Paper No. __
`
`Filed: July 1, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________
`
`TEVA PHARMACEUTICALS USA, INC.
`
`&
`
`FRESENIUS KABI USA, LLC
`
`PETITIONERS
`
`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
`
`___________________
`
`Teva-Fresenius
`Exhibit 1040-00001
`
`
`
`Filed: July 1, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________
`
`TEVA PHARMACEUTICALS USA, INC.
`
`&
`
`FRESENIUS KABI USA, LLC
`
`PETITIONERS
`
`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
`
`___________________
`
`Teva-Fresenius
`Exhibit 1040-00001
`
`
`
`DECLARATION OF MARK J. RATAIN, MD
`
`I, Mark J. Ratain, MD, hereby declare as follows:
`
`I.
`
`INTRODUCTION AND SCOPE OF WORK
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Teva
`
`Pharmaceuticals USA, Inc. (“Teva”) and Fresenius Kabi USA, LLC (“Fresenius”)
`
`for the above-captioned inter partes review (“IPR”). I understand that the petition
`
`for inter partes review involves U.S. Patent No. 7,772,209 (“the ’209 patent”),
`
`Exhibit 1001, which issued from U.S. Patent Application No. 11/776,329 (the
`
`“’329 Application”), filed July 11, 2007. (Ex. 1001 at Front Cover.) The ’209
`
`Patent claims priority to U.S. Patent App. No. 60/215,310 (filed June 30, 2000).
`
`The ’209 Patent names Clet Niyikiza as an inventor. The ’209 Patent issued on
`
`August 10, 2010. (Id.)
`
`3.
`
`I served as a testifying expert for Teva and Fresenius in a federal court
`
`action against Eli Lilly and Company involving the ’209 patent, captioned Eli Lilly
`
`and Co. v. Teva Parenteral Medicines, Inc. et al, Case No. 10-cv-1376-TWP-DKL.
`
`The opinions I offered in that litigation have not changed, and they are consistent
`
`with the opinions I set forth and agree to in this declaration.
`
`Teva-Fresenius
`Exhibit 1040-00002
`
`
`
`4.
`
`To prepare this Declaration, I have reviewed the ’209 Patent in light
`
`of general knowledge in the art as of June 30, 1999. In formulating my opinions, I
`
`have relied upon my experience, education and knowledge in the relevant art as
`
`would be relevant to the viewpoint of a person of ordinary skill in the art prior to
`
`June 30, 1999.
`
`5.
`
`I am being compensated for my time in connection with this IPR at
`
`my standard consulting rate, which is $800 per hour for general consulting and
`
`$8000 per day for testimony and preparation for testimony. My compensation is
`
`not contingent on the conclusions I reach herein or on the specifics of my
`
`testimony. I have no financial stake in the outcome of this proceeding.
`
`6.
`
`I understand that the ’209 patent is currently subject to three previous
`
`IPRs, including Neptune Generics, LLC v. Eli Lilly & Co. IPR2016-00237
`
`(“Neptune IPR 1”), Neptune Generics, LLC v. Eli Lilly & Co. IPR2016-00240
`
`(“Neptune IPR 2”), and Sandoz Inc. v. Eli Lilly & Co. IPR2016-00318 (“Sandoz
`
`IPR”). I understand that Petitioners Teva and Fresenius seek to become a party to
`
`each of the foregoing IPRs, and that this declaration is being submitted in
`
`furtherance of specifically Neptune IPR 2.
`
`7.
`
`I have reviewed the materials submitted with the petition filed in the
`
`Neptune IPR 2, including the petition (Paper No. 1), the Declaration of W. Archie
`
`Teva-Fresenius
`Exhibit 1040-00003
`
`
`
`Bleyer, MD, FRCP [GLASG] (filed as Exhibit 1024 in Neptune IPR 2) and
`
`materials cited therein, and the Board’s Decision Instituting Inter Partes Review
`
`(Paper No. 14.) I have also reviewed and considered other documents (such as the
`
`relevant prior art) in arriving at my opinions.
`
`8.
`
`I agree in all material respects with the analysis and opinions set forth
`
`by Dr. Bleyer in his declaration and submitted as Exhibit 1024 in Neptune IPR 2.
`
`Because my independent analysis of the claims and prior art led to the same
`
`substantive conclusions as Dr. Bleyer, coupled with the fact that the Petitioners
`
`Teva and Fresenius are seeking to become a party to the Neptune IPR 2, I adopt
`
`Dr. Bleyer’s substantive opinions as my own. I have appended those opinions after
`
`my signature of this declaration for convenience, and understand that a copy of Dr.
`
`Bleyer’s declaration is being submitted in this IPR as Exhibit 1024.
`
`9.
`
`I understand that in its Decision Instituting Inter Partes Review in
`
`connection with Neptune IPR 2, the Board concluded that Petitioner Neptune
`
`demonstrated a reasonable likelihood of prevailing on its assertion that claims 1-22
`
`of the ’209 patent are unpatentable. Specifically, the Board instituted review on
`
`the following basis: Rusthoven et al., Multitargeted Antifolate LY231514 as First-
`
`Line Chemotherapy for Patients with Advanced Non-Small-Cell Lung Cancer: A
`
`Phase II Study, Journal of Clinical Oncology, Vol. 17, No. 4, (April 1999), pp.
`
`Teva-Fresenius
`Exhibit 1040-00004
`
`
`
`1194-1199 (“Rusthoven”) (Ex. 1011) in view of European Patent Application No.
`
`0,595,005 A1 (“EP 005”). Because Petitioners Teva and Fresenius are seeking to
`
`join Neptune IPR 2, I have limited my opinions in this IPR to the references
`
`discussed in the petition (Paper No. 1) and supporting materials filed in that
`
`proceeding.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`10.
`
`I have been a practicing oncologist since 1986.
`
`11.
`
`I received an M.D. from the Yale University School of Medicine in
`
`1980.
`
`12.
`
`I am a Diplomate of the National Board of Medical Examiners (1981),
`
`and have been a Licensed Physician and Surgeon in the State of Illinois since 1983.
`
`I am Board Certified by the American Board of Internal Medicine in Internal
`
`Medicine (1983), Medical Oncology (1985) and Hematology (1986). I am also
`
`Board Certified by the American Board of Clinical Pharmacology (1993).
`
`13.
`
`I am the Leon O. Jacobson Professor of Medicine and Associate
`
`Director for Clinical Sciences at the University of Chicago Comprehensive Cancer
`
`Center, and I have held that title since 2002. I specialize in the use of
`
`investigational agents to treat advanced solid tumors. I also specialize in
`
`pharmacogenetics — the study of how genetic variation affects the body’s
`
`Teva-Fresenius
`Exhibit 1040-00005
`
`
`
`response to medications. I am the founder of the Pharmacogenetics of Anticancer
`
`Agents Research (PAAR) Group, which brought teams of experts to investigate
`
`advancements in pharmacogenetics. In addition, in 2010, I founded the Center for
`
`Personalized Therapeutics at the University of Chicago, of which I am the
`
`Director. I am also the Chief Hospital Pharmacologist at University of Chicago
`
`Medicine.
`
`14.
`
`I am internationally recognized as a leader in oncology and clinical
`
` pharmacology. I have previously served as Secretary-Treasurer (and Director) of
`
`the American Society of Clinical Oncology, the leading organization of oncology
`
`physicians. I have also served as a Director of the American Society for Clinical
`
`Pharmacology & Therapeutics, the leading organization of clinical
`
`pharmacologists, comprised of physicians and scientists from universities,
`
`pharmaceutical companies, and the Federal government.
`
`15.
`
`I also was the first Chair of the Steering Committee of the NIH
`
`Pharmacogenetics Research Network, and one of the first two Co-Chairs of the
`
`NIH’s National Cancer Institute Investigational Drug Steering Committee.
`
`16.
`
`I have received numerous awards in recognition of my work as an
`
`oncologist and clinical pharmacologist. I have received the Emil J. Freireich
`
`Award for Clinical Research from M.D. Anderson Cancer Center (the largest
`
`Teva-Fresenius
`Exhibit 1040-00006
`
`
`
`cancer center in the world, located in Houston, Texas), the Institute for
`
`Pharmacogenomics and Individualized Therapy Clinical Service Award from the
`
`University of North Carolina, the Director’s Service Award from the National
`
`Cancer Institute, the Research Achievement Award in Clinical Pharmacology and
`
`Translational Research from the American Association of Pharmaceutical
`
`Scientists, and the Rawls-Palmer Progress in Medicine Award from the American
`
`Society for Clinical Pharmacology and Therapeutics. Other recent awards are
`
`noted in my curriculum vitae, which is attached as Exhibit 1041.
`
`17.
`
`I have also held significant editorial responsibilities for numerous
`
`journals, as noted on my curriculum vitae.
`
`18.
`
`I have published more than 280 peer-reviewed original research
`
`papers (including those accepted for publication, and those pending actual
`
`publication) in medical and scientific journals. In addition, I have authored more
`
`than 180 other articles and book chapters, and I have edited two books. I am a co-
`
`inventor on five U.S. patents and two European patents.
`
`19. A copy of my curriculum vitae, providing a list of my publications
`
`(including those for the last ten years) and describing my education, training and
`
`experience in greater detail, is attached as Exhibit 1041.
`
`
`
`Teva-Fresenius
`Exhibit 1040-00007
`
`
`
`III. OPINION
`
`20.
`
`I have reviewed and agree with the opinions and conclusions set forth
`
`at Exhibit 1024 of this IPR (which is the declaration of Dr. Bleyer filed in Neptune
`
`IPR 2 at Ex. 1024). For convenience and expediency, I will not reiterate all those
`
`opinions again but instead have appended Dr. Bleyer’s declaration to this
`
`declaration, after my signature.
`
`I am providing no opinions in this IPR beyond
`
`those set forth in Dr. Bleyer’s declaration.
`
`IV.
`
`SIGNATURE
`
`21.
`
`I declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and belief are believed to be true.
`
`I understand that willful false statements may subject me to fines, imprisonment or
`
`both, pursuant to Section 1001 of Title 18 of the United States Code.
`
`Respectfully submitted,
`//
`
`’(./I/I/Z/I
`
`Signed:
`
`,.
`
`.
`
`0&1"
`
`Mark J. Ratain, MD
`
`Date: 7g / [Zn
`
`Teva - Fresenius
`
`lpélléblirlelslgliius
`Exhibit 1040-00008
`
`Teva-Fresenius
`Exhibit 1040-00008
`
`
`
` Paper No. __
`
`Filed: November 24, 2015
`
`
`
`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, M.D., FRCP[GLASG]
`
`NEPTUNE GENERICS 1024 - 00001
`
`Teva-Fresenius
`Exhibit 1040-00009
`
`
`
`I, W. Archie Bleyer, MD, FRCP hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of NEPTUNE
`
`GENERICS, LLC for the above-captioned inter partes review (“IPR”). I
`
`understand that the petition for inter partes review involves U.S. Patent No.
`
`7,772,209 (“the ’209 patent”), Exhibit 1001, which issued from U.S. Patent
`
`Application No. 11/776,329 (the “’329 Application”), filed July 11, 2007. (Ex.
`
`1001 at Front Cover.) The ’209 Patent claims priority to U.S. Patent App. No.
`
`60/215,310 (filed June 30, 2000). The ’209 Patent names Clet Niyikiza as an
`
`inventor. The ’209 Patent issued on August 10, 2010. (Id.)
`
`3.
`
`In preparing this Declaration, I have reviewed the ’209 Patent and
`
`considered each of the documents cited herein, in light of general knowledge in the
`
`art as of June 30, 1999. In formulating my opinions, I have relied upon my
`
`experience, education and knowledge in the relevant art. In formulating my
`
`opinions, I have considered the viewpoint of a person of ordinary skill in the art
`
`prior to June 30, 1999.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`4.
`
`I am a Clinical Research Professor in the Department of Radiation
`
`NEPTUNE GENERICS 1024 - 00002
`
`Teva-Fresenius
`Exhibit 1040-00010
`
`
`
`Medicine at The Knight Cancer Institute at the Oregon Health and Sciences
`
`University, Portland; a Professor of Pediatrics at The University of Texas Medical
`
`School at Houston; and a Senior Advisor for the Children’s Oncology Group
`
`Adolescent and Young Adult Committee.
`
`5. My teaching responsibilities are primarily based in adolescent and
`
`young adult oncology.
`
`6.
`
`I received an undergraduate degree (B.S.) (1965) in Life Sciences
`
`from the Massachusetts Institute of Technology, Cambridge, Massachusetts, and a
`
`medical degree (M.D.) (1969) from the University of Rochester School of
`
`Medicine and Dentistry, Rochester, New York.
`
`7.
`
`After medical school, I completed my internship (1970) and residency
`
`(1971) in medicine/pediatrics and pediatrics at the University of Washington and
`
`Children’s Hospital and Medical Center, Seattle, Washington.
`
`8.
`
`Following residency, I completed fellowships in pediatric oncology at
`
`the National Cancer Institute, Bethesda, Maryland (1974), Seattle Children’s
`
`Hospital and the University of Washington, Seattle, Washington (1975).
`
`9.
`
`I received Board Certification in Pediatrics and Pediatric
`
`Hematology/Oncology from the National Board of Medical Examiners (1970),
`
`American Board of Pediatrics (1975), and the American Board of Pediatrics
`
`(1976).
`
`NEPTUNE GENERICS 1024 - 00003
`
`Teva-Fresenius
`Exhibit 1040-00011
`
`
`
`10.
`
`I served as a Lieutenant Commander in the United States Public
`
`Health Services, and as a Clinical Associate at the National Cancer Institute, NIH,
`
`Bethesda, Maryland (1971-1974).
`
`11.
`
`I am a Fellow of the American Board of Pediatrics and the Royal
`
`College of Physicians (Glasgow).
`
`12.
`
`I am a member of multiple regional, national, and international
`
`organizations relating to pediatric, medical, and adolescent/young adult oncology.
`
`13.
`
`I have authored more than 250 peer-reviewed articles and over 60
`
`book chapters on pediatric oncology, medical oncology, adolescent/young adult
`
`oncology, and neuro-oncology, including articles and book chapters on the same
`
`topics.
`
`14.
`
`I am an Editor of the 8 books, monographs and special issues of
`
`oncology journals. The most important book is Cancer in Adolescents and Young
`
`Adults (Springer Verlag Publishers, 2007) that has 73 authors from 9 countries on
`
`4 continents, 534 pages, 199 figures, and 90 tables. A 2nd edition that will nearly
`
`double the contents is in preparation.
`
`15.
`
`I have prescribed and administered a wide variety of intravenous,
`
`intramuscular, subcutaneous and intrathecal medications, including antifolates.
`
`16.
`
`I consider myself to be an expert in the fields of pediatric oncology,
`
`adolescent/young adult oncology, neuro-oncology and cancer screening.
`
`NEPTUNE GENERICS 1024 - 00004
`
`Teva-Fresenius
`Exhibit 1040-00012
`
`
`
`17.
`
`I am being compensated at a rate of $300/hour.
`
`18. Additional details of my education and experience are listed in my
`
`curriculum vitae, a copy of which is attached as Attachment 1 (Ex. 1009).
`
`III. LIST OF DOCUMENTS CONSIDERED IN FORMULATING
`OPINION
`
`19.
`
`In formulating my opinion, I have considered the following
`
`documents: (a) the ’209 Patent (Ex. 1001), (b) portions of the ’209 Patent
`
`prosecution file history (Ex. 1002), and (c) the prior art relevant to the Petition –
`
`(1) Allen et al., “Diagnosis of Cobalamin Deficiency I: Usefulness of Serum
`
`Methylmalonic Acid and Total Homocysteine Concentrations.” American Journal
`
`of Hematology, 34, 1990, 90-98 (“Allen”) (Ex. 1017); (2) Refsum H & Ueland
`
`PM, “Clinical significance of pharmacological modulation of homocysteine
`
`metabolism.” Trends in Pharmacol. Sci., Vol. 11, No. 10, 1990, pp. 411-416
`
`(“Refsum”) (Ex. 1012); (3) Morgan et al., “The Effect of Folic Acid
`
`Supplementation on the Toxicity of Low-Dose Methotrexate in Patients with
`
`Rheumatoid Arthritis.” Arthritis and Rheumatism, Vol. 33, No. 1, January 1990,
`
`pp. 9-18 (“Morgan”) (Ex. 1023); (4) European Patent Application No. 0,595,005
`
`A1 (“EP 005”) (Ex. 1010); (5) Zervos et al., “Functional folate status as a
`
`prognostic indicator of toxicity in clinical trials of the multitargeted antifolate
`
`LY231514.” Proceedings of ASCO, Vol. 16, 1997, pg. 256a (“Zervos”) (Ex.
`
`1016); (6) Brönstrup et al., “Effects of folic acid and combinations of folic acid
`
`NEPTUNE GENERICS 1024 - 00005
`
`Teva-Fresenius
`Exhibit 1040-00013
`
`
`
`and vitamin B-12 on plasma homocysteine concentrations in healthy, young
`
`women.” Am. J. Clin. Nutr. Vol. 68, 1998, 1104-10 (“Bronstrup”) (Ex. 1019); (7)
`
`Calvert AH & Walling JM, “Clinical studies with MTA.” British Journal of Cancer
`
`(1998) 78 (Suppl. 3), 35-40 (“Clavert 1998”) (Ex. 1013); (8) Hammond et al., “A
`
`Phase I and pharmacokinetic (PK) study of the multitargeted antifolate (MTA,
`
`LY231514) with folic acid (FA).” Annals of Oncology, Vol. 9, Suppl. 4, 1998,
`
`Abstract 620P, pg. 129 (“Hammond”) (Ex. 1022); (9) Niyikiza et al., “MTA
`
`(LY231514): Relationship of vitamin metabolite profile, drug exposure, and other
`
`patient characteristics to toxicity.” Annals of Oncology, Vol. 9, Suppl. 4, 1998,
`
`Abstract 609P, pg. 126 (“Niyikiza”) (Ex. 1008); (10) Thödtmann et al., “Phase I
`
`study of different sequences of MTA (LY231514) in combination with cisplatin in
`
`patients with solid tumours.” Annals of Oncology, Vol. 9, Suppl. 4, 1998, Abstract
`
`618P, pg. 129 (“Thodtmann”) (Ex. 1021); (11) Calvert H, “An Overview of Folate
`
`Metabolism: Features Relevant to the Action and Toxicities of Antifolate
`
`Anticancer Agents,” Seminars in Oncology, Vol. 26, No. 2, Suppl 6 (April), 1999,
`
`pp. 3-10 (“Calvert 1999”) (Ex. 1014); (12) O’Dwyer et al., “Overview of Phase II
`
`Trials of MTA in Solid Tumors.” Seminars in Oncology, Vol. 26, No. 2, Suppl 6
`
`(April), 1999, pp. 99-104 (“O’Dwyer”) (Ex. 1015); (13) Carrasco et al., “Acute
`
`megaloblastic anemia: homocysteine levels are useful for diagnosis and follow-
`
`up.” Haematologica, Vol. 84(8), August 1999, 767-768 (“Carrasco”) (Ex. 1020);
`
`NEPTUNE GENERICS 1024 - 00006
`
`Teva-Fresenius
`Exhibit 1040-00014
`
`
`
`(14) Rusthoven et al., “Multitargeted Antifolate LY231514 as First-Line
`
`Chemotherapy for Patients with Advanced Non-Small-Cell Lung Cancer: A Phase
`
`II Study.” Journal of Clinical Oncology, Vol. 17, No. 4, (April 1999), pp. 1194-
`
`1199 (“Rusthoven”) (Ex. 1011).
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`
`20.
`
`I understand that a person of ordinary skill in the art (“POSA”) is a
`
`hypothetical person presumed to be aware of all pertinent art, understands
`
`conventional wisdom in the art, and is a person of ordinary creativity. In this case,
`
`a medical doctor with an M.D. degree who has significant experience in treating
`
`cancer patients, and a significant understanding of antineoplastic agents, including
`
`antifolates and their efficacies, safety, adverse effects, etc., is a POSA.
`
`21. A POSA may work as part of a multi-disciplinary team and draw upon
`
`not only his or her own skills, but also take advantage of certain specialized skills
`
`of others on the team, to solve a given problem. For example, an expert in
`
`nutrition, an expert in hematology, a basic scientist with expertise in biochemistry,
`
`and a clinician may be part of the team.
`
`V.
`
`THE ’209 PATENT SPECIFICATION
`
`22. This declaration is being submitted together with a petition for inter
`
`partes review of Claims 1-22 of the ’209 Patent.
`
`23.
`
`I have considered the ’209 Patent and portions of file history of the
`
`NEPTUNE GENERICS 1024 - 00007
`
`Teva-Fresenius
`Exhibit 1040-00015
`
`
`
`’209 Patent in light of the general knowledge in the art as of the earliest priority
`
`date of the ’209 Patent—June 30, 1999.
`
`24. The ’209 Patent is titled “Antifolate Combination Therapies,” and
`
`describes and claims “a method of administering an antifolate to a mammal in need
`
`thereof, comprising administering an effective amount of said antifolate in
`
`combination with a methylmalonic acid lowering agent and a FBP [folate binding
`
`protein] binding agent.” (Ex. 1001 at 3:1-5.) The ’209 Patent states that folic acid
`
`is the preferred FBP binding agent, and vitamin B12 is a preferred methylmalonic
`
`acid lowering agent. (Id. at 3:5-6, 4:47-50.)
`
`25. The patent states that antifolates are one of the most thoroughly
`
`studied classes of antineoplastic agents, with a long history, and aminopterin was
`
`the first antifolate that demonstrated clinical activity approximately 50 years ago.
`
`(Id. at 1:19-21.) Shortly thereafter, methotrexate was developed as an anticancer
`
`drug, and today methotrexate is used as a standard chemotherapy drug for several
`
`malignancies, including lymphoblastic leukemia, lymphoma, osteosarcoma, breast
`
`cancer, and head and neck cancer. (See, e.g., id. at 1:22-25.)
`
`26. The patent describes that “[a]ntifolates inhibit one or several key
`
`folate-requiring enzymes of the thymidine and purine biosynthetic pathways, in
`
`particular, thymidylate synthase (TS), dihydrofolate reductase (DHFR), and
`
`glycinamide ribonucleotide formyltransferase (GARFT), by competing with
`
`NEPTUNE GENERICS 1024 - 00008
`
`Teva-Fresenius
`Exhibit 1040-00016
`
`
`
`reduced folates for binding sites of these enzymes.” (Id. at 1:36-41.)
`
`27. The patent states that several antifolate drugs were in development,
`
`and pemetrexed disodium (Alimta®, Eli Lilly and Company, Indianapolis, Ind.)
`
`demonstrated inhibition at several key folate-requiring enzymes such as TS,
`
`DHFR, and GARFT. (Id. at 1:48-49; 1:58-61.)
`
`28. The major limitation of administering antifolates to patients is its
`
`adverse effects on organ and organ system function and of “life-threatening
`
`toxicity.” (Id. at 1:11-12.) For example, “antifolates as a class are associated with
`
`sporadic severe my[e]losuppression with gastrointestinal toxicity which, though
`
`infrequent, carries a high risk of mortality.” (Id. at 1:65-67.)
`
`29. The patent states that increased homocysteine levels have been known
`
`to increase the risk of severe antifolate toxicity in patients, and that folic acid was
`
`known to lower antifolate-induced homocysteine levels. (Id. at 2:14-17, 24-26.)
`
`30.
`
`It further states that antifolate increases methylmalonic acid levels,
`
`which cause toxicity, and the treatment with vitamin B12 reduces such antifolate-
`
`associated toxicity by lowering methylmalonic acid levels. (Id. at 2:41-46.)
`
`31. The patent also states that it was known that folic acid in combination
`
`with vitamin B12 was administered to treat and prevent cardiovascular disease. (Id.
`
`at 50-52.) And, the combination of folic acid and a methylmalonic acid lowering
`
`agent synergistically reduces antifolate toxicity. (Id. at 2:47-50.)
`
`NEPTUNE GENERICS 1024 - 00009
`
`Teva-Fresenius
`Exhibit 1040-00017
`
`
`
`32. The ’209 Patent’s alleged invention was purportedly conceived “to
`
`lower cytotoxic activity” associated with antifolate treatment. (Id. at 2:29-37.)
`
`33. The ’209 Patent mainly describes: (1) administration of pemetrexed
`
`disodium to a patient in combination with an effective amount of folic acid and an
`
`effective amount of a methylmalonic acid lowering agent, such as vitamin B12; (2)
`
`pretreatment with folic acid prior to pemetrexed disodium treatment; (3)
`
`pretreatment with folic acid and vitamin B12 prior to pemetrexed disodium
`
`treatment; (4) repetition of vitamin B12 administration; and (5) administration of
`
`cisplatin in combination with pemetrexed disodium to the patient. (Ex. 1001 at
`
`10:56-12:29.)
`
`34. The patent acknowledges that a physician determines the amount of
`
`methylmalonic acid lowering agent to be administered based on “the relevant
`
`circumstances, including the condition to be treated, the chosen route of
`
`administration, the actual agent administered, the age, weight, and response of the
`
`individual patient, and the severity of the patient’s symptoms.” (Id. at 5:37-50;
`
`6:41-52.)
`
`VI. THE ’209 PATENT CLAIMS
`
`A. The Language of the Claims
`35. Claim 1, one of two independent claims in the ’209 Patent, recites:
`
`A method for administering pemetrexed disodium to a patient in need
`thereof comprising administering an effective amount of folic acid and an
`
`NEPTUNE GENERICS 1024 - 00010
`
`Teva-Fresenius
`Exhibit 1040-00018
`
`
`
`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
`
`acid lowering agent is vitamin B12.” (Id. at 10:66-67.)
`
`37. Claim 3 depends from Claim 2, and recites that “the vitamin B12 is
`
`administered as an intramuscular injection of about 500 µg to about 1500 µg.” (Id.
`
`at 11:1-3.)
`
`38. Claim 4 depends from Claim 2, and recites that the vitamin B12 is
`
`administered as an intramuscular injection of about 1000 µg. (Id. at 11:4-5.)
`
`39. Claim 5 depends from Claims 2, 3, and 4, and recites that “the
`
`vitamin B12 administration is repeated about every 6 to about every 12 weeks
`
`following the administration of vitamin B12 until the administration of the
`
`pemetrexed disodium is discontinued.” (Id. at 11:6-9.)
`
`40. Claim 6 depends from Claim 5, and recites that “the folic acid is
`
`administered 1 to 3 weeks prior to the first administration of the pemetrexed
`
`disodium.” (Id. at 11:10-12.)
`
`41. Claim 7 depends from Claim 5, and recites that “the folic acid is
`
`NEPTUNE GENERICS 1024 - 00011
`
`Teva-Fresenius
`Exhibit 1040-00019
`
`
`
`administered from about 1 to about 24 hours prior to administration of the
`
`pemetrexed disodium.” (Id. at 11:13-15.)
`
`42. Claim 8 depends from Claims 1-4, and recites that “between 0.3 mg
`
`to about 5 mg of folic acid is administered orally.” (Id. at 11:16-18.)
`
`43. Claim 9 depends from Claim 8, and recites that “about 350 µg to
`
`about 1000 µg of folic acid is administered.” (Id. at 11:19-20.)
`
`44. Claim 10 depends from Claim 9, and recites that “350 µg to 600 µg
`
`of folic acid is administered.” (Id. at 11:21-22.)
`
`45.
`
` Claim 11 depends from Claim 1, and recites “the administration of
`
`cisplatin to the patient.” (Id. at 11:23-24.)
`
`46. Claim 12, the second of two independent claims in the ’209 Patent,
`
`recites:
`
`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.)
`
`47. Claim 13 depends from Claim 12, and recites “the administration of
`
`cisplatin to the patient.” (Id. at 12:5-6.)
`
`NEPTUNE GENERICS 1024 - 00012
`
`Teva-Fresenius
`Exhibit 1040-00020
`
`
`
`48. Claim 14 depends from Claim 12, and recites that “vitamin B12 is
`
`administered as an intramuscular injection of about 500 µg to about 1500 µg.” (Id.
`
`at 12:7-9.)
`
`49. Claim 15 depends from Claim 14, and recites that “vitamin B12 is
`
`administered as an intramuscular injection of about 1000 µg.” (Id. at 12:10-11.)
`
`50. Claim 16 depends from Claim 15, and recites that “between 0.3 mg
`
`to about 5 mg of folic acid is administered orally.” (Id. at 12:12-13.)
`
`51. Claim 17 depends from Claim 16, and recites that “about 350 µg to
`
`about 1000 µg of folic acid is administered.” (Id. at 12:14-15.)
`
`52. Claim 18 depends from Claim 17, and recites that “350 µg to 600 µg
`
`of folic acid is administered.” (Id. at 12:16-17.)
`
`53. Claim 19 depends from Claim 18, and recites that “folic acid is
`
`administered 1 to 3 weeks prior to the first administration of the pemetrexed
`
`disodium.” (Id. at 12:18-20.)
`
`54. Claim 20 depends from Claim 18, and recites that “the folic acid is
`
`administered from about 1 to about 24 hours prior to administration of the
`
`pemetrexed disodium.” (Id. at 12:21-23.)
`
`55. Claim 21 depends from Claims 12, 18, and 19, and recites that “the
`
`vitamin B12 administration is repeated about every 6 to about every 12 weeks
`
`following the administration of vitamin B12 until administration of pemetrexed
`
`NEPTUNE GENERICS 1024 - 00013
`
`Teva-Fresenius
`Exhibit 1040-00021
`
`
`
`disodium is discontinued.” (Id. at 12:24-27.)
`
`56. Claim 22 depends from Claim 21, and recites that “the administration
`
`of cisplatin to the patient.” (Id. at 12:28-29.)
`
`B.
`
`The Meaning of Selected Terms in the Claims
`
`57.
`
`It is my understanding that the claim terms in a patent subject to IPR
`
`must be understood to have their broadest reasonable interpretation in light of the
`
`specification of the patent.
`
`58. The terms in the claims of the ’209 Patent are used in accordance with
`
`their plain and ordinary meaning, as exemplified by the terms presented below.
`
`59.
`
`“Patient”
`
`“Patient” means “a human undergoing medical treatment.” (Ex. 1025 at 9.)
`
`60.
`
`“Methylmalonic acid lowering agent”
`
`“Methylmalonic acid lowering agent” means “vitamin B12 or its derivative
`
`that lowers the concentration of methylmalonic acid in a mammal.” (Ex. 1026 at 2;
`
`Ex. 1001 at 4:47-50.)
`
`61.
`
`“An effective amount of pemetrexed disodium”
`
`“An effective amount of pemetrexed disodium” means “an amount of
`
`pemetrexed disodium that is capable of providing a therapeutic benefit to the
`
`patient in need thereof.” (Ex. 1026 at 2; Ex. 1001 at 3:53-58.)
`
`“An effective amount of folic acid and an effective amount of a
`62.
`methylmalonic acid lowering agent”
`
`NEPTUNE GENERICS 1024 - 00014
`
`Teva-Fresenius
`Exhibit 1040-00022
`
`
`
`
`“An effective amount of folic acid and an effective amount of a
`
`methylmalonic acid lowering agent” mean “amounts of folic acid and a
`
`methylmalonic acid lowering agent that are capable of reducing the prevalence or
`
`severity of one or more toxicities associated with the administration of pemetrexed
`
`disodium.” (Ex. 1026 at 1; Ex. 1001 at 3:53-58.)
`
`63.
`
`“Toxicity”
`
`“Toxicity” means a toxic event associated with the administration of an
`
`antifolate. Such events include, but are not limited to, neutropenia, thrombopenia,
`
`mucositis, liver dysfunction diarrhea, fatigue, anorexia, nausea, vomiting, skin
`
`rash, immunosuppression, infection, diarrhea, anemia and toxic death. (Ex. 1001 at
`
`3:59-67.)
`
`64.
`
`“Antifolate” and “antifolate drug”
`
`“Antifolate” and “antifolate drug” mean “a chemical compound which
`
`inhibits at least one key folate requiring enzyme of the thymidine or purine
`
`biosynthetic pathways, preferably thymidylate synthase (‘TS’), dihydrofolate
`
`reductase (‘DHFR’), or glycinamide ribonucleotide formyltransferase (‘GARFT’),
`
`by competing with reduced folates for binding sites of these enzymes. Preferred
`
`examples of antifolates” include methotrexate, Tomudex® Lometrexol®,
`
`pyrido[2,3-d]pyrimidine derivatives, and “derivatives described by Akimoto in US.
`
`Pat. No. 4,997,838; thymidylate synthase inhibitors as found in EPO application
`
`NEPTUNE GENERICS 1024 - 00015
`
`Teva-Fresenius
`Exhibit 1040-00023
`
`
`
`239,362; and most preferred, Pemetrexed Disodium (ALIMTA), as manufactured
`
`by Eli Lilly & Co.” (Ex. 1001 at 4:28-44.)
`
`VII. THE STATE OF THE ART AS OF JUNE 30, 1999
`
`A. Antifolates
`
`65. By June of 1999, it was well known in the art that antifolates, such as
`
`pemetrexed, had anticancer properties. (Ex. 1013 at 35; Ex. 1008 at 126.)
`
`66. Antifolates, part of a large class of compounds known as
`
`antimetabolites, inhibit cellular reactions by inhibiting folate-dependent enzymes.
`
`(Ex. 1013 at 35.)
`
`67. As cancer cells actively proliferate, they require large quantities of
`
`DNA and RNA. (Id.) Because antifolates interfere with DNA and RNA synthesis
`
`and cause cell death or stasis, antifolates are used as chemotherapeutic drugs to
`
`treat certain types of cancer. (Id.; Ex. 1014 at 3; Ex. 1011 at 1194; Ex. 1008 at 126;
`
`Ex. 1015 at 99.)
`
`68. By June 1999, several antifolates, such as pemetrexed, methotrexate,
`
`aminopterin, Lometrexol®, 5-fluorouracil, and Tomudex®, were used for the
`
`treatment of, among other diseases, cancer, and autoimmune diseases, including
`
`rheumatoid arthritis and inflammatory bowel disease. (Ex. 1001 at 4:28-44; Ex.
`
`1023 at 9.)
`
`69. However, the major limitation of using these antifolates is that they
`
`NEPTUNE GENERICS 1024 - 00016
`
`Teva-Fres
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
