`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`DR. REDDY’S LABORATORIES, INC.
`Petitioner,
`v.
`CELGENE CORP.
`Patent Owner.
`————————————————
`CASE NO. IPR2018-01509
`
`Patent No. 7,189,740
`————————————————
`
`DECLARATION OF MARK LEVIN, M.D., IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 7,189,740
`
`
`
`DR. REDDY’S LABS., INC. EX. 1003 PAGE 1
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`

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`TABLE OF CONTENTS
`
`Page
`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND ............................................. 5
`A.
`Education and Experience .................................................................... 5
`B. Materials Considered .......................................................................... 10
`C.
`Scope of Work .................................................................................... 10
`SUMMARY OF OPINIONS ...................................................................... 10
`II.
`III. LEGAL STANDARDS ............................................................................... 13
`IV. PERSON OF ORDINARY SKILL IN THE ART ................................... 15
`V.
`BACKGROUND ......................................................................................... 17
`A. MDS and Its Classification and Treatment ........................................ 17
`B.
`Thalidomide ........................................................................................ 28
`C.
`Lenalidomide ...................................................................................... 30
`VI. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ....... 35
`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] ............................................................ 39
`2.
`Raza 2000d [Ex. 1022] ............................................................ 40
`3.
`Raza 2001 [Ex. 1023] .............................................................. 41
`4.
`Thomas 2000a [Ex. 1005] ........................................................ 44
`C. A POSA Had Knowledge of Revimid ............................................... 46
`1.
`Thomas 2000a [Ex. 1005] ........................................................ 48
`2.
`Corral 1999b [Ex. 1016] .......................................................... 49
`3. Marriott 2001 [Ex. 1017] ......................................................... 52
`4.
`Celgene Press Release 8/28/2001 [Ex. 1010] .......................... 55
`5.
`The ’230 patent [Ex. 1006] ...................................................... 57
`
`B.
`
`
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`D. A POSA Had Knowledge of the Clinical Administration of
`Revimid .............................................................................................. 58
`1.
`List 2001 [Ex. 1004] ................................................................ 58
`2.
`Ritter 2001 [Ex. 1014] ............................................................. 60
`3.
`Celgene Press Release 5/8/2001 [Ex. 1008] ............................ 61
`4.
`Celgene Press Release 6/7/2001 [Ex. 1009] ............................ 64
`VII. THE CONTESTED CLAIMS OF THE ’740 PATENT ARE
`UNPATENTABLE ..................................................................................... 65
`A. Ground 1: Claims 1–6, 11–12, and 14–34 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 ............................... 68
`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 ........................................................... 70
`a.
`Use of Revimid to treat MDS ........................................ 70
`b.
`Revimid’s chemical name and structure ........................ 72
`c.
`Administration of about 5–50 mg/day Revimid to
`treat MDS ....................................................................... 75
`Dependent claims 4–6 were obvious ....................................... 80
`2.
`Dependent claims 2 and 34 were obvious ............................... 82
`3.
`Dependent claims 3 and 23 were obvious ............................... 83
`4.
`Dependent claims 16–17 and 32–33 were obvious ................. 83
`5.
`Dependent claim 11 was obvious ............................................ 85
`6.
`Dependent claim 12 was obvious ............................................ 86
`7.
`Dependent claims 14–15 were obvious ................................... 87
`8.
`Dependent claims 24–28 were obvious ................................... 89
`9.
`10. Dependent claims 18–22 and 29–31 were obvious ................. 91
`
`
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`TABLE OF CONTENTS
`(continued)
`
`Page
`
`
`
`b.
`c.
`
`B. Ground 2: Claims 1–6, 11–12, and 14–34 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 ............................... 98
`1.
`Claim 1 was unpatentable as obvious over Thomas 2000a
`in view of the ’230 patent and the Celgene Press Releases
`5/8/2001 and 8/28/2001 ......................................................... 100
`a.
`Use of lenalidomide (and thalidomide) to treat
`MDS ............................................................................. 100
`Revimid’s chemical name and structure ...................... 104
`Administration of about 5–50 mg/day Revimid to
`treat MDS ..................................................................... 105
`Dependent claims 4–6 were obvious ..................................... 108
`2.
`Dependent claims 2 and 34 were obvious ............................. 109
`3.
`Dependent claims 3 and 23 were obvious ............................. 110
`4.
`Dependent claims 16–17 and 32–33 were obvious ............... 111
`5.
`Dependent claim 11 was obvious .......................................... 112
`6.
`Dependent claim 12 was obvious .......................................... 113
`7.
`Dependent claims 14–15 were obvious ................................. 115
`8.
`Dependent claims 24–28 were obvious ................................. 115
`9.
`10. Dependent claims 18–22 and 29–31 were obvious ............... 116
`VIII. CONCLUSION ......................................................................................... 117
`
`
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`DR. REDDY’S LABS., INC. EX. 1003 PAGE 4
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`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`A. Education and Experience
`1. My name is Mark Levin. I am a medical oncologist with 28 years of
`
`experience treating patients with myelodysplastic syndrome and multiple myeloma.
`
`Throughout my career, I have engaged in clinical research, including writing and
`
`conducting clinical trials, writing papers, and performing clinical as well as
`
`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.
`
`2.
`
`I received a Bachelor’s degree in Pre-Medical Studies from Yeshiva
`
`University in 1980. I received my M.D. from State University of New York (SUNY)
`
`in Brooklyn in 1984. I later completed an M.B.A. program from the Herriott-Watt
`
`University, Edinburgh Business School, in 2005.
`
`3.
`
`After graduating from medical school, I completed my internship at
`
`Hahnemann University Medical Center (now Drexel University College of
`
`Medicine) in 1985–1986 and my residency in Internal Medicine at New York
`
`Downtown Hospital in New York City from 1986–1987. Afterward, from 1987–
`
`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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`
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`4.
`
`I have received the following certifications: American Board of Internal
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`Medicine (1987), Oncology (1989), Hematology (1990), American Board of Quality
`
`Assurance and Utilization Review (2010).
`
`5.
`
`I have received several professional and academic honors, including the
`
`Certificate of Achievement in Medical Research & Scholarly Activity, Department
`
`of Medicine, Staten Island University Hospital (1997); honors by the Philadelphia
`
`County Medical Society for Humanity in Medicine (1985); honors in Physiology,
`
`Pathology, Pharmacology, Pediatrics by the American Society of Anesthesiology,
`
`Preceptorship (1980–1984); and B.A. with summa cum laude, Belkin, Manhattan
`
`Borough President’s Citizenship Award, Manicoff Award (1977–1980).
`
`6.
`
`I have held university appointments at three medical schools. I served
`
`as Assistant Professor of Clinical Medicine (1991–1998), and then Associate
`
`Professor of Clinical Medicine (1998–2000), at SUNY-Medical College’s
`
`Department of Medicine. In 2003, I joined Cornell’s Joan and Sanford I. Weil
`
`Medical College as Associate Professor of Medicine, where I served until 2005.
`
`Afterward, I joined the University of Medicine and Dentistry of New Jersey
`
`(UMDNJ) as an Associate Professor of Medicine (2005–2008) and later a Clinical
`
`Associate Professor of Medicine (2008–2009).
`
`7.
`
`I have held hospital appointments at eight hospitals, including Holy
`
`Name Hospital (2003–current, Associate Attending Physician), University Hospital
`
`
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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–
`
`2000, Associate Attending Physician), New York Community Hospital (1996–2000,
`
`Assistant Attending Physician), Staten Island University Hospital (1992–1996,
`
`Attending Physician), and New York Downtown Hospital (1992-1990, Assistant
`
`Attending Physician). I have held short-term privileges (up to one year) is several
`
`other hospitals during locum assignments.
`
`8.
`
`I have served in the following administrative responsibilities: Acting
`
`Chief of Hematology and Oncology, UMDNJ-Newark, New Jersey (2005–2008);
`
`Director of Sister Patricia Lynch Regional Cancer Center, Holy Name Hospital,
`
`Teaneck, New Jersey (2003–2005); Director of Cancer Center, Generations
`
`Manhattan + Network of the Health and Hospital Corporation, New York, New York
`
`(2002–2003); Chief, Section of Hematology and Oncology, Lincoln Medical and
`
`Mental Health Center, Bronx, New York (2000–2003); Associate Director of Cancer
`
`Center at Lincoln Medical and Mental Health Center; Chief of Service, Oncology/
`
`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
`
`York (1996–2000).
`
`
`
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`9.
`
`I have served in private practice at the following institutions:
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`Consultative Hematology and Oncology Practice at Renaissance General Medicine,
`
`Cliffside Park, New Jersey (2003–present); Locum Tenens Oncologist at Staten
`
`Island Physicians Groups, Staten Island, New York (2008–2009); Locum Tenens
`
`Oncologist at Catskills Regional Cancer Center, Harris, New York (2000); Part time
`
`Private Community Practice at HemOncare, PC and Brookdale University Hospital
`
`Faculty Practice, Brooklyn, New York (1996–2000); and multi-specialty group that
`
`functioned as de-facto faculty practice at Downtown Medical Associates, New York
`
`Downtown Hospital, New York, New York (1990–1992).
`
`10.
`
`I am president of Medical Review and Information Center, a company
`
`that provides consulting services,
`
`including case and utilization review,
`
`reimbursement policies, producing policies and guidelines, advising on FDA
`
`submissions, high level medical writing and strategic planning and other services in
`
`the field of Hematology and Oncology to clients such as pharmaceuticals, insurers,
`
`and other corporate clients in the field of healthcare.
`
`11.
`
`I serve on the medical advisory board for Actelion Pharmaceuticals,
`
`(2005–2010) and served on the medical advisory board for The Musella Foundation
`
`for Brain Tumor Research and Information (1993–2018).
`
`12.
`
`I have served on the following major committees and institutional
`
`assignments: Chair of the Cancer Center Steering Committee; Director of the
`
`
`
`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
`
`Service – Medicine; and Director of Research, Department of Medicine.
`
`13.
`
`I have served on the editorial boards of Cancer Therapy, Southern
`
`Medical Journal’s International Journal of Cancer (International Reviewer), Medical
`
`Science Monitor (International Reviewer), Drugs of Today, and Drugs of the Future.
`
`14.
`
`I have published 22 articles, 18 of which as the lead author. I have also
`
`published 10 abstracts, 6 of which as the lead author. I have also published 16
`
`reviews and 17 reports or letters.
`
`15.
`
`I have also been an invited speaker for 22 international, national, and
`
`local professional events, primarily on cancer treatment.
`
`B. Materials Considered
`16.
`In connection with forming my opinions and drafting this declaration,
`
`I considered my experience, education, and training, as well as the materials
`
`identified in this declaration and listed in Exhibit B, attached hereto.
`
`C.
`17.
`
`Scope of Work
`I have been retained by counsel for Dr. Reddy’s Laboratories, Inc.
`
`(“DRL”) in connection with this matter. I am being compensated at my usual rate
`
`of $840 per hour for my work on this matter. My compensation does not in any way
`
`depend on the outcome of this proceeding.
`
`
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`II.
`
`SUMMARY OF OPINIONS
`18.
`It is my opinion, as explained in Ground 1, that claims 1–6, 11–12, and
`
`14–34 of U.S. Patent No. 7,189,740 (“the ’740 patent”) (Ex. 1001) were obvious
`
`over List 2001 in view of the ’230 patent and Celgene Press Releases 5/8/2001 and
`
`8/28/2001.
`
`19.
`
`It is also my opinion, as explained in Ground 2, that claims 1–6, 11–12,
`
`and 14–34 were obvious over Thomas 2000a in view of the ’230 patent and Celgene
`
`Press Releases 5/8/2001 and 8/28/2001.
`
`20.
`
`In both combinations above, it is my opinion that these references show
`
`that a skilled artisan, by the time of patenting, understood that the known compound
`
`Revimid (lenalidomide) had already commenced clinical trials for myelodysplastic
`
`syndromes (MDS), as well as multiple myeloma (MM) and several solid tumors.
`
`The POSA likewise understood that Revimid was specifically designed to improve
`
`on its structural analog, thalidomide, which was a known therapy for many cancers
`
`including MDS as well as MM (multiple myeloma, another hematological cancer).
`
`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
`
`marked drawbacks including neuropathy side effects and teratogenicity.
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`21. Furthermore, a POSA would have understood that both MDS and MM
`
`patients exhibited heightened TNFα and angiogenesis, and both MDS and MM
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`
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`patients exhibited overlapping symptoms including anemia. Inhibiting TNFα was
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`in fact a well-recognized pathway in treating both conditions, and advances in MM
`
`were explicitly used as a map for MDS therapies. Both thalidomide and Revimid
`
`acted on TNFα, but Revimid was known to have improved anti-TNFα potency
`
`versus thalidomide.
`
`22. A POSA also recognized that Revimid had been successfully
`
`administered to treat multiple cancerous conditions—MM and several types of solid
`
`tumors—at 5–50 mg/day and “up to 25 mg per day,” and that doses of about 5–50
`
`mg/day had already been considered safe, well-tolerated, and even efficacious.
`
`These results, a POSA understood, were described as showing the “promising
`
`potential” of Revimid and motivated its “significantly accelerate[d]” development
`
`for additional cancer indications.
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`23. Armed with the praised phase I/II clinical trials showing the safety,
`
`efficacy, and toleration of 5–50 mg/day doses of Revimid in MM and various solid
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`tumors, evidence of Revimid’s increased potency over thalidomide, the POSA’s
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`expectation of customizing treatment to the individual patient’s needs, and the
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`knowledge that MDS clinical trials of Revimid were already underway, a skilled
`
`artisan would have had a more than reasonable expectation of success that
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`administration of Revimid at about 5–50 mg/day would demonstrate efficacy in
`
`treating MDS.
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`24. The dependent claims are likewise obvious. They were either explicitly
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`disclosed in the art (such as 5–50 mg/day doses of Revimid, the administration of
`
`Revimid by 1–100 mg oral capsules, or the separation of Revimid into substantially
`
`pure R- and S-stereoisomers) or were within the knowledge of a skilled artisan (such
`
`as the treatment of MDS including one or more of MDS’s five classifications, or the
`
`administration of Revimid via cycling (a standard approach in cancer and MDS
`
`treatment)). As detailed below, it is my opinion that claims 2–6, 11–12, and 14–34
`
`do not represent any invention over what was known in the art and understood by a
`
`skilled artisan, and were thus obvious.
`
`III. LEGAL STANDARDS
`25.
`I have been informed regarding the relevant legal principles. I have
`
`used my understanding of those principles in preparing and forming my opinions set
`
`forth in this declaration. My understanding of those legal principles is summarized
`
`below.
`
`26.
`
`I have been told that DRL bears the burden of proving unpatentability
`
`by a preponderance of the evidence. I am informed that this preponderance of the
`
`evidence standard means that DRL must show that unpatentability is more probable
`
`than not. I have taken this principle into account when forming my opinions here.
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`27.
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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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`28.
`
`I have also been told that the PTAB is considering a revised standard
`
`for claim construction, in which the claims should be construed in accordance with
`
`the ordinary and customary meaning of such claim as understood by one of ordinary
`
`skill in the art and the prosecution history pertaining to the patent at the time of the
`
`invention. I understand that this standard would take into account the intrinsic
`
`evidence—the claim language itself, specification, and prosecution history
`
`pertaining to the patent—but would also consider extrinsic evidence. Extrinsic
`
`evidence is particularly useful when it educates the fact-finder regarding the field of
`
`the invention or helps explain what a person of ordinary skill in the art would
`
`understand the claim terms to mean.
`
`29.
`
`I have been told that the concept of patent obviousness involves four
`
`factual inquiries: (1) the scope and content of the prior art; (2) the differences
`
`between the claimed invention and the prior art; (3) the level of ordinary skill in the
`
`art; and (4) secondary considerations of non-obviousness.
`
`30.
`
`I have also been informed that when there is some recognized reason to
`
`solve a problem—and there are a finite number of identified, predictable, known
`
`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
`
`than the product of innovation. Where a patent simply arranges old elements, with
`
`each element performing its known function and the whole yielding no more than
`
`would be expected, the combination is obvious.
`
`31.
`
`I have been informed that the priority date of the ’740 patent is October
`
`15, 2002, the date the ’740 patent lists U.S. Provisional Application No. 60/418,468
`
`as being filed.
`
`32.
`
`I have been informed that one way in which a person was not entitled
`
`to a patent was where the invention was patented or described in a printed
`
`publication anywhere in the world more than one year prior to the U.S. patent
`
`application date. I have therefore primarily considered “prior art” publications dated
`
`on or before October 15, 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
`33. As above, I have been informed by counsel that the obviousness
`
`analysis is to be conducted from the perspective of a person of ordinary skill in the
`
`art (a “person of ordinary skill,” or “POSA”) at the time of the invention.
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`34.
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`I have adopted the understanding of a POSA when discussing the
`
`teachings of the prior art. I have also reviewed the ’740 patent.1
`
`35.
`
`I have also been informed by counsel that in defining a POSA the
`
`following factors may be considered: (1) the educational level of the inventor;
`
`(2) the type of problems encountered in the art; (3) prior art solutions to those
`
`problems; (4) speed with which innovations are made; and (5) sophistication of the
`
`technology and educational level of active workers in the field.
`
`36. A POSA2 would typically have had a Ph.D. in pharmacology,
`
`pharmaceutical chemistry, or cancer biology (or a related discipline); a Pharm.D.
`
`with experience in clinical oncology; or an M.D. with experience in clinical
`
`oncology or pharmacology. Such a person would have had experience with the
`
`administration or formulation of therapeutic agents, dosing schedules and
`
`frequencies, and drug developmental study and design. Such a person would have
`
`been well-versed in the worldwide literature that was available as of October 15,
`
`2002—what I understand is the priority date of the ’740 patent. A physician would
`
`
`
` Ex. 1001 (’740 patent).
`
` 1
`
`2 All references herein to the knowledge or understanding of a POSA or a POSA’s
`
`interpretation or understanding of a prior art reference are as of the earliest possible
`
`priority date unless specifically stated otherwise.
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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
`
`POSA under any definition of that person’s qualifications.
`
`37. These qualifications are not rigid. Greater education or a specific skill
`
`may make up for less experience, and vice-versa. Moreover, one individual need
`
`not have every qualification. A multidisciplinary team with the necessary expertise
`
`in its ranks would suffice. Such a team could include—and the POSA would draw
`
`upon the skills of—a clinician having experience in treating MDS. However, in
`
`view of the relatively high level of skill on any reasonable POSA, the conclusions
`
`in this Petition would be unchanged under any reasonable definition of the POSA.
`
`V. BACKGROUND
`A. MDS and Its Classification and Treatment
`38.
`“Cancer” is a group of conditions that can occur throughout the body,
`
`from one’s outermost skin to one’s innermost bone marrow, and can affect all ages.
`
`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
`
`accrued, and instead keep growing and making new cells, which in turn crowd out
`
`the normal cells.
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`39. Some types of cancer affect cells inside the bone marrow. Bone
`
`marrow is the spongy, inner part of certain bones, and is comprised of blood stem
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`
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`cells, more mature blood-forming cells, fat cells, and supporting tissues. See, for
`
`example, the visualization below:
`
`
`There, pluripotential stem cells divide and mature into hematopoietic stem cells,
`
`which in turn mature into new blood cells, including red blood cells, which carry
`
`oxygen and carbon dioxide throughout our bodies; platelets, which are cell
`
`fragments that help the blood clot; and multiple classes of white blood cells, which
`
`are responsible for fighting infection. (There are several types of white blood cells,
`
`including neutrophils, which attack antigens such as bacteria, viruses, fungi, poisons,
`
`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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`
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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
`
`is called hematopoiesis.
`
`40. 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.
`
`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
`
`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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`41. 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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`42.
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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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`43. 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. See, e.g., Ex. 1039 at 10; Ex. 1033 at 1. Many MDS
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`patients were (and most eventually became) “transfusion dependent,” or were
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`considered to have “transfusion dependent anemia” (TDA), meaning that they
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`required ongoing RBC transfusions. Treatments which improved the number and
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`functionality of marrow and blood cells would have, correspondingly, improved the
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`anemia and reduced or eliminated transfusion dependence.
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`44. 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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`45. 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 Ex. 1039 at 10;
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`Ex. 1023 at 1. Blood stem cell transplantation, described in more detail below, was
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`the only curative therapy. Supportive therapies included red blood cell transfusions,
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`platelet 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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`46. 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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`47. 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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`48. 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