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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC.,
`and APOTEX INC.,
`Petitioners
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.
`Patent Owner.
`
`____________
`
`Case IPR2021-008801
`Patent 9,669,069 B2
`
`***
`
`Case IPR2021-00881
`Patent 9,254,338 B2
`____________
`
`
`
`
`EXPERT DECLARATION OF LUCIAN V. DEL PRIORE, M.D., PH.D.
`
`CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER
`
`
`1 IPR2022-00257, IPR2022-00258, IPR2022-00298, and IPR2022-00301 have been
`joined with this proceeding.
`
`
`
`Exhibit 2048
`Page 01 of 56
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page No.
`
`Contents
`I. 
`INTRODUCTION ........................................................................................... 1 
`QUALIFICATIONS AND EXPERIENCE ..................................................... 1 
`II. 
`SUMMARY OF OPINIONS ........................................................................... 4 
`III. 
`IV.  THE PERSON OF ORDINARY SKILL IN THE ART ................................. 5 
`V. 
`LEGAL STANDARDS ................................................................................... 6 
`A. 
`Burden of Proof ..................................................................................... 6 
`B. 
`Anticipation ........................................................................................... 6 
`VI.  THE ’338 PATENT ......................................................................................... 7 
`VII.  THE ’069 PATENT ......................................................................................... 9 
`VIII.  “A METHOD FOR TREATING AN ANGIOGENIC EYE
`DISORDER IN A PATIENT” ....................................................................... 11 
`IX.  EYLEA® ........................................................................................................ 11 
`X. 
`PRIOR ART REFERENCES ........................................................................ 13 
`A.  Dixon (Ex. 1006) ................................................................................. 13 
`B. 
`Adis R&D Profile (Ex. 1007) .............................................................. 15 
`C. 
`Regeneron (8-May-2008) (Ex. 1013) .................................................. 17 
`D.  NCT-795 and NCT-377 (Ex. 1014 and Ex. 1015) .............................. 18 
`E. 
`Heier-2009 (Ex. 1020) ......................................................................... 19 
`F. 
`Regeneron (30-April-2009) (Ex. 1028) ............................................... 20 
`XI.  THE CHALLENGED CLAIMS ARE NOT ANTICIPATED ..................... 20 
`A. 
`The POSA Would Not Have Known That “VEGF Trap-Eye”
`Necessarily Has the Same Amino Acid Sequence as Aflibercept ...... 20 
`
`
`
`–i–
`
`Exhibit 2048
`Page 02 of 56
`
`

`

`
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`The POSA Would Not Have Concluded That Dixon’s
`“Molecular Structure” Necessarily Corresponds to the Same
`Amino Acid Sequence .............................................................. 21 
`Regeneron Referred to “VEGF Trap-Eye” as an
`Ophthalmology Drug and “Aflibercept” as an Oncology
`Drug........................................................................................... 25 
`Dixon Refers to “Aflibercept” and “VEGF Trap-Eye” as
`Different Products for Different Uses ....................................... 29 
`The POSA Could Have Reasonably Concluded That
`“VEGF Trap-Eye” for Ophthalmology Was a Separate and
`Different Product than “Aflibercept” for Oncology ................. 30 
`The POSA Would Have Understood That VEGF-Trap-Eye
`Could Encompass a Genus of Protein Sequences ..................... 32 
`Even If the POSA Knew the Amino Acid Sequence of VEGF
`Trap-Eye, S/He Would Not Necessarily Be Able to Obtain a Drug
`Product That Would Provide Treatment Using the Claimed
`Dosing Regimen. ................................................................................. 35 
`Administration of VEGF Trap-Eye (Eylea®) Using the Disclosed
`Dosing Regimen Will Not Result in an Effective Treatment for
`All Patients .......................................................................................... 42 
`1. 
`Even Assuming a Very Low Level of Efficacy,
`Administration of VEGF Trap-Eye (Eylea®) Using the
`Claimed Dosing Regimen Will Not Necessarily Result in an
`Effective Treatment for All Patients ......................................... 43 
`Using a High Level of Efficacy—(Non-Inferior to
`Standard-Of-Care), the Disclosed Q8 Dosing Regimen Will
`Not Result in a Effective Treatment for Some Patients ............ 44 
`
`2. 
`
`B. 
`
`C. 
`
`
`
`
`
`
`
`
`
`–ii–
`
`Exhibit 2048
`Page 03 of 56
`
`

`

`
`
`I, Dr. Lucian V. Del Priore, declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained by counsel for Regeneron Pharmaceuticals, Inc.
`
`(“Regeneron”) as a technical expert in connection with the above-captioned
`
`proceeding. I have been asked to provide my opinions and views on the materials I
`
`have reviewed in relation to the Petition for Inter Partes review of U.S. Patent No.
`
`9,254,338 (the “’338 Patent”) (Ex. 1001),2 U.S. Patent No. 9,669,069 (“the ’069
`
`Patent”) (Ex. 1019) and, in particular, the state of the art as of the earliest filing date
`
`(“priority date”) of the ’338 and ’069 Patents and responses to the opinion and views
`
`of Petitioner’s declarant, Thomas A. Albini, M.D. I submit this declaration in
`
`support of Regeneron’s Patent Owner Responses (“PORs”).
`
`2.
`
`I am being paid at my usual and customary rate for my work on this
`
`matter. I have no personal or financial stake in, or affiliation with, the petitioner,
`
`real-parties-in-interest, or the patent owner. My compensation is not dependent upon
`
`the outcome of, or my testimony in, the present proceeding.
`
`II. QUALIFICATIONS AND EXPERIENCE
`3. My qualifications as an expert in the field of ophthalmology are
`
`established by my curriculum vitae, which is attached as Ex. 2081, and the
`
`
`2 Unless otherwise noted all citations to exhibits refer to exhibits filed in
`IPR2021-00881.
`
`
`
`–1–
`
`Exhibit 2048
`Page 04 of 56
`
`

`

`
`
`experience and publications cited therein, which includes a list of all publications
`
`authored by me in the previous 10 years. I summarize my most pertinent
`
`qualifications below.
`
`4.
`
`I am the Robert R. Young Professor of Ophthalmology and Visual
`
`Science at Yale University; Chair of the Department of Ophthalmology and Visual
`
`Science, Yale Eye Center; and Chief of Ophthalmology, Yale New Haven Hospital.
`
`5.
`
`I received a B.S. in Physics from Cooper Union for the Advancement
`
`of Science and Art; a M.S. and Ph.D. in Physics from Cornell University; and a M.D.
`
`with Distinction in Research from The University of Rochester School of Medicine
`
`and Dentistry. I was also awarded an Honorary Master of Arts degree by Yale
`
`University in 2017.
`
`6.
`
`After medical school, I completed my residency in ophthalmology, a
`
`glaucoma fellowship, and a vitreoretinal surgery fellowship at the Wilmer Eye
`
`Institute of the John Hopkins Hospital.
`
`7.
`
`I have more than thirty years of experience treating patients in the field
`
`of ophthalmology and, in particular in treating patients with diseases of the retina
`
`including age-related macular degeneration, diabetic macular edema, diabetic
`
`retinopathy, central retinal vein occlusion, branch retinal vein occlusion, and corneal
`
`neovascularization.
`
`
`
`–2–
`
`Exhibit 2048
`Page 05 of 56
`
`

`

`
`
`8.
`
`I have authored or co-authored more than 500 publications, including
`
`peer-reviewed journal articles, abstracts, and book chapters. My work has been
`
`published in a wide array of peer-reviewed journals, including Ophthalmology,
`
`British J. of Ophthalmology, Ophthalmology Retina, and Investigational
`
`Ophthalmology Visual Science. My abstracts have been presented at the annual
`
`meetings of the American Academy of Ophthalmology, the American Society of
`
`Retina Specialists, the Association for Research in Vision and Ophthalmology, the
`
`Macula Society, and the Retina Society. I have also given numerous invited lectures
`
`throughout the world on the treatment of retinal diseases.
`
`9.
`
`I am a Diplomate of the American Board of Ophthalmology and
`
`National Board of Medical Examiners. I am a fellow of the American Academy of
`
`Ophthalmology and the Association for Research in Vision and Ophthalmology. I
`
`am also a member of the Macula Society, the Retina Society, the American Society
`
`of Retinal Specialists, and the International Society for Eye Research.
`
`10.
`
`I have won a number of awards in my career as described in my
`
`curriculum vitae. For example, in 2021, I was inducted into the Retina Hall of Fame
`
`of the American Society of Retinal Specialist. In 2019, I was elected to the New
`
`York Ophthalmological Society. I was also given the Distinguished Alumnus Award
`
`in 2012 from the Wilmer Ophthalmological Institute at Johns Hopkins in recognition
`
`of outstanding contributions to ophthalmology as a Wilmer Graduate.
`
`
`
`–3–
`
`Exhibit 2048
`Page 06 of 56
`
`

`

`
`
`III. SUMMARY OF OPINIONS
`11. My opinions and views set forth in this declaration are based on my
`
`education, training, research, and clinical experience in ophthalmology, specifically
`
`in researching and treating retinal diseases, as well as the materials I reviewed in
`
`preparing this declaration and the state of scientific knowledge in the art pertaining
`
`to the subject matter of the ’338 and ’069 Patents at the time of the priority date.
`
`12.
`
`In forming my opinions, I have reviewed the following materials:
`
`(a) the Petition for Inter Partes Review of the ’338 Patent, IPR2021-00881,
`
`including all cited exhibits, (b) the ’069 Patent, IPR2021-00880, including all cited
`
`exhibits, (c) all other documents and references cited herein, and (d) Patent Owner’s
`
`Responses to which my declaration relates.
`
`13. My opinions are summarized below:
`
` It is my opinion that the POSA would not have known that
`“VEGF Trap-Eye” necessarily had the same amino acid
`sequence as aflibercept.
`
` It is my opinion that even if the POSA knew the amino acid
`sequence of VEGF Trap-Eye, s/he would not necessarily have
`been able to obtain a drug product that would provide treatment
`using the claimed dosing regimen.
`
` It is my opinion that administration of VEGF Trap-Eye (Eylea®)
`using the disclosed dosing regimen will not necessarily result in
`an effective treatment for all patients.
`
`
`
`–4–
`
`Exhibit 2048
`Page 07 of 56
`
`

`

`
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`14.
`I am informed that the person of ordinary skill in the art is a hypothetical
`
`person who is presumed to have access to, and be aware of, all of the relevant prior
`
`art at the time of the invention. At times I will refer to such person as the “POSA.”
`
`15.
`
`In forming my opinions, I have been asked to consider the level of
`
`ordinary skill in the art as it relates to the ’338 and ’069 Patents as of their effective
`
`filing date. I understand that the application that led to the ’338 Patent was filed on
`
`July 12, 2013. I understand that the application that led to the ’069 Patent was filed
`
`on December 17, 2015. I further understand that both applications claim priority to
`
`provisional applications filed on January 13, 2011, January 21, 2011, and November
`
`21, 2011. I have been informed and understand that the earliest filing date of the
`
`‘338 Patent and the ’069 Patent is January 13, 2011.
`
`16.
`
`I understand that Petitioner contends that a person of ordinary skill in
`
`the art of the ’338 and ’069 Patent would have:
`
`(1) knowledge regarding the diagnosis and treatment of
`angiogenic eye disorders, including the administration of
`therapies to treat said disorders; and (2) the ability to
`understand results and findings presented or published by
`others in the field, including the publications discussed
`herein. Typically, such a person would have an advanced
`degree, such as an M.D. or Ph.D. (or equivalent, or less
`education but considerable professional experience in the
`medical, biotechnological, or pharmaceutical field), with
`practical academic or medical experience
`in:
`(i)
`developing treatments for angiogenic eye disorders, such
`as AMD, including through the use of VEGF antagonists,
`
`
`
`–5–
`
`Exhibit 2048
`Page 08 of 56
`
`

`

`
`
`or (ii) treating of same, including through the use of VEGF
`antagonists.
`
`17.
`
`I understand that Patent Owner contends that the skilled artisan is an
`
`ophthalmologist with experience in treating angiogenic eye disorders, including
`
`through the use of VEGF antagonists.
`
`18. My opinions set forth in this declaration remain the same under either
`
`Petitioner’s or Patent Owner’s definition.
`
`V. LEGAL STANDARDS
`19.
`I am not an expert in the law. The legal standards I have applied where
`
`explained to me by counsel for Patent Owner.
`
`A. Burden of Proof
`20.
`I have been informed that each claim of an issued patent is presumed to
`
`be valid. To overcome that presumption of validity, the party challenging the claim’s
`
`validity must establish unpatentability by a preponderance of the evidence.
`
`B. Anticipation
`21.
`I have been informed that for a patent to be valid, the invention claimed
`
`must be novel (i.e., new). A claimed invention that is not novel is said to be
`
`“anticipated.”
`
`22.
`
` I have also been informed that for a claim to be anticipated, every
`
`limitation of the claimed invention must be found in a single prior art reference,
`
`
`
`–6–
`
`Exhibit 2048
`Page 09 of 56
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`

`

`
`
`either expressly or inherently. I understand that the words of a prior art reference do
`
`not have to use the same words as the claim but that all limitations must be present.
`
`23.
`
`I have been informed that a prior art reference may inherently anticipate
`
`a claimed invention if the claim limitations are necessarily present in the prior art
`
`reference. I also have been informed that inherency cannot be invoked where there
`
`is an incomplete description of a recited structure in the prior art. Likewise, the mere
`
`possibility that a prior art reference could disclose a claimed structure is insufficient
`
`to demonstrate inherency. Accordingly, I have been instructed that the POSA would
`
`have to understand the disclosure of “VEGF Trap-Eye” in Petitioner’s references to
`
`necessarily correspond to the recited protein sequence and nucleic acid sequence of
`
`the challenged claims or provide some other description of “VEGF Trap-Eye” that
`
`would necessarily put the POSA in possession of “VEGF Trap-Eye” for Petitioner
`
`to be able to show inherency of that limitation in the cited references.
`
`VI. THE ’338 PATENT
`24. The ’338 Patent provides methods for treating angiogenic eye
`
`disorders, including wet age-related macular degeneration (wAMD), by the
`
`administration of a specific VEGF antagonist in a specified dosing regimen. I
`
`understand that Petitioner has challenged claims 1, 3-11, 13-14, 16-24 and 26 of the
`
`’338 Patent.
`
`
`
`–7–
`
`Exhibit 2048
`Page 10 of 56
`
`

`

`25. The ’338 Patent has two independent claims, claim 1 and 14. Claim 1,
`
`reproduced below, is representative:
`
`
`
`A method for treating an angiogenic eye disorder in a
`patient,
`said method
`comprising
`sequentially
`administering to the patient a single initial dose of a VEGF
`antagonist, followed by one or more secondary doses of
`the VEGF antagonist, followed by one or more tertiary
`doses of the VEGF antagonist;
`
`wherein each secondary dose is administered 2 to 4 weeks
`after the immediately preceding dose; and
`
`wherein each tertiary dose is administered at least 8 weeks
`after the immediately preceding dose;
`
`wherein the VEGF antagonist is a VEGF receptor-based
`chimeric molecule comprising (1) a VEGFR1 component
`comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a
`VEGFR2 component comprising amino acids 130-231 of
`SEQ ID NO:2; and (3) a multimerization component
`comprising amino acids 232-457[ ]of SEQ ID NO:2.
`
`Ex. 1001 at 23:1-18.
`
`26. The dosing regimen of Claim 1 is directed to the treatment of an
`
`angiogenic eye disorder with a VEGF antagonist that has a particular amino acid
`
`sequence, SEQ ID NO:2.
`
`27. The dosing regimen of Claim 1 requires treatment of an angiogenic eye
`
`disorder by administration of an initial dose of the claimed VEGF antagonist
`
`followed by one or more “secondary” doses administered two to four weeks after
`
`
`
`–8–
`
`Exhibit 2048
`Page 11 of 56
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`

`

`
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`the preceding dose, and then one or more “tertiary” doses that are administered at
`
`least eight weeks following the immediately preceding dose.
`
`28. Claim 14 differs from Claim 1 only with respect to the last “wherein
`
`clause” specifying the nucleic acid sequence of SEQ ID NO:1. I understand that the
`
`nucleic acid sequence of SEQ ID NO:1 corresponds to the amino acid sequence of
`
`SEQ ID NO:2. I also understand that the amino acid sequence of SEQ ID NO:2
`
`corresponds to the amino acid sequence of aflibercept, the active ingredient in
`
`Eylea®.
`
`29. Challenged Claims 3-11 and 13 depend from Claim 1, and further limit
`
`the timing between dosage administration, the specific angiogenic eye disorder,
`
`administration route, and dosage amount. Similarly, Challenged Claims 16-24 and
`
`26 depend from Claim 14, and further limit the timing between dosage
`
`administration, the specific angiogenic eye disorder, administration route, and
`
`dosage amount.
`
`VII. THE ’069 PATENT
`30. The ’069 Patent provides methods for treating angiogenic eye
`
`disorders, including wet age-related macular degeneration (wAMD), by the
`
`administration of a specific VEGF antagonist in a specified dosing regimen. I
`
`understand that Petitioner has challenged claims 1 and 8-12 of the ’069 Patent.
`
`
`
`–9–
`
`Exhibit 2048
`Page 12 of 56
`
`

`

`31. Claim 1 of the ’069 Patent, the only independent claim, is reproduced
`
`below:
`
`
`
`A method for treating an angiogenic eye disorder in a
`patient,
`said method
`comprising
`sequentially
`administering to the patient a single initial dose of a VEGF
`antagonist, followed by one or more secondary doses of
`the VEGF antagonist, followed by one or more tertiary
`doses of the VEGF antagonist;
`
`wherein each secondary dose is administered 2 to 4 weeks
`after the immediately preceding dose; and
`
`wherein each tertiary dose is administered on an as-
`needed/pro re nata (PRN) basis, based on visual and/or
`anatomical outcomes as assessed by a physician or other
`qualified medical professional;
`
`wherein the VEGF antagonist is a receptor-based chimeric
`molecule comprising
`(1) a VEGFR1 component
`comprising amino acids 27 to 129 of SEQ ID NO:2; (2) a
`VEGFR2 component comprising amino acids 130-231 of
`SEQ ID NO:2; and (3) a multimerization component
`comprising amino acids 232-457 of SEQ ID NO:2.
`
`Ex. 1019 at 21:40-60.
`
`32. The dosing regimen of Claim 1 is directed to the treatment of
`
`angiogenic eye disorders with a VEGF antagonist that has a particular amino acid
`
`sequence, SEQ ID NO:2.
`
`33. Claims 8-12 also depend from Claim 1, and further limit the specific
`
`angiogenic eye disorder, the dosing regimen, administration route, and the nucleic
`
`acid sequence of the VEGF antagonist.
`
`
`
`–10–
`
`Exhibit 2048
`Page 13 of 56
`
`

`

`
`
`VIII. “A METHOD FOR TREATING AN ANGIOGENIC EYE DISORDER
`IN A PATIENT”
`34.
`I understand that the parties dispute the term “a method for treating an
`
`angiogenic eye disorder in a patient.”
`
`35.
`
`I have been informed that the Board has preliminarily found that the
`
`phrase “a method for treating an angiogenic eye disorder in a patient” is a positive
`
`limitation of the claim because it “sets forth the essences of the invention” and
`
`prescribes the “specific purpose of treating an angiogenic eye disorder.” Paper 21 at
`
`19.
`
`36.
`
`I understand that Dr. Do has offered an opinion that the claim term
`
`”method for treating” in Claims 1 and 14 of the ’338 Patent requires highly effective
`
`treatment that was non-inferior to the standard of care by the time the patent was
`
`filed in 2011.
`
`37.
`
`I agree that “method of treating” requires an effective treatment and,
`
`further, that by 2011, the POSA would have understood an effective treatment was
`
`one that was at least non-inferior to the standard of care, i.e., Lucentis.
`
`IX. EYLEA®
`38. Eylea® is a vascular endothelial growth factor (VEGF) antagonist that
`
`is indicated for, among other things, “the treatment of patients with: Neovascular
`
`
`
`–11–
`
`Exhibit 2048
`Page 14 of 56
`
`

`

`
`
`(Wet) Age-Related Macular Degeneration (AMD).” Ex. 1091 3 at section 1
`
`(INDICATIONS AND USAGE).
`
`39. The active ingredient in Eylea® is the recombinant fusion protein
`
`aflibercept, which consists of “portions of human VEGF receptors 1 and 2
`
`extracellular domains fused to the Fc portion of human IgG1.” Ex. 1091 at section
`
`11. Eylea® is believed to treat wAMD by binding to “VEGF-A and P1GF,” resulting
`
`in the inhibition of “binding and activation of the VEGF receptors.” Id. at section
`
`12.1.
`
`40. Eylea® is “formulated as an iso-osmotic solution for intravitreal
`
`administration.” Ex. 1091 at section 11.
`
`41. The Eylea® label instructs intravitreal injection of 2 mg (0.05 mL) of
`
`Eylea® every 4 weeks (approximately every 28 days, monthly) for the first 3 months,
`
`followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months)
`
`for the treatment of wAMD. Ex. 1091 at section 2.2.
`
`42.
`
` Eylea® was approved by FDA for the treatment of wAMD on
`
`November 18, 2011. Ex. 2075.4
`
`43.
`
`I began prescribing Eylea® soon after approval. Because I was not an
`
`investigator for Regeneron in its clinical testing of VEGF Trap-Eye, I (and my
`
`
`3 Eylea Prescribing Information.
`4 Eylea Approval Letter (November 18, 2011).
`
`
`
`–12–
`
`Exhibit 2048
`Page 15 of 56
`
`

`

`
`
`patients) did not have access to Eylea® (or VEGF Trap-Eye) until after it was
`
`approved by FDA on November 18, 2011.
`
`44. Eylea® was not generally available to clinicians before its approval on
`
`November 18, 2011. This is consistent with my experience that clinicians did not
`
`have access to and therefore could not administer VEGF Trap-Eye to patients unless
`
`the patient was enrolled in an ongoing clinical trial for VEGF Trap-Eye.
`
`X.
`
`PRIOR ART REFERENCES
`A. Dixon (Ex. 1006)5
`45. Dixon (Ex. 1006) is titled “VEGF Trap-Eye for the treatment of
`
`neovascular age-related macular degeneration. Dixon was published in 2009 in the
`
`journal Expert Opinion and Investigational Drugs. Dixon states that “VEGF
`
`Trap-Eye is a novel anti-VEGF drug currently in commercial development for the
`
`treatment of neovascular AMD.” Ex. 1006 at 1575 (emphasis added). Dixon further
`
`discloses that “[s]tructurally, VEGF Trap-Eye” is “a fusion protein of binding
`
`domains of VEGF receptors-1 and -2 attached to the Fc fragment of human IgG.”
`
`Id. at 1575-76.
`
`46. Dixon does not disclose the amino acid sequence or the nucleic acid
`
`sequence of the VEGF Trap-Eye or aflibercept. Dixon does not specify which amino
`
`
`5 Dixon et al., VEGF Trap-Eye for the Treatment of Neovascular Age-Related
`Macular Degeneration, 18 EXPERT OPINION ON INVESTIGATIONAL DRUGS 1573
`(2009).
`
`
`
`–13–
`
`Exhibit 2048
`Page 16 of 56
`
`

`

`
`
`acids of the VEGF receptor-1 or receptor-2 domains are included in “VEGF Trap-
`
`Eye,” and Dixon does not specify which amino acids of which Fc domain form “the
`
`Fc fragment” of “VEGF Trap-Eye.” Dixon also does not disclose that VEGF Trap-
`
`Eye and aflibercept share the same amino acid or nucleic acid sequence.
`
`47.
`
`In discussing VEGF Trap-Eye and Regeneron’s aflibercept drug
`
`candidate for oncology, Dixon notes that the two “have the same molecular structure,
`
`but there are substantial differences between the preparation of the purified drug
`
`product and their formulations.” Ex. 1006 at 1575 (emphasis added). Dixon states
`
`that while both aflibercept and VEGF Trap-Eye are manufactured from Chinese
`
`hamster ovary cells, “VEGF Trap-Eye undergoes further purification steps during
`
`manufacturing” and “is also formulated with different buffers and at different
`
`concentrations (for buffers in common)….” Id.
`
`48. Dixon also does not disclose whether treatment of patients with wAMD
`
`by administering VEGF Trap-Eye using the dosing regimen of the claimed invention
`
`would be effective, let alone whether the claimed dosing regimen would necessarily
`
`result in effective treatment of all patients with wAMD.
`
`49. Dixon also does not disclose any exclusion criteria for the treatment of
`
`wAMD.
`
`
`
`–14–
`
`Exhibit 2048
`Page 17 of 56
`
`

`

`
`
`B. Adis R&D Profile (Ex. 1007)6
`50. Adis R&D Profile is titled “Aflibercept” and lists a number of other
`
`names thereafter—AVE 0005, AVE 05, AVE0005, VEGF Trap - Regeneron, VEGF
`
`Trap (R1R2), and VEGF Trap-Eye. Ex. 1007 at 1. Adis was published in 2008 in
`
`Drugs in R&D and provides no information as to its author. Adis notes that
`
`“[a]flibercept is a member of Regeneron’s proprietary family of ‘Trap’ product
`
`candidates that catch, hold and block (i.e., trap) certain harmful cytokines or growth
`
`factors.” Id. Adis does not provide any amino acid or nucleic acid sequence
`
`information for aflibercept, VEGF Trap-Eye, or any other Trap product candidate.
`
`Id. Adis also never says that “VEGF Trap-Eye” corresponds to only aflibercept and
`
`as discussed below, some of these names that Adis lists next to aflibercept, e.g.,
`
`VEGF Trap-Regeneron and VEGF Trap (R1R2), were known in the art to
`
`encompass a genus of fusion proteins. Ex. 1004 7 at 11394 (describing several
`
`different Regeneron-developed VEGF-Traps (e.g., VEGF Trapparental, VEGF-
`
`TrapΔB1, VEGF-TrapΔB2, VEGF TrapR1R2).
`
`51. Adis also does not disclose whether treatment of patients with wAMD
`
`by administering VEGF Trap-Eye using the dosing regimen of the claimed invention
`
`
`6 Adis R&D Profile, Aflibercept: AVE 0005, AVE 005, AVE0005, VEGF Trap –
`Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye, 9 DRUGS IN R&D 261 (2008).
`7 Holash et al., A VEGF Blocker with Potent Antitumor Effects, 99 PROC. NATL.
`ACAD. SCI. USA 11393 (2002).
`
`
`
`–15–
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`Page 18 of 56
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`would be effective, let alone whether the claimed dosing regimen would necessarily
`
`result in effective treatment or all patients with wAMD.
`
`52. Adis also does not disclose any exclusion criteria for the treatment of
`
`wAMD.
`
`53. A POSA would not consider the information in Adis to be
`
`representative of the prior art as a whole. In particular, Regeneron’s clinical trial
`
`submissions (Ex. 1014, Ex. 1015, Ex. 2078, Ex 2079, Ex 2053, Ex. 2054), press
`
`releases (e.g., Ex. 1013 & Ex. 1028), and filings with the SEC (Ex. 1021)
`
`consistently use the term VEGF Trap-Eye for Regeneron’s ophthalmology product
`
`and aflibercept for its oncology product. A POSA would consider statements from
`
`Regeneron to government agencies and the public to be more authoritative than the
`
`generic statements made in Adis that cannot be attributed to any source. Moreover,
`
`Adis’s description of the trial design of the VIEW 1/2 studies appears to be
`
`inconsistent with the descriptions provided in Regeneron’s clinical trial submissions
`
`(Ex. 1014 & Ex. 1015), Regeneron’s press release (Ex. 1013), and even Dixon (Ex.
`
`1006). See also Ex. 20808 at 4 (“Two identical, noninferiority Phase 3 studies called
`
`VIEW 1 and VIEW 2 … are currently under way to examine the effects of VEGF
`
`Trap-Eye in wet AMD.”). As such, a POSA would not consider the statements in
`
`
`8 Heier, VEGF Trap-Eye for Exudative AMD, RETINAL PHYSICIAN, Apr. 2009
`(“Heier Retinal Physician 2009”)
`
`
`
`–16–
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`Page 19 of 56
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`
`Adis concerning aflibercept to establish that aflibercept and VEGF Trap-Eye are the
`
`same. Ex. 1002 at ¶ 176. Instead, a POSA would understand that the prior art as a
`
`whole did not disclose that VEGF Trap-Eye necessarily had the same amino acid
`
`sequence as aflibercept.
`
`C. Regeneron (8-May-2008) (Ex. 1013)9
`54. Regeneron (8-May-2008) is a press release from Regeneron titled
`
`“Bayer and Regeneron Dose First Patients in Second Phase 3 Study for VEGF
`
`Trap-Eye in Wet Age-Related Macular Degeneration.” Ex. 1013 at 1. The press
`
`release reports the initiation of the VIEW 2 clinical trials for “evaluating VEGF
`
`Trap-Eye for the treatment of the neovascular from of Age-related Macular
`
`Degeneration (wet AMD).” Id.
`
`55. Regeneron (8-May-2008) refers exclusively to administration of
`
`“VEGF Trap-Eye” and provides only that “VEGF Trap-Eye is a fully human, soluble
`
`VEGF receptor fusion protein that binds all forms of VEGF-A along with the related
`
`placental growth factor (PlGF) and VEGF-B.” Ex. 1013 at 2. Regeneron (May 8,
`
`2009) does not disclose an amino acid sequence or nucleic acid sequence for VEGF
`
`Trap-Eye.
`
`
`9 Press Release, Regeneron, Bayer and Regeneron Dose First Patient in Second
`Phase 3 Study for VEGF Trap-Eye in Wet Age-Related Macular Degeneration (May
`8, 2008), http://investor.regeneron.com/releasedetail.cfm?ReleaseID=394065.
`
`
`
`–17–
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`Page 20 of 56
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`56. Regeneron (May 8, 2008) also does not disclose whether treatment of
`
`patients with wAMD by administering VEGF Trap-Eye using the dosing regimen of
`
`the claimed invention would be effective, let alone whether the claimed dosing
`
`regimen would necessarily result in effective treatment or all patients with wAMD.
`
`57. Regeneron (8-May-2008) also does not disclose any exclusion criteria
`
`for the treatment of wAMD.
`
`58. A skilled artisan would not ordinarily view a press release as providing
`
`a complete description of a method of treatment and would certainly not read the
`
`Regeneron press release as describing any method of treatment. Instead, it would be
`
`understood as merely announcing a clinical trial to evaluate a drug through clinical
`
`testing.
`
`D. NCT-795 and NCT-377 (Ex. 101410 and Ex. 101511)
`59. NCT-795 and NCT-377 reflect historical changes for the VIEW 1 and
`
`VIEW 2 clinical trials, respectively. Ex. 1014 at 1; Ex. 1015 at 1. Both NCT-795
`
`and NCT-377 state that “2.0 mg VEGF Trap-Eye [was] administered every 8 weeks
`
`
`10 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of
`Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD) (VIEW 1),
`NCT00509795, ClinicalTrials.gov (Apr. 28, 2009),
`https://clinicaltrials.gov/ct2/show/NCT00509795.
`11 VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 2),
`NCT00637377, ClinicalTrials.gov (Mar. 17, 2008),
`https://clinicaltrials.gov/ct2/show/NCT00637377.
`
`
`
`–18–
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`Page 21 of 56
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`(including one additional 2.0 mg dose at Week 4) during the first year.” Ex. 1014 at
`
`8; Ex. 1015 at 6 (emphasis added). Neither NCT-795 nor NCT-377 provides any
`
`information regarding the amino acid or nucleic acid sequence of “VEGF Trap” or
`
`“VEGF Trap-Eye.”
`
`60. NCT-795 and NCT-377 also do not disclose whether treatment of
`
`patients with wAMD by administering VEGF Trap-Eye using the dosing regimen of
`
`the claimed invention would be effective, let alone whether the claimed dosing
`
`regimen would necessarily result in effective treatment for all patients with wAMD.
`
`61. NCT-795 and NCT-377 do not disclose the complete set of exclusion
`
`criteria used in the VIEW 1/2 clinical trials—i.e., the clinical trials that led to the
`
`approval of Eylea® for the treatment of wAMD which will be discussed further
`
`below.
`
`E. Heier-2009 (Ex. 1020)12
`62. Heier-2009 simply reports that “VEGF Trap-Eye is a purified
`
`formulation of VEGF Trap, a vascular endothelial growth factor (VEGF) receptor
`
`fusion protein that binds all forms of VEGF-A.” Ex. 1020 at 44-45 (Fig. 1).
`
`Heier-2009 does not disclose amino acid or nucleic acid sequence information for
`
`VEGF Trap-Eye.
`
`
`12 Heier, Intravitreal VEGF Trap for AMD: An Update, RETINA TODAY, Oct. 2009,
`44.
`
`
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`–19–
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`Page 22 of 56
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`F. Regeneron (30-April-2009) (Ex. 1028)13
`63. Regeneron (30-April-2009) states that “VEGF Trap-Eye is a fully
`
`human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A along
`
`with the related Placental Growth Factor (PlGF). Investigational VEGF Trap-Eye is
`
`a specific blocker of VEGF-A and PIGF that has been demonstrated in preclinical
`
`models to bind these growth factors with greater affinity than their natural receptors.”
`
`Ex. 1028 at 1.
`
`64. Regeneron (30-April-2009) does not disclose the amino acid sequence
`
`or nucleic acid sequence of VEGF Trap-Eye.
`
`XI. THE CHALLENGED CLAIMS ARE NOT ANTICIPATED
`A. The POSA Would Not Have Known That “VEGF Trap-Eye”
`Necessarily Has the Same Amino Acid Sequence as Aflibercept
`65. While I understand that tod