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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 ALEXANDER M. KLIBANOV, Ph.D.
`
`CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER
`
`
`1 IPR2022-00257, IPR2022-00258, IPR2022-00298, and IPR2022-00301 have been
`joined with this proceeding.
`
`
`
`
` 
`
`Exhibit 2049
`Page 01 of 55
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`

`

`
`
`TABLE OF CONTENTS
`
`Page No.
`
`Contents
`I. 
`Introduction ...................................................................................................... 1 
`Qualifications and Experience ......................................................................... 2 
`II. 
`Summary of Opinions ...................................................................................... 5 
`III. 
`IV.  A Person of Ordinary Skill in the Art .............................................................. 6 
`V. 
`Legal Standards ............................................................................................... 8 
`A. 
`Burden of Proof ..................................................................................... 8 
`B. 
`Anticipation ........................................................................................... 8 
`VI.  The ’338 Patent ................................................................................................ 9 
`VII.  The ’069 Patent .............................................................................................. 10 
`VIII.  Eylea® ............................................................................................................ 12 
`IX.  The Prior Art References Relied on by Dr. Albini Do Not Disclose
`the Amino Acid or the Nucleic Acid Sequence of VEGF Trap-Eye ............ 13 
`A.  Dixon (Ex. 1006) ................................................................................. 13 
`B. 
`Adis R&D Profile (Ex. 1007) .............................................................. 14 
`C. 
`Regeneron (8-May-2008) (Ex. 1013) .................................................. 16 
`D.  NCT-795 and NCT-377 (Ex. 1014 and Ex. 1015) .............................. 17 
`E. 
`Heier-2009 (Ex. 1020) ......................................................................... 17 
`F. 
`Regeneron (30-April-2009) (Ex. 1028) ............................................... 18 
`The Challenged Claims Are Not Anticipated ................................................ 18 
`A. 
`The Prior Art Did Not Disclose That VEGF Trap-Eye Necessarily
`Has the Same Amino Acid Sequence as Aflibercept .......................... 18 
`
`X. 
`
`
`
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`–i–
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`Exhibit 2049
`Page 02 of 55
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`

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`1. 
`
`
`
`A POSA would not understand Dixon’s phrase “molecular
`structure” to necessarily correspond to the amino acid
`sequence .................................................................................... 19 
`A POSA would understand that VEGF Trap-Eye could
`encompass a genus of protein sequences .................................. 28 
`None of Petitioner’s references discloses that VEGF Trap
`Eye corresponds to—and only to—the recited sequences ........ 38 
`Knowledge of the Amino Acid Sequence of VEGF Trap-Eye
`Alone Would Not Necessarily Result in Treatment ............................ 41 
`
`2. 
`
`3. 
`
`
`
`
`
`
`
`–ii–
`
`B. 
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`Exhibit 2049
`Page 03 of 55
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`
`
`I, Alexander Klibanov, Ph.D., 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 and the Petition for Inter Partes review of
`
`U.S. Patent No. 9,669,069 (“the ’069 Patent”) (Ex. 1019). In particular, I have been
`
`asked to comment on the state of the relevant art as of the earliest filing date
`
`(“priority date”) of the ’338 and ’069 Patents and to respond to the opinions 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 for my time spent working on this matter at my usual
`
`and customary hourly rate. 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.
`
`
`2 Unless otherwise noted, all citations to exhibits refer to exhibits filed in
`IPR2021-00881.
`
`
`
`
` 
`
`–1–
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`Exhibit 2049
`Page 04 of 55
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`

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`
`II. QUALIFICATIONS AND EXPERIENCE
`3.
`I am currently a Professor Emeritus of Chemistry and Bioengineering
`
`at the Massachusetts Institute of Technology (“M.I.T.”), where I taught and
`
`conducted research for over 40 years. From 2014 to 2019 (and also from 2007 to
`
`2012), I held the Novartis Endowed Chair Professorship at M.I.T. From 2012 to
`
`2014, I held the Roger and Georges Firmenich Endowed Chair Professorship in
`
`Chemistry. Prior to that, I was a Professor of Chemistry and a Professor of
`
`Bioengineering at M.I.T., positions I held from 1988 and 2000, respectively. From
`
`1979 to 1988, I was an Assistant Professor, then Associate Professor, and thereafter
`
`a Full Professor of Applied Biochemistry in the Department of Applied Biological
`
`Sciences (formerly the Department of Nutrition and Food Science) at M.I.T.
`
`4.
`
`I obtained my M.S. degree in Chemistry from Moscow University in
`
`Russia in 1971 and Ph.D. in Chemical Enzymology from the same University in
`
`1974. Thereafter, I was a Research Chemist at Moscow University's Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
`
`University of California in San Diego.
`
`5.
`
`Over the last 50 years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of chemistry, including
`
`biological, protein, medicinal, and formulation chemistry.
`
`
`
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` 
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`–2–
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`Exhibit 2049
`Page 05 of 55
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`6.
`
`I have earned numerous prestigious professional awards and honors.
`
`For example, I was elected to the U.S. National Academy of Sciences (considered
`
`among the highest honors that can be given to an American scientist) and also to the
`
`U.S. National Academy of Engineering (considered among the highest honors that
`
`can be given to an American engineer). I am also a Founding Fellow of the
`
`American Institute for Medical and Biological Engineering and a Corresponding
`
`Fellow of the Royal Society of Edinburgh (Scotland’s National Academy of Science
`
`and Letters). In addition, I have received the Arthur C. Cope Scholar Award, the
`
`Marvin J. Johnson Award, the Ipatieff Prize, and the Leo Friend Award, all from the
`
`American Chemical Society, as well as the International Enzyme Engineering Prize.
`
`7.
`
`I currently serve on the Editorial Boards of over a dozen scientific
`
`journals, including “Open Journal of Pharmacology”, “Applied Biochemistry and
`
`Biotechnology”, ”Nanocarriers”, “Open Access Academic Books in Chemistry”,
`
`“Biotechnology and Bioengineering”, “Journal of Biological Chemistry and
`
`Molecular Pharmacology”, “Recent Patents in Biotechnology”, “Archives of
`
`Medical Biotechnology”,
`
`“Current Pharmaceutical Biotechnology”,
`
`and
`
`“International Journal of Drug Design, Delivery, and Safety.”
`
`8.
`
`I have published over 315 scientific papers in various areas of chemistry.
`
`Of particular relevance to this proceeding are my numerous publications specifically
`
`dealing with protein chemistry,
`
`therapeutic proteins, and
`
`treatment of
`
`
`
`
` 
`
`–3–
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`Exhibit 2049
`Page 06 of 55
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`
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`ophthalmological disorders (i.e., diseases of the eye). I am also a named inventor of
`
`32 issued United States patents and of a number of pending ones. I have given over
`
`370 invited lectures, including many distinguished named lectureships, at
`
`professional conferences, universities, and corporations all over the world, many
`
`dealing with formulation, stability, stabilization, and biological evaluation of
`
`pharmaceutically active proteins (including enzymes and their inhibitors, as well as
`
`antibodies and growth factors). According to a recent Stanford University-led study,
`
`the overall impact of my published work places me in the top 0.01% of all scientists
`
`in the world.
`
`9.
`
`In addition to my research and teaching activities at M.I.T., I have
`
`consulted widely for pharmaceutical, medical device, and biotechnology companies.
`
`Those consulting relationships have included both innovator and generic
`
`pharmaceutical companies.
`
`10.
`
`I also have founded six pharmaceutical companies and have been on
`
`the scientific advisory boards and/or boards of directors of those companies and of
`
`many others. Of particular relevance to the present proceeding, one of the
`
`pharmaceutical companies founded by me focused on intravenous and subcutaneous
`
`delivery of therapeutic antibodies and fusion proteins.
`
`11. A number of the aforementioned consulting, advisory, and directorship
`
`activities have dealt specifically with formulation (such as liquid), stabilization,
`
`
`
`
` 
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`–4–
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`Exhibit 2049
`Page 07 of 55
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`administration (including parenteral), posttranslational modification, testing, and
`
`medical applications of therapeutically active proteins.
`
`12. My curriculum vitae, attached as Ex. 2082, summarizes my education
`
`and academic experience. Included in it is a list of all my professional publications
`
`and patents.
`
`III. SUMMARY OF OPINIONS
`13. My opinions and views set forth in this declaration are based on my
`
`education, training, and experience, 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 their earliest priority date.
`
`14.
`
`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 Petition for Inter Partes Review of the ’069
`
`Patent, IPR2021-00880, including all cited exhibits; (c) all other documents and
`
`references cited throughout this declaration; and (d) Patent Owner’s Responses to
`
`which my declaration relates.
`
`15.
`
`It is my opinion that the references identified by Dr. Albini—Dixon (Ex.
`
`1006), Adis R&D Profile (Ex. 1007), Regeneron (8-May-2008) (Ex. 1013), NCT-
`
`795 (Ex. 1014), NCT-377 (Ex. 1015), Heier-2009 (Ex. 1020), and Regeneron (30-
`
`
`
`
` 
`
`–5–
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`Exhibit 2049
`Page 08 of 55
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`
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`April-2009) (Ex. 1028)—do not disclose either the amino acid or the nucleic acid
`
`sequence of VEGF Trap-Eye.
`
`16.
`
`It is also my opinion that the prior art did not disclose that VEGF Trap-
`
`Eye necessarily had the same amino acid sequence as aflibercept.
`
`17. Further, it is my opinion that even if the amino acid sequence of VEGF
`
`Trap-Eye were known in the prior art, that knowledge alone would not be sufficient
`
`to produce an intact, properly folded, and biologically active in vivo VEGF Trap-
`
`Eye fusion protein, let alone a VEGF Trap-Eye fusion protein that could provide
`
`treatment if administered according the claimed dosing regimen.
`
`IV. A PERSON OF ORDINARY SKILL IN THE ART
`18.
`I am informed that a person of ordinary skill in the art (“POSA”) is a
`
`hypothetical person who is presumed to have access to, and be aware of, all of the
`
`relevant publicly available prior art at the time of the invention.
`
`19.
`
`In forming my opinions expressed herein, 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, and 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
`
`
`
`
` 
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`–6–
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`Exhibit 2049
`Page 09 of 55
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`
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`21, 2011. I have been informed that the earliest filing date of both the ’338 Patent
`
`and the ’069 Patent is January 13, 2011.
`
`20. Petitioner contends that a POSA with respect to the ’338 and ’069
`
`Patents 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,
`or (ii) treating of same, including through the use of VEGF
`antagonists.
`
`See Paper 1 (Petition) at 22.
`
`21.
`
`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.
`
`22. My opinions set forth in this declaration remain the same under either
`
`Petitioner’s or Patent Owner’s definition.
`
`
`
`
` 
`
`–7–
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`Exhibit 2049
`Page 10 of 55
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`

`

`
`
`V. LEGAL STANDARDS
`23.
`I am not an attorney or an expert in the U.S. patent law. The following
`
`legal standards I have applied in forming my opinions expressed in this declaration
`
`were explained to me by counsel for Patent Owner (“counsel”).
`
`A. Burden of Proof
`24. 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 (i.e., more likely than not).
`
`B. Anticipation
`25. For a patent to be valid, the claimed invention must be novel (i.e., new).
`
`A claimed invention that is not novel is said to be “anticipated.”
`
`26. For a patent claim to be deemed anticipated, every limitation of the
`
`claimed invention must be found in a single prior art reference, either expressly or
`
`inherently. A prior art reference may inherently anticipate a claimed invention if the
`
`claim limitations are necessarily present in the prior art reference. The words of a
`
`prior art reference do not have to be the same as in the claim, but all limitations must
`
`be present.
`
`27.
`
`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
`
`
`
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` 
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`–8–
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`Exhibit 2049
`Page 11 of 55
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`

`

`
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`possibility that a prior art reference could disclose a claimed structure is insufficient
`
`to demonstrate inherency. Accordingly, I have been instructed that a 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 a 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
`28. The ’338 Patent is titled “Use of a VEGF [where VEGF stands for the
`
`protein Vascular Endothelial Growth Factor] Antagonist to Treat Angiogenic Eye
`
`Disorders.” I understand that Petitioner has challenged claims 1, 3-11, 13-14, 16-
`
`24, and 26 of the ’338 Patent.
`
`29. The ’338 Patent has two independent claims, 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;
`
`
`
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` 
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`–9–
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`Exhibit 2049
`Page 12 of 55
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`
`
`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.
`
`30. A POSA would understand that claim 1 is directed to the treatment of
`
`an angiogenic eye disorder with a VEGF (a signaling protein that stimulates the
`
`formation of blood vessels) antagonist that has the amino acid sequence of SEQ ID
`
`NO:2.
`
`31. Claim 14 differs from claim 1 with respect to the last “wherein” clause
`
`which recites the nucleic acid sequence of SEQ ID NO:1 corresponding to the amino
`
`acid sequence of SEQ ID NO:2.
`
`32. Dependent claims 3-11, 13, 16-24, and 26 of the ’338 Patent further
`
`limit the time between dose administrations, the specific angiogenic eye disorder,
`
`administration route, and dose amount.
`
`VII. THE ’069 PATENT
`33. The ’069 Patent is titled “Use of a VEGF Antagonist to Treat
`
`Angiogenic Eye Disorders.” I understand that Petitioner has challenged claims 1
`
`and 8-12 of the ’069 Patent.
`
`
`
`
` 
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`–10–
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`Exhibit 2049
`Page 13 of 55
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`

`

`34. 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 [or “as the situation calls for” in
`Latin]) 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.
`
`35. A POSA would understand that claim 1 is directed to the treatment of
`
`angiogenic eye disorders with a VEGF antagonist that has a particular amino acid
`
`sequence—namely, SEQ ID NO:2.
`
`36. Claims 8-12 depend from claim 1 and further limit the specific dosing
`
`regimen, the types of angiogenic eye disorders, administration route, and the nucleic
`
`acid sequence of the VEGF antagonist.
`
`
`
`
` 
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`–11–
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`Exhibit 2049
`Page 14 of 55
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`

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`
`
`VIII. EYLEA®
`37. Eylea® is a marketed drug containing vascular endothelial growth factor
`
`(VEGF) antagonist as the active pharmaceutical ingredient (“API”) that is indicated,
`
`among other things, for “the treatment of patients with: Neovascular (Wet) Age-
`
`Related Macular Degeneration (AMD).” Ex. 10913 at 1 (INDICATIONS AND
`
`USAGE). Eylea® was approved by the FDA for the treatment of wet AMD
`
`(“wAMD”) on November 18, 2011. See Ex. 2075.4
`
`38. The API 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.
`
`39. Eylea® is “formulated as an iso-osmotic solution for intravitreal
`
`administration [i.e., injection into the eye].” Ex. 1091 at section 11.
`
`
`3 Eylea® Prescribing Information.
`4 Eylea® Approval Letter (November 18, 2011).
`
`
`
`
` 
`
`–12–
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`Exhibit 2049
`Page 15 of 55
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`

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`
`
`IX. THE PRIOR ART REFERENCES RELIED ON BY DR. ALBINI DO
`NOT DISCLOSE THE AMINO ACID OR THE NUCLEIC ACID
`SEQUENCE OF VEGF TRAP-EYE
`A. Dixon (Ex. 1006)5
`40. 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 on Investigational Drugs. Dixon states 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.” Ex. 1006, 1575-76. Dixon also
`
`reports that “VEGF Trap-Eye and [Regeneron’s] aflibercept (the oncology product)
`
`have the same molecular structure, but there are substantial differences between the
`
`preparation of the purified drug product and their formulations.” Id. at 1575
`
`(emphasis added). In the same paragraph, Dixon subsequently states that “VEGF
`
`Trap-Eye undergoes further purification steps during manufacturing” and “is also
`
`formulated with different buffers and at different concentrations (for buffers in
`
`common)” compared to the oncology product aflibercept. Id.
`
`41. Dixon does not disclose (i) the amino acid sequence or the nucleic acid
`
`sequence of either VEGF Trap-Eye or aflibercept; (ii) which particular amino acid
`
`residues of the VEGF receptor-1 or receptor-2 domains are included in VEGF Trap-
`
`
`5 Dixon et al., VEGF Trap-Eye for the Treatment of Neovascular Age-Related
`Macular Degeneration, 18 EXPERT OPINION ON INVESTIGATIONAL DRUGS 1573
`(2009).
`
`
`
`
` 
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`–13–
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`Exhibit 2049
`Page 16 of 55
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`

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`
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`Eye; (iii) which particular amino acid residues of the Fc domain (the crystallizable,
`
`i.e., the tail, region of an antibody) form “the Fc fragment” of VEGF Trap-Eye; and
`
`(iv) that VEGF Trap-Eye has the same amino acid sequence as aflibercept.
`
`B. Adis R&D Profile (Ex. 1007)6
`42. Adis R&D Profile (“Adis”) is titled “Aflibercept” and lists a number of
`
`other names in the subtitle—AVE 0005, AVE 005, AVE0005, VEGF Trap -
`
`Regeneron, VEGF Trap (R1R2), and VEGF Trap-Eye. Ex. 1007 at 1. The Adis
`
`paper was published in the journal Drug in R&D in 2008. It is anonymous, i.e.,
`
`conspicuously provides no information as to who its authors are or their affiliations,
`
`which is contrary to generally-accepted publishing norms. Adis provides no amino
`
`acid or nucleic acid sequence information for aflibercept, VEGF Trap-Eye, or any
`
`other Trap product candidate. Nor does Adis state that the term “VEGF Trap-Eye”
`
`corresponds to only aflibercept; furthermore, some of the 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. See Ex. 10047 at 11393-94.
`
`43.
`
`In addition, Adis reads as a piece of commercial intelligence in the
`
`pharmaceutical industry rather than a scientific article. According to the Drugs in
`
`
`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).
`
`
`
`
` 
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`–14–
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`Exhibit 2049
`Page 17 of 55
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`
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`R&D web site, the journal was re-launched in 2010 and has been since peer-
`
`reviewed. However, I have seen no evidence that it had been also peer-reviewed in
`
`2008 when Adis was published, especially since it is clearly not a regular scientific
`
`article. Due to all of the foregoing, it is my opinion that a POSA would not view
`
`Adis as a source of accurate and/or reliable protein chemistry information. Nor
`
`would a POSA 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), press releases (Ex. 1013 & Ex. 1028), and filings with the SEC (Ex. 1021)
`
`consistently use the term VEGF Trap-Eye for Regeneron’s ophthalmology product
`
`and the term aflibercept for its oncology product. Moreover, Adis’s description of
`
`the trial design of the VIEW 1/2 clinical studies appears to be inconsistent with the
`
`descriptions provided in Regeneron’s clinical trial submissions (Ex. 1014 & Ex.
`
`1015) and press release (Ex. 1013), or even with Dixon (Ex. 1006). See also Ex.
`
`20808 (“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.”).
`
`A POSA would consider Regeneron’s repeated statements to government agencies
`
`and to the public to be more authoritative than the generic statements made in Adis
`
`that cannot be attributed to any specific source. As such, and in context, a POSA
`
`
`8 Heier, VEGF Trap-Eye for Exudative AMD, RETINAL PHYSICIAN, Apr. 2009
`(“Heier Retinal Physician 2009”).
`
`
`
`
` 
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`–15–
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`Page 18 of 55
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`would not consider the statements in Adis concerning aflibercept to establish that
`
`aflibercept and VEGF Trap-Eye are one and the same. See 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
`44. 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. Regeneron
`
`(8-May-2008) refers only to administration of VEGF Trap-Eye and provides merely
`
`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.” Id. at 2. Regeneron (May 8, 2009) does not disclose the amino acid
`
`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.
`
`
`
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` 
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`–16–
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`Page 19 of 55
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`D. NCT-795 and NCT-377 (Ex. 101410 and Ex. 101511)
`45. 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. NCT-795 and
`
`NCT-377 provide no information regarding the amino acid or the nucleic acid
`
`sequence of either VEGF Trap or VEGF Trap-Eye.
`
`E. Heier-2009 (Ex. 1020)12
`46. Heier-2009, a 2-page article in the publication Retina Today, reports on
`
`the CLEAR-IT 2 extension clinical study and states 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 (see
`
`also Fig. 1). Heier-2009 does not disclose the amino acid or the nucleic acid
`
`sequence information for VEGF Trap-Eye.
`
`
`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.
`12 Heier, Intravitreal VEGF Trap for AMD: An Update, RETINA TODAY, Oct. 2009,
`44.
`
`
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`–17–
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`Exhibit 2049
`Page 20 of 55
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`F. Regeneron (30-April-2009) (Ex. 1028)13
`47. Regeneron (30-April-2009) is a press release from Regeneron titled
`
`“Bayer and Regeneron Extend Development Program for VEGF Trap-Eye to
`
`Include Central Retinal Vein Occlusion.” Ex. 1028 at 1. 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 PlGF
`
`that has been demonstrated in preclinical models to bind these growth factors with
`
`greater affinity than their natural receptors.” Id. Regeneron (30-April-2009) does
`
`not disclose the amino acid or the nucleic acid sequence of VEGF Trap-Eye.
`
`X. THE CHALLENGED CLAIMS ARE NOT ANTICIPATED
`A. The Prior Art Did Not Disclose That VEGF Trap-Eye Necessarily
`Has the Same Amino Acid Sequence as Aflibercept
`48. While today it is recognized that VEGF Trap-Eye has the same amino
`
`acid sequence as aflibercept, in 2011 this fact was not known from any publicly
`
`available prior-art disclosures, including the prior art identified by Petitioner and its
`
`declarant Dr. Albini.
`
`
`13 Press Release, Regeneron, Bayer and Regeneron Extend Development Program
`for VEGF Trap-Eye to Include Central Retinal Vein Occlusion (Apr. 30, 2009),
`https://investor.regeneron.com/news-releases/news-release-details/bayer-and-
`regeneron-extend-development-program-vegf-trap-eye.
`
`
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` 
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`–18–
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`Exhibit 2049
`Page 21 of 55
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`1.
`
`A POSA would not understand Dixon’s phrase “molecular
`structure” to necessarily correspond to the amino acid
`sequence
`49. Dr. Albini opines that Dixon’s statement that VEGF Trap-Eye and
`
`aflibercept “have the same molecular structure” (Ex. 1006) somehow establishes that
`
`their amino acid sequences are the same. Ex. 1002 at ¶ 44 (the last bullet point). In
`
`its Institution Decision, the PTO Board “credit[ed] Dr. Albini’s testimony that a
`
`[POSA] at the time of the invention would have known the molecular composition
`
`of Dixon’s disclosed VEGF Trap-Eye /aflibercept.” Paper 21 at 29-30. For the
`
`reasons that follow, I disagree with Dr. Albini’s opinion and the Board’s decision to
`
`credit his testimony with regard to this particular issue.
`
`50.
`
`It is well established that protein molecules, like VEGF Trap-Eye, have
`
`multiple levels of “structure,” including primary, secondary, tertiary, and quaternary
`
`structures. Ex. 201014 at 4.
`
`51. Proteins are formed by covalently linking the α-carboxyl group of one
`
`of the 20 standard amino acids to the α-amino group of another by means of a peptide
`
`bond. Ex. 2010 at 9. A series of amino acids joined by peptide bonds form a linear
`
`polypeptide chain. Id. The primary structure of a protein refers to the sequential
`
`order in which the amino acids (referred to as amino acid residues when within a
`
`
`14 Excerpts from the textbook by J.M. Berg et al., BIOCHEMISTRY (5th Edn., Freeman,
`New York, 2002).
`
`
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` 
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`–19–
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`Exhibit 2049
`Page 22 of 55
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`polypeptide) are arranged in a polypeptide chain—i.e., the amino acid sequence. Id.
`
`at 10. Each protein “has a unique, precisely defined amino acid sequence.” Id. For
`
`example, an amino acid sequence for the protein bovine insulin is shown below
`
`(where each three-letter abbreviation corresponds to a particular one of the 20
`
`standard amino acid residues):
`
`
`
`Id.
`
`52. Polypeptide chains can spontaneously fold into localized, regular three-
`
`dimensional structures, such as α-helices or β-sheets. Ex. 2010 at 12-13. The
`
`distribution of such structures as α-helices or β-sheets along a protein chain is often
`
`referred to as its “secondary structure.” Id. at 12. A pictorial depiction of an α-helix
`
`is reproduced below as an example:
`
`
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`–20–
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`Exhibit 2049
`Page 23 of 55
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`Ex. 2010 at 13.
`
`53. The overall three-dimensional structure of a protein is referred to as its
`
`“tertiary structure.” Ex. 2010 at 14-15. Typical proteins under physiological
`
`conditions fold into compact, roughly globular structures with non-polar cores. A
`
`pictorial depiction of the muscle protein myoglobin (with its bound heme moiety) is
`
`shown below:
`
`
`
`Id. at 14.
`
`54. The tertiary structure of many proteins consists of two or more distinct,
`
`compact, and nearly mutually independent regions called “domains” connecte