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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`GENOME & COMPANY,
`Petitioner,
`
`v.
`
`THE UNIVERSITY OF CHICAGO,
`Patent Owner
`
`––––––––––––––
`
`PGR2019-00002
`Patent 9,855,302 B2
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`
`
`DECLARATION OF SRIDHAR MANI, M.D.,
`IN SUPPORT OF PATENT OWNER RESPONSE
`
`

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`PGR2019-00002
`Patent 9,855,302 B2
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`
`Declaration of Sridhar Mani, M.D.
`
`Table of Contents
`I.
`PRELIMINARY STATEMENT ..................................................................... 1
`ACADEMIC AND PROFESSIONAL QUALIFICATIONS ......................... 2
`II.
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 5
`III.
`IV. PETITIONER’S ENABLEMENT CHALLENGE (GROUND 1) ................. 7
`A.
`Level of ordinary skill in the art ............................................................ 7
`B.
`Persons skilled in the art recognized that all cancer types are
`amenable to immune checkpoint inhibitor therapy. .............................. 8
`1.
`Persons in the art understood that all cancer cells have
`antigens that can be recognized by immune cells, requiring
`all cancers to evade immune system attack to persist. ................ 9
`Persons in the art understood that checkpoint inhibitors
`counteract the immune system’s inherent suppressor signals,
`independent of cancer type. ......................................................16
`Because checkpoint inhibitors target the immune system,
`persons in the art predicted they would treat every cancer
`type. ...........................................................................................21
`Persons in the art considered checkpoint inhibitor therapy to be
`successful, notwithstanding not “all” cancer patients responded. ......30
`D. Dr. Braun disregards standard clinical practice in asserting
`selecting a checkpoint inhibitor for a particular cancer patient
`would have required extensive testing. ...............................................35
`Neither O’Mahony nor Lopez supports Dr. Braun’s conclusion
`that Bifidobacteria had species- and strain-specific immune
`effects rendering them “unpredictable.” .............................................38
`1.
`O’Mahony does not provide enough data to conclude its two
`strains, let alone other strains, produce different immune
`effects. .......................................................................................40
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`C.
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`2.
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`3.
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`E.
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`2.
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`Declaration of Sridhar Mani, M.D.
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`V.
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`3.
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`4.
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`2.
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`3.
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`C.
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`Dr. Braun does not explain how any of the reported
`differences for O’Mahony’s two strains would have
`amounted to “diverse activity” of Bifidobacteria on cancer. ...46
`Lopez does not report enough information to conclude there
`is “diverse activity” across the twelve strains tested. ...............49
`Dr. Braun does not explain how any differences that were
`observed in Lopez amount to unpredictability in cancer
`treatment. ...................................................................................61
`PETITIONER’S OBVIOUSNESS CHALLENGES (GROUNDS 2–
`11) .................................................................................................................. 62
`A. None of Singh, Dong, Reddy or Lee supports Dr. Braun’s
`conclusions that B. longum had been shown to have antitumor
`activity against human colon cancer or had been shown to be
`“immunostimulatory” (grounds 2–4). .................................................62
`1.
`Singh’s report that dietary B. longum can inhibit AOM-
`induced tumor formation in rats would not have led a skilled
`person to believe that B. longum has activity against colon
`cancer in humans. ......................................................................63
`Neither Reddy nor Lee supports Dr. Braun’s conclusion that
`certain Bifidobacteria were known to have antitumor
`activity. ......................................................................................69
`A skilled person would not have concluded that B. longum is
`immunostimulatory based on Dong’s limited data, obtained
`from flawed experimental methodologies. ...............................74
`Kohwi would not have shown a skilled person that
`Bifidobacterium strains have antitumor activity against human
`cancer and are immunostimulatory, such that they should be
`combined with a checkpoint inhibitor (grounds 5–8). ........................85
`The combination of Mohania and Prakash would not have
`shown that B. bifidum has antitumor effect or modulates PD-1
`expression on immune cells (grounds 9–11). ......................................96
`1. Mohania does not provide sufficient information to conclude
`that B. bifdum has an antitumor effect or modulates PD-1
`expression on immune cells. .....................................................96
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`B.
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`2.
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`Prakash reported no antitumor effect of B. bifidum in the
`Example 3 mouse study. .........................................................114
`VI. CONCLUSION ............................................................................................ 115
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`Declaration of Sridhar Mani, M.D.
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`PGR2019-00002
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`I, Sridhar Mani, hereby declare and state as follows:
`
`Declaration of Sridhar Mani, M.D.
`
`I.
`
`PRELIMINARY STATEMENT
`I have been retained as an expert on behalf of Patent Owner, The
`1.
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`University of Chicago, and I am being compensated at my usual and customary
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`hourly rate for my expert services in connection with this post grant review
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`proceeding. My compensation is not dependent upon the outcome of the
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`proceeding.
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`2.
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`I have reviewed the Petition for post grant review of Patent No.
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`9,855,302 (“the ’302 patent”) filed by Petitioner, Genome & Company, and
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`Dr. Braun’s Declaration (Ex. 1002), as well as the exhibits cited in those two
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`documents. I have also reviewed the articles and documents I cite in this
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`declaration.
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`3.
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`I am aware of information generally available to, and relied upon by,
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`persons of ordinary skill in the art at the relevant time. Some statements I make
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`below are expressly based on such awareness. My statements are also informed by
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`my twenty-two years of practicing clinical oncology, and in particular immunology
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`and clinical drug discovery and development, as well as my fifteen years of
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`treating cancer patients as a board-certified oncologist.
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`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS
`I am Professor of Medicine, Molecular Pharmacology and Genetics at
`4.
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`Declaration of Sridhar Mani, M.D.
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`the Albert Einstein College of Medicine, in Bronx, New York, where I joined the
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`faculty in 1999.
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`5.
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`I received my undergraduate degree from the Sophie Davis School for
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`Biomedical Education, City College, City University of New York in 1988.
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`Subsequently, I earned my Doctor of Medicine degree (M.D.) from the then Mount
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`Sinai School of Medicine, NY, NY (now renamed The Icahn School of Medicine
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`at Mount Sinai). From 1990 to 1995, I completed an Internal Medicine Residency
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`at Yale-New Haven Hospital, New Haven, CT, and a clinical fellowship in
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`Hematology & Oncology at Yale University School of Medicine, New Haven, CT.
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`Concurrently, I was a postdoctoral fellow at Yale University School of Medicine
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`(Eric Fearon Laboratory) from 1993–1995.
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`6.
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`I joined the Department of Hematology and Oncology at The
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`University of Chicago, Chicago, IL in 1995 as an Instructor in Medicine. While at
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`Chicago, I led clinical practice and research in gastrointestinal oncology. My
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`research focused on developing oncology drugs for first-in-human studies as well
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`as later phase studies for gastrointestinal cancer. While conducting this clinical
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`research, I also typically saw 20–40 cancer patients per week as a board-certified
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`oncologist.
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`Declaration of Sridhar Mani, M.D.
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`7.
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`In 1998, I was recruited to Montefiore Medical Center/Albert Einstein
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`College of Medicine as an Assistant Attending and Assistant Professor of
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`Medicine. In 2000, I was appointed as the Founding Director of the Phase I
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`Experimental Therapeutics Program (in Oncology) at Montefiore Medical
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`Center/Albert Einstein College of Medicine, and I served in this role for several
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`years. As Director, I was a principal investigator of several phase I studies and
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`managed clinicians treating trial subjects, oversaw the implementation of clinical
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`trial protocols, and met with regulatory bodies (Food & Drug Administration,
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`Institutional Review Boards) to discuss the trials.
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`8.
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`In 2002, I received the Lilly Clinical Investigator Award from the
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`Damon Runyon Foundation for Cancer Research, which lead to my promotion to
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`Associate Professor in 2003, followed by a secondary appointment in Molecular
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`Genetics (now the Department of Genetics) in 2006. In 2011, I was promoted to
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`Professor of Medicine and Genetics. Subsequently in 2018, I received a further
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`secondary appointment as Professor of Molecular Pharmacology.
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`9.
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`I maintained both clinical practice and laboratory research throughout
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`most of my career as a medical oncologist. I continued to see patients in the clinic
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`until mid-2010, when I decided to work full time in the laboratory. I received my
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`first grant award, Damon Runyon Clinical Investigator Award, in 2002, and since
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`then my laboratory work has been funded continuously by The National Institutes
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`of Health (NIH), as well as by grants from The Crohn’s and Colitis Foundation of
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`Declaration of Sridhar Mani, M.D.
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`America (CCFA) and more recently from the Department of Defense (DOD). My
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`research interests focus on intestinal immunity, orphan nuclear receptors, anti-
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`cancer therapies, and the microbiome. As principal investigator of a research
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`laboratory, I have trained graduate students and post-doctoral researchers, among
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`others.
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`10.
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`I also routinely review grant applications for NIH and DOD and other
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`agencies and foundations within the U.S., as well as for granting agencies in India
`
`and Europe.
`
`11.
`
`I am Associate Editor of the journals Molecular Pharmacology and
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`Nuclear Receptors Research, and I serve on the editorial boards of various other
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`journals including Current Cancer Drug Targets, Current Medicinal Chemistry –
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`Anti-Cancer Agents, Genes & Cancer, Clinical Cancer Research, Molecular
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`Cancer Therapeutics, Journal of Biological Chemistry, and Journal of Visual
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`Experiments.
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`12.
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`I have published 162 peer-reviewed scientific articles. All relevant
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`publications pertaining to my qualifications are presented in my curriculum vitae,
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`which is appended as Appendix A.
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`13.
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`I have obtained awards and recognition throughout my medical career,
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`including an appointment as a Fellow in the American College of Physicians, USA
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`in 2003. I also received an outstanding scientist award from the Society of Asian
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`Declaration of Sridhar Mani, M.D.
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`American Scientists in Cancer Research (AASCR) in 2011. I have been a guest
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`lecturer at major institutions and conferences around the world, as detailed in my
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`curriculum vitae.
`
`14.
`
`I am a named inventor on at least nine patents and patent applications.
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`15. My qualifications in this field are represented by my curriculum vitae.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`
`16.
`
`I understand from Patent Owner’s counsel that the ’302 patent claims
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`the benefit of earlier-filed patent applications, the earliest of which was filed on
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`June 1, 2015, and that this date is the date by which to assess the knowledge and
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`understanding of persons of ordinary skill in the art.
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`17. Dr. Braun states that a person of ordinary skill in the art in the
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`relevant field as of June 1, 2015 “would have an advanced degree or its substantial
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`equivalent in the biological sciences, including specifically in the fields of
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`immunology, microbiology and the microbiome, and oncology, coupled with
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`research experience in those fields.” Ex. 1002 ¶ 40. For the purposes of this
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`declaration, I apply Dr. Braun’s definition of a person of ordinary skill in the art. I
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`consider a physician with clinical experience as a medical oncologist and research
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`experience in immunology, microbiology, the microbiome, and oncology, to meet
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`Dr. Braun’s definition.
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`18.
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`I consider my training and experience to qualify me to provide
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`opinions on the understanding of a person of ordinary skill in the relevant field as
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`of June 1, 2015, as the field pertains to treating cancer in humans. I am a board-
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`certified medical oncologist, and my experience as an oncologist includes treating
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`cancer patients from 1995–2010 and thereafter (until the present) continuing to
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`advise physicians and their patients undergoing anticancer therapy (including
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`checkpoint inhibitor therapy); conducting clinical research to develop new
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`oncology agents from 1995–2005; and conducting laboratory research as a
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`principal investigator of my laboratory from 2002 until the present. Before the
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`checkpoint inhibitors nivolumab and pembrolizumab had received FDA approval, I
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`referred patients to clinical trials of these agents and monitored their response
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`while they were being treated in the studies. More recently, in a consultative
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`capacity, I have provided advice to patients undergoing pembrolizumab therapy. I
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`have also trained residents and fellows in treating cancer patients and continue to
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`work with physicians treating cancer patients, and I understand the expectations of
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`persons working in the field with respect to clinical responses to anticancer
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`therapies. I also have experience studying the microbiome. My laboratory
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`research has focused on delineating the role the microbiome plays in regulating
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`immunity, including the role of microbiota in immunotherapy.
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`IV. PETITIONER’S ENABLEMENT CHALLENGE (GROUND 1)
`In this section, I address Dr. Braun’s assertions and conclusions in
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`sections VI.A, VI.B, and VI.C of his “State of the Art” discussion (¶¶ 93–117) and
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`in sections VII.B.2 and VII.B.6 of his enablement discussion (¶¶ 132–134, 152–
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`155). In these sections, Dr. Braun concludes that cancer therapy, including the use
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`of checkpoint inhibitors to treat cancer in humans, was “highly unpredictable” (¶
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`105, ¶ 109), and that resolving the unpredictability for checkpoint inhibitor therapy
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`required “extensive testing” (¶ 154). Dr. Braun also asserts that different
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`Bifidobacterium species and strains “affect the immune system in different and
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`unpredictable ways” (¶ 117), such that “there is significant unpredictability in the
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`efficacy of a given species of Bifidobacterium on a particular cancer” (¶ 155).
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`Here I explain why a skilled person would not have drawn such conclusions based
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`on the documents and literature cited, as well as the general knowledge and
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`understanding in the field as to how physicians treat cancer patients.
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`A. Level of ordinary skill in the art
`20. Dr. Braun states that the level of ordinary skill in the art is “high”
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`because a person of ordinary skill would need “specialized knowledge of cancer,
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`immunology, and microbiota.” Ex. 1002 ¶ 132. For the purposes of this
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`declaration, I accept that the level of skill is “high.” I address Dr. Braun’s
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`assertions regarding the uncertainty of cancer therapy development and of the
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`Declaration of Sridhar Mani, M.D.
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`effects of Bifidobacteria below.
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`B.
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`21.
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`Persons skilled in the art recognized that all cancer types are
`amenable to immune checkpoint inhibitor therapy.
`In ¶¶ 93–105, Dr. Braun discusses cancer and cancer therapies,
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`including immune checkpoint inhibitor therapy, and finally concludes “cancer and
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`cancer therapy are highly unpredictable.” In discussing checkpoint inhibitor
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`therapy alongside other cancer treatments, he suggests that the “unpredictability”
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`of other cancer treatments also applies to immune checkpoint inhibitor therapy.
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`Ex. 1002 ¶¶ 93–105. He then discusses checkpoint inhibitor therapy specifically in
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`¶¶ 106–109, and concludes that, because checkpoint inhibitor therapy had “only
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`been proven in a limited number of cancers,” and had “only been proven effective
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`in a subset of patients with those specific cancers” (¶ 106), checkpoint inhibitor
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`therapy was “highly unpredictable” (¶ 109).
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`22. However, as I explain in this section, immune checkpoint inhibitor
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`therapy was in 2015 (and still is) understood to be unique among cancer
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`therapies—it targets the immune system, not the cancer. By June 2015, immune
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`checkpoint inhibitors were reported to be effective in a “diverse”1 range of human
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`1 Schumacher (Ex. 2030) at 69.
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`cancer types, and researchers reported that, because of their unique mechanism of
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`Declaration of Sridhar Mani, M.D.
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`action (to target the immune system, rather than the cancer itself), there was no
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`reason to doubt that immune checkpoint inhibitors would have an effect in all
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`cancer types, as all cancers must evade the immune system to grow. In other
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`words, the field recognized that the unique mechanism underlying checkpoint
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`inhibition would make immune checkpoint inhibitors useful in treating the full
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`spectrum of human cancer types.
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`1.
`
`Persons in the art understood that all cancer cells have
`antigens that can be recognized by immune cells, requiring
`all cancers to evade immune system attack to persist.
`“At first glance, cancer appears to be a vast and bewildering array of
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`23.
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`diseases, with as many different types of cancer as there are types of cells in the
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`body.” Butterfield (Ex. 2024) at 573. However, by 2015 it was understood that all
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`cancers arise through genetic changes (e.g., mutations) that confer upon cancer
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`cells the ability to escape the regulatory mechanisms that would otherwise control
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`cell survival, proliferation, and migration. Butterfield (Ex. 2024) at 575;
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`Vogelstein (Ex. 2025) at 1546 (providing a detailed review of the types of
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`mutations, and the frequency of mutations in representative human cancers (Fig.
`
`1)). While some genetic changes allow cancer cells to escape these regulatory
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`mechanisms, other genetic changes also occur as cancer cells continuously divide.
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`Segal (Ex. 2026) at 889, 1st column, 2nd paragraph (“Somatic mutations can be
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`classified as either ‘drivers’ or ‘passengers’. Passenger mutations provide no
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`Declaration of Sridhar Mani, M.D.
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`positive or negative selective advantage to the tumor but are retained by chance
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`during cell division and clonal expansion. In contrast, driver mutations provide a
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`selective advantage that promotes the tumorigenic process. The generation of
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`mutations is continuous due to the imperfect nature of DNA replication and
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`repair.”); Vogelstein (Ex. 2025) at 1546–48 (discussing the timing of mutations
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`during tumorigenesis, as well as driver versus passenger mutations); Kandoth
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`(Ex. 1021) (examining mutational frequencies across various human cancer types).
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`24. Because of their genetic changes, cancer cells harbor proteins that
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`look different and function differently from proteins in non-malignant cells. By
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`being “different,” such proteins are antigenic and can be recognized by the host
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`immune cells. As Pardoll stated, “The myriad of genetic and epigenetic alterations
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`that are characteristic of all cancers provide a diverse set of antigens that the
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`immune system can use to distinguish tumour cells from their normal
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`counterparts.” Ex. 1026 at 1 (emphasis added); Coulie (Ex. 2027) at 142 (“The
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`presence of several tumour-specific antigens on every tumour provides a
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`rationale” for cancer immunotherapy. (emphasis added)). Furthermore, “[t]he
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`generation of mutations is continuous due to the imperfect nature of DNA
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`replication and repair. Thus, the generation of additional antigens during tumor
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`progression . . . provides a continuously renewable source of antigen.” Segal
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`(Ex. 2026) at 889, 1st column, 2nd paragraph. Accordingly, by 2015 it was
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`understood that all cancers have antigens that can engage the immune system.
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`25. The tumor bed (another name for the tumor microenvironment)
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`harbors cells of the immune system, including T cells and specialized immune cells
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`called antigen presenting cells (APCs), along with other immune cells including
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`dendritic cells, B-cells, and natural killer cells. Pardoll (Ex. 1026) at 3 (Figure 1);
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`Sharma (Ex. 2035) at 56 (discussing immune cells in the tumor
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`microenvironment); Mellman (Ex. 2036) at 481 (Figure 1). APCs capture peptides
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`from tumor cells and present these peptides (antigens) to T cells in the context of
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`major histocompatibility complex (MHC). Ex. 1026 at 7 (Figure 3); Ex. 1016 at 2
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`(Figure 1); Sharma (Ex. 2035) at 56 (Figure 1); Mellman (Ex. 2036) at 481 (Figure
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`1); Shih (Ex. 2034) at 1994 (Figure 1). Cancer cells also can present antigens in
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`the context of MHC.2 The discussions in the literature of how the immune system
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`2 E.g., Vogelstein (Ex. 2025) at 6230 (“An implicit conclusion from these clinical
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`data is that in a substantial fraction of patients, the endogenous T cell compartment
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`is able to recognize peptide epitopes that are displaced on major histocompatibility
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`complexes (MHCs) on the surface of the malignant cells.”); Sharma (Ex. 2035) at
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`56 (“T cells attack tumor cells that express tumor-specific antigens in the form of
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`interacts with cancer cells are not limited to any specific cancer types; the process
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`of tumor antigen recognition by T cells was not described as being contingent on
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`where the tumor is located (lung, breast, kidney, etc.) or the tumor tissue type
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`(carcinoma, sarcoma, lymphoma, etc.). E.g., Ex. 1026 at 1–2; Ex. 1016 at 2
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`(Figure 1), 3 (“CTLA4 background”), 4–5 (“PD-1/PD-L1 background”); Mellman
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`(Ex. 2036) at 481 (Figure 1); Shih (Ex. 2034) at 1993–1994 (Introduction and
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`Figure 1).
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`26. Thus, by 2015, researchers in the field understood that, because of
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`their antigens, cancer cells can be recognized by the immune system and can elicit
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`an immune response. Pierre G. Coulie commented in 2013 that “It is now widely
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`accepted that human tumors are immunogenic, meaning that they elicit adaptive
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`immune responses in vivo. These responses are largely mediated by T cells.”
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`Blankenstein (Ex. 2028) at 307. While the field had also appreciated that the
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`antigenicity of cancer cells may vary (across cancer types, across patients with a
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`given cancer, and even across cells within a patient’s cancer), potentially rendering
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`one cancer more immunogenic than another, it was understood that antigenicity is
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`a feature common to the full spectrum of human cancers. For example, Kandoth
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`complexes of tumor-derived peptides bound to major histocompatibility complex
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`(MHC) molecules on the cell.”).
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`(Ex. 1021) and Alexandrov (Ex. 2029) discuss the prevalence of somatic mutations
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`across human cancer types (e.g., Ex. 1021 at 1, Figure 1; Ex. 2029, Figure 1), and
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`Vogelstein (Ex. 2025) further discusses genetic heterogeneity within a patient’s
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`tumor and among different metastatic lesions in the patient (e.g., Ex. 2025, Figures
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`1 and 6). Such mutations and other genetic changes—present across the spectrum
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`of human cancer types—were (and still are) understood to give rise to cancer
`
`antigens that can be recognized by the immune system, as discussed in Pardoll
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`(Ex. 1026 at 2), Rizvi (Ex. 1029 at 3–5), and Schumacher (Ex. 2030 at 69–70 and
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`Figure 2). It is this antigenicity, which is common to all cancer types, that gives
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`rise to immunogenicity and the potential for cancer cells to be attacked and
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`eradicated by the immune system. Vesely (Ex. 2031) at 1 (“A central tenet of
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`tumor immunology in general, and the cancer immunoediting process in particular,
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`is that tumor cells express antigens that distinguish them from their
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`nontransformed counterparts, thus permitting their recognition by T cells and their
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`eventual destruction by immunological mechanisms.”).
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`27. T cell activation, however, requires more than recognition of tumor
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`antigen. “[I]t has been recognized that, on its own, tumor peptide presentation by
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`major histocompatibility complex (MHC) to T-cell receptors is inadequate for
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`successful T-cell activation and immune destruction of cancer cells.” Shih
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`(Ex. 2034) at 1994, 1st paragraph.3 Rather, T cell activation is tightly controlled
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`Declaration of Sridhar Mani, M.D.
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`through co-stimulatory and co-inhibitory molecules, and it is the outcome of this
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`“checks and balances” that determines the level and type of immune response.
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`Shih (Ex. 2034) at 1994, 1st paragraph (“T cells play a critical role in cell-
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`mediated tumor immunity, and do so through an intricate counterbalance of co-
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`stimulatory and co-inhibitory cell-to-cell signals between various components of
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`the immune system.” Figure 2)); Ex. 1026 at 1, 1st paragraph (“In the case of T
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`cells, the ultimate amplitude and quality of the response, which is initiated through
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`antigen recognition by the T cell receptor (TCR), is regulated by a balance between
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`co-stimulatory and inhibitory signals (that is, immune checkpoints) (FIG. 1).”).
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`These co-stimulatory and co-inhibitory signals are “crucial for the maintenance of
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`self-tolerance” and to “protect tissues from damage when the immune system is
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`responding to pathogenic infection.” Ex. 1026 at 1, 1st paragraph.
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`28. By 2015, researchers recognized that cancer cells can efficiently
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`exploit the inhibitory signals in order to escape attack by the immune system.
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`Ex. 1026 at 1, Abstract (“It is now clear that tumours co-opt certain immune-
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`3 Sharma (Ex. 2035) at 56–57 (“Recognition of antigen-MHC complexes by T cell
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`antigen receptor is not sufficient activation of naïve T cells—additional
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`costimulatory signals are required . . . .” (citations omitted)).
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`checkpoint pathways as a major mechanism of immune resistance.”). As was
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`understood in the field, because all cancer cells have antigens that can be
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`recognized by immune cells, cancer cells must have a mechanism for evading
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`immune activation in order to persist and continue growing. Butterfield (Ex. 2024)
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`at 573 (“[A]lmost by definition a tumor cell has escaped immunologic recognition
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`and progressed to cancer because the affected patient’s immune system did not
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`control tumor growth.”). Again, as Pardoll explained:
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`The huge number of genetic and epigenetic changes that are inherent
`to most cancer cells provide plenty of tumour-associated antigens that
`the host immune system can recognize, thereby requiring tumours to
`develop specific immune resistance mechanisms. An important
`immune resistance mechanism involves immune-inhibitory pathways,
`termed immune checkpoints, which normally mediate immune
`tolerance and mitigate collateral tissue damage.
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`Ex. 1026 at 2 (“At a glance” 1st bullet). Immune checkpoint inhibitors were
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`designed to interrupt the immune system’s inhibitory signals so that immune cells
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`can mount an attack against cancer. Ex. 1026 at 1 (“[T]he blockade of immune
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`checkpoints seems to unleash the potential of the antitumour immune response in a
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`fashion that is transforming human cancer therapeutics.”). Examples of these
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`inhibitory signals are described in Pardoll (Ex. 1026, Figures 1 and 3), Sharon
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`(Ex. 1016, Figure 1), and Mellman (Ex. 2036, Figures 1–3).
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`29.
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`In sum, cancer cells are antigenic and therefore must develop a way to
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`evade immune system attack, and blocking immune suppression, as through
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`checkpoint inhibitor therapy, was understood to help a patient’s immune system
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`counter these evasion mechanisms and respond to cancer antigens, as described in
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`Pardoll (Ex. 1026). Thus, by 2015, the field recognized that there is an intrinsic
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`immunological ability of an individual to combat cancer, and that this ability exists
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`across the full spectrum of human cancers.
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`2.
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`Persons in the art understood that checkpoint inhibitors
`counteract the immune system’s inherent suppressor
`signals, independent of cancer type.
`30. As was reported in the literature, and the ’302 patent explains, there
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`are several immune checkpoint proteins. Ex. 1026 at 3 (Figure 1); Zou (Ex. 2008)
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`at 468 (Figure 1); Ex. 1001, 24:20–23. These proteins and their associated
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`checkpoint pathways are inherent features of an individual’s immune system.
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`Dr. Braun acknowledges as much in his declaration: “Immune checkpoints are a
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`normal part of pathways in the immune system.” Ex. 1002 ¶ 100.
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`31. Also, as I explained above, cancer antigen presentation by APCs and
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`recognition by T cells can occur irrespective of cancer type. Likewise, checkpoint
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`proteins are present and function in the immune system to suppress immune
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`activation, irrespective of cancer type. E.g., Pardoll (Ex. 1026) (discussing
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`checkpoint pathways and using inhibitors of these pathways to evoke an antitumor
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`immune response, without limiting the discussion to any particular cancer type);
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`Zou (Ex. 2008) at 468–469, Tables 1 and 2 (discussing the expression of several
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`checkpoint signaling ligands in various human cancer types).
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`32. Researchers in the field understood that blocking any of the
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`checkpoints and inhibiting a checkpoint that otherwise would be operating
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`normally, alters the balance of co-stimulatory and co-inhibitor signals on T cells,
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`and alters this balance in favor of T cell activation. Pardoll (Ex. 1026) at 3 (Figure
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`1 “Multiple co-stimulatory and inhibitory interactions regulate T cell response”), 7
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`(Figure 3, illustrating the mechanism of two different checkpoint proteins, CTLA4
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`and PD-1, and explaining how the CTLA4-mediated checkpoint is induced in T
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`cells at the time of their initial response to antigen, while the PD-1-mediated
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`checkpoint regulates responses by effector T cells recognizing antigen in
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`peripheral tissues). For example, as PD-1 and CTLA-4 inhibitors were understood
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`to “regulate immune responses at different levels and by different mechanisms,”
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`and because of the clinical response observed from each of these inhibitors, skilled
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`persons in the art believed that “antitumour immunity can be enhanced at multiple
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`levels” with immune checkpoint inhibitors. Ex. 1026 at 2.
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`33.
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`In turn, by June 2015, researchers in the field believed that targeting
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`any of the inhibitory checkpoints would lead to a clinical benefit because each of
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`these checkpoints is inherently present and functions to suppress immune
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`activation. Pardoll (Ex. 1026) at 9–11 (“Preclinical mouse models of cancer have
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`shown that blockade of many of these individual immune-checkpoint ligands or
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`receptors can enhance antitumour immunity, and dual blockade of coordinately
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`expressed receptors can produce additive or synergistic antitumour activities.
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`Inhibitors for a number of these immune-checkpoint targets are either entering the
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`clinic or are under active development.”). Examples of preclinical studies
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`illustrating the field’s interest in and pursuit of different checkpoint inhibitors
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`include Romagné (Ex. 2009) and Kohrt (Ex. 2011) (both anti-KIR antibody); Woo
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`(Ex. 2012) (anti-LAG3 antibody, alone and in combination wit