`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.: IPR2022-01226
`
`
`U.S. Patent No. 10,888,601 B2
`Filed: April 29, 2019
`Issued: January 12, 2021
`Inventor: George D. Yancopoulos
`
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`
`EXPERT DECLARATION OF MARY E. GERRITSEN, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,888,601 B2
`
`
`
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 1
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`
`
`TABLE OF CONTENTS
`
`INTRODUCTION. ........................................................................................... 1
`
`I.
`
`II. QUALIFICATIONS. ........................................................................................ 2
`
`III. SCOPE OF ENGAGEMENT. .......................................................................... 5
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART. ................................. 7
`
`V. LEGAL STANDARDS. ................................................................................... 8
`
`VI. U.S. PATENT NO. 10,888,601. ....................................................................... 9
`
`VII. PROSECUTION HISTORIES OF THE ’601 PATENT AND ITS
`EUROPEAN EQUIVALENTS. ....................................................................11
`
`VIII. DISCLOSURES, KNOWLEDGE, & INFORMATION AVAILABLE
`IN THE ART BEFORE JANUARY 13, 2011. .............................................20
`
`A.
`
`B.
`
`C.
`
`D.
`
`JOURNAL ARTICLES. .............................................................................20
`
`REGENERON PRESS RELEASES. .............................................................21
`
`1. May 2008 Press Release. ..........................................................23
`
`2.
`
`3.
`
`September 2008 Press Release. ................................................26
`
`Additional Regeneron Press Releases. ......................................29
`
`CLINICALTRIALS.GOV. .........................................................................35
`
`SEC FILINGS. .......................................................................................44
`
`X. CONCLUDING STATEMENTS. ..................................................................48
`
`
`
`i
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 2
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`
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`I, Mary E. 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.
`
`10,888,601 B2 (the “’601 patent”) (Ex.1001).
`
`
`
`I am the same Mary E. Gerritsen, Ph.D. who submitted declarations in
`
`support of Mylan in connection with the currently-pending inter partes reviews of
`
`U.S. Patent Nos. 9,669,069 B2 (“the ’069 patent”) and 9,254,338 B2 (“the ’338
`
`patent”), instituted as IPR2021-00880 and IPR2021-00881, respectively. I
`
`understand that the ’069 and ’338 patents are related to the ’601 patent being
`
`challenged here.
`
`
`
`This Declaration contains my qualifications; my opinions based on my
`
`expertise and my review of the ’601 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
`
`’601 patent, as well as my knowledge and experience in the pharmaceutical and
`
`biotechnology industries.
`
`
`
`1
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 3
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`
`
`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-
`
`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
`
`
`
`2
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 4
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`
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`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.
`
`
`
`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 1,000 patent applications in which
`
`over forty such applications issued as patents.
`
`
`
`3
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 5
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`
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` 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.
`
` 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.
`
`
`
`4
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 6
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`
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` 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 ’601 patent, discussed in more detail below.
`
` My time spent on this project is compensated at $400 per hour. My
`
`compensation does not depend in any way on the outcome of Petitioner’s petition
`
`for inter partes review of the ’601 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 ’601 patent and relevant sections of its prosecution
`
`history before the USPTO, (see Ex.1017, ’601 FH). I have also reviewed and
`
`considered various other documents in arriving at my opinions, and cite them in this
`
`Declaration.
`
`
`
`5
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 7
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`
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`
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`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 ’601 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 January 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
`
`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 ’601
`
`
`1 I have been asked to assume that the priority date of the ’601 patent is January 13,
`
`2011, the date of the earliest filed provisional application that appears on the ’601
`
`patent cover page. I have formed no opinion regarding the merit of the ’601 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 ’601 patent in ¶¶ 22-24, below.
`
`
`
`6
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 8
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`
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`patent, exercising reasonable diligence, before January 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,
`
`e.g., ¶¶ 53, 61, 76, 83, 98 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 ’601 patent’s
`
`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 ’601 patent).
`
`
`
`7
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 9
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`
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` With respect to the ’601 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.
`
`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.
`
`
`
`8
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 10
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`
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`
`
`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 ’601 patent would be considered prior art to the ’601
`
`patent.
`
`VI. U.S. PATENT NO. 10,888,601.
`
`
`
`I understand that the ’601 patent issued on January 12, 2021 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, ’601 patent, cover). I also understand that the
`
`’601 patent issued from U.S. Application No. 16/397,267 (“the ’267 Application”),
`
`a continuation of U.S. Application No. 16/159,282, filed on October 12, 2018, which
`
`is a continuation of U.S. Application No. 15/471,506 (“the ’506 Application”), filed
`
`on March 28, 2017, which is a continuation of U.S. Application No. 14/972,560,
`
`filed on December 17, 2015, which issued as the ’069 patent, which is a continuation
`
`of U.S. Application No. 13/940,370 (“the ’370 Application”), filed on July 12, 2013,
`
`which issued as the ’338 patent, which is a continuation-in-part of International
`
`
`
`9
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 11
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`
`
`Application No. PCT/US2012/020855, filed on 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 U.S.
`
`Provisional Application No. 61/561,957, filed on November 21, 2011. (Id.).
`
`
`
`I understand that the ’601 patent contains five independent claims and
`
`forty-two dependent claims. I understand Petitioner is challenging claims 1-9, 34-
`
`39, 41-43, and 45 (“the Challenged Claims”). Independent Challenged Claims 1 and
`
`34 are listed below:
`
`*
`
`*
`
`*
`
`
`
`
`
`
`
`10
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`Mylan Exhibit 1003
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`
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`(Ex.1001, ’601 patent, 21:41-47 (claim 1); id., 24:4-19 (claim 34)). I also understand
`
`that claims 2-9 depend from claim 1, directly or indirectly, and claims 35-39, 41-43,
`
`and 45 depend from claim 34, directly or indirectly. (Id., 21:47-67 (claims 2-9); id.,
`
`24:20-51 (claims 35-39, 41-43, and 45)).
`
`VII. PROSECUTION HISTORIES OF THE ’601 PATENT AND ITS EURO-
`PEAN EQUIVALENTS.
`
`
`
`I have reviewed the prosecution history for the ’601 patent, which I
`
`understand appears at Ex.1001. It is my understanding that the ’267 Application
`
`was filed on April 29, 2019 (see Ex.1017, ’601 FH, 4/29/2019 Preliminary
`
`Amendment, 1) and included twenty-nine claims directed towards a method of
`
`treating “age related macular degeneration,” “diabetic macular edema,” “diabetic
`
`retinopathy,” and “diabetic retinopathy in a patient with diabetic macular edema”
`
`with “aflibercept.” (Id., 2-5).
`
`
`
`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 ’267 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.).
`
`
`
`11
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 13
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`
`
` As outlined above, EP-325 is from the same family as the ’601 patent
`
`and contained claims covering 8-week dosing regimens for angiogenic eye disorders
`
`such as age related macular degeneration. (Ex.1062, EP-325, [0020]-[0024];
`
`Ex.1063, EP-325-FH, 7/5/2013 Amendments, 19-20). 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 ’601
`
`patent.
`
` According to the prosecution history of EP-325, the International
`
`Searching Authority identified a September 28, 2008 Regeneron Press Release as a
`
`“prior art document” that it “considered” in its May 22, 2012 written opinion
`
`(referencing the document as “D13”)):
`
`
`
`
`
`
`
`
`
`
`
`12
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 14
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`
`
`(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”:
`
`(Id., 5/14/2012 International Searching Authority Written Opinion, 5).
`
` The European Patent Office cited to this same Regeneron Press Release
`
`(as “D13”) in reaching its conclusions in its August 21, 2014 Communication:
`
`
`
`
`
`(Id., 8/21/2014 Communication, 8; see also id., 3-5).
`
`
`
`Indeed, multiple Third-Party Observations were submitted during
`
`prosecution of EP 325. The first Third Party Observation included reference to, inter
`
`alia, Regeneron Press Releases, a ClinicalTrials.gov record from the VIEW2 study,
`
`and Regeneron’s Form 10-Q from November 2007—all submitted as “prior art”:
`
`
`
`13
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`
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`(Id., 9/5/2016 Third Party Observations, 2; see also id., 3-4). The second Third Party
`
`Observation additionally identified the following:
`
`
`
`(Id., 9/7/2016 Third Party Observations, 2).
`
`
`
`
`
`14
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`Mylan Exhibit 1003
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`
`
`I have also reviewed EP 3 222 285 (Ex.1066, EP-285), which cites EP-
`
`325 as an earlier application and also 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., cover page).
`
` EP-285 also contained claims covering 8-week dosing regimens for
`
`angiogenic eye disorders such as age related macular degeneration. (Ex.1066, EP-
`
`285, 18; Ex.1067, EP-285-FH, 4/28/2017 New Divisional Application, Claims). As
`
`I describe in more detail in the following paragraphs, several references were cited
`
`as prior art against EP-285, confirming, in my opinion their public availability and
`
`relevance to the ’601 patent.
`
` According to the prosecution history of EP-285, the International
`
`Searching Authority identified three Regeneron Press Releases as “prior art
`
`documents” that it “considered” in its June 27, 2017 written opinion (referencing the
`
`documents as “D1”, “D2”, and “D10”)):
`
`
`
`15
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`Mylan Exhibit 1003
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`Page 17
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`
`
`D1: XP002770953
`
`2010 (2010-11-22),
`
`Retrieved from the Internet:
`URL: http: //investor.regeneron.com/released
`etail.cfm?releaseid=532099
`[retrieved on 2017-10-09]
`* the whole document *
`
`
`
`
`"Bayer and Regeneron Report
`Regeneron:
`Positive Top-Line Results of Two Phase 3
`Studies with VEGF Trap-Eye in Wet
`Age-related Macular Degeneration",
`Regeneron.com
`5
`
`after the immediately preceding dose.
`
`D1 discloses thatVEGF Trap-Eye was administered every two months after three monthly
`
`improving vision whe
`monthly, or 2mg every two months (following three monthly loading doses), as compared with
`
`intravitreal ranibizumab administered 0.4mg every month during the first year of the studies"
`
`In this context, the 2 mg aflibercept dose administeredin the first visit correspondsto the
`
`single initial dose of the claimed VEGF antagonist, the 2 mg aflibercept dosas administered at
`weeks 4 and
`respond to two secondary doses of the claimed
`VEGF antagonist, wherein
`
`ach secondary
`2
`is administered 4 weeks after the immediately preceding dose, and the
`2 mg aflibercept doses administered thereafter every 8 weeks correspond to thetertiary
`doses of the claimed VEGF antagonist, wherein each tertiary dose is administered & weeks
`
`
`
`
`
`16
`
`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 18
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`
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`(Ex.1067, EP-285-FH, 6/27/2017 International Searching Authority Written Opin-
`
`ion, 1, 3-4; id., 6/12/2017 International Search Report, 1).
`
`
`
`
`
`
`
`
`
`17
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 19
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`
`
`(Ex.1067, EP-285-FH, 6/27/2017 International Searching Authority Written Opin-
`
`ion, 1, 4; id., 6/12/2017 International Search Report, 1).
`
`
`
`
`
`
`
`
`
`
`
`18
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 20
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`
`
`(Ex.1067, EP-285-FH, 6/27/2017 International Searching Authority Written Opin-
`
`ion, 1-2; id., 6/12/2017 International Search Report, 3). The International Search
`
`Authority then continued to discuss “D1” as the “closest prior art”:
`
`(Ex.1067, EP-285-FH, 6/27/2017 International Searching Authority Written Opin-
`
`
`
`ion, 5).
`
` The European Patent Office cited to these same Regeneron Press
`
`Releases (the same “D1,” “D2,” and “D10”) in reaching its conclusions in its March
`
`26, 2020 Communication:
`
`
`
`(Id., 3/26/2020 Communication, 7; see also id., 4-6).
`
` The European Patent Office’s reliance on the above-mentioned
`
`documents confirms, in my opinion, that each was publicly accessible to persons
`
`interested and ordinarily skilled in the subject matter or art of the ’601 patent,
`
`exercising reasonable diligence, before 2011. I further note that, as far as I can tell
`
`
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 21
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`from reviewing the EP-325 and EP-285 file histories, Regeneron never contested the
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`public availability of those documents.
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`VIII. DISCLOSURES, KNOWLEDGE, & INFORMATION AVAILABLE IN
`THE ART BEFORE JANUARY 13, 2011.
`
`A.
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`JOURNAL ARTICLES.
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`
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`Journal articles are routinely provided online prior to being made
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`available in the printed journal, and their public availability and dissemination online
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`would have allowed persons interested and ordinarily skilled in the art exercising
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`reasonable diligence to locate them. Not only would a person of ordinary skill in the
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`art have been interested in, and sought out, the information contained in printed
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`journals, but this person would have been able to easily obtain these articles from
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`the journal’s website on the date of, or earlier than, the date of printed publication.
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`In fact, journals routinely publish articles on their website earlier than the printed
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`journal in order to disseminate them to the public more quickly and in an easily
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`accessible manner. Additionally, these articles typically appear in web search results
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`when a person of ordinary skill in the art conducts a search using various search
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`engines (e.g., via Google Scholar, Google, PubMed, etc.).
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` For example, the Mitchell article analyzes data from several
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`ranibizumab clinical trials in an assessment of various dosing schedules. (See
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`Ex.1030, Mitchell, 5-7). Mitchell published in print in the British Journal of
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`Ophthalmology (“BJO”) in January 2010, but the article states that it was first
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`20
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 22
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`published online on May 20, 2009. (Id., 2 (“Published Online First 20 May 2009”)).
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`“Online First” was the BJO’s advanced online publication of manuscripts in PDF
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`form. (Ex.1064, Wayback-BJO-Online First, 1 (Wayback Machine record from
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`February 12, 2009, describing the BJO’s “Online First” advanced publication
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`procedure)). According to the BJO’s website from February 12, 2009, the articles
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`published through “Online First” were “indexed by PubMed,” and would appear, at
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`least, in PubMed search results. (Id.). Furthermore, the BJO retains online
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`download statistics for all their articles and shows that in the first month that Mitchell
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`was available online, May 2009, the PDF was downloaded 299 times. (Ex.1065,
`
`BJO-Article Metrics, 1). As such, as of May 20, 2009, a person of ordinary skill in
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`the art exercising reasonable diligence would have been able to locate the article on,
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`among other things, the BJO’s website or PubMed, and easily download an
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`electronic copy.
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`B. REGENERON PRESS RELEASES.
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`
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`In my experience in the pharmaceutical and biotechnology industries,
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`companies like Regeneron and Bayer routinely issue press releases that include, e.g.,
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`information on product development and/or clinical trials. These press releases can
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`include information regarding, among other things, the specific product in
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`development, the study design of a clinical trial, and/or preliminary or final results
`
`from a specific clinical trial(s). A person of ordinary skill in the art would be
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`21
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 23
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`
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`interested in this type of information regarding ongoing product development within
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`the industry, including information regarding the development of products of a direct
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`competitor. For example, this type of information continually updates the
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`competitive landscape for a particular market and would assist the person of ordinary
`
`skill in the art in evaluating the same. As these press releases are a rich source of
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`information about the ongoing development for a particular treatment, persons of
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`ordinary skill in the art routinely review such press releases, whether as a result of
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`exercising diligence, received from email alerts (e.g., via Google Alerts), or website
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`updates (e.g., Seeking Alpha, Evaluate Pharma, and FiercePharma). Indeed, I
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`myself have searched for, reviewed and relied upon such press releases throughout
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`my professional career.
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` Regeneron’s and Bayer’s press releases regarding VEGF Trap-Eye
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`were no different, and, in my opinion, a person of ordinary skill in the art would
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`have sought out this information. As specifically noted below, the Regeneron and
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`Bayer press releases regarding VEGF Trap-Eye disclosed the ongoing development
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`of VEGF Trap-Eye as a therapy for angiogenic eye disorders, including different
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`treatment regimens using VEGF Trap-Eye.
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` Not only would a person of ordinary skill in the art have been interested
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`in, and sought out, the information contained in the Regeneron and Bayer press
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`releases, but this person would have been able to easily obtain these press releases
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`22
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 24
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`
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`directly from Regeneron’s website on the date of each release. In fact, companies
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`routinely publish press releases and other information on the company website under
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`a “News” menu or something similar (e.g., “Media” menu or “Investors & Media”
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`menu) in order to disseminate them to the public in an easily accessible manner, and
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`press releases are well-known to the community interested in the subject matter of
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`the reference as a source of useful information. Additionally, documents such as
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`press releases typically appear in web search results (e.g., via Google) when a person
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`of ordinary skill in the art conducts a search using various search engines.
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` Thus, as of the date of each press release, a person of ordinary skill in
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`the art would have been able to locate the specific press release on, among other
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`things, Regeneron’s website exercising reasonable diligence, easily access each
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`press release via Regeneron’s website, and easily download an electronic copy.
`
`1. May 2008 Press Release.
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` Regeneron and Bayer HealthCare AG issued a press release dated May
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`8, 2008 (Ex.1013, Regeneron (8-May-2008)), which described the Phase 3 age-
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`related macular degeneration VIEW 2 clinical trial as well as results of a Phase 2
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`clinical trial. (Id., 1-2; see also Ex.1032, Bayer (8-May-2008), 1-3).
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` Specifically, Regeneron (8-May-2008) stated that both the complete
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`VIEW 1 trial and the VIEW 2 trial were “designed to evaluate the efficacy and safety
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`of VEGF Trap-Eye administered by intravitreal injection, at dosing intervals of 4
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`23
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 25
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`and 8 weeks.” (Ex.1013, Regeneron (8-May-2008), 1; Ex.1032, Bayer (8-May-
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`2008), 1). Moreover, the Phase 2 clinical trial described “met both primary and
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`secondary key endpoints” and that “[f]ollowing the initial 12-week fixed-dosing
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`phase of the trial, patients continued to receive therapy at the same dose on a PRN
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`(as needed) dosing schedule based upon the physician assessment of the need for re-
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`treatment.” (Ex.1013, Regeneron (8-May-2008), 1-2).
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` Regeneron (8-May-2008) also described the dosing regimens used in
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`the VIEW 2 clinical trial, including “2.0 mg at an 8-week dosing interval, including
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`one additional 2.0 mg dose at week four,” in which one of the dosing arms included
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`a regimen of 2 mg every 8 weeks, with an additional injection at week 4. (Ex.1013,
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`Regeneron (8-May-2008), 1).
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` Regeneron (8-May-2008) concluded that in the Phase 2 clinical trial,
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`“on average, patients on the PRN dosing schedule maintained the gain in visual
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`acuity and decrease in retinal thickness achieved at week 12 through week 32 of the
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`study.” (Ex.1013, Regeneron (8-May-2008), 2).
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` A person of ordinary skill in the art would have understood that the
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`dosing regimens disclosed in Regeneron (8-May-2008) included the experimental
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`group that received VEGF Trap-Eye 2 mg every other month or on a PRN3 dosing
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`3 “PRN” (or pro re nata) is commonly understood as “as needed” dosing.
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`24
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`Mylan Exhibit 1003
`Mylan v. Regeneron, IPR2022-01226
`Page 26
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`schedule following the initial monthly injections over the first twelve weeks.
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`(Ex.1013, Regeneron (8-May-2008), 1).
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` A person of ordinary skill in the art would have been interested in, and
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`sought out, the information disclosed in Regeneron (8-May-2008) because it pertains
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`to ongoing product development within the industry, including dosing regimens of
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`a known therapy (VEGF Trap-Eye or aflibercept) in patients with age-related
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`macular degeneration. (Ex.1013, Regeneron (8-May-2008), 1). Again, my opinion
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`in this regard is, in fact, confirmed by other contemporaneous prior art to the ’601
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`patent that expressly refers to similar Regeneron and Bayer pre
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