`571.272.7822
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` Paper No. 9
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` Entered: October 6, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`TEVA PHARMACEUTICALS USA, INC.
`and FRESENIUS KABI USA, LLC,
`Petitioner,
`
`v.
`
`ELI LILLY & COMPANY
`Patent Owner.
`____________
`
`Case IPR2016-01340
`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 and Grant of Motion for Joinder
`37 C.F.R. § 42.108; 37 C.F.R. § 42.122(b)
`
`
`
`
`
`IPR2016-01340
`Patent 7,772,209 B2
`
`
`INTRODUCTION
`I.
`Teva Pharmaceuticals USA, Inc. and Fresenius Kabi USA, LLC
`
`(collectively, “Petitioner” or “Teva”), filed a Petition requesting an inter
`partes review of claims 1–22 of U.S. Patent 7,772,209 B2 (Ex. 1001, “the
`’209 patent”). Paper 2 (“Pet.”). Concurrent with the filing of the Petition,
`Petitioner filed a Motion for Joinder seeking to join the current proceeding
`to IPR2016-00318.1 Motion for Joinder, Paper 3. Patent Owner and
`Petitioner filed a Joint Notice of Stipulation Concerning Joinder that states,
`among other things, that Patent Owner waives its right to file a Preliminary
`Response to the Petition. Paper 8. We have jurisdiction under 35 U.S.C.
`§ 314.
`To institute an inter partes review, we must determine that the
`
`information presented in the Petition shows “a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” 35 U.S.C. § 314(a). For the reasons set forth below, upon
`considering the Petition, we conclude that the information presented in the
`Petition establishes a reasonable likelihood that Petitioner will prevail in
`challenging claims 1–22 of the ’209 patent. We authorize an inter partes
`review to be instituted as to those claims. Our Decision to Institute in this
`proceeding is consistent with our institution of inter partes review in
`IPR2016-00318. IPR2016-00318, Paper 14 (“’318 Inst. Dec.”).
`
`Additionally, all parties have stipulated that, subject to our approval,
`Teva shall join the proceeding with Sandoz designated as Lead Petitioner
`and that Teva will act as a silent understudy and will not file any papers or
`
`1 Sandoz Inc. (“Sandoz”) v. Eli Lilly & Company (“Patent Owner”),
`IPR2016-00318.
`
`2
`
`
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`
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`IPR2016-01340
`Patent 7,772,209 B2
`
`exhibits in the Joined Proceeding, except pro hac vice motions and
`administrative filings. Paper 8, 3. For the reasons provided below, we grant
`Teva’s Motion for Joinder and exercise our discretion to join Teva and the
`present proceeding to the IPR2016-00318 proceeding.
`
`Our factual findings and conclusions at this stage of the proceeding are
`based on the evidentiary record developed thus far. This decision to institute
`trial is not a final decision as to the patentability of claims for which inter
`partes review is instituted. Our final decision will be based on the full
`record developed during trial.
`
`
`A. Related Proceedings
`The ’209 patent is the subject of litigation in the Southern District of
`Indiana, including Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., Case
`No. 1:10-cv-1376. Pet. 4–5.
`The ’209 patent also has been challenged in the following instituted
`inter partes reviews IPR2016-00237 and IPR2016-00240 by Neptune
`Generics, LLC, and in IPR2016-00318 by Sandoz. Several parties,
`including Petitioner, seek to join the instituted reviews. Specifically, in
`addition to the current case, IPR2016-01393 (Wockhardt) and IPR2016-
`01429 (Apotex et al.) seek to join IPR2016-00318.2 Also, IPR2016-01190
`(Apotex), IPR2016-01335 (Wockhardt) and IPR2016-01341 (Teva) seek to
`join IPR2016-00237.3 Additionally, IPR2016-01191 (Apotex), IPR2016-
`
`
`2 Apotex et al.’s request to join was granted. IPR2016-00318, Paper 37.
`3 Apotex’s request to join was granted. IPR2016-00237, Paper 31.
`3
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`IPR2016-01340
`Patent 7,772,209 B2
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`01337 (Wockhardt) and IPR2016-01343 (Teva) seek to join IPR2016-
`00240.4
`
`
`B. The ’209 Patent
`The ’209 patent claims priority benefit of a series of applications, the
`earliest of which was filed on June 30, 2000. Ex. 1001, 1:2–10.
`Rapidly-dividing cancer cells generally have a higher folate
`requirement than normal cells. Declaration of Ron D. Schiff, Ex. 1004 ¶ 29.
`Antifolates are a well-studied class of antineoplastic agents that “inhibit one
`or several key folate-requiring enzymes of the thymidine and purine
`biosynthetic pathways.” Ex. 1001, 1:19–20, 1:36–41. As antifolates
`interfere with DNA synthesis, antifolates are used as chemotherapeutic
`drugs to treat certain types of cancer. Ex. 1004 ¶ 28.
`A limitation on the use of antifolate drugs is “that the cytotoxic
`activity and subsequent effectiveness of antifolates may be associated with
`substantial toxicity for some patients.” Ex. 1001, 1:62–64. Homocysteine
`levels have been shown to be a predictor of cytotoxic events 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 levels. Id.
`Additionally, the patent states that it was known in the art to treat and
`prevent cardiovascular disease with a combination of folic acid and vitamin
`B12. Id. at 2:50–54.
`The ’209 patent describes “[a] method of administering an antifolate
`to a mammal in need thereof.” Ex. 1001, abstract. The method is said to
`
`
`4 Apotex’s request to join was granted. IPR2016-00240, Paper 33.
`4
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`IPR2016-01340
`Patent 7,772,209 B2
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`improve the therapeutic utility of antifolate drugs by administering a
`methylmalonic acid (“MMA”) lowering agent, such as vitamin B12, to the
`host undergoing treatment. Id. at 2:37–46. The ’209 patent also states that a
`combination of a MMA lowering agent, such as B12, and folic acid
`“synergistically reduces the toxic events associated with the administration
`of antifolate drugs.” Id. at 2:47–50
`The term antifolate is said to encompass “chemical compound[s]
`[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 preferred antifolate for the ’209 patent. Id. at 4:28–43. Pemetrexed is
`also referred to in the art as a “multitargeted antifolate” (“MTA”). Ex. 1004
`¶ 35.
`
`
`C. Illustrative Claims
`The ’209 patent contains twenty-two claims, all of which are
`challenged by Petitioner. Independent claim 1 is directed to a method for
`administering pemetrexed disodium to a patient in need thereof, where folic
`acid and a MMA lowering agent, such as B12, is administered, followed by
`administering an effective amount of the pemetrexed disodium. Independent
`claim 12 is written in a Jepson claim format, where the preamble defines the
`admitted prior art as administering pemetrexed disodium to a patient in need
`of a chemotherapeutic treatment. Independent claim 12 further recites
`specific dosage amounts of folic acid and vitamin B12 that are administered
`to the patient prior to the first administration of the pemetrexed disodium.
`Dependent claim 2 requires the MMA lowering agent of claim 1 to be
`vitamin B12 and the remaining dependent claims recite various dosages of
`
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`IPR2016-01340
`Patent 7,772,209 B2
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`folic acid and B12, and times for administering folic acid. Certain claims
`also require the administration of cisplatin to the patient.
`Claims 1 and 12 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.
`
`
`D. Prior Art Relied Upon
`
`In the grounds challenging the claims, Petitioner relies on the
`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)
`
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`6
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`IPR2016-01340
`Patent 7,772,209 B2
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`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 I”) (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. 8):
`References
`Basis
`Claims challenged
`
`Calvert in view of Niyikiza I,
`Worzalla, EP 005 and the
`’974 Patent5
`
`§ 103
`
`1–22
`
`
`5 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. 8. 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
`7
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`IPR2016-01340
`Patent 7,772,209 B2
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`Calvert in view of Niyikiza I,
`Hammond I, EP 005 and the
`’974 Patent
`
`
`
`§ 103
`
`1–22
`
`II. ANALYSIS
`
`A.
`Claim Interpretation
`Petitioner identifies several claim terms in the challenged claims and
`provides definitions for those terms. Pet. 19–23. Patent Owner did not take
`a position on claim construction at this time.
`We determine that it is unnecessary to construe explicitly the claim
`terms for purposes of this Decision. See Wellman, Inc. v. Eastman Chem.
`Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms need only be
`construed ‘to the extent necessary to resolve the controversy.’” (quoting
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999))).
`
`
`Section 103 Obviousness Challenge
`B.
`Petitioner raises two challenges based on 35 U.S.C. § 103. Generally,
`Petitioner contends that the challenged claims merely require administering
`a specific antifolate cancer drug, which was known to elevate a patient’s
`homocysteine levels, with compounds known to decrease homocysteine
`levels, folic acid and vitamin B12. Pet. 9–12.
`
`
`cited as showing the knowledge of a person of skill in the art, EP 005 and
`the ’974 Patent. Cf. Genzyme Therapeutic Prods. Ltd. P’ship v. Biomarin
`Pharm. Inc., Nos. 2015-1720, 2015-1721, 2016 WL 3254734, at *6 (Fed.
`Cir. June 14, 2016) (“[T]he Board may consider a prior art reference to show
`the state of the art at the time of the invention.”).
`8
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`IPR2016-01340
`Patent 7,772,209 B2
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`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. Id.
`at 10–12. 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 14 (citing Niyikiza I, Ex. 1006, 126). Petitioner
`explains that it was known in the art that homocysteine could be
`reduced by folic acid and vitamin B12. Id. at 11 (citing Calvert, Ex.
`1007, 8–9). Additionally, Petitioner states that one skilled in the art
`would have understood from Calvert, Worzalla, and Hammond I 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 11, 26–27.
`
`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 33. Petitioner relies upon the teachings of the ’974 Patent
`as confirming that it was known in the art that folic acid pretreatment
`reduces toxicity without destroying the therapeutic benefits of MTA.
`Id. at 41–42, 50–51 (citing Ex. 1005, 1:47–58, 5:31–48, 6:51–56,
`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. Id. at 28–33. Petitioner’s contention is supported by the
`
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`IPR2016-01340
`Patent 7,772,209 B2
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`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.
`In Sandoz IPR2016-00318, we instituted inter partes review on the
`same grounds, same evidence, and same claims. We incorporate our
`analysis from our institution decision in IPR2016-00318. ’318 Inst. Dec.
`10–20. For the same reasons, we determine that Petitioner has demonstrated
`a reasonable likelihood that it will prevail with respect to its challenge to
`claims 1–22 of the ’209 patent.
`
`C. Motion for Joinder
`Teva seeks to join the present proceeding with IPR2016-00318.
`Paper 3. Teva contends that joinder is appropriate as it will promote the
`efficient determination of patentability of the ’209 patent without prejudice
`to prior Petitioners (Sandoz) or Patent Owner. Id. at 1. Teva states that the
`present Petition raises the same grounds of unpatentability over the same
`prior art as those instituted by the Board in the IPR2016-00318. Id. at 3–5.
`Teva represents that it is willing to agree to consolidated filings with Sandoz
`and that joinder will not affect the pending schedule in IPR2016-00318. Id.
`at 5–7.
`The parties in the present proceeding and IPR2016-00318 filed a Joint
`Notice of Stipulation Concerning Joinder. Paper 8. The Joint Stipulation
`generally provides that Sandoz and Patent Owner do not oppose the joinder
`of the present proceeding with IPR2016-00318. Id. at 2. Patent Owner
`waives its right to file a preliminary response in the present proceeding. Id.
`
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`IPR2016-01340
`Patent 7,772,209 B2
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`at 3. As long as Sandoz is not terminated as a party, Sandoz will be Lead
`Petitioner and will conduct all argument and examination of witnesses for
`that side, and will submit all substantive written submissions for that side.
`Id. The Joint Stipulation further provides that Teva will act as a silent
`understudy. Id. The Joint Stipulation also provides that the presence of
`Joined Petitioners shall not be a basis for alteration of the schedule or time
`allotted for cross-examination, redirect, or re-cross examination of any
`witness. Id. at 4.
`We hold that Petitioner has satisfied the requirements of 35 U.S.C.
`§ 315(c) and we grant Petitioner’s Motion for Joinder. We exercise our
`discretion and join the present inter partes review, IPR2016-01340, to
`IPR2016-00318 subject to the conditions set forth in the Joint Stipulation.
`
`IV. CONCLUSION
`For the foregoing reasons, we determine that the information
`presented in the Petition 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. Additionally, for the foregoing reasons,
`we join the present proceeding with IPR2016-00318 subject to the
`conditions set forth in the Joint Stipulation.
`
`V. ORDER
`Accordingly, it is:
`Ordered that Teva’s Motion for Joinder is granted;
`
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`IPR2016-01340
`Patent 7,772,209 B2
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`Further Ordered that the instant proceeding is instituted, joined with
`IPR2016-00318, and terminated under 37 C.F.R. § 42.72, and all further
`filings in the joined proceeding shall be made only in IPR2016-00318;
`Further Ordered that trial is instituted on the grounds of
`unpatentability on which trial was instituted in IPR2016-00318 and that
`there is no change to the Scheduling Order in IPR2016-00318;
`Further Ordered that the parties shall abide by the Joint Stipulation;
`Further Ordered that the case caption in IPR2016-00318 shall be
`changed to reflect the joinder of Teva as a Petitioner in accordance with the
`attached example; and,
`Further Ordered that a copy of this Decision shall be entered into the
`file of IPR2016-00318.
`
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`12
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`IPR2016-01340
`Patent 7,772,209 B2
`
`For Petitioner SANDOZ:
`Ralph J. Gabric
`rgabric@brinksgilson.com
`Bryan T. Richardson
`brichardson@brinksgilson.com
`Joshua H. James
`jjames@brinksgilson.com
`Laura A. Lydigsen
`llydigsen@brinksgilson.com
`
`For Petitioner TEVA:
`Gary J. Speier
`gspeier@carlsoncaspers.com
`Mark D. Schuman
`MSchuman@carlsoncaspers.com
`Cynthia Lambert Hardman
`chardman@goodwinprocter.com
`
`For Patent Owner:
`Dov P. Grossman
`dgrossman@wc.com
`David M. Krinsky
`dkrinsky@wc.com
`James P. Leeds
`leeds_james@lilly.com
`Adam L. Perlman
`aperlman@wc.com
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`SANDOZ INC.,
`APOTEX INC., APOTEX CORP.,
`EMCURE PHARMACEUTICALS LTD.,
`HERITAGE PHARMA LABS INC.,
`HERITAGE PHARMACEUTICALS INC.,
`GLENMARK PHARMACEUTICALS, INC., USA,
`GLENMARK HOLDING SA,
`GLENMARK PHARMACEUTICALS, LTD.,
`MYLAN LABORATORIES LIMITED,
`TEVA PHARMACEUTICALS USA, INC.
`and FRESENIUS KABI USA, LLC,
`Petitioners,
`
`v.
`
`ELI LILLY & COMPANY
`Patent Owner.
`____________
`
`Case IPR2016-003181
`Patent 7,772,209 B2
`____________
`
`
`1 Cases IPR2016-01340 and IPR2016-01429 have been joined with the
`instant proceeding.
`
`