UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________________
`
`APOTEX INC.,
`Petitioner
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`____________________
`
`Inter Partes Review No.: Unassigned
`____________________
`
`U.S. Patent No. 11,253,572
`Filed: June 21, 2021
`Issued: February 22, 2022
`Inventor: George D. Yancopoulos
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`
`
`
`
`
`
`DECLARATION OF ANGELO P. TANNA, M.D.
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`Declaration of Angelo Tanna, Ph.D.
`U.S. Patent No 11,253,572
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`
`TABLE OF CONTENTS
`INTRODUCTION .......................................................................................... 1 
`I. 
`QUALIFICATIONS ....................................................................................... 1 
`II. 
`III.  MATERIALS CONSIDERED ....................................................................... 4 
`IV.  LEGAL STANDARDS .................................................................................. 4 
`V. 
`BACKGROUND OF THE TECHNOLOGY ............................................... 12 
`A.  Angiogenic Eye Disorders ................................................................. 12 
`1. 
`Age-Related Macular Degeneration (AMD) ........................... 14 
`2. 
`Diabetic Retinopathy (DR) ...................................................... 15 
`3. 
`Diabetic Macular Edema (DME) ............................................. 16 
`4. 
`Retinal Vein Occlusion (RVO) ................................................ 16 
`VEGF Antagonists ............................................................................. 17 
`B. 
`Aflibercept .......................................................................................... 18 
`C. 
`VI.  DETAILED OPINIONS ............................................................................... 24 
`A. 
`Level of Skill in the Art ...................................................................... 24 
`B. 
`Claim Construction ............................................................................ 24 
`1. 
`“initial dose,” “secondary dose,” and “tertiary dose.” ............. 24 
`2. 
`“4 weeks” and “8 weeks,” after the immediately
`preceding dose .......................................................................... 25 
`“wherein the patient achieves/gains…” ................................... 26 
`“wherein exclusion criteria for the patient include both
`of…” ......................................................................................... 26 
`Scope and Content of the Prior Art References ................................. 27 
`1. 
`Regeneron Press Releases and Clinical Trials ......................... 27 
`2. 
`ClinicalTrials.gov ..................................................................... 48 
`3. 
`SEC Filings .............................................................................. 58 
`D.  Grounds for Unpatentability—Detailed Analysis .............................. 62 
`1. 
`Ground 1: Dixon anticipates Claims 1-5, 8-11, 14, and
`26-30 ........................................................................................ 62 
`i
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`3. 
`4. 
`
`C. 
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`Declaration of Angelo Tanna, Ph.D.
`U.S. Patent No 11,253,572
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`
`2. 
`
`3. 
`
`4. 
`
`Ground 2: Regeneron (8-May-2008) anticipates Claims
`1-5, 8-11, 14, and 26-30 ........................................................... 76 
`Grounds 3 and 4: NCT-795 and NCT-377 each
`anticipates Claims 1-5, 8-11, 14, and 26-30 ............................ 88 
`Ground 5: Claims 6, 7, 12, and 13 are obvious over
`Dixon, or Regeneron (8-May-2008), or NCT-795, or
`NCT-377 in combination with Hecht. ................................... 100 
`
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`ii
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`I, Angelo Tanna, M.D., declare and state as follows:
`I.
`INTRODUCTION
`1.
`I am over the age of eighteen (18) and otherwise competent to make
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`this declaration.
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`2.
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`I have been retained as an expert witness on behalf of Apotex, Inc. for
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`the above captioned inter partes review (“IPR”) regarding U.S. Patent No.
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`11,253,572 (“the ’572 patent”). I am being compensated for my time in connection
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`with this IPR at my standard consulting rate, which is $750 per hour. My
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`compensation is not contingent on the conclusions I reach herein or on the
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`specifics of my testimony. I have no financial stake in the outcome of this
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`proceeding.
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`II. QUALIFICATIONS
`3.
` I received an M.D. from Columbia University College of Physicians
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`and Surgeons in 1994 and served as an intern in internal medicine at Graduate
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`Hospital in Philadelphia, Pennsylvania from 1994-1995. From 1995-1998, I
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`completed my ophthalmology residency at The Wilmer Ophthalmological Institute
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`at Johns Hopkins University School of Medicine. From 1998 to 1999, I completed
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`my glaucoma fellowship at The Wilmer Ophthalmological Institute. During my
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`fellowship, I was also an ophthalmology attending at the Johns Hopkins Bayview
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`Medical Center, primarily managing patients with glaucoma.
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`1
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`4.
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`I joined the faculty of the Northwestern University School of
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`Medicine as an Instructor in the Department of Ophthalmology and served in that
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`position from 1999 to 2002. When I joined the Northwestern faculty, I became
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`Director of the Glaucoma Service and continue to hold that position. I was
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`promoted to Assistant Professor of Ophthalmology at Northwestern University
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`Feinberg School of Medicine in 2002, Associate Professor in 2012 and Professor in
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`2019. In 2010, I became the Vice Chairman of the Department of Ophthalmology
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`at Northwestern University Feinberg School of Medicine, a position I currently
`
`maintain.
`
`5.
`
`From 1999 to 2014, I served as an attending ophthalmologist in
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`charge of the Glaucoma Service at the Veterans Administration Hospital in
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`Chicago. In that role (which ranged from 0.125 to 0.25 "full time equivalent"), I
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`supervised the education of ophthalmology residents in the surgical and medical
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`management of patients with glaucoma.
`
`6.
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`I was inducted as a member of Alpha Omega Alpha Medical Honor
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`Society in my senior year as a medical student at Columbia University College of
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`Physicians and Surgeons. Since 2005, I have been continuously listed in Best
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`Doctors in America. I was recipient of the American Academy of
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`Ophthalmology's Achievement Award in 2009, its Senior Achievement Award in
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`2017 and its Secretariat Award in 2019. I was recipient of the Teacher of the Year
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`2
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`award at the Northwestern University Feinberg School of Medicine Department of
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`Ophthalmology in 2019 and Outstanding Teacher Awards at Northwestern
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`University Feinberg School of Medicine in 2011, 2019, and 2020.
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`7.
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`I am an author of over 100 peer-reviewed publications, abstracts, and
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`textbook chapters on topics relating to ophthalmology. I also have given over 100
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`invited lectures and presentations on the surgical and medical management of
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`glaucoma, glaucoma diagnostics, and cataract surgery.
`
`8.
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`I am a member of the Association for Research in Vision and
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`Ophthalmology, American Academy of Ophthalmology, and Chicago Glaucoma
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`Society. I am a member of the American Glaucoma Society and have twice
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`previously served on its Board of Directors. I also served previously on the
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`Scientific Advisory Board of Prevent Blindness America.
`
`9.
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`I currently serve as a member of the editorial boards of the peer-
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`reviewed journals Survey of Ophthalmology, Ophthalmology, Scientific Reports,
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`and Ophthalmology Glaucoma. I am a member of the editorial board of the trade
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`magazines, Ophthalmology Management and Glaucoma Physician. I was guest
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`editor of the February 2017 issue of Ophthalmology Management, the focus of
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`which was novel glaucoma surgery.
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`3
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`10. A copy of my curriculum vitae is attached as Exhibit 1003, which
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`contains further details regarding my experience, education, and my other
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`qualifications to render an expert opinion in connection with this matter.
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`III. MATERIALS CONSIDERED
`11.
`In addition to my education, knowledge of the relevant published art,
`
`training, and experience, in forming the opinions I provide in this declaration, I
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`have also considered the documents referred to herein, as well as the Declaration
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`of Dr. Mary Gerritsen, filed in IPR2021-00881 (Mylan’s Exhibit 1003); and U.S.
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`Patent Nos. 9,254,338 and 9,669,069.
`
`IV. LEGAL STANDARDS
`12.
`In this section I describe my understanding of certain legal standards.
`
`I have been informed of these legal standards by Petitioner’s attorneys. I am not an
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`attorney, and I am relying only on instructions from Petitioner’s attorneys for these
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`legal standards. I have applied these understandings in my analysis as detailed
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`below.
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`13.
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`I understand that in order to receive a patent an inventor must invent
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`or discover a new and useful process, machine, manufacture, or composition of
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`matter.
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`4
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`14.
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`I understand that patent protection may be granted for any new and
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`useful process, machine, manufacture, or composition of matter, or any new and
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`useful improvement thereof.
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`15. With respect to the level of ordinary skill in the art at the relevant
`
`times applicable to the subject patent, I understand that factors such as the
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`education level of those working in the field, the sophistication of the technology,
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`the types of problems encountered in the art, the prior art solutions to those
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`problems, and the speed at which innovations are made may help establish the
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`level of skill in the art. One with ordinary skill has the ability to understand the
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`technology and make modest adaptations or advances. A person of ordinary skill in
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`the art is also a person of ordinary creativity, not an automaton.
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`16.
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`In my opinion, a person of ordinary skill in the art (“POSA”) at the
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`time of the alleged invention described in the subject patent is presumed to be
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`aware of all pertinent art, think along the lines of conventional wisdom, and
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`possess common sense and ordinary creativity in the pertinent field. A skilled
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`artisan here would have: (1) knowledge regarding the diagnosis and treatment of
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`angiogenic eye disorders, including the administration of therapies to treat said
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`disorders; and (2) the ability to understand results and findings presented or
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`published by others in the field, including the publications discussed herein.
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`Typically, such a person would have an advanced degree, such as an M.D. or Ph.D.
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`5
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`(or equivalent, or less education but considerable professional experience in the
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`medical, biotechnological, or pharmaceutical field), with practical academic or
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`medical experience in (i) developing treatments for angiogenic eye disorders (such
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`as AMD), including through the use of VEGF antagonists, or (ii) treating of same,
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`including through the use of VEGF antagonists.
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`17.
`
`In determining the qualifications of a POSA I considered, among
`
`other factors, the field of the alleged invention and use thereof described in the
`
`subject patent, and my experience with the educational level of practitioners in the
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`field of protein refolding or related disciplines. In addition, my opinion is based
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`upon my background, education, and personal experience.
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`18.
`
`I consider myself to be an expert in the art of the subject patent at the
`
`time of the alleged inventions claimed therein.
`
`19.
`
`I understand that the first step in comparing prior art to patent claims
`
`is to properly construe the claims to determine claim scope and meaning. I have
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`also been told that when I review and consider the claims, the claim term(s) should
`
`be analyzed under their ordinary and customary meaning as understood from the
`
`perspective of one of ordinary skill in the art, taking into account the claim
`
`language itself, specification, and prosecution history pertaining to the patent, as
`
`well as relevant extrinsic evidence. I also understand that if an inventor acts as his
`
`or her own lexicographer, the definition must be set forth in the specification with
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`6
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`reasonable clarity, deliberateness, and precision. I have applied this standard in
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`formulating my opinions, and set forth my understanding of the scope of particular
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`claim terms discussed below.
`
`20.
`
`I understand that a patent or other publication must first qualify as
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`prior art before it can be used to invalidate a patent claim. I understand that a
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`reference, publication, document, etc. is a “printed publication” if the document is
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`“publicly accessible.” I also understand that a reference is considered “publicly
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`accessible” if it was disseminated or otherwise made available to the extent that
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`persons interested and ordinarily skilled in the subject matter or art, exercising
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`reasonable diligence, can locate it. Thus, a reference that could be classified as a
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`“printed publication” before the priority date of the ’572 patent would be
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`considered prior art to the ’572 patent.
`
`21.
`
`I understand that documents and materials that qualify as prior art can
`
`be used to render a claim unpatentable as anticipated under 35 U.S.C. § 102 or as
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`obvious under 35 U.S.C. § 103.
`
`22.
`
`I understand that the “priority date” of a patent is taken to be the date
`
`on which it is filed. I further understand that the “critical date” for a patent is one
`
`year prior to its effective filing date. It is my understanding that the critical date is
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`significant because published information prior to the critical date is prior art that
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`can render a patent claim unpatentable regardless of the purported date of
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`invention.
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`23.
`
`I understand that, once the claims of a patent have been properly
`
`construed, the second step in determining anticipation of a patent claim requires a
`
`comparison of the properly construed claim language to the prior art on a
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`limitation-by-limitation basis.
`
`24.
`
`I understand that a prior art reference “anticipates” a claim, and thus
`
`renders the claim unpatentable, if all elements of the claim are disclosed in that
`
`prior art reference. I also understand that an anticipatory reference does not need
`
`to explicitly describe each element because anticipation can occur when a claimed
`
`limitation is necessarily inherent or otherwise implicit in the relevant reference.
`
`25.
`
`I understand that a claim is unpatentable under 35 U.S.C. § 102(b) of
`
`the Patent Act if the invention was patented or published anywhere, or was in
`
`public use, on sale, or offered for sale in this country, more than one year prior to
`
`the filing date of the patent application. I understand that a U.S. or foreign patent
`
`qualifies as prior art under § 102(b) to a patent claim if the date of issuance of the
`
`patent is more than one year before the filing date of the patent claim. I further
`
`understand that a printed publication, such as an article published in a magazine or
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`trade publication or a U.S. or foreign patent application, also qualifies as prior art
`
`8
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`under § 102(b) to a patent claim if the publication occurs more than one year
`
`before the filing date of the patent.
`
`26.
`
`I have been instructed by counsel on the law regarding obviousness,
`
`and understand that even if a patent is not anticipated, it will be unpatentable if the
`
`differences between the claimed subject matter and the prior art are such that the
`
`subject matter as a whole would have been obvious at the time the invention was
`
`made to a person of ordinary skill in the pertinent art.
`
`27.
`
`I have been instructed by counsel that the priority date of the ‘572
`
`patent is January 13, 2011. In my analyses below, I consider the ordinarily skilled
`
`artisan’s understanding as January 13, 2011.
`
`28.
`
`I understand that a person of ordinary skill in the art provides a
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`reference point from which the prior art and claimed invention should be viewed.
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`This reference point prevents one from using his or her own insight or hindsight in
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`deciding whether a claim is obvious. Thus, “hindsight reconstruction” cannot be
`
`used to combine references together to reach a conclusion of obviousness.
`
`29.
`
`I also understand that an obviousness determination includes the
`
`consideration of various factors such as (1) the scope and content of the prior art,
`
`(2) the differences between the prior art and the claims, (3) the level of ordinary
`
`skill in the pertinent art, and (4) the existence of secondary considerations of non-
`
`obviousness.
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`30.
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`I have been informed and understand that the obviousness analysis
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`requires a comparison of the properly construed claim language to the prior art to
`
`determine whether the claimed subject matter as a whole would have been obvious.
`
`A claimed invention can be obvious when, for example, there is some teaching,
`
`suggestion, or motivation in the prior art that would have led one of ordinary skill
`
`to modify the prior art reference or to combine prior art reference teachings to
`
`arrive at the claimed invention. In other words, even if one reference does not
`
`show the whole of the invention, if it would have been obvious to a person of
`
`ordinary skill in the art at the relevant time to add the missing pieces to the
`
`invention (for example as a matter of standard engineering practice or application
`
`of a well-known principle in the field), then a single reference can render a claim
`
`invalid even if it does not show the whole invention. Moreover, a combination of
`
`two or more references can render a claim invalid as obvious whether or not there
`
`is an explicit suggestion in one of the references to combine the two references, if
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`as a matter of engineering skill or practice in the field it would be known to do so.
`
`31.
`
`I am also informed that when there is some recognized reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
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`options within his or her technical grasp. If such an approach leads to the expected
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`success, it is likely not the product of innovation but of ordinary skill and common
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`sense. In addition, when a patent simply arranges old elements with each
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`performing its known function and yields no more than what one would expect
`
`from such an arrangement, the combination is obvious.
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`32. And as stated above, secondary considerations must be examined to
`
`determine whether a certain invention would have been obvious to one of ordinary
`
`skill in the art. I understand that secondary considerations of non-obviousness are
`
`part of the obviousness inquiry under § 103, and that some examples of secondary
`
`considerations include:
`
`(1) any long-felt and unmet need in the art that was satisfied
`by the invention of the patent;
`(2) any failure of others to achieve the results of the invention;
`(3) any commercial success or lack thereof of the products and
`processes covered by the invention;
`(4) any deliberate copying of the invention by others in the field;
`(5) any taking of licenses under the patent by others;
`(6) any expression of disbelief or skepticism by those skilled in
`the art upon learning of the invention;
`(7) any unexpected results achieved by the invention;
`(8) any praise of the invention by others skilled in the art; and
`(9) any lack of contemporaneous and independent invention by
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`others.
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`33. However, I understand that secondary considerations will not
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`overcome a strong showing of obviousness.
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`V. BACKGROUND OF THE TECHNOLOGY
`34.
`I understand that the ’572 patent is directed to dosing regimens for
`
`treating angiogenic eye disorders, including AMD, via the known method of: (1)
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`administering a single initial dose of 2 mg of aflibercept, followed by (2) one or
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`more “secondary doses” of 2 mg of aflibercept administered approximately four
`
`weeks after the immediately preceding dose, followed (3) by one or more “tertiary
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`doses” of 2 mg of aflibercept administered approximately eight weeks following
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`the immediately preceding dose. (See, e.g., id., Claim 1). The concept of treating
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`angiogenic eye disorders, such as age-related macular degeneration (“AMD”), and
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`diabetic macular edema (“DME”), with vascular endothelial growth factor
`
`(“VEGF”) inhibition was well known prior to the priority date of the ‘572 patent.
`
`(Ex.1001, ‘572 patent, 1:40-65)
`
`35. To assist the reader in understanding the discussion of my opinions,
`
`pertinent prior art, and relevant scientific concepts, I provide the following
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`background on the underlying technology and terminology.
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`A. Angiogenic Eye Disorders
`36. The following Figure illustrates the normal anatomy of the eye:
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`(Ex.1034, NIH AMD, 2). Vitreoretinal disorders relate to problems involving the
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`choroid, retina and macula (the central portion of the retina), and vitreous fluid (or
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`gel). The retina is the light-sensitive neural tissue lining the posterior segment of
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`the eye, which converts light into neuronal impulses that travel through the optic
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`nerve to the brain, where they are interpreted as images. The macula is the small
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`area at the center of the retina, which, because of the high concentration of cones in
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`that region, is responsible for high-acuity vision, which enables one to recognize
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`letters when reading or the characteristics of a person’s face that allows us to
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`recognize them. The vitreous fluid (or gel) is the clear, gel-like substance that fills
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`the inside of the posterior segment of the eye from the lens to the retina.
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`37. Several eye disorders are associated with abnormalities of the blood
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`vessels that comprise the choroid and those that serve the retina. As a part of
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`normal growth of tissues, homeostasis and wound healing processes, formation of
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`new blood vessels is called angiogenesis. Pathological angiogenesis is central to
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`many human retinal vascular disease processes such as age-related macular
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`degeneration, diabetic retinopathy and diabetic macular edema, and retinal vein
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`occlusion. (Ex.1038, Rudge, 1, 4), also Ex. 1001, 1:40-65).
`
`1.
`Age-Related Macular Degeneration (AMD)
`38. The NIH’s National Eye Institute describes AMD as “a common eye
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`condition and a leading cause of vision loss among people age 60 and older. It
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`causes damage to the macula, a small spot near the center of the retina and the part
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`of the eye needed for sharp, central vision, which lets us see objects that are
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`straight ahead.” (Ex.1034, NIH AMD, 1).
`
`39. AMD can be classified as either “dry” (nonexudative) or “wet”
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`(exudative). (See, e.g., Ex.1036, Regeneron (28-April-2008), 2). In wet AMD, new
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`blood vessels grow beneath the retina and leak blood and/or fluid, causing
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`disruption and dysfunction of the retina, as I have illustrated in the following
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`modification of Figure 1 from NIH AMD:
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`(Ex.1034, NIH AMD, 2 (modified to illustrate neovascular (wet) AMD); see also
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`Ex.1036, Regeneron (28-April-2008), 2). This results in loss of central vision. As
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`the disorder progresses, sub-macular scar formation occurs. This is known as a
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`disciform scar and represents the end-stage of AMD and associated vision loss.
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`(Id.).
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`40. AMD “affects > 1.75 million individuals in the US and it is estimated
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`that by 2020 this number will increase to almost 3 million” and “[w]orldwide,
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`AMD is estimated to affect 14 million people.” (Ex.1006, Dixon, 1573).
`
`2.
`Diabetic Retinopathy (DR)
`41. Diabetes frequently causes damage to blood vessels throughout the
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`body. When this damage affects the vasculature in the retina, it is known as
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`diabetic retinopathy (DR). DR “occurs when diabetes damages the tiny blood
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`vessels in the retina, which is the light-sensitive tissue at the back of the eye.”
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`(Ex.1035, NIH DR, 1). DR “can cause blood vessels in the retina to leak fluid or
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`hemorrhage (bleed), distorting vision.” (Id., 1-2). Further, “[i]n its most advanced
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`stage, new abnormal blood vessels proliferate (increase in number) on the surface
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`of the retina which can lead to scarring and cell loss in the retina.” (Id., 2). DR is
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`the “leading cause of vision impairment and blindness among working-age adults.”
`
`(Id., 1).
`
`3.
`Diabetic Macular Edema (DME)
`42. DME is a consequence of DR. “DME is the build-up of fluid (edema)
`
`in a region of the retina called the macula.” (Ex.1035, NIH DR, 3). “DME is the
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`most common cause of vision loss among people with diabetic retinopathy.” (Id.).
`
`4.
`Retinal Vein Occlusion (RVO)
`43. RVO is a disorder characterized by obstruction of a retinal vein,
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`which leads to leakage and accumulation of blood and fluid in the retina and can
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`lead to reduced arteriolar blood flow into the retina. Central RVO (CRVO) results
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`from the blockage of the central retinal vein while branch RVO (BRVO) results
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`from the blockage of one of the smaller branch veins. VEGF signaling can be
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`associated with both conditions and anti-VEGF therapy can be a critical tool in
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`their treatment. Ex. 1049 (Campochiaro).
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`B. VEGF Antagonists
`44. Vascular Endothelial Growth Factor (VEGF) is “a naturally occurring
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`protein in the body whose normal role is to trigger formation of new blood vessels
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`(angiogenesis) to support the growth of the body’s tissues and organs.” (Ex.1036,
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`Regeneron (28-April-2008), 2, also Ex.1008, Semeraro, 711). However, additional
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`research identified a role for VEGF in tumor angiogenesis, with studies showing an
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`upregulation of VEGF in various tumor types. (Ex.1037, Ferrara-2005, 968). As a
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`result, anti-angiogenic VEGF inhibitors were identified as potential therapies, and
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`were soon developed and entered clinical testing. (Id., 971).
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`45. One of the first of these was bevacizumab, a humanized monoclonal
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`antibody approved for the treatment of metastatic colon cancer in combination with
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`5-fluoruracil (5FU). (Id., 967, 971).
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`46. VEGF has also been identified as a factor in the abnormal growth and
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`fragility of new blood vessels in the eye, a condition associated with wet AMD.
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`(Ex.1036, Regeneron (28-April-2008), 2 (“Blockade of VEGF, which can prevent
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`abnormal blood vessel formation and vascular leak, has proven beneficial in the
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`treatment of wet AMD and a VEGF inhibitor, ranibizumab, has been approved for
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`treatment of patients with this condition.”), also Ex.1018, Brown, 627-28).
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`47.
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`In addition, based on the recognition that neovascularization and
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`vascular leakage are a major cause of vision loss in wet AMD, anti-VEGF agents
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`were also developed for the specific purpose of treating AMD.
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`48. One of these, ranibizumab, is a humanized monoclonal Fab fragment
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`capable of blocking the activity of VEGF-A, and marketed under the name
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`LUCENTIS®. Approved in 2006, it was originally indicated for the treatment of
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`wet AMD via monthly intravitreal administration of 0.5 mg. The prescribing
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`information available in 2006 also suggested a regimen of three monthly
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`intravitreal injections followed by less frequent dosing. (Ex.1019, Lucentis, 1).
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`Indeed, using a regimen that involved less frequent dosing was a preferred option
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`over monthly dosing at the time, due to the nature of intravitreal injections.
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`C. Aflibercept
`49. Aflibercept is an engineered prior art fusion protein consisting of
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`domain 2 of the human VEGF receptor 1 (VEGFR1); domain 3 of the human
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`VEGF receptor 2 (VEGFR2); fused to the Fc portion of human IgG, as depicted
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`below:
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` (See Ex.1004, Holash, 11394 (Fig.1A), Ex.1006, Dixon, 1575-76, Fig.1; also
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`Ex.1036, Regeneron (28-April-2008), 2 (“VEGF Trap-Eye is a fully human,
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`soluble VEGF receptor fusion protein that binds all forms of VEGF-A along with
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`the related Placental Growth Factor (PIGF).”). As Dixon states, aflibercept is a
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`VEGF receptor decoy with “high affinity for all VEGF isoforms, binding more
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`tightly than their native receptors.” Ex.1006, Dixon, 1575, 1577.
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`50.
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`In 2002, Regeneron published an article detailing its development of
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`VEGF Trap-Eye, a high-affinity VEGF blocker “that has prolonged in vivo
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`pharmacokinetics and pharmacodynamics, lacks nonspecific toxicities, and can
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`effectively suppress the growth and vascularization of a number of different types
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`of tumors in vivo,” and was intended to treat disorders associated with increased
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`angiogenesis. (Ex.1004, Holash, 11393).
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`51. Based on the reported studies, the authors concluded that “although
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`the parental VEGF-Trap and its VEGF-TrapR1R2 derivative are quite comparable in
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`vitro (see above), the VEGF-TrapR1R2 performs much better in vivo, presumably
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`because of its dramatically enhanced pharmacokinetic profile.” (Id., 11395-96).
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`The authors closed with a report of studies comparing VEGF-TrapR1R2 with anti-
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`VEGF monoclonal antibodies, and concluded that efficacy was equal to or better
`
`than anti-VEGF monoclonal antibodies. This led the authors to conclude that given
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`the comparable half-lives of fusion proteins in humans, the efficacious dose of the
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`VEGF-Trap may be much lower than that of a monoclonal anti-VEGF antibodies.
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`(See id., 11397). Holash et al. also concluded that VEGF-Trap may be useful in the
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`treatment of retinopathies, given the contribution of pathological angiogenesis to
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`such disorders. (See id., also Ex.1016 (2009 10Q), Ex.1007 (Adis) (“Aflibercept is
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`in clinical development with Regeneron Pharmaceuticals and sanofi-aventis [sic]
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`for the treatment of cancer, while Regeneron and Bayer are developing the agent
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`for eye disorders.)).
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`52. Subsequent work by Regeneron reinforced VEGF Trap’s potential as
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`a possible anti-angiogenic therapy for retinal vascular diseases, such as AMD,
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`DME, and RVO. For example, Rudge noted that blocking VEGF-A exhibited
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`impressive results in the treatment of wet AMD, suggesting that a VEGF blockade
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`like VEGF Trap could be useful in treating eye disorders characterized by leaky
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`and proliferating vasculature. (Ex.1038, Rudge, 411).
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`53. Rudge also includes experimental work which indicated a role for
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`VEGF in the pathology of other vascular eye disorders, including diabetic edema,
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`DR, and AMD. (Id., 414). Preclinical studies with VEGF Trap showed that it was
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`able to inhibit choroidal and corneal neovascularization, suppress vascular leak in
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`the retina, and promote the survival of corneal transplants by inhibiting
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`neovascularization. (Id.). Following the promising preclinical trials, VEGF Trap
`
`entered clinical trials assessing its effectiveness in treating AMD and diabetic
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`edema and retinopathy. The preliminary results showed that “VEGF Trap can
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`rapidly and impressively decrease retinal swelling, and that these changes can be
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`associated with improvement in visual acuity.” (Id., 414-15). The authors also
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`noted that the VEGF Trap was in the process of entering even more clinical trials
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`related to vascular eye diseases. (Id, 415).
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`54. The prior art states that aflibercept, VEGF Trap–Regeneron, VEGF
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`Trap-Eye, and VEGF-TrapR1R2, among others, are simply different names for the
`
`same active ingredient. E.g., Ex.1007 (Adis); Ex.1006, Dixon, 1575 (“VEGF Trap-
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`Eye and aflibercept (the oncology product) have the same molecular structure....”);
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`Ex.1016, 2009 10-Q, 20 (“VEGF Trap-Eye is a specially purified and formulated
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`form of VEGF Trap for use in intraocular applications.”)). Nguyen cites to a
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`different publication directed to VEGF-TrapR1R2 (Ex.1029 (Saishin)) when
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`concluding that “[i]ntravitreal administration of VEGF Trap strongly suppressed
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`laser-induced CNV in mice and primates.” Ex.1005, N