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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`————————————————
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`————————————————
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`v.
`CELGENE CORP.
`Patent Owner.
`————————————————
`CASE NO. IPR2018-01507
`Patent No. 8,404,717
`————————————————
`
`DECLARATION OF MARK LEVIN, M.D., IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,404,717
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 1
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`TABLE OF CONTENTS
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`Page
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`I.
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`QUALIFICATIONS AND BACKGROUND ............................................. 5
`A.
`Education and Experience .................................................................... 5
`B. Materials Considered ............................................................................ 9
`C.
`Scope of Work ...................................................................................... 9
`SUMMARY OF OPINIONS ...................................................................... 10
`II.
`III. LEGAL STANDARDS ............................................................................... 12
`IV. PERSON OF ORDINARY SKILL IN THE ART ................................... 15
`V.
`BACKGROUND ......................................................................................... 16
`A. MDS and Its Classification and Treatment ........................................ 16
`B.
`Thalidomide ........................................................................................ 27
`C.
`Lenalidomide ...................................................................................... 29
`VI. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ....... 34
`A.
`TNFα Was a Focus for MDS Treatment ............................................ 36
`1.
`Shetty 1996 [Ex. 1015] ............................................................ 37
`Thalidomide Clinical Trials in MDS Were Successful and
`Promising ............................................................................................ 38
`1.
`Raza 2000b [Ex. 1021] ............................................................ 38
`2.
`Raza 2000d [Ex. 1022] ............................................................ 39
`3.
`Raza 2001 [Ex. 1023] .............................................................. 41
`4.
`Thomas 2000a [Ex. 1005] ........................................................ 43
`C. A POSA Had Knowledge of Revimid ............................................... 46
`1.
`Thomas 2000a [Ex. 1005] ........................................................ 48
`2.
`Corral 1999b [Ex. 1016] .......................................................... 48
`3. Marriott 2001 [Ex. 1017] ......................................................... 51
`4.
`Celgene Press Release 8/28/2001 [Ex. 1010] .......................... 54
`5.
`The ’230 Patent [Ex. 1006] ...................................................... 56
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`B.
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 2
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`TABLE OF CONTENTS
`(continued)
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`Page
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`D. A POSA Had Knowledge of the Clinical Administration of
`Revimid .............................................................................................. 57
`1.
`List 2001 [Ex. 1004] ................................................................ 57
`2.
`Ritter 2001 [Ex. 1014] ............................................................. 59
`3.
`Celgene Press Release 5/8/2001 [Ex. 1008] ............................ 59
`4.
`Celgene Press Release 6/7/2001 [Ex. 1009] ............................ 63
`VII. THE CONTESTED CLAIMS OF THE ’717 PATENT ARE
`UNPATENTABLE ..................................................................................... 64
`A. Ground 1: Claims 1–10 were unpatentable as obvious over List
`2001 in view of the ’230 patent and the Celgene Press Releases
`5/8/2001 and 8/28/2001 ...................................................................... 65
`1.
`Claim 1 was unpatentable as obvious over List 2001 in
`view of the ’230 patent and Celgene Press Releases
`5/8/2001 and 8/28/2001 ........................................................... 67
`a.
`Use of Revimid to treat MDS-caused TDA .................. 67
`b.
`Revimid’s chemical name and structure ........................ 72
`c.
`Administration of about 5–25 mg/day Revimid to
`Treat MDS-caused TDA ................................................ 74
`Dependent claim 10 was obvious ............................................ 82
`2.
`Dependent claims 2, 4, 6, and 8 were obvious ........................ 83
`3.
`Dependent claims 3, 5, 7, and 9 were obvious ........................ 84
`4.
`B. Ground 2: Claims 1–10 were unpatentable as obvious over
`Thomas 2000a in view of the ’230 patent and the Celgene Press
`Releases 5/8/2001 and 8/28/2001 ....................................................... 86
`1.
`Claim 1 was unpatentable as obvious over Thomas 2000a
`in view of the 230 patent and Celgene Press Releases
`5/8/2001 and 8/28/2001 ........................................................... 88
`a.
`Use of lenalidomide (and thalidomide) to treat
`MDS-caused TDA ......................................................... 88
`Revimid structure .......................................................... 93
`
`b.
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 3
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`TABLE OF CONTENTS
`(continued)
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`Page
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`c.
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`Administration of about 5–25 mg/day Revimid to
`treat MDS-caused TDA ................................................. 94
`Dependent claim 10 was obvious ............................................ 97
`2.
`Dependent claims 2, 4, 6, and 8 were obvious ........................ 98
`3.
`Dependent claims 3, 5, 7, and 9 were obvious ........................ 98
`4.
`VIII. CONCLUSION ......................................................................................... 100
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 4
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`I.
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`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`1. My name is Mark Levin. I am a medical oncologist with 28 years of
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`experience treating patients with myelodysplastic syndrome and multiple myeloma.
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`Throughout my career, I have engaged in clinical research, including writing and
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`conducting clinical trials, writing papers, and performing clinical as well as
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`administrative work related to cancer medicine in a variety of settings. My full
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`curriculum vitae (CV) is attached hereto as Exhibit A and is incorporated herein.
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`2.
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`I received a Bachelor’s degree in Pre-Medical Studies from Yeshiva
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`University in 1980. I received my M.D. from State University of New York (SUNY)
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`in Brooklyn in 1984. I later completed an M.B.A. program from the Herriott-Watt
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`University, Edinburgh Business School, in 2005.
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`3.
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`After graduating from medical school, I completed my internship at
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`Hahnemann University Medical Center (now Drexel University College of
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`Medicine) in 1985–1986 and my residency in Internal Medicine at New York
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`Downtown Hospital in New York City from 1986–1987. Afterward, from 1987–
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`1990, I completed a three-year program in Hematology and Oncology at the Long
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`Island Jewish Hillside Hospital Medical Center, in New Hyde Park, New York.
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 5
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`4.
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`I have received the following certifications: American Board of Internal
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`Medicine (1987), Oncology (1989), Hematology (1990), American Board of Quality
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`Assurance and Utilization Review (2010).
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`5.
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`I have received several professional and academic honors, including the
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`Certificate of Achievement in Medical Research & Scholarly Activity, Department
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`of Medicine, Staten Island University Hospital (1997); honors by the Philadelphia
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`County Medical Society for Humanity in Medicine (1985); honors in Physiology,
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`Pathology, Pharmacology, Pediatrics by the American Society of Anesthesiology,
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`Preceptorship (1980–1984); and B.A. with summa cum laude, Belkin, Manhattan
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`Borough President’s Citizenship Award, Manicoff Award (1977–1980).
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`6.
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`I have held university appointments at three medical schools. I served
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`as Assistant Professor of Clinical Medicine (1991–1998), and then Associate
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`Professor of Clinical Medicine (1998–2000), at SUNY-Medical College’s
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`Department of Medicine. In 2003, I joined Cornell’s Joan and Sanford I. Weil
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`Medical College as Associate Professor of Medicine, where I served until 2005.
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`Afterward, I joined the University of Medicine and Dentistry of New Jersey
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`(UMDNJ) as an Associate Professor of Medicine (2005–2008) and later a Clinical
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`Associate Professor of Medicine (2008–2009).
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`7.
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`I have held hospital appointments at eight hospitals, including Holy
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`Name Hospital (2003–current, Associate Attending Physician), University Hospital
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 6
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`of UMDNJ (2005–2009, Attending Physician), Lincoln Medical and Mental Health
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`Center (2000–2003, Attending Physician), Brookdale University Hospital (1996–
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`2000, Associate Attending Physician), New York Community Hospital (1996–2000,
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`Assistant Attending Physician), Staten Island University Hospital (1992–1996,
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`Attending Physician), and New York Downtown Hospital (1992-1990, Assistant
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`Attending Physician). I have held short-term privileges (up to one year) is several
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`other hospitals during locum assignments.
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`8.
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`I have served in the following administrative responsibilities: Acting
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`Chief of Hematology and Oncology, UMDNJ-Newark, New Jersey (2005–2008);
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`Director of Sister Patricia Lynch Regional Cancer Center, Holy Name Hospital,
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`Teaneck, New Jersey (2003–2005); Director of Cancer Center, Generations
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`Manhattan + Network of the Health and Hospital Corporation, New York, New York
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`(2002–2003); Chief, Section of Hematology and Oncology, Lincoln Medical and
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`Mental Health Center, Bronx, New York (2000–2003); Associate Director of Cancer
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`Center at Lincoln Medical and Mental Health Center; Chief of Service, Oncology/
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`Medicine (2000–2003); Director, Palliative Care Program (2002–2003); and
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`Medical Director, Hospice of New York (2002–2003); and Co-Director, Division of
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`Medical Oncology and Hematology, Brookdale University Hospital, Brooklyn, New
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`York (1996–2000).
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 7
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`9.
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`I have served in private practice at the following institutions:
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`Consultative Hematology and Oncology Practice at Renaissance General Medicine,
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`Cliffside Park, New Jersey (2003–present); Locum Tenens Oncologist at Staten
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`Island Physicians Groups, Staten Island, New York (2008–2009); Locum Tenens
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`Oncologist at Catskills Regional Cancer Center, Harris, New York (2000); Part time
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`Private Community Practice at HemOncare, PC and Brookdale University Hospital
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`Faculty Practice, Brooklyn, New York (1996–2000); and multi-specialty group that
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`functioned as de-facto faculty practice at Downtown Medical Associates, New York
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`Downtown Hospital, New York, New York (1990–1992).
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`10.
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`I am president of Medical Review and Information Center, a company
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`that provides consulting services,
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`including case and utilization review,
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`reimbursement policies, producing policies and guidelines, advising on FDA
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`submissions, high level medical writing and strategic planning and other services in
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`the field of Hematology and Oncology to clients such as pharmaceuticals, insurers,
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`and other corporate clients in the field of healthcare.
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`11.
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`I serve on the medical advisory board for Actelion Pharmaceuticals,
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`(2005–2010) and served on the medical advisory board for The Musella Foundation
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`for Brain Tumor Research and Information (1993–2018).
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`12.
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`I have served on the following major committees and institutional
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`assignments: Chair of the Cancer Center Steering Committee; Director of the
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 8
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`Palliative Care Program; Chair of the Cancer Committee; Member of the
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`Transfusion Committee; Institutional Review Board; Ethics Committee; Chief of
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`Service – Medicine; and Director of Research, Department of Medicine.
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`13.
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`I have served on the editorial boards of Cancer Therapy, Southern
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`Medical Journal’s International Journal of Cancer (International Reviewer), Medical
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`Science Monitor (International Reviewer), Drugs of Today, and Drugs of the Future.
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`14.
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`I have published 22 articles, 18 of which as the lead author. I have also
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`published 10 abstracts, 6 of which as the lead author. I have also published 16
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`reviews and 17 reports or letters.
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`15.
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`I have also been an invited speaker for 22 international, national, and
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`local professional events, primarily on cancer treatment.
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`B. Materials Considered
`16.
`In connection with forming my opinions and drafting this declaration,
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`I considered my experience, education, and training, as well as the materials
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`identified in this declaration and listed in Exhibit B, attached hereto.
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`C.
`17.
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`Scope of Work
`I have been retained by counsel for Dr. Reddy’s Laboratories, Inc.
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`(“DRL”) in connection with this matter. I am being compensated at my usual rate
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`of $840 per hour for my work on this matter. My compensation does not in any way
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`depend on the outcome of this proceeding.
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 9
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`II.
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`SUMMARY OF OPINIONS
`18.
`It is my opinion, as explained in Ground 1, that claims 1–10 of U.S.
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`Patent No. 8,404,717 (“the ’717 patent”) (Ex. 1001) were obvious over List 2001 in
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`view of the ’230 patent and Celgene Press Releases 5/8/2001 and 8/28/2001.
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`19.
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`It is also my opinion, as explained in Ground 2, that claims 1–10 were
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`obvious over Thomas 2000a in view of the ’230 patent and Celgene Press Releases
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`5/8/2001 and 8/28/2001.
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`20.
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`In both combinations above, it is my opinion that these references show
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`that a skilled artisan, by the time of patenting, understood that the known compound
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`Revimid (lenalidomide) had already commenced clinical trials for myelodysplastic
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`syndromes (MDS), as well as multiple myeloma (MM) and several solid tumors.
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`The POSA likewise understood that Revimid was specifically designed to improve
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`on its structural analog, thalidomide, which was a known therapy for many cancers
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`including MDS as well as MM (multiple myeloma, another hematological cancer).
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`And the POSA understood that MDS treatment options were limited, with
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`thalidomide having been a notable expansion in therapeutic options, though with
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`marked drawbacks including neuropathy side effects and teratogenicity.
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`21. Furthermore, a POSA would have understood that both MDS and MM
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`patients exhibited heightened TNFα and angiogenesis, and both MDS and MM
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`patients exhibiting overlapped symptoms including anemia. Inhibiting TNFα was
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 10
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`in fact a well-recognized pathway in treating both conditions, and advances in MM
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`were explicitly used as a map for MDS therapies. Both thalidomide and Revimid
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`acted on TNFα, but Revimid was known to have improved anti-TNFα potency
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`versus thalidomide.
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`22. A POSA also recognized that Revimid had been successfully
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`administered to treat multiple cancerous conditions—MM and several types of solid
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`tumors—at up to 25 mg/day or at 5–50 mg/day, and doses of about 5–50 mg/day had
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`already been considered safe, well-tolerated, and even efficacious. These results, a
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`POSA understood, were described as showing the “promising potential” of Revimid
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`and motivated its “significantly accelerate[d]” development for additional cancer
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`indications.
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`23. Armed with the praised phase I/II clinical trials showing the safety,
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`efficacy, and toleration of “up to 25 mg” and 5–50 mg/day doses of Revimid in MM
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`and various solid tumors, evidence of Revimid’s increased potency over
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`thalidomide, the POSA’s expectation of customizing treatment to the individual
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`patient’s needs, and the knowledge that MDS clinical trials of Revimid were already
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`underway, a skilled artisan would have had a more than reasonable expectation of
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`success that administration of Revimid at about 5–25 mg/day would demonstrate
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`efficacy in MDS.
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`24. A POSA understood that the underlying MDS disease caused MDS
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`patients to develop defective blood cells—most commonly, red blood cells (RBCs).
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`This anemia in turn resulted in many MDS patients requiring ongoing RBC
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`transfusions, i.e., they developed transfusion-dependent anemia due to their MDS.
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`A POSA understood that a treatment targeting the MDS disease would, at the same
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`time, target the basis for a patient’s transfusion dependent anemia (TDA). Thus, a
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`where 5–25 mg/day Revimid was obvious to treat MDS, it was likewise obvious to
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`treat the TDA due to MDS.
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`25. The dependent claims are likewise obvious. They either recite specific
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`dosages within the range of claim 1—specifically, 5, 10, 15, or 25 mg/day (claims
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`2, 4, 6, and 8)—or go on to recite these same doses administered in an oral capsule
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`(claims 3, 5, 7, and 9), with claim 10 reciting the administration of lenalidomide as
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`a free base. As detailed below, it is my opinion that claims 2–10 do not represent
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`any invention over what was known in the art and understood by a skilled artisan,
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`and were thus obvious.
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`III. LEGAL STANDARDS
`26.
`I have been informed regarding the relevant legal principles. I have
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`used my understanding of those principles in preparing and forming my opinions set
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`forth in this declaration. My understanding of those legal principles is summarized
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`below.
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`27.
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`I have been told that DRL bears the burden of proving unpatentability
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`by a preponderance of the evidence. I am informed that this preponderance of the
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`evidence standard means that DRL must show that unpatentability is more probable
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`than not. I have taken this principle into account when forming my opinions here.
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`28.
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`I have also been told that claims should currently be construed given
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`their broadest reasonable interpretation in light of the specification, from the
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`perspective of a person of ordinary skill in the art at the time of the invention.
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`29.
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`I have also been told that the PTAB is considering a revised standard
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`for claim construction, in which the claims should be construed in accordance with
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`the ordinary and customary meaning of such claim as understood by one of ordinary
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`skill in the art and the prosecution history pertaining to the patent at the time of the
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`invention. I understand that this standard would take into account the intrinsic
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`evidence—the claim language itself, specification, and prosecution history
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`pertaining to the patent—but would also consider extrinsic evidence. Extrinsic
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`evidence is particularly useful when it educates the fact-finder regarding the field of
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`the invention or helps explain what a person of ordinary skill in the art would
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`understand the claim terms to mean.
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`30.
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`I have been told that the concept of patent obviousness involves four
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`factual inquiries: (1) the scope and content of the prior art; (2) the differences
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`between the claimed invention and the prior art; (3) the level of ordinary skill in the
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`art; and (4) secondary considerations of non-obviousness.
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`31.
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`I have also been informed that when there is some recognized reason to
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`solve a problem—and there are a finite number of identified, predictable, known
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`solutions—a person of ordinary skill in the art is motivated and has good reason to
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`pursue the known options within her technical grasp. If this approach leads to the
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`expected success, it is likely the product of ordinary skill and common sense rather
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`than the product of innovation. Where a patent simply arranges old elements, with
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`each element performing its known function and the whole yielding no more than
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`would be expected, the combination is obvious.
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`32.
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`I have been informed that the priority date of the ’717 patent is October
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`15, 2002, the date the ’717 patent lists U.S. Provisional Application No. 60/418,468
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`as being filed.
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`33.
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`I have been informed that one way in which a person was not entitled
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`to a patent was where the invention was patented or described in a printed
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`publication anywhere more than one year prior to the U.S. patent application date. I
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`have therefore considered “prior art” publications dated on or before October 15,
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`2001, what I have been informed may be referred to as “§ 102(b)” prior art.
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`34. As above, I have been informed by counsel that the obviousness
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`analysis is to be conducted from the perspective of a person of ordinary skill in the
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`art (a “person of ordinary skill,” or “POSA”) at the time of the invention.
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`35.
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`I have adopted the understanding of a POSA when discussing the
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`teachings of the prior art. I have also reviewed the ’717 patent.1
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`36.
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`I have also been informed by counsel that in defining a POSA the
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`following factors may be considered: (1) the educational level of the inventor;
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`(2) the type of problems encountered in the art; (3) prior art solutions to those
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`problems; (4) speed with which innovations are made; and (5) sophistication of the
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`technology and educational level of active workers in the field.
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`37. A POSA2 would typically have had a Ph.D. in pharmacology,
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`pharmaceutical chemistry, or cancer biology (or a related discipline); a Pharm.D.
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`with experience in clinical oncology; or an M.D. with experience in clinical
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`oncology or pharmacology. Such a person would have had experience with the
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`1Ex. 1001 (’717 patent).
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`2 All references herein to the knowledge or understanding of a POSA or a POSA’s
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`interpretation or understanding of a prior art reference are as of the earliest possible
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`priority date unless specifically stated otherwise.
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`administration or formulation of therapeutic agents, dosing schedules and
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`frequencies, and drug developmental study and design. Such a person would have
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`been well-versed in the worldwide literature that was available as of October 15,
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`2002—what I understand is the priority date of the ’717 patent. A physician would
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`have been responsible for prescribing the finished pharmaceutical product. The prior
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`art and the POSA’s understanding thereof as discussed herein would be known to a
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`POSA under any definition of that person’s qualifications.
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`38. These qualifications are not rigid. Greater education or a specific skill
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`may make up for less experience, and vice-versa. Moreover, one individual need
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`not have every qualification. A multidisciplinary team with the necessary expertise
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`in its ranks would suffice. Such a team could include—and the POSA would draw
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`upon the skills of—a clinician having experience in treating MDS. However, in
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`view of the relatively high level of skill on any reasonable POSA, the conclusions
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`in this Petition would be unchanged under any reasonable definition of the POSA.
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`V. BACKGROUND
`A. MDS and Its Classification and Treatment
`39.
`“Cancer” is a group of conditions that can occur throughout the body,
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`from one’s outermost skin to one’s innermost bone marrow, and can affect all ages.
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`At its simplest, cancer occurs when normal cells, which should die and be replaced
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`when they are damaged or worn out, become abnormal due to mutations that they
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`accrued, and instead keep growing and making new cells, which in turn crowd out
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`the normal cells.
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`40. Some types of cancer affect cells inside the bone marrow. Bone
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`marrow is the spongy, inner part of certain bones, and is comprised of blood stem
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`cells, more mature blood-forming cells, fat cells, and supporting tissues. See, for
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`example, the visualization below:
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`There, pluripotential stem cells divide and mature into hematopoietic stem cells,
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`which in turn mature into new blood cells, including red blood cells, which carry
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`oxygen and carbon dioxide throughout our bodies; platelets, which are cell
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`fragments that help the blood clot; and multiple classes of white blood cells, which
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`are responsible for fighting infection. (There are several types of white blood cells,
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`including neutrophils, which attack antigens such as bacteria, viruses, fungi, poisons,
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`and cancer cells; lymphocytes, which include B cells that produce antibodies that
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`are used to attack invading bacteria, viruses, and toxins and T cells that destroy the
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`body’s own cells that have themselves been taken over by viruses or become
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`cancerous; monocytes, which “eat” foreign particles; basophils, which secrete
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`chemicals such as histamine that help control the body’s immune response; and
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`eosinophils, eosinophils, which attack and kill parasites, destroy cancer cells, and
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`help with allergic responses.) This process of transforming and maturing blood cells
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`is called hematopoiesis.
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`41. There is a complex microenvironment in the bone marrow, with
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`complex feedback and regulatory systems. Cells within the bone marrow
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`communicate with one another through cytokines, growth factors, and hormones.
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`Just as the cells in the finger communicate with each other so that boundaries and
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`tissue planes are respected, and the finger does not overgrow and stays within a
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`defined shape, so do the marrow cells remain functional and produce the numbers
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`of effective cells that the body exactly needs. When this process of feedback
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`regulation is disturbed, the number and the functionality of marrow cells and their
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`descendants in the blood can become diminished.
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`42. A decreased number of red blood cells, anemia, can cause tiredness,
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`weakness, and shortness of breath because too little oxygen is reaching a person’s
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`body tissues. A deficiency of platelets, thrombocytopenia, makes a person more
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`prone to bleeding and bruising. A deficiency of a specific type of white blood cells
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`called a neutrophil, neutropenia, makes a person more susceptible to getting
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`infections and reduces a person’s ability to fight them off.
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`43.
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`In
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`the Myelodysplastic Syndrome (sometimes referred
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`to as
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`“myelodysplastic syndromes,” “myelodysplasia,” or MDS), the bone marrow is
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`abnormal (“dysplastic”) and creates fewer and less functional marrow and blood
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`cells. MDS produces cytopenias, meaning a reduction in the number of mature
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`blood cells. Specifically, these may include anemia (low red blood cells),
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`leukopenia and/or neutropenia (low white blood cell counts), and thrombocytopenia
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`(low platelets).
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`44. Anemia is the most common symptomatic problem that stems from the
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`MDS. MDS patients nearly always experience anemia, and thus by October 2001,
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`the standard of care was to transfuse them with packed red blood cells (RBCs) when
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`they became symptomatic. Ex. 1039 at 10; Ex. 1033 at 1. Many MDS patients were
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`(and most eventually became) “transfusion dependent,” or were considered to have
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`“transfusion dependent anemia,” meaning that they required ongoing RBC
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`transfusions. Treatments which improved the number and functionality of marrow
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`and blood cells would have, correspondingly, improved the anemia and reduced or
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`eliminated transfusion dependence.
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`45. MDS patients also experienced neutropenia (shortage of neutrophils, a
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`type of white blood cell type) and thrombocytopenia (shortage of platelets). Ex.
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`1039 at 8. Because of their depressed white blood cell counts, the primary cause of
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`MDS morbidity and mortality was infection.
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`46. By the mid-1990s, therapies to induce MDS remission were limited—
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`there were few palliative and essentially no curative therapies. See id. at 10; Ex.
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`1023 at 1. Supportive therapies included red blood cell transfusions, platelet
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`transfusions, blood cell growth factors, and antibiotics, as well as several
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`chemotherapeutic, immunosuppressive, and immunomodulating drugs—all of these
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`were longer-term, non-single-administration therapies, and many would be
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`administered over the course of months or even years. (Additionally, some MDS
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`therapies could themselves cause depressed blood counts. See, e.g., Ex. 1038.)
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`Accordingly, alternative therapies, particularly ones addressing the underlying
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`disease, were and would have been highly attractive to a POSA. By October 2001,
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`the field of known MDS therapies remained limited. However, thalidomide and
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`Revimid—both of which acted on TNFα, an underlying mechanism of MDS
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`disease—had advanced into MDS clinical trials.
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`47. Blood stem cell transplantation—a high risk proposition (or even an
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`impossible one) for many MDS patients because of their more advanced age
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`(typically 50–80) and low red, white, and platelet blood cell counts—provided the
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`only possibility of a cure, and success was not guaranteed. Two stem cell transplant
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`types were available at that time. The first was allogenic, where the patient’s bone
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`marrow is destroyed from high-dose chemotherapy and/or total body irradiation, and
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`then the patient receives blood-forming stem cells from a donor with a close “match”
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`to the recipient’s cell type. (Syngeneic marrow from an identical twin was
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`exceedingly rarely available.) The other was autologous, meaning that the patient’s
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`own stem cells were removed before treatment, and then given back to the patient
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`after chemotherapy or irradiation. Allogenic stem cell transplantation was the norm;
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`autologous stem cell transplants were rarely used in MDS because the patient’s bone
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`marrow contained abnormal stem cells. Allogenic stem cell transplantation
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`produced severe short-term side effects, including low blood counts, bleeding,
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`serious infections, acute graft-versus-host disease, and death. Even if initially
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`successful, chronic graft versus host disease was often fatal, and there were no drugs
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`at the time to fight it (with the exception of steroids, which often failed and were
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`fraught with substantial morbidity and mortality over the long period that they
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`needed to be used). Older MDS patients—and most MDS patients fell into this
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`group—have a lower success rate, tolerated the toxicity of this approach poorer, and
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`did not do well. It was a treatment of last resort for the vast majority of patients.
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`48. Multiple systems have been used over the years to classify MDS in
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`order to assign a prognosis, which is useful in determining outlook and treatment
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`options. The first of these was the French-American-British (FAB) classification,
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`which grouped MDS into five classifications or subtypes: refractory anemia (RA),
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`refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess
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`blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t),
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`and chronic myelomonocytic leukemia (CMML). Ex. 1039 at 6. In simplistic terms,
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`these can be viewed on a scale of severity, with RA being the least severe (white
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`blood cell and platelet counts are normal, for example). These classifications, or
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`subtypes, tended to progress from one to the other over time.
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`49. Under a second classification system, the Revised International
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`Prognostic Scoring System (IPSS-R), MDS was sorted into very low, low,
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`intermediate, high, and very high risk, based on a patient’s scores in five areas: the
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`percentage of early blood cells (blasts) in the patient’s bone marrow; the type and
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`number of chromosome abnormalities in the cells; the level of red blood cells in the
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`patient’s blood; and the level of neutrophils (the white blood cell) in the patient’s
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`blood.
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`50. Additionally, other factors may influence prognosis and treatment,
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`including for example a patient’s age, how low were the patient’s blood cell counts
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`(based on blood cell count tests), and other prognostic factors.
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`51. Because of
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`the broad clinical spectrum of MDS, specific,
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`individualized care planning was necessary. See Ex. 1039 at 10 (“Further
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`complicating therapy of MDS is the heterogenous nature of these disorders…. This
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`wide clinical spectrum necessitates that the patient care be individualized.”). This
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`heterogeneity implied multiple mechanisms interacting in individual p