 patent (see infra, ¶¶ 41).
`
`
`
`10
`
`Novartis Exhibit 2204.0013
`Regeneron v. Novartis, IPR2021-00816
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`

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`polymeric coating that was in contact with the drug product, where the coating had
`
`never been demonstrated to be safe for use with drugs being injected into the eye
`
`and/or where the coating had not been approved by the FDA for this use.
`
`29.
`
`In my opinion, ophthalmologists as of 2012 would not have had a
`
`reasonable expectation of success in administering a VEGF-antagonist prefilled
`
`syringe to patients for intravitreal injection without some evidence demonstrating
`
`that the syringe would reasonably be expected to be safe and effective for this use.
`
`C. Long-Felt Need
`30.
`In my opinion, by 2006, ophthalmologists had recognized an unsolved
`
`need for a PFS having low levels of silicone oil while at the same time maintaining
`
`low break-loose and sliding forces, that could be used for sterile, intravitreal
`
`administration of VEGF antagonists to treat wet AMD and other retinal vascular
`
`
`
`11
`
`Novartis Exhibit 2204.0014
`Regeneron v. Novartis, IPR2021-00816
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`

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`diseases. The desire to solve this problem was long-felt by 2012,5 and remained
`
`unsolved until the 2016 approval of the Lucentis® PFS in the United States.6
`
`
`5 I understand that Regeneron has agreed that the ʼ631 patent is entitled to a
`
`priority date of at least as early as October 23, 2012. I also understand that
`
`Regeneron’s expert witness, Horst Koller, has employed a priority date of July 3,
`
`2012 in support of his opinion that the ʼ631 patent would have been obvious. My
`
`opinions would not change if the relevant date were October 23, 2012 or July 3,
`
`2012.
`
`6 The Lucentis PFS was approved in October 2013 in the European Union. See Ex.
`
`2280 (Michaud, J., et al., “Ranibizumab pre-filled syringe approved in the
`
`European Union: innovation to improve dose accuracy, reduce potential infection
`
`risk, and offer more efficient treatment administration,” (April 2014) 55: Invest.
`
`Ophthalmol. & Visual Sci. 1949,
`
`https://iovs.arvojournals.org/article.aspx?articleid=2267240 (last accessed on
`
`1/17/2022)). In my opinion, the need that was satisfied by the Lucentis PFS was
`
`long-felt by the time of both its European approval in 2013 and by the time of its
`
`U.S. approval in 2016.
`
`
`
`12
`
`Novartis Exhibit 2204.0015
`Regeneron v. Novartis, IPR2021-00816
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`

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`D. Coverage of Lucentis® PFS by Claims 24 and 25 of the ’631
`Patent
`It is my opinion in view of the assumptions and analysis described
`
`31.
`
`below that the use of the Lucentis® PFS as instructed by its FDA-approved
`
`prescribing information is covered by claims 24 and 25 of the ’631 patent.
`
`E. Nonobviousness of Claims 24–26 of the ʼ631 Patent
`32.
`I understand that Regeneron’s expert witness, Mr. Koller, opines that
`
`it would have been obvious to combine the Sigg or Lam patent applications with
`
`the Boulange patent application to make a syringe meeting the limitations of claim
`
`1 of the ʼ631 patent.
`
`33.
`
`I have reviewed the Declaration of John Dillberger and, in my
`
`opinion, the risks he identifies associated with the use of the Parylene-C coating of
`
`Boulange in a VEGF-antagonist PFS would have been of concern to an
`
`ophthalmologist who was a member of a product development team working on a
`
`PFS for intravitreal injection of a VEGF antagonist. In my opinion, without
`
`evidence to support the safety and efficacy of such a syringe, an ophthalmologist
`
`as of 2012 would not have been motivated to use such a syringe and would not
`
`have had a reasonable expectation of success in using it to treat patients via
`
`intravitreal injection.
`
`34.
`
`I have also reviewed the Declaration of Michael Miller and, in my
`
`opinion, the risks he identifies associated with the use of the sterilization methods
`
`
`
`13
`
`Novartis Exhibit 2204.0016
`Regeneron v. Novartis, IPR2021-00816
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`

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`of Sigg or Lam in a VEGF-antagonist PFS would have been of concern to an
`
`ophthalmologist who was a member of a product development team working on a
`
`PFS for intravitreal injection of a VEGF antagonist. In my opinion, without
`
`evidence to support the safety and efficacy of such a syringe, an ophthalmologist
`
`as of 2012 would not have been motivated to use such a syringe and would not
`
`have had a reasonable expectation of success in using it to treat patients via
`
`intravitreal injection.
`
`35.
`
`In my opinion, even if it were determined that it would have been
`
`obvious for a POSA to combine Sigg or Lam with Boulange to create a PFS
`
`containing a VEGF-antagonist that would satisfy the limitations of claim 1,
`
`ophthalmologists would not have had a motivation to combine these references to
`
`treat patients for ocular disease with a VEGF-antagonist drug by practicing the
`
`method of claims 24–26 without some reason to believe that doing so would be at
`
`least as safe, and at least as effective, for the patient as administering the vial
`
`presentation of the same drug.
`
`36. Furthermore, in my opinion, even if it were determined that it would
`
`have been obvious for a POSA to combine Sigg or Lam with Boulange to create a
`
`PFS containing a VEGF-antagonist that would satisfy the limitations of claim 1,
`
`ophthalmologists would not have had a reasonable expectation of success in using
`
`this syringe in a method of treating patients for ocular disease, as required by
`
`
`
`14
`
`Novartis Exhibit 2204.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`claims 24–26 of the ʼ631 patent, without evidence supporting an expectation that
`
`the VEGF-antagonist would remain safe and effective for injection into the eye
`
`until the expiration date for the PFS.
`
`V. PERSON OF ORDINARY SKILL IN THE ART
`37.
`I have been informed that expert Karl Leinsing has offered the
`
`following definition of a POSA:
`
`38. 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.
`
`39. Claim 1 of the ʼ631 patent is directed to a syringe “for intravitreal
`
`injection” of an “ophthalmic solution.”7 In addition, Claims 24–26 of the ’631
`
`patent are dependent from claim 1, and are each directed to a method of treating a
`
`
`7 Ex. 1001 (ʼ631 patent at claim 1).
`
`
`
`15
`
`Novartis Exhibit 2204.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`patient having one of several ocular diseases by administering an ophthalmic
`
`solution to the patient using a PFS according to claim 1.
`
`40. Under the definition of a POSA that Mr. Leinsing has proposed, it is
`
`my opinion that the product development team would have included someone who
`
`would have had an M.D. with a specialty in clinical ophthalmology and some
`
`experience administering VEGF-antagonist intravitreal injections.
`
`41.
`
`I understand Regeneron has proposed that a POSA for claims 24–26 is
`
`“an ophthalmologist with some experience administering VEGF-antagonist drugs
`
`to patients via the intravitreal route.”8 Unlike Mr. Leinsing’s definition,
`
`Regeneron’s POSA definition for claims 24–26 is limited to an ophthalmologist
`
`who, in my experience, would not ordinarily have had expertise regarding the
`
`design of a PFS or terminal sterilization techniques for a PFS, as referenced in
`
`claim 1.
`
`42.
`
`In 2012, I was a person with specialized skills in ophthalmology that
`
`would have served on a development team as outlined by Mr. Leinsing. I was also
`
`a POSA as defined by Dr. Kiss. As noted above, my opinions herein are
`
`unchanged if either POSA definition is adopted.
`
`
`8 Ex. 1031¶ 23 (Declaration of Szilard Kiss).
`
`
`
`16
`
`Novartis Exhibit 2204.0019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`VI. BACKGROUND REGARDING RETINAL VASCULAR DISEASES
`AND THEIR TREATMENTS
`A. VEGF as a therapeutic target for retinal vascular diseases
`43. Vascular endothelial growth factor (VEGF) is an angiogenesis factor
`
`that has a role in the growth and permeability of blood vessels. By the early 2000s,
`
`researchers had shown that inhibition of the activity of VEGF could potentially be
`
`useful in the treatment of retinal vascular diseases.9
`
`44. Age-related macular degeneration (AMD) is a retinal vascular disease
`
`that can cause vision loss through degeneration, destruction and/or scarring of the
`
`macula, which is the central part of the retina. Broadly speaking, AMD is divided
`
`into two types: (1) exudative or “wet” AMD and (2) non-exudative or “dry” AMD.
`
`Exudative AMD is also sometimes referred to as “neovascular” AMD or “nAMD.”
`
`45. When abnormal blood vessels known as neovascularization develop
`
`under and/or within the retina, “wet” or “neovascular” AMD (nAMD) is
`
`diagnosed. These vessels frequently leak fluid and/or blood, which can block
`
`vision directly or cause secondary damage to the retina and adjacent structures.
`
`
`9 See, e.g., Ex. 2281.001, .008 (Krzystolik, M.G., et al., “Prevention of
`
`Experimental Choroidal Neovascularization With Intravitreal Anti-Vascular
`
`Endothelial Growth Factor Antibody Fragment,” (2002) 120 Arch. Ophthalmol.
`
`338, 345).
`
`
`
`17
`
`Novartis Exhibit 2204.0020
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`46. Other retinal vascular diseases include diabetic macular edema
`
`(DME), macular edema following retinal vein occlusion (MEfRVO), and diabetic
`
`retinopathy (DR).
`
`B.
`
`FDA-approved VEGF antagonists for use in treating retinal
`vascular conditions
`47. Anti-VEGF (or, in the language of the ʼ631 patent, VEGF-antagonist)
`
`drugs have been used to treat retinal vascular disease since the mid-2000s.
`
`Ophthalmologists administer VEGF-antagonist drugs for this purpose by injecting
`
`them into a part of the eye called the vitreous, in a procedure called intravitreal
`
`injection.
`
`48. Most patients with retinal vascular conditions treated with anti-VEGF
`
`intravitreal injections are initially treated with periodic injections. Most patients
`
`with nAMD, and some patients with MEfRVO and DME, will require ongoing
`
`periodic injections for an indefinite period of time, in order to prevent disease
`
`recurrence and potential vision loss.
`
`49. VEGF-antagonist drugs for intravitreal injection are generally
`
`available as a sterile liquid drug formulation either in sterile vials and/or sterile
`
`pre-filled syringes, depending on the drug. As of 2012, ophthalmologists such as
`
`myself were generally familiar with the clinical requirements for container systems
`
`for VEGF-antagonist drugs used for intravitreal injection.
`
`
`
`18
`
`Novartis Exhibit 2204.0021
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`50. The VEGF-antagonist drugs used for intravitreal injection are
`
`sensitive to their storage conditions, and all of them require storage under
`
`refrigeration in order to ensure the drug formulations remain safe and effective
`
`until their expiration dates10 (i.e., dates after which the drug is to be discarded and
`
`not used).
`
`51. The first VEGF antagonist to be approved for use in treating retinal
`
`vascular conditions was Macugen® (pegaptanib), in December 2004.11 Until its
`
`sale in the U.S. was discontinued,12 Macugen® was sold as a PFS, meaning that
`
`the Macugen® drug formulation was contained inside the syringe until it was
`
`administered to patients or discarded after its expiration date.
`
`
`10 Or, in the case of Avastin® syringes prepared by compounding pharmacies or
`
`bulk-outsourcing facilities, their “beyond-use dates.”
`
`11 Ex. 2282.002 (FDA Approval for Macugen®,
`
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-
`
`756_Macugen_approv.pdf (last accessed on 01/17/2022)).
`
`12 See Ex. 2283 (Drugs@FDA: FDA Approved Drugs Page for Macugen,
`
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.proces
`
`s&ApplNo=021756 (last accessed on 1/17/2022) (indicating “Marketing Status” as
`
`“Discontinued”)).
`
`
`
`19
`
`Novartis Exhibit 2204.0022
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`52. After Macugen® was approved, ophthalmologists began using
`
`Avastin® (bevacizumab), which is a VEGF-antagonist drug approved for treating
`
`certain cancers, off label to treat nAMD.13 Avastin® is sold as a vial for
`
`intravenous infusion in cancer patients.14 Compounding pharmacies and bulk
`
`outsourcing facilities repackage Avastin® vials into syringes that contain single
`
`doses of the drug for intravitreal injection. Repackaged Avastin® is generally
`
`stored in these syringes for a relatively short time before it is administered to
`
`patients.15
`
`
`13 Ex. 2284.001, .003 (Rich R.M., et. al., “Short-Term Safety and Efficacy of
`
`Intravitreal Bevacizumab (Avastin) for Neovascular Age-related Macular
`
`Degeneration,” (2006) 26 Retina 495, 497).
`
`14 Ex. 2285.001 (Avastin® FDA label,
`
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/