Trials@uspto.gov
`571.272.7822
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` Paper No. 14
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` Entered: June 16, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`ELI LILLY & COMPANY
`Patent Owner.
`____________
`
`Case IPR2016-00318
`Patent 7,772,209 B2
`____________
`
`
`Before MICHAEL P. TIERNEY, JACQUELINE WRIGHT BONILLA, and
`TINA E. HULSE, Administrative Patent Judges.
`
`TIERNEY, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper No. 14
`
` Entered: June 16, 2016
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`ELI LILLY & COMPANY
`Patent Owner.
`____________
`
`Case IPR2016-00318
`Patent 7,772,209 B2
`____________
`
`
`Before MICHAEL P. TIERNEY, JACQUELINE WRIGHT BONILLA, and
`TINA E. HULSE, Administrative Patent Judges.
`
`TIERNEY, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`I.
`
`INTRODUCTION
`
`
`
`Sandoz Inc. (“Petitioner”) filed a Petition requesting an inter partes
`
`review of claims 1–22 of U.S. Patent 7,772,209 B2 (Ex. 1001, “the ’209
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`patent”). Paper 2 (“Pet.”). Patent Owner, Eli Lilly & Company, (“Patent
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`Owner”) timely filed a Preliminary Response (Paper 11, “Prelim. Resp.”) to
`
`the Petition. We have jurisdiction under 35 U.S.C. § 314.
`
`
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`To institute an inter partes review, we must determine that the
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`information presented in the Petition shows “a reasonable likelihood that the
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`petitioner would prevail with respect to at least 1 of the claims challenged in
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`the petition.” 35 U.S.C. § 314(a). For the reasons set forth below, upon
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`considering the Petition and the Preliminary Response, we conclude that the
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`information presented in the Petition establishes a reasonable likelihood that
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`Petitioner will prevail in challenging claims 1–22 of the ’209 patent. We
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`authorize an inter partes review to be instituted as to those claims.
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`
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`Our factual findings and conclusions at this stage of the proceeding are
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`based on the evidentiary record developed thus far. This decision to institute
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`trial is not a final decision as to patentability of claims for which inter partes
`
`review is instituted. Our final decision will be based on the full record
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`developed during trial.
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`
`
`A. Related Proceedings
`
`The ’209 patent is the subject of litigation in the Southern District of
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`Indiana, including Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., et al.,
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`2
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`IPR2016-00318
`Patent 7,772,209 B2
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`Case No. 1:10-cv-1376 and Eli Lilly & Co. v. Sandoz Inc., No. 1:14-cv-
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`2008. Pet. 2–4, Prelim. Resp. 2–3.
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`Additionally, Petitioner notes that the ’209 patent also was challenged
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`in IPR2013-00356 by Accord Healthcare, Inc. Pet. 4.1
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`The ’209 patent has also been challenged in IPR2016-00237 and
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`IPR2016-00240 by Neptune Generics, LLC. Pet. 4–5.
`
`
`
`B. The ’209 Patent
`
`The ’209 patent claims priority benefit of a series of applications, the
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`earliest of which was filed on June 30, 2000. Ex. 1001, 1:2–10.
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`Rapidly-dividing cancer cells generally have a higher folate
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`requirement than normal cells. Declaration of Ron D. Schiff, Ex. 1004,
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`¶ 29. Antifolates are a well-studied class of antineoplastic agents that
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`“inhibit one or several key folate-requiring enzymes of the thymidine and
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`purine biosynthetic pathways.” Ex. 1001, 1:36–41. As antifolates interfere
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`with DNA synthesis, antifolates are used as chemotherapeutic drugs to treat
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`certain types of cancer. Ex. 1004 ¶ 28.
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`A limitation on the use of antifolate drugs is “that the cytotoxic
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`activity and subsequent effectiveness of the antifolates may be associated
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`with substantial toxicity for some patients.” Ex. 1001, 1:62–64.
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`Homocysteine levels have been shown to be a predictor of cytotoxic events
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`related to the use of certain antifolate enzyme inhibitors. Id. at 2:16–26.
`
`The ’209 patent states that folic acid has been shown to lower homocysteine
`
`
`
`1 The Board declined to institute in IPR2013-00356, holding that the petition
`was not filed within the time limit imposed by 35 U.S.C. § 315(b). Accord
`Healthcare, Inc., USA v. Eli Lilly and Co., Case IPR2013-00356, slip op. 4
`(PTAB Oct. 1, 2013) (Paper 13).
`
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`IPR2016-00318
`Patent 7,772,209 B2
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`levels. Id. Additionally, the patent states that it was known in the art to treat
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`and prevent cardiovascular disease with a combination of folic acid and
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`vitamin B12. Id. at 2:50–54.
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`The ’209 patent describes “[a] method of administering an antifolate
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`to a mammal in need thereof.” Ex. 1001, abstract. The method is said to
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`improve the therapeutic utility of antifolate drugs by administering a
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`methylmalonic acid (“MMA”) lowering agent, such as vitamin B12, to the
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`host undergoing treatment. Id. at 2:37–46. The ’209 patent also states that a
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`combination of a MMA lowering agent, such as B12, and folic acid
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`“synergistically reduces the toxic events associated with the administration
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`of antifolate drugs.” Id. at 2:47–50
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`The term antifolate is said to encompass “chemical compounds [that]
`
`inhibit at least one key folate-requiring enzyme of the thymidine or purine
`
`biosynthetic pathways.” Id. at 4:28–34. Pemetrexed disodium is the most
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`preferred antifolate for the ’209 patent. Id. at 4:28–43. Pemetrexed is also
`
`referred to in the art as the “multitargeted antifolate” (“MTA”). Ex. 1004
`
`¶ 35.
`
`
`
`C. Illustrative Claims
`
`The ’209 patent contains twenty-two claims, all of which are
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`challenged by Petitioner. Independent claim 1 is directed to a method for
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`administering pemetrexed disodium to a patient in need thereof, where folic
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`acid and an MMA lowering agent, such as B12, is administered, followed by
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`administering an effective amount of the pemetrexed disodium. Independent
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`claim 12 is written in a Jepson claim format, where the preamble defines the
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`admitted prior art as administering pemetrexed disodium to a patient in need
`
`of a chemotherapeutic treatment. Independent claim 12 further recites
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`IPR2016-00318
`Patent 7,772,209 B2
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`specific dosage amounts of folic acid and vitamin B12 that are administered
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`to the patient prior to the first administration of the pemetrexed disodium.
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`Dependent claim 2 requires the MMA lowering agent of claim 1 to be
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`vitamin B12 and the remaining dependent claims recite various dosages of
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`folic acid and B12, and times for administering folic acid. Certain claims
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`also require the administration of cisplatin to the patient. Claims 1 and 12
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`are illustrative of the challenged claims and are reproduced below:
`
`
`1. A method for administering pemetrexed disodium to a patient
`in need thereof comprising administering an effective amount
`of folic acid and an 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.
`
`12. An
`for administering pemetrexed
`improved method
`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.
`
`
`
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`Patent 7,772,209 B2
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`D. Prior Art Relied Upon
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`In the ground challenging the claims, Petitioner relies on the
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`following prior art:
`
`
`
`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”)
`(Ex. 1007)
`
`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. 1015)
`
`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 I”) (Ex.
`1006)
`
`Worzalla et al., Role of Folic Acid in Modulating the Toxicity and Efficacy of
`the Multitargeted Antifolate, LY231514, Anticancer Research 18:3235-3240
`(1998) (“Worzalla”) (Ex. 1013)
`
`
`
`
`Petitioner also points us to numerous pieces of prior art, including:
`
`
`U.S. Patent No. 5,217,974 (“the ’974 Patent”) (Ex. 1005)
`
`European Patent Application No. 0,595,005 A1 (“EP 005”) (Ex. 1033)
`
`
`Petitioner contends that the challenged claims are unpatentable under
`
`35 U.S.C. § 103 based on the following grounds (Pet. 15–48):
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`Patent 7,772,209 B2
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`References
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`Basis
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`Claims challenged
`
`Calvert in view of Niyikiza I,
`Worzalla, EP 005 and the
`’974 Patent2
`Calvert in view of Niyikiza I,
`Hammond I, EP 005 and the
`’974 Patent
`
`
`
`§ 103
`
`1–22
`
`§ 103
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`1–22
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`E.
`
`Level of Ordinary Skill in the Art
`
`Petitioner’s declarant, Dr. Schiff, testifies that, a person of
`
`ordinary skill in connection with the ’209 patent would have had an
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`M.D. degree and “experience in oncology with knowledge and/or
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`several years of experience regarding the use of antifolates in the
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`treatment of cancer and []qualifications or experience in the field of
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`nutritional sciences.” Ex. 1004 ¶ 13. At this stage of the proceeding,
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`Patent Owner does not dispute this recitation of the level of ordinary
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`skill in the art. We adopt the level of ordinary skill in the art
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`identified by Dr. Schiff, as it is consistent with the prior art of record.
`
`See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (the
`
`prior art itself can reflect the appropriate level of ordinary skill in the
`
`
`
`2 Petitioner states that the claims are obvious over Calvert, Niyikiza I, and
`Worzalla or Hammond I, taking into account the knowledge of a person of
`ordinary skill in the art. Pet. 7. Petitioner cites numerous references as
`demonstrating the knowledge of a person of skill in the art. We exercise our
`discretion and modify Petitioner’s grounds for challenge (Calvert, Niyikiza
`I, and Worzalla or Hammond I) to additionally include two of the references
`cited as showing the knowledge of a person of skill in the art, EP 005 and
`the ’974 Patent. Cf. Genzyme Therapeutic Prods. Ltd. Partnership v.
`Biomarin Pharm. Inc., Nos. 2015-1720, 2015-1721, 2016 WL 3254734 at *6
`(Fed. Cir. June 14, 2016) (stating that “the Board may consider a prior art
`reference to show the state of the art at the time of the invention”).
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`7
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`Patent 7,772,209 B2
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`art).
`
`
`
`
`
`
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`II.
`
`PRIOR LITIGATION
`
`Patent Owner contends that the Petition should be denied because a
`
`district court has already considered and rejected similar arguments in its
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`decision on validity of claims 9, 10, 12, 14, 15, 18, 19, and 21. Prelim.
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`Resp. 1, 5–12, citing Ex. 1003 (“Findings of Fact and Conclusions of Law
`
`Following Bench Trial August 19, 2013”). Patent Owner contends that the
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`prior district court decision currently is pending before the Federal Circuit
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`and will precede any ruling by the Board. Id. at 12–13. Patent Owner
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`argues that the upcoming Federal Circuit decision will be dispositive of the
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`issues raised by Petitioner. Id. at 13–18.
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`
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`We have considered Patent Owner’s contentions but do not find them
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`persuasive on this record. Patent Owner does not contend that Petitioner is
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`barred from raising its specific challenges before this tribunal. Also, the
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`district court decision did not address the patentability of claims 1–8, 11, 13,
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`16, 17, 20 and 22. Ex. 1003. Further, the district court’s analysis relied
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`heavily on the testimony of Patent Owner’s experts, Drs. Chabner and
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`Zeisel. Ex. 1003, 10–16. In contrast, the testimonial evidence presented at
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`this stage of the proceeding is distinct from that in the district court. Pet.
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`2–59. Specifically, Petitioner’s expert, Dr. Schiff, does not appear to have
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`testified in the district court proceeding, and Patent Owner has not submitted
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`testimony in this proceeding from Drs. Chabner and Zeisel.
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`
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`Based upon the facts presented, we are not persuaded that the decision
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`by the Federal Circuit will dispose of the issues raised in the Petition. In re
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`Swanson, 540 F.3d 1368, 1377 (Fed. Cir. 2008) (“[A] finding that a patent is
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`valid operates only on the parties and does not extend from one … case to
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`IPR2016-00318
`Patent 7,772,209 B2
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`the next. A future challenger with new or better information may
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`subsequently raise, and succeed on … invalidity”).
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`
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`
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`III. MERITS ANALYSIS
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`
`
`A.
`
`Claim Interpretation
`
`In an inter partes review, the Board interprets claim terms in an
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`unexpired patent according to the broadest reasonable construction in light
`
`of the specification of the patent in which they appear. 37 C.F.R. § 100(b).
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`Under that standard, and absent any special definitions, we give claim terms
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`their ordinary and customary meaning, as would be understood by one of
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`ordinary skill in the art at the time of the invention. In re Translogic Tech.,
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`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions for
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`claim terms must be set forth with reasonable clarity, deliberateness, and
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`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
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`Petitioner identifies several claim terms (“patient,” “effective amount”
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`and “methylmalonic acid lowering agent”) in the challenged claims and
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`provides definitions for those terms. For example, Petitioner defines the
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`term “patient” as including mammals, given that the ’209 patent
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`specification repeatedly refers to “mammals” and “patients”
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`interchangeably. Pet. 18–23 (citing Ex. 1001, 4:4–27, 6:35–54). Patent
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`Owner does not dispute Petitioner’s definitions for the terms “effective
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`amount” and “methylmalonic acid lowering agent,” but contends that the
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`term “patient” is limited to a human undergoing medical treatment. Prelim.
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`Resp. 21–29.
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`For the reasons provided in detail below, we determine that it is
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`unnecessary to construe explicitly the claim terms for purposes of this
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`Decision. See Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361
`
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`Patent 7,772,209 B2
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`(Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the extent
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`necessary to resolve the controversy.’”) (quoting Vivid Techs., Inc. v. Am.
`
`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`
`
`B.
`
`Section 103 Obviousness Challenges
`
`Petitioner raises two challenges based on 35 U.S.C. § 103. Generally,
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`Petitioner contends that the challenged claims merely require administering
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`a specific antifolate cancer drug, which was known to elevate a patient’s
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`homocysteine levels, with compounds known to decrease homocysteine
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`levels, folic acid and vitamin B12. Pet. 8–11. Based on the current record,
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`we determine that Petitioner has established a reasonable likelihood that it
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`would prevail in showing claims 1–22 are unpatentable as obvious over the
`
`cited art.
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`
`
`1. Background on Obviousness
`
`An invention is not patentable under 35 U.S.C. § 103 if it is obvious.
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007). Under § 103:
`
`the scope and content of the prior art are to be determined;
`differences between the prior art and the claims at issue are to
`be ascertained; and the level of ordinary skill in the pertinent art
`resolved. Against this background, the obviousness or
`nonobviousness of the subject matter is determined.
`
`Graham v. John Deere Co., 383 U.S. 1, 17 (1966). In addressing the
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`findings of fact, “[t]he combination of familiar elements according to known
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`methods is likely to be obvious when it does no more than yield predictable
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`results.” KSR, 550 U.S. at 416. As explained in KSR:
`
`If a person of ordinary skill can implement a predictable
`variation, § 103 likely bars its patentability. For the same
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`IPR2016-00318
`Patent 7,772,209 B2
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`reason, if a technique has been used to improve one device, and
`a person of ordinary skill in the art would recognize that it
`would improve similar devices in the same way, using the
`technique is obvious unless its actual application is beyond his
`or her skill.
`
`Id. at 417. Accordingly, a central question in analyzing obviousness is
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`“whether the improvement is more than the predictable use of prior art
`
`elements according to their established functions.” Id.
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`
`
`2. The Prior Art References
`
`a. Calvert (Ex. 1007)
`
`Calvert provides an overview of folate metabolism and describes
`
`features relevant to the action and toxicities of antifolate cancer agents. Ex.
`
`1007, 3. According to Calvert, the development of cancer therapeutics has
`
`been linked intimately to the study of folic acid metabolism and the action of
`
`antifolate drugs. Id. Calvert depicts the chemical structures of various
`
`antifolates, including methotrexate, lometrexol and MTA. Id. at 6. Folic
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`acid supplementation is said to reduce the toxicity of antifolate drugs. Id. at
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`8. Calvert also discusses, however, how it had been difficult to correlate
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`antifolate-induced toxicity with pretreatment folate levels. Id.
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`Calvert teaches that intracellular homocysteine can be reduced by
`
`converting it to methionine through remethylation by methionine synthase.
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`Id. at 8–9. As depicted below, methionine synthase requires folate (5-
`
`methyltetrahydrofolate) as a methyl donor and vitamin B12 as a cofactor for
`
`the remethylation reaction:
`
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`Id. at 9. Calvert states that an increase in the plasma level of homocysteine
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`occurs when there is a functional deficiency in either B12 or folate. Id.
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`
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`
`
`b. Niyikiza I (Ex. 1006)
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`Niyikiza I states that MTA (pemetrexed) is a multitargeted antifolate
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`with inhibitory activity against multiple enzymes. Ex. 1006, 126, Abstract
`
`609P. Niyikiza I describes treating 139 patients with tumors in a Phase II
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`study with MTA and monitoring the patients for homocysteine,
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`cystathionine and methylmalonic acid (“MMA”) levels. Id. Toxicities
`
`resulting from the MTA treatment were found to be predictable from
`
`pretreatment homocysteine levels. Id. at 127. Niyikiza I states that further
`
`studies are underway in patients with renal impairment or patients who
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`received prior cisplatin. Id.
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`
`
`c. Worzalla (Ex. 1013).
`
`Worzalla states that “[s]everal animal studies have [shown] that folic
`
`acid supplementation in combination with antifolate cancer therapy can
`
`prevent delayed toxicity and enhance the therapeutic potential.” Ex. 1013,
`
`3235. Worzalla describes the role of folic acid in modulating the toxicity of
`
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`and antitumor efficacy of MTA. Id. The lethality of MTA was compared in
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`mice maintained on a standard diet and a low folate diet. Id. Worzalla
`
`reported that the dosage of folic acid ingested for standard diet mice was
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`about 1 to 2 mg/kg/day and 0.001 to 0.008 mg/kg/day for the low folate diet
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`mice. Id. at 3236–27. Table II of Worzalla reported the results of the
`
`treatment and showed that MTA-treated mice fed a standard diet
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`demonstrated 100% tumor inhibition at a dose of 30 mg/kg with 11 of 14
`
`mice tumor-free on day 100 after tumor implantation. Id. Worzalla
`
`concluded that high levels of folate supplementation demonstrated decreased
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`lethality of MTA compared to conventional diet animals. Id. at 3238.
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`Worzalla stated that the combination of MTA and folic acid may provide a
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`mechanism for clinical tumor selectivity. Id. at 3235.
`
`
`
`d. Hammond I (Ex. 1015)
`
`Hammond I is an abstract that describes a phase I clinical study, the
`
`objective of which was to determine if folic acid supplementation allowed
`
`for dose escalation of MTA of greater than 500–600 mg/m2. Ex. 1015. The
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`study involved giving 33 patients 5 mg/day folic acid for 5 days starting 2
`
`days before MTA therapy. Id. The patients were treated with MTA at
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`escalating doses of 600, 700, 800 and 925 mg/m2. Id. Hammond I stated
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`that folic acid supplementation appeared to permit MTA dose escalation by
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`ameliorating toxicity. Id.
`
`
`
`e. EP 005 (Ex. 1033)
`
`EP 005 describes pharmaceutical preparations for lowering blood and
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`tissue levels of homocysteine and counteracting harmful effects associated
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`with homocysteine. Ex. 1033, 2:1–3. Elevated homocysteine levels are
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`highly undesirable and normalization of elevated levels constitutes a
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`therapeutic goal. Id. at 3:7–9.
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`Three pathways are said to exist to control homocysteine including
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`remethylation to methionine, which requires folate and vitamin B12 as a
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`co-factor. Id. at 2:25–30. EP 005 identifies a number of publications that
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`are said to describe the relationship between B12 and folate levels
`
`individually and blood levels of homocysteine. Id. at 3:37–45. EP 005
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`seeks to lower total homocysteine blood levels elevated by any known
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`cause, including drugs that induce elevated homocysteine levels, such as
`
`methotrexate, a well-known antifolate. Id. at 4:43–48.
`
`EP 005 discloses a pharmaceutical preparation comprising vitamin
`
`B6, folate, and vitamin B12 for prophylaxis or treatment of elevated levels
`
`of homocysteine in a patient. Id. at 4:37–42. According to EP 005, for
`
`purposes of controlling blood homocysteine levels, the combination of
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`folate, vitamin B12, and B6 produces advantageous effects and provides an
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`unexpected synergism that goes substantially beyond what would be
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`expected from a simple additive effect of the action of these compounds. Id.
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`at 11:20–25. A suitable daily dosage of the pharmaceutical preparation is
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`described as:
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`Id. at 8:14–51. As represented in the chart above, PL (pyridoxal) is the
`
`
`
`preferred form of vitamin B6. Id. at 6:12–17.
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`
`
`f. The ’974 Patent (Ex. 1005)
`
`The ’974 Patent describes the administration of a folate binding
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`protein binding agent in conjunction with the use of an antifolate. Ex. 1005,
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`abstract, 1:54–58, 2:60–65. The folate binding agent is administered to a
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`mammal prior to treatment with the antifolate. Id. at 6:22–24. A preferred
`
`embodiment involves administering about 1 mg to about 5 mg of folic acid
`
`as the folate binding agent, with the folic acid administered orally about 1 to
`
`24 hours prior to treatment with lometrexol (an antifolate). Id. at 6:37–42.
`
`Multiple doses of folic acid may be made up to weeks before treatment to
`
`ensure that folate binding protein is sufficiently bound. Id. at 6:32–37.
`
`
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`15
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`IPR2016-00318
`Patent 7,772,209 B2
`
`3. Independent Claims 1 and 12
`
`
`
`Generally, Petitioner contends that it was well known in the art
`
`that antifolates, such as MTA, had anticancer properties, and that it
`
`was known that toxicity had limited the administration of antifolates,
`
`such as methotrexate and MTA. Pet. 8–10. Petitioner states that it
`
`was known in the art that MTA has activity in a variety of tumors and
`
`that elevated levels of homocysteine were observed in patients treated
`
`with antifolates, such as MTA. Id. at 10 and 24–25 (citing Niyikiza I,
`
`Ex. 1006, 126–27). Petitioner explains that it was known in the art
`
`that homocysteine could be reduced by folic acid and vitamin B12.
`
`Id. at 10 and 23–24 (citing Calvert, Ex. 1007, 8–9). Additionally,
`
`Petitioner states that one skilled in the art would have understood
`
`from Calvert, Worzalla, Hammond I and Hammond II that it was
`
`desirable to treat patients with MTA and that administering an
`
`effective amount of folic acid would have reduced a patient’s MTA
`
`toxicity. Id. at 10, 25–27.
`
`
`
`Petitioner states that EP 005 teaches that one skilled in the art
`
`can control drug-induced homocysteine levels from any known cause,
`
`including antifolate drug induced levels, by treatment with vitamin
`
`B12. Id. at 32. Petitioner relies upon the testimony of Dr. Schiff to
`
`support its contention that pretreating an MTA patient with folic acid
`
`and vitamin B12 was suggested by the prior art, which recognized the
`
`benefit of the combination of folic acid and vitamin B12 for
`
`controlling homocysteine levels in antifolate patients. Pet. 32, 52; Ex.
`
`1004 ¶ 96. Petitioner relies upon the teachings of the ’974 Patent as
`
`confirming that it was known in the art that folic acid pretreatment
`
`16
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`IPR2016-00318
`Patent 7,772,209 B2
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`reduces toxicity without destroying the therapeutic benefits of MTA.
`
`Pet. 40–41, 49 (citing Ex. 1004, 1:47–58, 3:1–22, 5:31–48, 6:51–56
`
`and 10:12–21).
`
`
`
`According to Petitioner, one skilled in the art would have added
`
`vitamin B12 to the folic acid pretreatment regime of Worzalla or
`
`Hammond I to reduce high homocysteine levels linked to MTA
`
`toxicity. Pet. 27–33. Petitioner’s contention is supported by the
`
`testimony of Dr. Schiff, who testifies that it was known in the art that
`
`MTA toxicity was linked to elevated baseline homocysteine levels
`
`and that high levels of homocysteine are caused by deficiencies in
`
`either vitamin B12 and/or folate. Ex. 1004 ¶¶ 66–90.
`
`
`
`Patent Owner chose not to address the merits of the Petition in
`
`its Preliminary Response other than contend that Worzalla’s teachings
`
`are directed to mice whereas the claims are directed to treating
`
`humans. Prelim. Resp. 10, 1 n.1 and 20–29. Additionally, Patent
`
`Owner requests that, should the Board institute as to Hammond I, the
`
`Board should exercise its discretion and deny institution as to
`
`Worzalla as the grounds are redundant. Id. at 29–32.
`
`We have considered Patent Owner’s contention that Worzalla’s
`
`teachings are limited to mice but do not find them persuasive at this
`
`time. We understand Dr. Schiff as testifying that one skilled in the art
`
`would have understood Worzalla’s teachings as having applicability
`
`to humans and that pretreatment of patients, including humans, would
`
`lead to reduced MTA toxicity. Ex. 1004 ¶¶ 24, 53, 65. We credit Dr.
`
`Schiff’s testimony as Worzalla does not suggest that its teachings,
`
`which encompass in vitro treatment of human tumor cell lines and
`
`17
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`IPR2016-00318
`Patent 7,772,209 B2
`
`discuss antitumor activity in phase I and II clinical trials, are limited
`
`to treatment of cancer in mice. Ex. 1013.
`
`Additionally, we determine that Hammond I adds material,
`
`human phase I dose escalation data, which is not disclosed by
`
`Worzalla. We decline to adopt Patent Owner’s suggestion to not
`
`institute trial on Hammond I based on an alleged redundancy with
`
`Worzalla.
`
`Based upon the record presented, we credit Dr. Schiff’s
`
`testimony as follows. On this record we find that Niyikiza I
`
`demonstrates that one of ordinary skill would have understood that
`
`MTA toxicity was linked to elevated baseline homocysteine levels.
`
`Ex. 1004 ¶¶ 66–69. We also find that Worzalla, Hammond I and the
`
`’974 Patent taught one skilled in the art at the time of the invention
`
`that it was recognized that folic acid treatment may reduce the patient
`
`toxicity when administering MTA. Id. ¶¶ 52–65, 93, 97.
`
`Additionally, we are persuaded sufficiently that Calvert and EP 005
`
`would have led one of ordinary skill in the art to understand that
`
`pretreatment with folic acid and vitamin B12 would stimulate
`
`recycling of methionine in the body and control homocysteine levels.
`
`Id. ¶¶ 70–73, 96. We credit Dr. Schiff’s testimony, as it is consistent
`
`with the references of record.
`
`Based upon the record presented, we conclude that Petitioner
`
`has shown a reasonable likelihood of prevailing in its assertion that
`
`independent claims 1 and 12 are unpatentable over Calvert in view of
`
`Niyikiza I, EP 005, the ’974 Patent and Worzalla or Hammond I.
`
`Specifically, Petitioner has established sufficiently that administering
`
`folic acid and vitamin B12 followed by the administration of MTA to
`
`18
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`IPR2016-00318
`Patent 7,772,209 B2
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`a patient in need represents a combination of known treatments, used
`
`for their known purpose (treating cancer patients, controlling
`
`homocysteine levels) to achieve a predictable result (controlling
`
`homocysteine levels in a cancer patient).
`
`
`
`
`
`4. Dependent Claims 2–11, 13–22
`
`
`
`Dependent claims 2–11 and 13–22 generally recite various
`
`dosages of folic acid and B12, as well as times for administering folic
`
`acid. Certain dependent claims require the administration of cisplatin
`
`to the patient. For example, dependent claim 13 further requires the
`
`administration of cisplatin, and dependent claim 14 requires vitamin
`
`B12 be administered as an intramuscular injection of about 500 μg to
`
`about 1500 μg.
`
`Petitioner contends that the dependent claims merely add
`
`limitations already known in the field and would have been obvious to
`
`one of ordinary skill in the art. Pet. 51–57. Similarly, Petitioner
`
`contends that a person of ordinary skill in the art would have been
`
`aware that cisplatin was a chemotherapy drug frequently used to treat
`
`non-small cell lung cancer in combination with other agents. Id. at
`
`57. Petitioner states that the combination of MTA and cisplatin
`
`represents the combined use of known treatment regimes, for their
`
`known purpose (treating cancer), to achieve a predictable result
`
`(antitumor activity while reducing severity and/or prevalence of MTA
`
`toxicity). Id. at 58. As mentioned above, Patent Owner chose not to
`
`address the merits of the Petition in its Preliminary Response. Paper
`
`10, 1 n.1.
`
`19
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`IPR2016-00318
`Patent 7,772,209 B2
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`
`
`Petitioner’s contentions are supported by the testimony of Dr.
`
`Schiff and are consistent with the evidence of record. For example,
`
`Dr. Schiff cites EP 005 for its teaching that 7.5–50 micrograms/d/kg
`
`of body weight folic acid and 105–5250 microgram/d/kg body weight
`
`vitamin B12 were preferred daily dosage amounts and that they could
`
`be administered via infusion or intramuscular injection. Ex. 1024
`
`¶¶ 96, 107. Similarly, the ’974 Patent describes pretreatment from
`
`about 1 to 24 hours prior to administration of the antifolate. Pet.
`
`53–54 (citing Ex. 1005, 6:22–48).
`
`Based on the record presented, Petitioner has shown a
`
`reasonable likelihood of prevailing in its assertion that dependent
`
`claims 2–11 and 13–22 are unpatentable. Specifically, Petitioner has
`
`established sufficiently that administering folic acid and vitamin B12
`
`in the specified ranges followed by the administration of MTA, alone
`
`or with cisplatin, to a patient in need represents a combination of
`
`known treatments using known ranges, used for their known purpose
`
`(treating cancer patients, controlling homocysteine levels) to achieve a
`
`predictable result (controlling homocysteine levels in a cancer
`
`patient). Ex. 1004 ¶¶ 91–119.
`
`
`
`20
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`IPR2016-00318
`Patent 7,772,209 B2
`
`IV. CONCLUSION
`
`For the foregoing reasons, we determine that the information
`
`presented in the Petition, notwithstanding the Preliminary Response,
`
`establishes that there is a reasonable likelihood that Petitioner would prevail
`
`in demonstrating unpatentability of claims 1–22. The Board has not yet
`
`made a final determination of the patentability of any of claims 1–22 of the
`
`’209 patent.
`
`
`
`V. ORDER
`
`Accordingly, it is
`
`ORDERED that pursuant to 35 U.S.C. § 314, an inter partes review is
`
`hereby instituted as to claims 1–22 of the ’209 patent on the following
`
`grounds:
`
`References
`
`Basis
`
`Claims challenged
`
`Calvert in view of Niyikiza I,
`Worzalla, EP 005 and the
`’974 Patent
`Calvert in view of Niyikiza I,
`Hammond I, EP 005 and the
`’974 Patent
`
`
`
`§ 103
`
`1–22
`
`§ 103
`
`1–22
`
`FURTHER ORDERED that pursuant to 35 U.S.C. § 314(c) and 37
`
`C.F.R. § 42.4, notice is hereby given of the institution of a trial commencing
`
`on the entry date of this decision.
`
`
`
`
`
`
`
`21
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`IPR2016-00318
`Patent 7,772,209 B2
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`PETITIONER:
`
`Ralph Gabric
`rgabric@brinksgilson.com
`
`Bryan Richardson
`brichardson@brinksgilson.com
`
`
`
`PATENT OWNER:
`
`Dov Grossman
`dgrossman@wc.com
`
`David Krinsky
`dkrinsky@wc.com
`
`James Leeds
`leeds_james@lilly.com
`
`
`
`
`22
`
`
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