UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`Inter Partes Review No.: IPR2021-00880
`
`U.S. Patent No. 9,669,069 B2
`Filed: December 17, 2015
`Issued: June 6, 2017
`Inventor: George D. Yancopoulos
`
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`EXPERT DECLARATION OF MARY GERRITSEN, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,669,069 B2
`
`CELLTRION - EXHIBIT 1003
`
`

`

`TABLE OF CONTENTS
`
`INTRODUCTION. ........................................................................................... 1
`
`I.
`
`II. QUALIFICATIONS. ........................................................................................ 1
`
`III. SCOPE OF ENGAGEMENT. .......................................................................... 4
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART. ................................. 7
`
`V. LEGAL STANDARDS. ................................................................................... 9
`
`VI. U.S. PATENT NO. 9,669,069. ......................................................................... 9
`
`VII. PROSECUTION HISTORIES OF THE ’069 PATENT AND ITS
`EUROPEAN EQUIVALENT, EP-325. ........................................................10
`
`VIII. DISCLOSURES, KNOWLEDGE, & INFORMATION AVAILABLE
`IN THE ART BEFORE JANUARY 13, 2011. .............................................23
`
`A.
`
`B.
`
`C.
`
`D.
`
`JOURNAL ARTICLES. .............................................................................23
`
`REGENERON PRESS RELEASES. .............................................................25
`
`1. May 2008 Press Release. ..........................................................27
`
`2.
`
`3.
`
`4.
`
`5.
`
`September 2008 Press Release. ................................................30
`
`April 2009 Press Release. .........................................................33
`
`February 2010 Press Release. ...................................................35
`
`Additional Regeneron Press Releases. ......................................37
`
`CLINICALTRIALS.GOV. .........................................................................42
`
`SEC FILINGS. .......................................................................................53
`
`IX. CONCLUDING STATEMENTS. ..................................................................56
`
`
`
`i
`
`

`

`I, Mary Gerritsen, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION.
`
`
`
`I submit this declaration on behalf of Mylan Pharmaceuticals Inc.
`
`(“Petitioner”). I understand that Petitioner is filing a petition with the United States
`
`Patent and Trademark Office (“USPTO”) for inter partes review of U.S. Patent No.
`
`9,669,069 B2 (the “’069 patent”) (Ex.1001).
`
`
`
`This Declaration contains my qualifications; my opinions based on my
`
`expertise and my review of the ’069 patent and other documents cited within this
`
`Declaration; the factual basis for those opinions; and data or other information I
`
`considered in forming my opinions. The opinions and facts set forth in this
`
`Declaration are based upon information and my analysis of documents related to the
`
`’069 patent, as well as my knowledge and experience in the pharmaceutical and
`
`biotechnology industries.
`
`II. QUALIFICATIONS.
`
`
`
`I am a pharmacologist with over thirty years of experience in the
`
`pharmaceutical and biotechnology industries.
`
`
`
`In 2010, I founded Gerritsen Consulting, and I have been a consultant
`
`for the biotechnology industry on topics related to biotherapeutics and drug
`
`discovery in the therapeutic areas of oncology, immuno-oncology, ophthalmology,
`
`autoimmune diseases/inflammation, cardiovascular disease, and angiogenesis-
`
`
`
`1
`
`

`

`related diseases. Specifically, I have collaborated with companies in numerous areas
`
`of product development, including research strategy, target selection and
`
`assessment, preclinical pharmacology and mechanism of action studies, preparation
`
`of Investigational New Drug applications, procedures for clinical trials, and
`
`evaluation of pipeline portfolio strategies.
`
`
`
`Prior to my consulting work, I was the Vice President of Molecular and
`
`Cellular Pharmacology at Exelixis, Inc. from 2004-2010.
`
` Exelixis is a
`
`biotechnology company focused on the development of small molecular therapeutics
`
`for the treatment of oncology and metabolic disease. I supervised many of the
`
`processes involved in preclinical to early clinical development, including target
`
`identification and validation, early lead discovery and validation, lead optimization,
`
`cellular and molecular pharmacology studies, pharmacodynamic assays, and early
`
`translational medicine studies. I also collaborated with the clinical groups in the
`
`early stages of Phase I clinical trials.
`
`
`
`From 2003-2004, I was a consultant with Frazier Health Care Ventures
`
`in which I was involved in the founding of MacuSight, Inc., a pharmaceutical
`
`company focused on angiogenesis disorders, specifically focused on age-related
`
`macular degeneration and diabetic macular edema. I was an inventor on several of
`
`the patents that were the basis for the foundation of the company which included
`
`U.S. Patent Nos. 8,222,271, 8,486,960, and 9,452,156.
`
`
`
`2
`
`

`

`
`
`From 2002-2003, I was the Senior Director, Vascular Biology with
`
`Millennium Pharmaceuticals (formerly COR Therapeutics) where I was responsible
`
`for development of the strategic plan for vascular biology and oversaw numerous
`
`small molecule development programs
`
`in
`
`the
`
`therapeutic
`
`indications of
`
`atherosclerosis, peripheral vascular disease, and fibrosis.
`
`
`
`Prior to the above, I was Associate Director of the Department of
`
`Cardiovascular Research at Genentech, Inc. from 1997-2001. Separately, I was a
`
`senior investigator in the angiogenesis group whose focus was the identification of
`
`novel targets for protein-based therapeutics. Throughout my time at Genentech, I
`
`was involved in the drafting and filing of over 1000 patent applications in which
`
`over forty such applications issued as patents.
`
`
`
` Before joining Genentech, I was a Principal Staff Scientist and Group
`
`Leader, Institute for Inflammation and Autoimmunity at Bayer Pharmaceuticals
`
`(formerly Miles Pharmaceuticals) from 1990-1997. During this time, I led the
`
`screening efforts for small molecule inhibitors of leukocyte adhesion, cyclo-
`
`oxygenase, and cytokine release/action while also supervising six laboratories within
`
`the Institute. Additionally, I developed collaborations with other industrial
`
`development laboratories as well as academic laboratories in order to promote
`
`advances in target discovery and assay development.
`
`
`
`3
`
`

`

` Prior to my roles in the pharmaceutical and biotechnology industry, I
`
`received a Bachelor of Science degree in Zoology and a Ph.D. in Endocrinology and
`
`Pharmacology from the University of Calgary. I completed my post-doctoral studies
`
`in Pharmacology at the University of California, San Diego. Following my post-
`
`doctoral work, I was an Assistant and later an Associate Professor of Physiology at
`
`New York Medical College from 1980-1989. During this time, I conducted research
`
`in therapeutic areas including stroke, inflammation, ophthalmology and diabetic
`
`vascular disease.
`
` Throughout my career, I have more than 100 publications in peer-
`
`reviewed journals, written numerous book chapters, and authored three books. I am
`
`currently, or have been, a member of numerous professional organizations, and I
`
`have been presented with numerous awards and honors throughout my career.
`
` Additional information about my professional and educational
`
`experience, and other background information, is described in my curriculum vitae
`
`(Ex.1061).
`
`III. SCOPE OF ENGAGEMENT.
`
`
`
`I have been retained by Petitioner as a technical expert to offer my
`
`analysis and opinions regarding various issues related to certain prior art references
`
`as they relate to the ’069 patent, discussed in more detail below.
`
`
`
`4
`
`

`

` My time spent on this project is compensated at $350 per hour. My
`
`compensation does not depend in any way on the outcome of Petitioner’s petition
`
`for inter partes review of the ’069 patent. Furthermore, I have no financial interest
`
`in this matter.
`
` My opinions and views set forth in this Declaration are based on my
`
`education and training, my experience in academia and the pharmaceutical and
`
`biotechnology industries, and on the materials I have reviewed for this case.
`
`
`
`I have reviewed the ’069 patent and relevant sections of its prosecution
`
`history before the USPTO, (see Ex.1017, ’069 FH). I have also reviewed and
`
`considered various other documents in arriving at my opinions, and cite them in this
`
`Declaration.
`
`
`
`5
`
`

`

`
`
`I have been asked to consider the level of education, skill set and
`
`training possessed by persons of ordinary skill in the field relevant to the ’069 patent
`
`as of at least January 13, 2011.1, 2
`
`
`
`I have also been asked to consider, from the perspective of the person
`
`of ordinary skill in the art as of at least January 13, 2011, whether certain references
`
`or documents were available as printed publications, or in other words, whether
`
`certain references or documents would have been publicly accessible to persons
`
`interested and ordinarily skilled in the subject matter or art, exercising reasonable
`
`diligence, before Jan. 13, 2011.
`
`
`
`I have formed certain opinions on these issues, which I set forth in
`
`greater detail below. In sum, it is my opinion that each of the references I discuss in
`
`
`1 I have been asked to assume that the priority date of the ’069 patent is January 13,
`
`2011, the date of the earliest filed provisional application that appears on the ’069
`
`patent cover page. However, I note that the Applicant of the application that issued
`
`as the ’069 patent argued that the priority date of the ’069 patent was November
`
`2011. (See Ex.1017, ’069 FH, 1/20/17 Amendment, 6). I have formed no opinion
`
`regarding the merit of the ’069 patent’s claim to any priority date.
`
`2 I provide my understanding of the qualifications for a person of ordinary skill in
`
`the art relevant to the ’069 patent in ¶¶ 22-24, below.
`
`
`
`6
`
`

`

`this declaration are printed publications in that they were publicly accessible to
`
`persons interested and ordinarily skilled in the subject matter or art of the ’069
`
`patent, exercising reasonable diligence, before Jan. 13, 2011. Moreover, my
`
`opinions in this regard are repeatedly confirmed by other contemporaneous prior art
`
`documents, which expressly cite the references I have been asked to evaluate. (See
`
`¶¶ 50, 58, 64, 70, 81, 88-93, 103, below).
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART.
`
` As I mentioned above, it is my understanding that my analysis is to be
`
`conducted from the perspective of a person of ordinary skill in the art at the time of
`
`the invention.
`
`
`
`I also understand that in defining a person of ordinary skill in the art the
`
`following factors may be considered: (1) the educational level of the inventor; (2)
`
`the type of problems encountered in the art; (3) prior art solutions to those problems;
`
`(4) rapidity with which innovations are made; and (5) sophistication of the
`
`technology and educational level of active workers in the field.
`
`
`
`I understand that a person of ordinary skill in the art is a hypothetical
`
`person who is presumed to be aware of all pertinent art, thinks along conventional
`
`wisdom in the art, and is a person of ordinary creativity at the time of the invention.
`
`I further understand that the relevant timeframe for assessing the ’069 patent’s
`
`
`
`7
`
`

`

`claims from the perspective of a person of ordinary skill in the art is assumed to be
`
`January 13, 2011 (the earliest possible priority date for the ’069 patent).
`
` With respect to the ’069 patent, a person of ordinary skill in the art
`
`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 age-related macular
`
`degeneration (“AMD”), including through the use of VEGF antagonists, or (ii)
`
`treating of same, including through the use of VEGF antagonists.
`
` A person of ordinary skill in the art would have been aware of the
`
`references and teachings described below, as well as other important information
`
`and references relating to angiogenic eye disorders, the causes of said disorders, and
`
`useful treatments for said disorders.
`
`
`
`8
`
`

`

`V. LEGAL STANDARDS.
`
`
`
`I am not a lawyer and do not purport to offer any legal opinions. In
`
`forming my opinions set forth herein, I have been asked to apply certain standards
`
`regarding printed publications.
`
`
`
`I understand that a reference, publication, document, etc. is a “printed
`
`publication” if the document is “publicly accessible.” I also understand that a
`
`reference is considered “publicly accessible” if it was disseminated or otherwise
`
`made available to the extent that persons interested and ordinarily skilled in the
`
`subject matter or art, exercising reasonable diligence, can locate it.
`
` Thus, a reference that could be classified as a “printed publication”
`
`before the priority date of the ’069 patent would be considered prior art to the ’069
`
`patent.
`
`VI. U.S. PATENT NO. 9,669,069.
`
`
`
`I understand that the ’069 patent issued on June 6, 2017 to Regeneron
`
`Pharmaceuticals, Inc. and is titled “USE OF A VEGF ANTAGONIST TO TREAT
`
`ANGIOGENIC EYE DISORDERS” with George D. Yancopoulos listed as the sole
`
`inventor. (Ex.1001, ’069 patent, cover). I also understand that the ’069 patent issued
`
`from U.S. Application No. 14/972,560 (“the ’560 Application”), a continuation of
`
`U.S. Application No. 13/940,370, filed on July 12, 2013, which issued as U.S. Patent
`
`No. 9,254,338 (“the ’338 patent”), which is a continuation-in-part of International
`
`
`
`9
`
`

`

`Application No. PCT/US2012/020855, filed January 11, 2012, and claims priority
`
`to U.S. Provisional Application No. 61/432,245, filed on January 13, 2011, U.S.
`
`Provisional Application No. 61/434,836, filed on January 21, 2011, and US.
`
`Provisional Application No. 61/561,957, filed on November 21, 2011. (d.).
`
`29.
`
`[understand that the ’069 patent contains one independentclaim and
`
`eleven dependent claims. The independentclaim is listed below:
`
`ID NO:2.
`
`1. 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 VEGFantagonist,
`followed by one or more secondary doses of the VEGF
`antagonist, followed by one or more tertiary doses of the
`VEGFantagonist;
`wherein each secondary dose is administered 2 to 4 weeks
`afier 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 chime-
`ric 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
`
`(Ex.1001, 069 patent, 21:42-60).
`
`I also understand that claims 2-12 depend from
`
`claim 1, directly or indirectly. (/d., 21:61-22:66).
`
`VII. PROSECUTION HISTORIES OF THE ’069 PATENT AND ITS
`EUROPEAN EQUIVALENT,EP-325.
`
`30.
`
`I have reviewed the prosecution history for the ’069 patent, which I
`
`understand appears at Ex.1001.
`
`It is my understanding that the *560 Application
`
`10
`
`

`

`was filed on December 17, 2015 (see Ex.1017, ’069 FH, 12/17/2015 Preliminary
`
`Amendment, 2) and originally included twelve claims directed towards a method of
`
`treating “an angiogenic eye disorder” with a “VEGF antagonist,” (id., 2-3).
`
`
`
`I have also reviewed EP 2 663 325 (Ex.1062, EP-325), which appears
`
`to be the European equivalent to the ’370 Application, that issued as the ’338 patent.
`
`(Id., cover). EP-325 claims the same priority chain as the ’370 Application—
`
`specifically, EP-325 claims priority
`
`to
`
`International Application No.
`
`PCT/US2012/020855, filed January 11, 2012, which claims priority to U.S.
`
`Provisional Application No. 61/432,245, filed on January 13, 2011, U.S. Provisional
`
`Application No. 61/434,836, filed on January 21, 2011, and U.S. Provisional
`
`Application No. 61/561,957, filed on November 21, 2011. (Id.).
`
` As originally filed, it is my understanding that EP-325 included claims
`
`similar to those prosecuted in the ’370 Application that issued as the ’338 patent and
`
`those prosecuted in the ’560 Application that issued as the ’069 patent. (Ex.1062,
`
`EP-325, [0020]-[0024]; Ex.1063, EP-325-FH, 7/5/2013 Amendments, 19-20;
`
`Ex.1017, ’069 FH, 12/17/2015 ’370 Application Original Claims, 22-23). I have
`
`prepared the following chart to illustrate the similarities between the ’560
`
`Application claims, the ’370 Application claims, and the EP-325 claims:
`
`
`
`
`
`11
`
`

`

`*560 Application
`Original Claims*4
`
`*370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`1. (Currently Amended)
`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 moretertiary doses
`of the VEGFantagonist;
`
`1. A method fortreating
`an
`angiogenic
`eye
`disorder in a patient, said
`method
`comprising
`sequentially
`the
`to
`administering
`initial
`patient a
`single
`VEGF
`dose
`of
`a
`antagonist,
`followed by
`one or more secondary
`doses
`of
`the VEGF
`antagonist,
`followed by
`one or moretertiary doses
`of the VEGFantagonist;
`
`1. A method fortreating
`an
`angiogenic
`eye
`disorder in a patient, said
`method
`comprising
`sequentially
`the
`to
`administering
`initial
`patient a
`single
`VEGF
`dose
`of
`a
`antagonist,
`followed by
`one or more secondary
`doses
`of
`the VEGF
`antagonist,
`followed by
`one or moretertiary doses
`of the VEGFantagonist;
`
`wherein each secondary
`dose is administered 2 to
`4
`weeks
`after
`the
`immediately
`preceding
`dose; and
`
`wherein each secondary
`dose is administered 2 to
`4
`weeks
`after
`the
`immediately
`preceding
`dose; and
`
`wherein each secondary
`dose is administered 2 to
`4
`weeks
`after
`the
`immediately
`preceding
`dose; and
`
`the
`
`whereineachtertiary dose
`whereineachtertiary dose
`whereineachtertiary dose
`
`is administered atleast8is administered at least 8 is administered at least 8
`
`weeks
`after
`the
`weeks
`after
`
`Weeksafterthe
`
`.
`
`liatel
`
`i
`
`taste
`
`on
`
`an
`
`as-
`
`> It is my understanding that the language to Claims 1, 8, 13, and 18 of the *560
`
`Application wasinitially amendedas notedin the chart.
`
`* Based on my review of the *560 Application’s original claims, it appears that
`
`Claims 4-5, 9-12, and 15-17 were cancelled during prosecution.
`
`12
`
`

`

`*560 Application
`Original Claims* ¢
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`immediately
`preceding
`immediately
`preceding
`needed/pro__re__nata
`dose.
`(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
`
`
`
`a
`1
`comprisin
`component
`VEGFRI1
`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.
`
`2. (Original) The method
`of claim 1, wherein only a
`single secondary dose is
`administered
`to
`the
`patient, and wherein the
`single secondary dose is
`administered
`4 weeks
`after the initial dose of the
`VEGFantagonist.
`
`2. The method of claim 1,
`wherein only a
`single
`secondary
`dose
`is
`administered
`to
`the
`patient, and wherein the
`single secondary dose is
`administered
`4 weeks
`after the initial dose ofthe
`VEGFantagonist.
`
`2. The method of claim 1,
`wherein only a
`single
`secondary
`dose
`is
`administered
`to
`the
`patient, and wherein the
`single secondary dose is
`administered
`4 weeks
`after the initial dose ofthe
`VEGFantagonist.
`
`3. (Original) The method|3. The method of claim 1,|3. The method ofclaim 1,
`
`
`
`of claim 1, wherein only|wherein two|whereinonl onl two
`
`
`13
`
`

`

`*560 Application
`Original Claims* ¢
`two secondary doses are
`administered
`to
`the
`patient, and wherein each
`secondary
`dose
`is
`administered
`4 weeks
`after
`the
`immediately
`preceding dose.
`
`4. (Canceled)
`
`5. (Canceled)
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`are
`doses
`secondary
`the
`to
`administered
`patient, and wherein each
`secondary
`dose
`is
`administered
`4 weeks
`after
`the
`immediately
`preceding dose.
`
`are
`doses
`secondary
`the
`to
`administered
`patient, and wherein each
`secondary
`dose
`is
`administered
`4 weeks
`after
`the
`immediately
`preceding dose.
`
`4. The method of claim 3,
`wherein eachtertiary dose
`is administered 8 weeks
`after
`the
`immediately
`preceding dose.
`
`4. The method of claim 3,
`wherein eachtertiary dose
`is administered 8 weeks
`after
`the
`immediately
`preceding dose.
`
`diabetic
`
`5. The methodof claim 1,
`wherein at least 5 tertiary
`doses
`of
`the VEGF
`antagonist
`are
`to
`administered
`the
`patient, and wherein the
`first four tertiary doses are
`administered
`8 weeks
`after
`the
`immediately
`preceding
`dose,
`and
`wherein each subsequent
`tertiary
`dose
`is
`administered 8
`12
`weeks
`after
`the
`immediately
`preceding
`dose.
`
`5. The methodof claim 1,
`wherein at least 5 tertiary
`doses
`of
`the VEGF
`antagonist
`are
`to
`administered
`the
`patient, and wherein the
`first four tertiary doses are
`administered
`8 weeks
`after
`the
`immediately
`preceding
`dose,
`and
`wherein each subsequent
`tertiary
`dose
`is
`administered 8
`12
`weeks
`after
`the
`immediately
`preceding
`dose.
`
`or
`
`or
`
`6. The methodof claim 1,
`6. The methodof claim 1,
`6. The methodof claim 1,
`wherein the angiogenic
`wherein the angiogenic
`wherein the angiogenic
`eye disorder is selected
`eye disorder is selected
`eye disorder is selected
`from the group consisting
`from the group consisting
`from the group consisting
`of: age related macular
`of: age related macular
`of: age related macular
`
`
`degeneration,_—diabetic degeneration,_—diabetic degeneration,_—diabetic
`retinopathy,
`diabetic
`retinopathy,
`diabetic
`retinopathy,
`
`14
`
`

`

`*560 Application
`Original Claims* ¢
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`macular edema, central
`macular edema, central
`macular edema, central
`retinal
`vein
`occlusion,
`retinal
`vein
`occlusion,
`retinal vein occlusion and
`
`
`
`
`branch retinal~=svein retinal~=sveinbranch corneal
`occlusion,
`and corneal
`occlusion,
`and corneal
`neovascularization.
`neovascularization.
`neovascularization.
`
`7. The methodof claim 6,
`wherein the angiogenic
`eye disorderis age related
`macular degeneration.
`
`7. The methodof claim 6,
`wherein the angiogenic
`eye disorderis age related
`macular degeneration.
`
`8. The method of claim 1,
`8. The method of claim 1,
`8. (Currently Amended)
`The method of claim 1,
`wherein
`the
`VEGF
`wherein
`the
`VEGF
`antagonist
`is
`an anti-
`antagonist
`is
`an anti-
`wherein all doses of the
`VEGF antagonist
`is—an
`VEGF
`antibody
`or
`VEGF
`antibody
`or
`fragment thereof, an anti-
`fragment thereof, an anti-
`
`ant-VEGHantibeds—or
`VEGFreceptor antibody
`VEGFreceptor antibody
`or fragment thereof, or a
`or fragment thereof, or a
`VEGF
`receptor-based
`VEGF
`receptor
`based
`chimeric molecule.
`chimeric molecule.
`
`7. (Original) The method
`of claim 6, wherein the
`angiogenic eye disorderis
`age
`related macular
`degeneration.
`
`molecule.
`
`are
`the
`to
`administered
`topical
`patient
`by
`administration or by
`intraocular
`
`administration.
`
`9. (Canceled)
`
`9. The method of claim 8,
`wherein
`the
`VEGF
`antagonist
`is
`a VEGF
`receptor-based
`chimeric
`molecule.
`
`9. The methodof claim 8,
`wherein
`the
`VEGF
`antagonist
`is
`a VEGF
`receptor-based
`chimeric
`
`15
`
`

`

`*560 Application
`3,4
`
`Original Claims
`
`10. (Canceled)
`
`11. (Canceled)
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`10. The method of claim
`9, wherein the VEGF
`receptor-based
`chimeric
`molecule
`comprises
`VEGFR1R2-FcAC1 (a)
`encoded by the nucleic
`acid sequence of SEQ ID
`NO:1.
`
`10. The methodof claim
`9. wherein the VEGF
`receptor-based chimeric
`molecule comprises
`VEGFR1R2-FcAC1 (a)
`encoded bythe nucleic
`acid sequence of SEQ ID
`NO:1.
`
`11. The method of claim
`9, wherein the VEGF
`receptor-based
`chimeric
`molecule comprises (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.
`
`administration.
`
`11. The method of claim
`9, wherein the VEGF
`receptor-based
`chimeric
`molecule comprises (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.
`
`12. (Canceled)
`
`12. The method of claim
`1, wherein all doses of the
`VEGF
`antagonist
`are
`administered
`to
`the
`patient
`by
`topical
`administration
`or
`by
`intraocular
`administration.
`
`12. The method of claim
`1, wherein all doses of the
`VEGF
`antagonist
`are
`administered
`to
`the
`patient
`by
`topical
`administration
`or
`by
`intraocular
`
`16
`
`

`

`*560 Application
`Original Claims* ¢
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`(Currently
`13.
`Amended) The method
`of claim 2 #2, wherein all
`doses
`of
`the VEGF
`antagonist
`are
`administered
`the
`to
`patient
`by
`intraocular
`administration.
`
`The
`(Original)
`14.
`method of
`claim 13,
`wherein the intraocular
`administration
`is
`intravitreal
`administration.
`
`15. (Canceled)
`
`13. The method of claim
`12, wherein all doses of
`the VEGF antagonist are
`administered
`to
`the
`patient
`by
`intraocular
`administration.
`
`13. The method of claim
`12, wherein all doses of
`the VEGF antagonist are
`administered
`to
`the
`patient
`by
`intraocular
`administration.
`
`14. The method of claim
`13,
`wherein
`the
`intraocular administration
`iS
`intravitreal
`administration.
`
`14. The method of claim
`13,
`wherein
`the
`intraocular administration
`iS
`intravitreal
`administration.
`
`15. The method of claim
`11, wherein all doses of
`the VEGFantagonist are
`administered
`to
`the
`patient
`by
`topical
`administration
`or
`by
`intraocular
`administration.
`
`the
`
`15. The method of claim
`11, wherein all doses of
`the VEGFantagonist are
`administered
`to
`the
`patient
`by
`topical
`administration
`or
`by
`intraocular
`administration.
`
`16. (Canceled)
`
`16. The method of claim
`15, wherein all doses of
`the VEGFantagonist are
`administered
`to
`the
`patient
`by
`intraocular
`administration.
`
`16. The method of claim
`15, wherein all doses of
`the VEGFantagonist are
`administered
`to
`the
`patient
`by
`intraocular
`administration.
`
`17. (Canceled)
`
`17. The method of claim
`16,
`wherein
`the
`
`17. The method of claim
`16,
`wherein
`
`17
`
`

`

`*560 Application
`Original Claims* ¢
`
`°370 Application
`
`EP-325
`
`Original Claims
`
`Original Claims
`
`intraocular administration
`1S
`intravitreal
`administration.
`
`intraocular administration
`1S
`intravitreal
`administration.
`
`18. The method of claim
`17, wherein all doses of
`the VEGF
`antagonist
`comprise from about 0.5
`mg to about 2 mg of the
`VEGFantagonist.
`
`18. The method of claim
`17, wherein all doses of
`the VEGF
`antagonist
`comprise from about 0.5
`mg to about 2 mg of the
`VEGFantagonist.
`
`19. The method of claim
`18, wherein all doses of
`the VEGF
`antagonist
`comprise 0.5 mg of the
`VEGFantagonist.
`
`19. The method of claim
`18, wherein all doses of
`the VEGF
`antagonist
`comprise 0.5 mg of the
`VEGFantagonist.
`
`20. The method ofclaim
`18, wherein all doses of
`the VEGFantagonist
`comprise 2 mg ofthe
`VEGFantagonist.
`
`20. The methodof claim
`18, wherein all doses of
`the VEGFantagonist
`comprise 2 mg ofthe
`VEGFantagonist.
`
`The
`(Original)
`19.
`method of
`claim 18,
`wherein all doses of the
`VEGF
`antagonist
`comprise 0.5 mg of the
`VEGFantagonist.
`
`The
`(Original)
`20.
`method of
`claim 18,
`wherein all doses of the
`VEGF
`antagonist
`comprise 2 mg of the
`VEGFantagonist.
`
`(Currently
`18.
`Amended) The method
`of claim 13 44, wherein
`all doses of the VEGF
`antagonist comprise from
`about 0.5 mg to about 2
`mg
`of
`the
`VEGF
`antagonist.
`
`NO:1.
`
`21. (New) The method
`10. The method of claim
`10. The method of claim
`9, wherein the VEGF
`9, wherein the VEGF
`of claim 1, wherein the
`receptor-based chimeric
`receptor-based
`chimeric
`VEGFantagonistis
`molecule
`comprises
`molecule comprises
`VEGFR1R2-FcACl(a)
`
`
`encoded by the nucleic VEGFR1R2-FcAC1(a) VEGFR1R2-FcAC1(a)
`encoded by the nucleic
`encoded by the nucleic
`acid sequence of SEQ ID
`acid sequence of SEQ ID
`NO:1.
`
`18
`
`

`

`
`
`*560 Application
`Original Claims**
`acid sequence of SEQ ID
`NO:1.°
`
`°370 Application
`Original Claims
`
`EP-325
`Original Claims
`
`(Ex.1017, ’069 FH, 12/17/2015 Preliminary Amendment, 2-3; id., 12/17/2015 °370
`
`Application Original Claims, 22-23; Ex.1063, EP-325-FH, 1/23/2012 Claims, 19-
`
`20). As noted above,the original claims of the °560 Application are very similar, if
`
`not the same but for a few amendmentsto the claims, to the original claims of the
`
`°370 Application, and the original claims of EP-325. (/d.).
`
`33. As I describe in more detail in the following paragraphs, several
`
`references were cited as prior art against EP-325, confirming, in my opinion their
`
`public availability and relevance to the ’069 patent.
`
`34. According to the prosecution history of EP-325,
`
`the International
`
`Searching Authority identified a September 28, 2008 Regeneron Press Release as a
`
`> Based on my review of the *560 Application’s Original Claims,
`
`the °370
`
`Application’s Original Claims, and EP-325’s Original Claims, Claim 21 of the ’560
`
`Application appears to add the sameclaim limitation that was present in Claim 10
`
`of the 370 Application and EP-325; however, the *560 Application’s applicants
`
`cancelled Claim 10 during prosecution.
`
`19
`
`

`

`“prior art document” that it “considered” in its May 22, 2012 written opinion
`
`(referencing the documentas “D13”)):
`
`D13: XP002674126
`
`"VEGF Trap-Eye
`Thomson Reuters Integrity:
`final phase II results in age-related
`macular degeneration presented at 2008
`Retina Society Meeting",
`
`2008 (2008-09-28), pages 1-1,
`
`a PNR (as needed) dosing schedule.
`
`D13 (phaseII study) describes the improvementof visual acuity in age-related
`macular degeneration patients after VEGF Trap-Eye monthly or quarterly
`administration for 12 weeks followed by an 40 additional weeks-treatment on
`
`(Ex.1063, EP-325-FH, 5/14/2012 International Searching Authority Written
`
`Opinion, 3-4; id., 7/19/2012 International Search Report, 1; see also id., 9/5/2016
`
`Third Party Observations, 2 (D13)). The International Search Authority then
`
`continued to discuss “D13”as the “closest prior art”:
`
`schedule.
`
`The closestprior art, D13 (phase |! study summary), describes the
`improvementof visual acuity in age-related macular degeneration patients
`after VEGF Trap-Eye monthly or quarterly administration for 12 weeks
`followed by 40 additional weeks treatment on a PNR (as needed) dosing
`
`(d., 5/14/2012 International Searching Authority Written Opinion,5).
`
`35.
`
`The European Patent Office cited to this same Regeneron Press Release
`
`(as “D13”) in reaching its conclusionsin its August 21, 2014 Communication:
`
`20
`
`

`

`The problem to be solved "provision of improved protocols to treat age
`related macular degeneration, diabetic retinopathy, diabetic macular edema,
`central retinal vein occlusion and corneal neovascularization" has not been
`
`are obviousin view of D13.
`
`shownto be solved by the claimed solutions in the present application. The
`objective technical problem needsto be reformulated to the less ambitious
`one "provision of alternative protocols to treat age related macular
`degeneration, diabetic retinopathy, diabetic macular edema, central retinal
`vein occlusion and corneal neovascularization” for which the claimed solutions
`
`(Ud., 8/21/2014 Communication, 8; see also id., 3-5).
`
`36.
`
`Indeed, multiple Third-Party Observations were submitted during
`
`prosecution ofEP 325. Thefirst Third Party Observatio