Paper No. __
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`Filed: November 24, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`NEPTUNE GENERICS, LLC
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`PETITIONER
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`V.
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`ELI LILLY & COMPANY
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`PATENT OWNER
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`___________________
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`CASE NO.: UNASSIGNED
`PATENT NO. 7,772,209
`FILED: JULY 11, 2007
`ISSUED: AUGUST 10, 2010
`INVENTOR: CLET NIYIKIZA
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`TITLE: ANTIFOLATE COMBINATION THERAPIES
`___________________
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`DECLARATION OF W. ARCHIE BLEYER, MD, FRCP[GLASG]
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`Wockhardt Exhibit 1025 - 1
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`
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`Filed: November 24, 2015
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`NEPTUNE GENERICS, LLC
`
`PETITIONER
`
`V.
`
`ELI LILLY & COMPANY
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: UNASSIGNED
`PATENT NO. 7,772,209
`FILED: JULY 11, 2007
`ISSUED: AUGUST 10, 2010
`INVENTOR: CLET NIYIKIZA
`
`TITLE: ANTIFOLATE COMBINATION THERAPIES
`___________________
`
`DECLARATION OF W. ARCHIE BLEYER, MD, FRCP[GLASG]
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`Wockhardt Exhibit 1025 - 1
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`I, W. Archie Bleyer, MD, FRCP hereby declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I am over the age of eighteen (18) and otherwise competent to make
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`this declaration.
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`2.
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`I have been retained as an expert witness on behalf of NEPTUNE
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`GENERICS, LLC for the above-captioned inter partes review (“IPR”). I
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`understand that the petition for inter partes review involves U.S. Patent No.
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`7,772,209 (“the ’209 patent”), Exhibit 1001, which issued from U.S. Patent
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`Application No. 11/776,329 (the “’329 Application”), filed July 11, 2007. (Ex.
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`1001 at Front Cover.) The ’209 Patent claims priority to U.S. Patent App. No.
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`60/215,310 (filed June 30, 2000). The ’209 Patent names Clet Niyikiza as an
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`inventor. The ’209 Patent issued on August 10, 2010. (Id.)
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`3.
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`In preparing this Declaration, I have reviewed the ’209 Patent and
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`considered each of the documents cited herein, in light of general knowledge in the
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`art as of June 30, 1999. In formulating my opinions, I have relied upon my
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`experience, education and knowledge in the relevant art. In formulating my
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`opinions, I have considered the viewpoint of a person of ordinary skill in the art
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`prior to June 30, 1999.
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`II. BACKGROUND AND QUALIFICATIONS
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`4.
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`I am a Clinical Research Professor in the Department of Radiation
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`Wockhardt Exhibit 1025 - 2
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`Medicine at The Knight Cancer Institute at the Oregon Health and Sciences
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`University, Portland; a Professor of Pediatrics at The University of Texas Medical
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`School at Houston; and a Senior Advisor for the Children’s Oncology Group
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`Adolescent and Young Adult Committee.
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`5. My teaching responsibilities are primarily based in adolescent and
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`young adult oncology.
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`6.
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`I received an undergraduate degree (B.S.) (1965) in Life Sciences
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`from the Massachusetts Institute of Technology, Cambridge, Massachusetts, and a
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`medical degree (M.D.) (1969) from the University of Rochester School of
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`Medicine and Dentistry, Rochester, New York.
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`7.
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`After medical school, I completed my internship (1970) and residency
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`(1971) in medicine/pediatrics and pediatrics at the University of Washington and
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`Children’s Hospital and Medical Center, Seattle, Washington.
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`8.
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`Following residency, I completed fellowships in pediatric oncology at
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`the National Cancer Institute, Bethesda, Maryland (1974), Seattle Children’s
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`Hospital and the University of Washington, Seattle, Washington (1975).
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`9.
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`I received Board Certification in Pediatrics and Pediatric
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`Hematology/Oncology from the National Board of Medical Examiners (1970),
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`American Board of Pediatrics (1975), and the American Board of Pediatrics
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`(1976).
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`Wockhardt Exhibit 1025 - 3
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`10.
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`I served as a Lieutenant Commander in the United States Public
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`Health Services, and as a Clinical Associate at the National Cancer Institute, NIH,
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`Bethesda, Maryland (1971-1974).
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`11.
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`I am a Fellow of the American Board of Pediatrics and the Royal
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`College of Physicians (Glasgow).
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`12.
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`I am a member of multiple regional, national, and international
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`organizations relating to pediatric, medical, and adolescent/young adult oncology.
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`13.
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`I have authored more than 250 peer-reviewed articles and over 60
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`book chapters on pediatric oncology, medical oncology, adolescent/young adult
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`oncology, and neuro-oncology, including articles and book chapters on the same
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`topics.
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`14.
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`I am an Editor of the 8 books, monographs and special issues of
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`oncology journals. The most important book is Cancer in Adolescents and Young
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`Adults (Springer Verlag Publishers, 2007) that has 73 authors from 9 countries on
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`4 continents, 534 pages, 199 figures, and 90 tables. A 2nd edition that will nearly
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`double the contents is in preparation.
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`15.
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`I have prescribed and administered a wide variety of intravenous,
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`intramuscular, subcutaneous and intrathecal medications, including antifolates.
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`16.
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`I consider myself to be an expert in the fields of pediatric oncology,
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`adolescent/young adult oncology, neuro-oncology and cancer screening.
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`Wockhardt Exhibit 1025 - 4
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`17.
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`I am being compensated at a rate of $300/hour.
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`18. Additional details of my education and experience are listed in my
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`curriculum vitae, a copy of which is attached as Attachment 1 (Ex. 1024).
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`III. LIST OF DOCUMENTS CONSIDERED IN FORMULATING
`OPINION
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`19.
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`In formulating my opinion, I have considered the following
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`documents: (a) the ’209 Patent (Ex. 1001), (b) portions of the ’209 Patent
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`prosecution file history (Ex. 1002), and (c) the prior art relevant to the Petition –
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`(1) Allen et al., “Diagnosis of Cobalamin Deficiency I: Usefulness of Serum
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`Methylmalonic Acid and Total Homocysteine Concentrations.” American Journal
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`of Hematology, 34, 1990, 90-98 (“Allen”) (Ex. 1017); (2) Refsum H & Ueland
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`PM, “Clinical significance of pharmacological modulation of homocysteine
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`metabolism.” Trends in Pharmacol. Sci., Vol. 11, No. 10, 1990, pp. 411-416
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`(“Refsum”) (Ex. 1012); (3) Morgan et al., “The Effect of Folic Acid
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`Supplementation on the Toxicity of Low-Dose Methotrexate in Patients with
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`Rheumatoid Arthritis.” Arthritis and Rheumatism, Vol. 33, No. 1, January 1990,
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`pp. 9-18 (“Morgan”) (Ex. 1023); (4) U.S. Patent No. 5,217,974 (“the ’974 Patent”)
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`(Ex. 1009); (5) European Patent Application No. 0,595,005 A1 (“EP 005”) (Ex.
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`1010); (6) Zervos et al., “Functional folate status as a prognostic indicator of
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`toxicity in clinical trials of the multitargeted antifolate LY231514.” Proceedings of
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`ASCO, Vol. 16, 1997, pg. 256a (“Zervos”) (Ex. 1016); (7) Brönstrup et al.,
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`Wockhardt Exhibit 1025 - 5
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`“Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma
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`homocysteine concentrations in healthy, young women.” Am. J. Clin. Nutr. Vol.
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`68, 1998, 1104-10 (“Bronstrup”) (Ex. 1019); (8) Calvert AH & Walling JM,
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`“Clinical studies with MTA.” British Journal of Cancer (1998) 78 (Suppl. 3), 35-40
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`(“Clavert 1998”) (Ex. 1013); (9) Hammond et al., “A Phase I and pharmacokinetic
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`(PK) study of the multitargeted antifolate (MTA, LY231514) with folic acid (FA).”
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`Annals of Oncology, Vol. 9, Suppl. 4, 1998, Abstract 620P, pg. 129 (“Hammond”)
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`(Ex. 1022); (10) Niyikiza et al., “MTA (LY231514): Relationship of vitamin
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`metabolite profile, drug exposure, and other patient characteristics to toxicity.”
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`Annals of Oncology, Vol. 9, Suppl. 4, 1998, Abstract 609P, pg. 126 (“Niyikiza”)
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`(Ex. 1008); (11) Thödtmann et al., “Phase I study of different sequences of MTA
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`(LY231514) in combination with cisplatin in patients with solid tumours.” Annals
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`of Oncology, Vol. 9, Suppl. 4, 1998, Abstract 618P, pg. 129 (“Thodtmann”) (Ex.
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`1021); (12) Calvert H, “An Overview of Folate Metabolism: Features Relevant to
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`the Action and Toxicities of Antifolate Anticancer Agents,” Seminars in Oncology,
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`Vol. 26, No. 2, Suppl 6 (April), 1999, pp. 3-10 (“Calvert 1999”) (Ex. 1014); (13)
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`O’Dwyer et al., “Overview of Phase II Trials of MTA in Solid Tumors.” Seminars
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`in Oncology, Vol. 26, No. 2, Suppl 6 (April), 1999, pp. 99-104 (“O’Dwyer”) (Ex.
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`1015); (14) Carrasco et al., “Acute megaloblastic anemia: homocysteine levels are
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`useful for diagnosis and follow-up.” Haematologica, Vol. 84(8), August 1999, 767-
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`Wockhardt Exhibit 1025 - 6
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`768 (“Carrasco”) (Ex. 1020); (15) Rusthoven et al., “Multitargeted Antifolate
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`LY231514 as First-Line Chemotherapy for Patients with Advanced Non-Small-
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`Cell Lung Cancer: A Phase II Study.” Journal of Clinical Oncology, Vol. 17, No.
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`4, (April 1999), pp. 1194-1199 (“Rusthoven”) (Ex. 1011).
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`IV. PERSON OF ORDINARY SKILL IN THE ART
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`20.
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`I understand that a person of ordinary skill in the art (“POSA”) is a
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`hypothetical person presumed to be aware of all pertinent art, understands
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`conventional wisdom in the art, and is a person of ordinary creativity. In this case,
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`a medical doctor with an M.D. degree who has significant experience in treating
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`cancer patients, and a significant understanding of antineoplastic agents, including
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`antifolates and their efficacies, safety, adverse effects, toxicities, etc., is a POSA.
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`21. A POSA may work as part of a multi-disciplinary team and draw upon
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`not only his or her own skills, but also take advantage of certain specialized skills
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`of others on the team, to solve a given problem. For example, an expert in
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`nutrition, an expert in hematology, a basic scientist with expertise in biochemistry,
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`and a clinician may be part of the team.
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`V.
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`THE ’209 PATENT SPECIFICATION
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`22. This declaration is being submitted together with a petition for inter
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`partes review of Claims 1-22 of the ’209 Patent.
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`23.
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`I have considered the ’209 Patent and portions of file history of the
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`Wockhardt Exhibit 1025 - 7
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`’209 Patent in light of the general knowledge in the art as of the earliest priority
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`date of the ’209 Patent—June 30, 1999.
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`24. The ’209 Patent is titled “Antifolate Combination Therapies,” and
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`describes and claims “a method of administering an antifolate to a mammal in need
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`thereof, comprising administering an effective amount of said antifolate in
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`combination with a methylmalonic acid lowering agent and a FBP [folate binding
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`protein] binding agent.” (Ex. 1001 at 3:1-5.) The ’209 Patent states that folic acid
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`is the preferred FBP binding agent, and vitamin B12 is a preferred methylmalonic
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`acid lowering agent. (Id. at 3:5-6, 4:47-50.)
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`25. The patent states that antifolates are one of the most thoroughly
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`studied classes of antineoplastic agents, with a long history, and aminopterin was
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`the first antifolate that demonstrated clinical activity approximately 50 years ago.
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`(Id. at 1:19-21.) Shortly thereafter, methotrexate was developed as an anticancer
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`drug, and today methotrexate is used as a standard chemotherapy drug for several
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`malignancies, including lymphoblastic leukemia, lymphoma, osteosarcoma, breast
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`cancer, and head and neck cancer. (See, e.g., id. at 1:22-25.)
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`26. The patent describes that “[a]ntifolates inhibit one or several key
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`folate-requiring enzymes of the thymidine and purine biosynthetic pathways, in
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`particular, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and
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`glycinamide ribonucleotide formyltransferase (GARFT), by competing with
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`Wockhardt Exhibit 1025 - 8
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`
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`reduced folates for binding sites of these enzymes.” (Id. at 1:36-41.)
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`27. The patent states that several antifolate drugs were in development,
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`and pemetrexed disodium (Alimta®, Eli Lilly and Company, Indianapolis, Ind.)
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`demonstrated inhibition at several key folate-requiring enzymes such as TS,
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`DHFR, and GARFT. (Id. at 1:48-49; 1:58-61.)
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`28. The major limitation of administering antifolates to patients is its
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`adverse effects on organ and organ system function and of “life-threatening
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`toxicity.” (Id. at 1:11-12.) For example, “antifolates as a class are associated with
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`sporadic severe my[e]losuppression with gastrointestinal toxicity which, though
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`infrequent, carries a high risk of mortality.” (Id. at 1:65-67.)
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`29. The patent states that increased homocysteine levels have been known
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`to increase the risk of severe antifolate toxicity in patients, and that folic acid was
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`known to lower antifolate-induced homocysteine levels. (Id. at 2:14-17, 24-26.)
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`30.
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`It further states that antifolate increases methylmalonic acid levels,
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`which cause toxicity, and the treatment with vitamin B12 reduces such antifolate-
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`associated toxicity by lowering methylmalonic acid levels. (Id. at 2:41-46.)
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`31. The patent also states that it was known that folic acid in combination
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`with vitamin B12 was administered to treat and prevent cardiovascular disease. (Id.
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`at 2:50-52.) And, the combination of folic acid and a methylmalonic acid lowering
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`agent synergistically reduces antifolate toxicity. (Id. at 2:47-50.)
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`Wockhardt Exhibit 1025 - 9
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`32. The ’209 Patent’s alleged invention was purportedly conceived “to
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`lower cytotoxic activity” associated with antifolate treatment. (Id. at 2:29-37.)
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`33. The ’209 Patent mainly describes: (1) administration of pemetrexed
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`disodium to a patient in combination with an effective amount of folic acid and an
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`effective amount of a methylmalonic acid lowering agent, such as vitamin B12; (2)
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`pretreatment with folic acid prior to pemetrexed disodium treatment; (3)
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`pretreatment with folic acid and vitamin B12 prior to pemetrexed disodium
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`treatment; (4) repetition of vitamin B12 administration; and (5) administration of
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`cisplatin in combination with pemetrexed disodium to the patient. (Ex. 1001 at
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`10:56-12:29.)
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`34. The patent acknowledges that a physician determines the amount of
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`methylmalonic acid lowering agent to be administered based on “the relevant
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`circumstances, including the condition to be treated, the chosen route of
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`administration, the actual agent administered, the age, weight, and response of the
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`individual patient, and the severity of the patient’s symptoms.” (Id. at 5:37-50;
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`6:41-52.)
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`VI. THE ’209 PATENT CLAIMS
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`A. The Language of the Claims
`35. Claim 1, one of two independent claims in the ’209 Patent, recites:
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`A method for administering pemetrexed disodium to a patient in need
`thereof comprising administering an effective amount of folic acid and an
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`Wockhardt Exhibit 1025 - 10
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`effective amount of a methylmalonic acid lowering agent followed by
`administering an effective amount of pemetrexed disodium, wherein the
`methylmalonic acid lowering agent is selected from the group consisting of
`vitamin B12, hydroxycobalamin, cyano-10-chlorocobalamin, aquocobalamin
`perchlorate, aquo-10-cobalamin perchlorate, azidocobalamin, cobalamin,
`cyanocobalamin, or chlorocobalamin.
`(Ex. 1001 at 10:56-65.)
`36. Claim 2 depends from Claim 1, and recites that “the methylmalonic
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`acid lowering agent is vitamin B12.” (Id. at 10:66-67.)
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`37. Claim 3 depends from Claim 2, and recites that “the vitamin B12 is
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`administered as an intramuscular injection of about 500 µg to about 1500 µg.” (Id.
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`at 11:1-3.)
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`38. Claim 4 depends from Claim 2, and recites that the vitamin B12 is
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`administered as an intramuscular injection of about 1000 µg. (Id. at 11:4-5.)
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`39. Claim 5 depends from Claims 2, 3, and 4, and recites that “the
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`vitamin B12 administration is repeated about every 6 to about every 12 weeks
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`following the administration of vitamin B12 until the administration of the
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`pemetrexed disodium is discontinued.” (Id. at 11:6-9.)
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`40. Claim 6 depends from Claim 5, and recites that “the folic acid is
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`administered 1 to 3 weeks prior to the first administration of the pemetrexed
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`disodium.” (Id. at 11:10-12.)
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`41. Claim 7 depends from Claim 5, and recites that “the folic acid is
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`Wockhardt Exhibit 1025 - 11
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`administered from about 1 to about 24 hours prior to administration of the
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`pemetrexed disodium.” (Id. at 11:13-15.)
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`42. Claim 8 depends from Claims 1-4, and recites that “between 0.3 mg
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`to about 5 mg of folic acid is administered orally.” (Id. at 11:16-18.)
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`43. Claim 9 depends from Claim 8, and recites that “about 350 µg to
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`about 1000 µg of folic acid is administered.” (Id. at 11:19-20.)
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`44. Claim 10 depends from Claim 9, and recites that “350 µg to 600 µg
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`of folic acid is administered.” (Id. at 11:21-22.)
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`45.
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` Claim 11 depends from Claim 1, and recites “the administration of
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`cisplatin to the patient.” (Id. at 11:23-24.)
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`46. Claim 12, the second of two independent claims in the ’209 Patent,
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`recites:
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`An improved method for administering pemetrexed disodium to a patient in
`need of chemotherapeutic treatment, wherein the improvement comprises:
`a) administration of between about 350 µg and about 1000 µg of folic
`acid prior to the first administration of pemetrexed disodium;
`b) administration of about 500 µg to about 1500 µg of vitamin B12,
`prior to the first administration of pemetrexed disodium; and
`c) administration of pemetrexed disodium.
`Id. at (11:25-12:4.)
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`47. Claim 13 depends from Claim 12, and recites “the administration of
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`cisplatin to the patient.” (Id. at 12:5-6.)
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`Wockhardt Exhibit 1025 - 12
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`48. Claim 14 depends from Claim 12, and recites that “vitamin B12 is
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`administered as an intramuscular injection of about 500 µg to about 1500 µg.” (Id.
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`at 12:7-9.)
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`49. Claim 15 depends from Claim 14, and recites that “vitamin B12 is
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`administered as an intramuscular injection of about 1000 µg.” (Id. at 12:10-11.)
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`50. Claim 16 depends from Claim 15, and recites that “between 0.3 mg
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`to about 5 mg of folic acid is administered orally.” (Id. at 12:12-13.)
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`51. Claim 17 depends from Claim 16, and recites that “about 350 µg to
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`about 1000 µg of folic acid is administered.” (Id. at 12:14-15.)
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`52. Claim 18 depends from Claim 17, and recites that “350 µg to 600 µg
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`of folic acid is administered.” (Id. at 12:16-17.)
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`53. Claim 19 depends from Claim 18, and recites that “folic acid is
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`administered 1 to 3 weeks prior to the first administration of the pemetrexed
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`disodium.” (Id. at 12:18-20.)
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`54. Claim 20 depends from Claim 18, and recites that “the folic acid is
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`administered from about 1 to about 24 hours prior to administration of the
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`pemetrexed disodium.” (Id. at 12:21-23.)
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`55. Claim 21 depends from Claims 12, 18, and 19, and recites that “the
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`vitamin B12 administration is repeated about every 6 to about every 12 weeks
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`following the administration of vitamin B12 until administration of pemetrexed
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`Wockhardt Exhibit 1025 - 13
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`disodium is discontinued.” (Id. at 12:24-27.)
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`56. Claim 22 depends from Claim 21, and recites that “the administration
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`of cisplatin to the patient.” (Id. at 12:28-29.)
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`B.
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`The Meaning of Selected Terms in the Claims
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`57.
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`It is my understanding that the claim terms in a patent subject to IPR
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`must be understood to have their broadest reasonable interpretation in light of the
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`specification of the patent.
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`58. The terms in the claims of the ’209 Patent are used in accordance with
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`their plain and ordinary meaning, as exemplified by the terms presented below.
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`59.
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`“Patient”
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`“Patient” means “a human undergoing medical treatment.” (Ex. 1026 at 9.)
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`60.
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`“Methylmalonic acid lowering agent”
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`“Methylmalonic acid lowering agent” means “vitamin B12 or its derivative
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`that lowers the concentration of methylmalonic acid in a mammal.” (Ex. 1027 at 2;
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`Ex. 1001 at 4:47-50.)
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`61.
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`“An effective amount of pemetrexed disodium”
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`“An effective amount of pemetrexed disodium” means “an amount of
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`pemetrexed disodium that is capable of providing a therapeutic benefit to the
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`patient in need thereof.” (Ex. 1027 at 2; Ex. 1001 at 3:53-58.)
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`“An effective amount of folic acid and an effective amount of a
`62.
`methylmalonic acid lowering agent”
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`Wockhardt Exhibit 1025 - 14
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`“An effective amount of folic acid and an effective amount of a
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`methylmalonic acid lowering agent” mean “amounts of folic acid and a
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`methylmalonic acid lowering agent that are capable of reducing the prevalence or
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`severity of one or more toxicities associated with the administration of pemetrexed
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`disodium.” (Ex. 1027 at 1; Ex. 1001 at 3:53-58.)
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`63.
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`“Toxicity”
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`“Toxicity” means a toxic event associated with the administration of an
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`antifolate. Such events include, but are not limited to, neutropenia, thrombopenia,
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`mucositis, liver dysfunction diarrhea, fatigue, anorexia, nausea, vomiting, skin
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`rash, immunosuppression, infection, diarrhea, and anemia and toxic death. (Ex.
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`1001 at 3:59-67.)
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`64.
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`“Antifolate” and “antifolate drug”
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`“Antifolate” and “antifolate drug” mean “a chemical compound which
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`inhibits at least one key folate requiring enzyme of the thymidine or purine
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`biosynthetic pathways, preferably thymidylate synthase (‘TS’), dihydrofolate
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`reductase (‘DHFR’), or glycinamide ribonucleotide formyltransferase (‘GARFT’),
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`by competing with reduced folates for binding sites of these enzymes. Preferred
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`examples of antifolates” include methotrexate, Tomudex® Lometrexol®,
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`pyrido[2,3-d]pyrimidine derivatives, and “derivatives described by Akimoto in US.
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`Pat. No. 4,997,838; thymidylate synthase inhibitors as found in EPO application
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`Wockhardt Exhibit 1025 - 15
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`239,362; and most preferred, Pemetrexed Disodium (ALIMTA), as manufactured
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`by Eli Lilly & Co.” (Ex. 1001 at 4:28-44.)
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`VII. THE STATE OF THE ART AS OF JUNE 30, 1999
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`A. Antifolates
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`65. By June of 1999, it was well known in the art that antifolates, such as
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`pemetrexed, had anticancer properties. (Ex. 1013 at 35; Ex. 1008 at 126.)
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`66. Antifolates, part of a large class of compounds known as
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`antimetabolites, inhibit cellular reactions by inhibiting folate-dependent enzymes.
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`(Ex. 1013 at 35.)
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`67. As cancer cells actively proliferate, they require large quantities of
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`DNA and RNA. (Id.) Because antifolates interfere with DNA and RNA synthesis
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`and cause cell death or stasis, antifolates are used as chemotherapeutic drugs to
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`treat certain types of cancer. (Id.; Ex. 1014 at 3; Ex. 1011 at 1194; Ex. 1008 at 126;
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`Ex. 1015 at 99.)
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`68. By June 1999, several antifolates, such as pemetrexed, methotrexate,
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`aminopterin, Lometrexol®, 5-fluorouracil, and Tomudex®, were used for the
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`treatment of, among other diseases, cancer, and autoimmune diseases, including
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`rheumatoid arthritis and inflammatory bowel disease. (Ex. 1001 at 4:28–44; Ex.
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`1023 at 9.)
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`69. However, the major limitation of using these antifolates is that they
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`Wockhardt Exhibit 1025 - 16
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`act on all proliferating cells, not just on actively proliferating cancer cells, and
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`cause severe side effects (i.e., toxicity). (Ex. 1013 at 35.) Some of these severe
`
`toxic effects are related to hematopoietic system and epithelial cells that may be
`
`severe and even life-threatening. (Id.)
`
`70. Pemetrexed is a folate analog that suppresses tumor growth by
`
`interfering with both DNA synthesis and folate metabolism. (Ex. 1013 at 35.)
`
`71. The structures of folic acid and pemetrexed are depicted below:
`
`Folic acid
`
`Pemetrexed
`
`
`
`
`
`(Ex. 1014 at 4.)
`
`(Id. at 6.)
`
`72. Pemetrexed is also a multi-targeted antifolate (“MTA”) that inhibits
`
`several enzymes in the folate pathway, such as thymidylate synthase (TS),
`
`glycinamide ribonucleotide formyltransferase (GARFT), dihydrofolate reductase
`
`(DHFR), and aminoimidazole carboxamide ribonucleotide formyltransferase
`
`Wockhardt Exhibit 1025 - 17
`
`
`
`(AICARFT). (Ex. 1013 at 35.)
`
`73. Before 1999, a POSA would have known that several phase I and
`
`phase II trials were conducted with pemetrexed to treat solid tumors, particularly
`
`breast, pancreatic, colorectal, and non-small-cell lung (“NSCLC”) cancers. (Id. at
`
`38; Ex. 1008 at 126; Ex. 1011 at 1194; Ex. 1015 at 99; Ex. 1021 at 129.)
`
`74. Like other antifolates, pemetrexed is also known to cause severe side
`
`effects. (Ex. 1008 at 126.)
`
`B.
`
`The combination of pemetrexed, folic acid, and vitamin B12
`administration was obvious
`
`75. Prior to 1999, it was well known in the art that folic acid and vitamin
`
`B12 prevent and ameliorate antifolate toxicity. (Ex. 1010 at 2, 4, 9.)
`
`1.
`
`Relationship between antifolate and blood homocysteine levels
`
`76. By June 1999, extensive research into antifolate-associated toxicity
`
`indicated that elevated levels of blood homocysteine were observed in patients
`
`treated with antifolate, such as pemetrexed. (Ex. 1001 at 2:14-26; Ex. 1008 at 126-
`
`27, Ex. 1016 at 256a.) These studies showed that folic acid supplementation
`
`reduced antifolate-associated toxicity by lowering elevated homocysteine levels.
`
`(Ex. 1016 at 256a; Ex. 1013 at 39.)
`
`77.
`
`It was known in the art that the intracellular homocysteine could be
`
`reduced by two pathways: (a) salvage to methionine through remethylation by
`
`methionine synthase, and (b) conversion to cysteine via the trans-sulfuration
`
`Wockhardt Exhibit 1025 - 18
`
`
`
`pathway. (Ex. 1012 at 411.) Methionine synthase requires folate (5-
`
`methyltetrahydrofolate) as a methyl donor and vitamin B12 as a cofactor for the
`
`remethylation reaction. (Id.; Ex. 1014 at 8-9.) Calvert’s figure, depicting
`
`remethylation of homocysteine to methionine, is reproduced below:
`
`
`
`Fig. 8. Role of 5-methyl tetrahydrofolic acid: a reduction in functional folate
`increases plasma homocysteine levels.
`
`(Ex. 1014 at 9 (red outline emphasis added).)
`
`2.
`
`Relationship between folic acid, vitamin B12, and blood
`homocysteine levels
`
`78. Prior to June 1999, the studies showed that antifolate raised
`
`methylmalonic acid levels along with homocysteine levels. (See, e.g., Ex. 1008 at
`
`126-27; Ex. 1010 at 4, 9; Ex. 1017 at 90, 93.) In fact, as early as 1990, it was well
`
`known in the art that the elevated levels of methylmalonic acid are linked to
`
`Wockhardt Exhibit 1025 - 19
`
`
`
`vitamin B12 (cobalamin) deficiency, because there are only two vitamin B12-
`
`dependent enzymes in vertebrates: methionine synthase, which requires
`
`methylcobalamin (vitamin B12) as a co-factor, and methylmalonyl CoA mutase.
`
`(Ex. 1012 at 411, Ex. 1017 at 92.)
`
`79. And, “methylmalonic acid and homocysteine accumulate when the
`
`two enzymatic reactions are impaired.” (Ex. 1018 at 239.) The relationship
`
`between vitamin B12 and homocysteine and methylmalonic acid is further
`
`explained in the figure below:
`
`
`
`
`
`
`
`
`
`Wockhardt Exhibit 1025 - 20
`
`
`
`
`
`
`
`
`
`(Ex. 1017 at 92 (Figure is divided and red outline emphasis added).)
`
`80. As shown in the above figure, in vitamin B12 deficiency, the
`
`enzymatic activity of L-methylmalonyl-CoA mutase is impaired because it requires
`
`vitamin B12 as a co-factor. Thus, L-methylmalonyl-CoA accumulates and is
`
`converted to D-methylmalonyl-CoA, which is then hydrolyzed to methylmalonic
`
`Wockhardt Exhibit 1025 - 21
`
`
`
`acid. This leads to high levels of methylamalonic acid in blood in vitamin B12
`
`deficiency. (Id.)
`
`81. Similarly, in vitamin B12 deficiency, homocysteine to methionine
`
`reaction is impaired because the enzyme that catalyzes this remethylation reaction,
`
`methionine synthase, is vitamin B12-dependent. Thus, homocysteine accumulates
`
`in vitamin B12 deficiency. (Id.)
`
`82. The medical peer-reviewed literature has reports as early as 1990 that
`
`both folic acid and vitamin B12 are required to maximally lower homocysteine
`
`levels in the body. (Ex. 1012 at 411-12).
`
`83.
`
`It was known in the art before 1999 that monitoring homocysteine and
`
`methylmalonic acid levels in patients treated with antifolate could predict which
`
`patients were at risk of toxicity. (See e.g., Ex. 1008 at 126, Ex. 1017 at 93.) For example, in
`
`1998, Niyikiza reported that 139 patients in a phase II study with pemetrexed
`
`treatment for homocysteine and methylmalonic acid levels demonstrated a strong
`
`correlation between elevated homocysteine levels and pemetrexed toxicity. (Ex.
`
`1008 at 126-27.)
`
`84. Further, a synergistic effect was shown when both vitamin B12 and
`
`folate were administered concurrently to control blood homocysteine levels. (Ex.
`
`1010 at 11.)
`
`85. Also, Brönstrup reported in 1998 that folate and vitamin B12
`
`Wockhardt Exhibit 1025 - 22
`
`
`
`administered together have a synergistic effect in increasing methionine synthase
`
`activity. (Ex. 1019 at 1109.) However, “a higher availability of only one cofactor,
`
`especially in subjects with an already good supply of this cofactor, might lead to
`
`only a limited increase in enzyme activity.” (Id.)
`
`86. Thus, in the case of antifolate administration, a POSA would have
`
`been motivated to combine the antifolate administration with a combination of
`
`folic acid and vitamin B12 administration to ameliorate antifolate toxicity in a
`
`patient with elevated homocysteine levels, with a reasonable expectation of success
`
`of reducing the antifolate toxicity but not the intended clinical benefit. (See Ex.
`
`1020 at 767.)
`
`87.
`
`In 1999, in a study of a 45-year old male chronic myelogenous
`
`leukemia patient, both folic acid and vitamin B12 were administered to ameliorate
`
`toxic effects caused by antifolate methotrexate treatment. (Ex. 1020 at 767-68.)
`
`Specifically, the patient received folinic acid (12 mg in one single dose), folic acid
`
`(5 mg/day for 14 days) and parenteral vitamin B12 (2 mg/day for 4 consecutive
`
`days), and after 10 days of treatment, the patient’s “serum HCY [homocysteine]
`
`level decreased to [a] normal value (9 μmol/L).” (Id. at 768.)
`
`88.
`
`It was also known in the art before 1999 that patients with cancer tend
`
`to have elevated levels of plasma homocysteine and that antifolates elevated
`
`homocysteine levels. (Ex. 1010 at 4, 9; Ex. 1008 at 126.) Therefore, by 1999, it
`
`Wockhardt Exhibit 1025 - 23
`
`
`
`was obvious to a POSA to reduce pretreatment homocysteine levels, so that the
`
`patient could better tolerate antifolate therapy. Thus, a POSA had reason to pretreat
`
`the patient with folic acid and vitamin B12 before starting the patient on antifolate
`
`therapy.
`
`89. Treating patients with acute lymphoblastic leukemia would be
`
`exempted from this guideline, unless they were known to be folate or vitamin B12
`
`deficient. The reason for the exception was the observation in the 1940s at The
`
`Children’s Hospital in Boston by Sidney Farber, MD that folic acid therapy
`
`accelerated the rate of leukemia cell proliferation in the children he treated with
`
`folic acid.
`
`90. Before 1999, it was routine practice for a POSA when treating a
`
`cancer patient with a chemotherapy agent to determine effective amounts of the
`
`chemotherapy drug and other supplements to reduce toxicity from chemotherapy,
`
`without adversely affecting therapeutic efficacy.
`
`91. Accordingly, a POSA treating a patient with antifolate, such as
`
`pemetrexed, would adjust the duration of the treatment and pretreatment periods
`
`and dosages of folic acid and vitamin B12 depending on the patient’s clinical
`
`condition. For example, a POSA would tailor the treatment to a patient condition,
`
`and determine the amount of folic acid and vitamin B12 to be administered, route
`
`of administration, and length and frequency of administration.
`
`Wockhardt Exhibit 1025 - 24
`
`
`
`92. Additionally, before 1999, a POSA would have known that folic acid
`
`and vitamin B12 can lower blood homocysteine levels and that pretreatment of
`
`patients with elevated homocysteine levels with folic acid and vitamin B12 would
`
`lead less side effects and to better compliance with antifolate treatment.
`
`VIII. LEGAL STANDARDS GOVERNING OBVIOUSNESS
`
`93.
`
`I understand that an obviousness analysis involves comparing a claim
`
`to the prior art references to determine whether the claimed invention would have
`
`been obvious to a POSA in view of the prior art, and in light of the general
`
`knowledge in the art. I also understand that when a POSA would have reached the
`
`claimed invention through routine practices without any undue experimentation,
`
`with a reasonable expectation of success, the invention may be deemed obvious.
`
`94.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art to achieve the claimed invention. It is
`
`further my understanding that where there is a reason to modify or combine the
`
`prior art to achieve the claimed invention, there must also be a reasonable
`
`expectation of success in so doing to render the claimed invention obvious. I
`
`understand that the reason to combine prior art references can come from a variety
`
`of sources, not just the prior art itself or the specific problem the patentee was
`
`trying to solve. I also understand that the references themselves need not provide a
`
`specific hint or suggestion of the alteration needed to arrive at the claimed
`
`Wockhardt Exhibit 1025 - 25
`
`
`
`invention; the analysis may include recourse to logic, judgment, and common
`
`sense available to a POSA.
`
`95.
`
`I understand that claims may be considered obvious if they recite
`
`subject matter that would have been obvious to a POSA to try and develop. I
`
`further understand that claims ar
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