UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEPTUNE GENERICS, LLC,
`
`APOTEX INC., APOTEX CORP.,
`
`and FRESENIUS KABI USA, LLC,
`
`PETITIONERS,
`
`V.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`Case IPR2016-002371
`
`Patent 7,772,209
`
`PETITIONERS’ AMENDED JOINT NOTICE OF APPEAL
`
`1 IPR2016-01190, IPR2016-01335, and IPR2016-01341 were joined with this
`proceeding.
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEPTUNE GENERICS, LLC,
`
`APOTEX INC., APOTEX CORP.,
`
`and FRESENIUS KABI USA, LLC,
`
`PETITIONERS,
`
`V.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`Case IPR2016-002371
`
`Patent 7,772,209
`
`PETITIONERS’ AMENDED JOINT NOTICE OF APPEAL
`
`1 IPR2016-01190, IPR2016-01335, and IPR2016-01341 were joined with this
`proceeding.
`
`
`
`Office of the General Counsel
`
`Patent and Trademark Office
`
`Madison East
`
`10B20 600 Dulany Street
`Alexandria, VA 22314
`
`Notice is hereby given, pursuant to 37 C.F.R. § 90.2(a), that Petitioners
`
`Neptune Generics, LLC, Apotex, Inc., Apotex Corp., and Fresenius Kabi USA,
`
`LLC (“Petitioners”) jointly appeal under 35 U.S.C. §§ 139, 141 and 142 to the
`
`United States Court of Appeals for the Federal Circuit from the Final Written
`
`Decision entered on October 5, 2017 (Paper No. 84 in IPR2016-002372) (the “Final
`
`Written Decision”), and all underlying orders, decisions, rulings, and opinions. A
`
`copy of the Final Written Decision is attached.
`
`For the limited purpose of providing the Director with the information
`
`requested in 37 CPR. § 90.2(a)(3)(ii), Petitioners anticipate that the issues on
`
`appeal may include the following as well as any underlying findings,
`
`determinations, rulings, decisions, opinions, or other related issues:
`
`0 Whether the Board erred in finding that claims 1-22 of US. Patent
`
`7,772,209 are patentable, and any findings or determinations
`
`2 The same decision was entered in IPR2016-01190 (Paper No. 10) and IPR2016—
`01341 (Paper No. 13). These IPRs were joined with IPR2016-00237 and
`terminated under 37 C.F.R. § 42.72 on September 30, 2016 (IPR2016-01190 at
`Paper No. 10) and October 6, 2016 (IPR2016—01341 at Paper No. 10) with an
`Order that “all further filings in the joined proceeding shall be made only in
`IPR2016—00237” (see, e.g., IPR2016-01190, Paper No. 10 at 10).
`2
`
`
`
`supporting or related to that issue, including the weight the Board
`
`gave to Petitioners’ evidence, as well as all other issues decided
`
`adversely to Petitioners in any orders, decisions, rulings, and opinions.
`
`Copies of this Amended Notice of Appeal are being filed simultaneously
`
`with the Director, the Patent Trial and Appeal Board, and the Clerk of the United
`
`States Court of Appeals for the Federal Circuit.
`
`
`
`Dated: December 6, 2017
`
`Respectfully Submitted,
`
`/Sarah E. Spires/
`Sarah E. Spires (61,501)
`Dr. Parvathi Kota (65,122)
`Paul Skiermont
`
`SKIERMONT DERBY LLP
`
`1601 Elm Street, Suite 4400
`
`Dallas, TX 75201
`23 7Neptune@skiermontderby.com
`P: 214-978-6600/F: 214-978-6601
`
`Mieke Malmberg
`SKIERMONT DERBY LLP
`
`800 Wilshire Blvd, Suite 1450
`
`Los Angeles, CA 90017
`23 7Neptune@skiermontderby.com
`P: 213-788-4500/F: 213—788-4501
`
`Counselfor Neptune Generics, LLC
`
`/Patrick C. Kilgore/
`John D. Polivick (57,926)
`Deanne M. Mazzochi (50,158)
`Patrick C. Kilgore (69,131)
`Rakoczy Molino
`Mazzochi Siwik LLP
`
`6 West Hubbard Street, Suite 500
`
`Chicago, Illinois 60654
`jpolivick@rmmslegal.com
`dmazzochi@rmmslegal.com
`pkilgore@rmmslegal.com
`
`Counselfor Apotex Inc. and
`Apotex Corp.
`
`/C nthia Lambert Hardman]
`1
`Cynthia Lambert Hardman (53,179)
`Michael B. Cottler
`
`Goodwin Procter LLP
`
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`mcottler@goodwinlaw.com
`chardman@goodwinlaw.com
`
`Counselfor Fresenius Kabi USA, LLC
`
`
`
`CERTIFICATE OF FILING
`
`I hereby certify that a true and correct copy of the foregoing “Petitioners’
`
`Amended Joint Notice of Appeal,” was filed electronically through the Patent Trial
`
`and Appeal Board’s E2E on this 6th day of December, 2017.
`
`CERTIFICATE OF FILING
`
`I hereby certify that a true and correct copy of the foregoing “Petitioners’
`
`Amended Joint Notice of Appeal,” was filed electronically by CM/ECF on this 6th
`
`day of December, 2017, with the United States Court of Appeals for the Federal
`
`Circuit.
`
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), I certify that I caused to be served on the
`
`counsel for Patent Owner a true and correct copy of the foregoing “Petitioners’
`
`Joint Notice of Appeal,” on December 6‘“, 2017, by Federal Express to counsel for
`
`Patent Owner at the following addresses of record:
`
`Dov P. Grossman (72,525)
`David M. Krinsky (72,339)
`Adam L. Perlman
`
`WILLIAMS & CONNOLLY LLP
`
`725 Twelfth St. NW
`
`Washington, DC 20005
`dgrossman@wc.com
`dkrinsky@wc.com
`aperlman@wc.com
`Counselfor Patent Owner
`
`James P. Leeds (35,241)
`John C. Demeter (30,167)
`ELI LILLY AND COMPANY
`
`Lilly Corporate Center
`Indianapolis, IN 46285
`leeds_james@lilly.com
`demeter_john_c@lilly.com
`Counselfor Patent Owner
`
`Dated: December 6, 2017
`
`Respectfully Submitted,
`
`/Sarah E. S ircs/
`
`Sarah E. Spires
`
`
`
`EXHIBIT A
`
`
`
`Trials@uspto.gov
`571.272.7822
`
`Paper No. 84
`Entered: October 5, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NEPTUNE GENERICS, LLC,
`APOTEX INC., APOTEX CORP,
`TEVA PHARMACEUTICALS USA, INC.,
`FRESENIUS KABI USA, LLC, and WOCKHARDT BIO AG,
`Petitioner,
`
`V.
`
`ELI LILLY & COMPANY,
`Patent Owner.
`
`Case IPR2016-002371
`
`Patent 7,772,209 B2
`
`Before JACQUELINE WRIGHT BONILLA, MICHAEL P. TIERNEY,
`Vice ChiefAdministrative Patent Judges, and LORA M. GREEN,
`Administrative Patent Judge.
`
`GREEN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`Determining That Claims 1—22 Have Not Been Shown to Be Unpatentable
`35 US. C. § 318(a) and 37 CFR. § 42. 73
`
`1 Cases IPR2016-01190, IPR2016-01335, and IPR2016-01341 have been
`joined with the instant proceeding.
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`'
`
`I.
`
`INTRODUCTION
`
`Neptune Generics, LLC, filed a Petition requesting an inter partes
`
`review of claims 1-22 of US. Patent No. 7,772,209 B2 (Ex. 1001, “the ’209
`
`patent”). Paper 1 (“Pet”). Eli Lilly & Company (“Patent Owner” or
`
`“Lilly”) filed a Preliminary Response to the Petition. Paper 10 (“Prelim
`
`Resp”). We determined that the information presented in the Petition and
`
`the Preliminary Response demonstrated that there was a reasonable
`
`likelihood that Petitioner would prevail in challenging claims 1—22 as
`
`unpatentable under 35 U.S.C. § 103(a). Pursuant to 35 U.S.C. § 314, the
`
`Board instituted trial on June 3, 2016, as to all of the challenged claims of
`
`the ’209 patent. Paper 13 (“Institution Decision” or “Dec. Inst”).
`
`Thereafter, other parties filed three additional Petitions challenging
`
`the same claims based on the same ground of unpatentability over the same
`
`prior art as those instituted by the Board in the instant case, as well as
`
`motions for joinder. Specifically, Apotex Inc. and Apotex Corp. requested
`
`inter partes review of claims 1—22 of the ’209 patent in IPR2016-01190, and
`
`joinder to the instant proceeding. IPR2016-01190, Papers 2 and 3. On
`
`October 6, 2016, the Board instituted inter partes review in that case and
`
`granted joinder. IPR2016-01190, Paper 11. Wockhardt Bio AG also
`
`requested inter partes review of claims 1—22 of the ’209 patent in IPR2016-
`
`01335, as well as joinder to the instant proceeding. IPR2016-01335, Papers
`
`1 and 3. Inter partes review was instituted in that case and joinder granted
`
`on November 18, 2016. IPR2016-01335, Paper 8. Finally, Teva
`
`Pharmaceuticals USA, Inc., and Fresenius Kabi USA, LLC, also requested
`
`inter partes review of claims 1—22 of the ’209 patent in IPR2016-01341, and
`
`joinder to the instant proceeding. IPR2016-01341, Papers 2 and 3. Inter
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`partes review was instituted and joinder granted on October 6, 2016.
`
`IPR2016—01341, Paper 10. We collectively refer to all enjoined Petitioners
`
`in this Final Written Decision as “Petitioner.”
`
`Patent Owner filed a Response (Paper 33, “PO Resp”), Petitioner
`
`filed a Reply (Paper 48), and Patent Owner filed a Sur—reply (Paper 63).
`
`Petitioner filed a Motion to Exclude (Paper 57, “Mot. Exclude”), to which
`
`Patent Owner filed an Opposition (Paper 67, “Opp. Mot. Exclude”), and
`
`Petitioner filed a Reply (Paper 74). Oral hearing was held on March 16,
`
`2017, and a transcript of that hearing has been entered into the record. Paper
`
`80 (“Tr.”).
`
`We have jurisdiction under 35 U.S.C. § 6. Petitioner bears the burden
`
`of proving unpatentability of the challenged claims, and the burden of
`
`persuasion never shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat ’l
`
`Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015). To prevail, Petitioner
`
`must establish facts supporting its challenge by a preponderance of the
`
`evidence. See 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d). This Final Written
`
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`
`Based on the record before us, we conclude that Petitioner has failed
`
`to demonstrate by a preponderance of the evidence that claims 1—22 of the
`
`’209 patent are unpatentable. We also deny Petitioner’s Motion to Exclude.
`
`A.
`
`Related Proceedings
`
`The ’209 patent is the subject of litigation in the US. District Court
`
`for the Southern District of Indiana, including Eli Lilly & Co. v. Teva
`
`Parenteral Medicines, Inc., No. 1:10-cv—1376 (SD. 1nd.) (filed Oct. 29,
`
`2010). Pet. 2—3; Prelim. Resp. 2.
`
`
`
`IPR2016—00237
`
`Patent 7,772,209 B2
`
`The ’209 patent also has been challenged in IPR2016-00240 by
`
`Neptune Generics, LLC, and in IPR2016-00318 by Sandoz Inc. Proceedings
`
`IPR2016-01191, IPR2016-01337, and IPR2016-01343 have beenjoined
`
`with IPR2016-00240, and proceedings IPR2016-01393, IPR2016-01340,
`
`and IPR2016-01429 have been joined with IPR2016-00318.
`
`B.
`
`The ’209 Patent
`
`The ’209 patent issued on August 10, 2010, listing Clet Niyikiza as
`
`the sole inventor. Ex. 1001. The ’209 patent claims priority to a series of
`
`applications, the earliest of which was filed on June 30, 2000. Id. at 1:2—10.
`
`“As cancer cells are actively proliferating, they require large
`
`quantities of DNA and RNA.” Ex. 1025 1| 67. Antifolates are a well-studied
`
`class of antineoplastic agents that inhibit one or several key folate—requiring
`
`enzymes of the thymidinc and purine biosynthctic pathways. Ex. 1001,
`
`1:19—20, 1:36—41. Because antifolates interfere with DNA and RNA
`
`synthesis, antifolates are used as chemotherapeutic drugs to treat certain
`
`types of cancer. Ex. 1025 1167.
`
`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, but that “the use of the combination for the treatment of toxicity
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`associated with the administration of antifolate drugs was unknown
`
`heretofore.” Id. at 2:50—54.
`
`The ’209 patent describes “[a] method of administering an antifolate
`
`to a mammal in need thereof.” Id, Abstract. The method is said to 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 vitamin 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 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
`
`preferred antifolate for the ’209 patent. Id. at 4:28—43. Pemetrexed is also
`
`referred to in the art as the “multitargeted antifolate” (“MTA”).2 Ex. 1022,
`
`129,3 Abstract 620P.
`
`C.
`
`Illustrative Claims
`
`Petitioner challenges claims 1—22 of the ’209 patent. Claims 1 and 12
`
`are independent, 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
`
`2 We use “pemetrexed” and “MTA” interchangeably throughout this
`Decision.
`
`3 We note that, unless otherwise indicated, the page numbers refer to the
`page numbers of the original references, and not to those added by a party.
`
`5
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`administering an effective amount of pemetrexed
`disodium, wherein
`
`the methylmalonic acid lowering agent is selected
`from the group consisting of vitamin B12,
`hydroxycobalamin, cyano-l O—chlorocobalamin,
`aquocobalamin perchlorate, aquo—lO-cobalamin
`perchlorate, azidocobalamin, cobalamin,
`cyanocobalamin, or chlorocobalamin.
`12. 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 ug and about
`1000 pg of folic acid prior to the first administration of
`pemetrexed disodium;
`b) administration of about 500 ug to about 1500 pg of
`vitamin B12, prior to the first administration of
`pemetrexed disodium; and
`
`c) administration of pemetrexed disodium.
`
`Ex. 1001,10:56—65,11:25—12:4.
`
`D.
`
`Prior Litigation
`
`On March 31, 2014, the US. District Court for the Southern District
`
`of Indiana upheld claims 9, 10, 12, 14, 15, 18, 19, and 21 ofthe ’209 patent
`
`as unobvious under the clear and convincing evidence evidentiary standard.
`
`Eli Lilly & Co. v. Teva Parenteral Meds., Inc, No. 1:10-cv-01376-TWP-
`
`DKL, 2014 WL 1350129, at *1 (SD. Ind. Mar. 31, 2014), afl’d, 845 F.3d
`
`1357 (Fed. Cir. 2017). The court summarized the ’209 patent as describing
`
`a method of co-administering folic acid and vitamin B12 with pcmctrcxcd,
`
`which is an antifolate and chemotherapy drug marketed under the trade
`
`name ALIMTA®, to reduce side effects referred to as “toxicities.” Id. at *1—
`
`2. The court concluded that there was not clear and convincing evidence
`
`that the ordinary artisan would have had reason to administer (1) folic acid
`
`6
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`pretreatment with pemetrexed, (2) vitamin B12 pretreatment with
`
`pemetrexed, or (3) each of folic acid and vitamin B12 according to the
`
`claimed doses and schedules. Id. at *6. Additionally, the court found that
`
`secondary considerations—namely, skepticism, failure of others, and
`
`unexpected results—supported the conclusion that the claims at issue were
`
`not obvious. Id. at *14—16.
`
`In making the first fmding—that the administration of folic acid with
`pemetrexed was not obvious—the court discussed Worzalla} 5 Hammond I,6
`
`Rinaldi,7 and the ’974 patent.8 Id. at *6-9. Both Worzalla and Hammond I
`
`reported the results of oncology research involving the administration of
`
`folic acid with pemetrexed—to mice in Worzalla, and to Phase I patients in
`
`Hammond 1. Id. at *6—8. Although both studies indicated a reduction of
`
`toxicity associated with pemetrexed, the court concluded that the ordinary
`
`artisan would not have had the goal of reducing toxicity at the expense of
`
`4 John F. Worzalla et al., Role ofFolic Acid in Modulating the Toxicity and
`Eflicacy of the Multitargeted Antifolate, LY231514, 18 ANTICANCER RES.
`3235 (1998) (Ex. 1005) (“Worzalla”).
`
`5 Note that the exhibit numbers referenced in the footnotes containing the
`citation to reference refer to the reference’s exhibit numbers in the instant
`
`proceeding.
`
`6 L. Hammond et al., A Phase I and Pharmacokinetic (PK) Study ofthe
`Multitargeted Antifolaie (MTA, LY231514) with Folic Acid (FA), 9 ANNALS
`ONCOLOGY 129, Abstract 620P (Supp. 4 1998) (Ex. 1022) (“Hammond I”).
`
`7 DA. Rinaldi et al,, A Phase I Evaluation ofLY231514, A Novel Multi—
`Targeted Antifolate, Administered Every 21 Days, PROC. AM. SOC’Y
`CLINICAL ONCOLOGY, May 18—21, 1996, at 489, Abstract 1559 (Ex. 2022)
`(“Rinaldi”).
`
`8 Grindey et al., US. Patent No. 5,217,974, issued June 8, 1993 (Ex. 1009)
`(“the ’974 patent”).
`
`
`
`IPR2016—00237
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`Patent 7,772,209 B2
`
`either reducing the efficacy of pemetrexed or requiring higher doses of the
`
`drug. Id. at *8. In this regard, Rinaldi published the results of an
`
`unsupplemented Phase I pemetrexed study, and showed better efficacy than
`
`Hammond I’s study. Id. The court also found that, when supplementing
`
`pemetrexed with folic acid, much higher doses of pemetrexed would have
`
`been required, which would have raised other concerns such as kidney
`
`toxicity. Id. at *7—8. Furthermore, the court distinguished the ’974 patent
`
`because it did not mention pemetrexed, but instead specifically considered
`
`folic acid pretreatment with a different drug, lometrexol. Id. at 9.
`
`In making the second finding—that the administration of Vitamin B12
`
`with pemetrexed was not obvious—the court considered Niyikiza9 and
`
`Niyikiza 111° (collectively, the “Niyikiza Abstracts”). Id. at * 10. The
`
`Niyikiza Abstracts showed a correlation between pemetrexed toxicities and
`
`patients’ levels of homocysteine. Id. at *4, *10. As the court explained,
`
`however, elevated homocysteine levels, standing alone, did not indicate a
`
`Vitamin B12 deficiency—instead, both elevated homocysteine and elevated
`
`MMA levels were necessary to establish a vitamin B12 deficiency. Id. at *4.
`
`The court further explained that in the Niyikiza Abstracts, there was no
`
`correlation between toxicity and other measured variables, including MMA,
`
`which suggested at the time that there was no correlation between toxicity
`
`9 C. Niyikiza et al., MTA (LY231514): Relationship of Vitamin Metabolite
`Profile, Drug Exposure, and Other Patient Characteristics To Toxicity, 9
`ANNALS ONCOLOGY 126, Abstract 609P (Supp. 4 1998) (Ex. 1008)
`(“Niyikiza”).
`
`1° C. Niyikiza et al., LY2315I4 (MTA): Relationship of Vitamin Metabolite
`Profile To Toxicity, PROC. AM. Soc’Y CLINICAL ONCOLOGY, May 16—19,
`1998, at 558a, Abstract 2139 (Ex. 2015) (“Niyikiza II”).
`
`8
`
`
`
`IPR2016-00237
`
`Patent 7,772,209 B2
`
`and vitamin B12 levels. Id The court therefore found that the ordinary
`
`artisan would have concluded that vitamin B12 deficiency was not the
`
`problem in pemetrexed toxicity. Id. at * 10.
`
`Also, the court was not persuaded by evidence indicating that vitamin
`
`B12 was routinely added to folic acid pretreatment to prevent “masking,” a
`
`problem in which a vitamin B12 deficiency was misdiagnosed as a folate
`
`deficiency. Id. at *9—10. The court found this evidence to be in the context
`
`of treating rheumatoid arthritis, where vitamin B12’s interference with the
`
`antiproliferative effects of the active drug was less of a concern than in
`
`treating cancer. Id. at * 10. Likewise, the court described other evidence
`
`showing that in patients who were vitamin B12 deficient, folate became
`
`“trapped” in cells, and when patients were later administered vitamin B12,
`
`that administration released the folates from the trap, counteracting the
`
`efficacy of an antifolate drug. Id. at *11.
`
`In making the third fmding—that the claimed doses and schedules
`
`would not have been obvious—the court found no prior art disclosure of the
`
`ranges of folic acid and vitamin B12, as set forth in the claims at issue, for
`
`use with pemetrexed in the treatment of cancer. Id. at * 13. In particular, the
`
`court explained that no prior art references disclosed any amount of vitamin
`
`B12 pretreatment for use with an antifolate in treating cancer. Id
`
`On January 12, 2017, the US. Court of Appeals for the Federal
`
`Circuit affirmed the district court. Eli Lilly & Co. v. Teva Parenteral Meds.,
`
`Inc, 845 F.3d 1357 (Fed. Cir. 2017). Specifically, the Federal Circuit
`
`affirmed the district court’s findings that the ordinary artisan would not have
`
`been motivated to use vitamin B12 pretreatment with pemetrexed, let alone
`
`at the appropriate doses and schedules of vitamin B12 pretreatment. Id. at
`
`
`
`IPR2016—00237
`
`Patent 7,772,209 B2
`
`1373. The Federal Circuit did not reach the issue of whether the prior art
`
`provided a motivation for the use of folic acid pretreatment to counter
`
`pemetrexed toxicity. Id. at 1373—74.
`
`The Federal Circuit summarized the district court’s findings that the
`
`ordinary artisan “would have concluded that vitamin B12 deficiency was not
`
`the problem in pemetrexed toxicity” and “would not have used vitamin B12
`
`supplementation to address antifolate toxicities because of ‘concem[ ] about
`
`.
`
`.
`
`. a reduction of efficacy of the antifolate’ treatment.” Id. at 1373
`
`(alteration in original) (quoting Eli Lilly, 2014 WL 1350129, at *10—11).
`
`Like the district court, the Federal Circuit explained that elevated
`
`homocysteine levels alone did not specifically indicate a vitamin B12
`
`deficiency—instead, MMA levels specifically indicated a vitamin B12
`
`deficiency. Id. at 1373. The Federal Circuit then quoted from Niyikiza II,
`
`that “no correlation between toxicity .
`
`.
`
`. and [MMA levels] was seen.” Id.
`
`(alteration in original).
`
`Accordingly, the Federal Circuit found a “missing link between
`
`vitamin B12 deficiency and pemetrexed toxicity” that was not overcome by
`
`the evidence of record. Id. That is, there was no evidence that even if folic
`
`acid supplementation was known to improve pemetrexed toxicity, the
`
`ordinary artisan would have thought the same of vitamin B12. Id. at 1374.
`
`Also, expert testimony provided that vitamin B 12 pretreatment would have
`
`affected pemetrexed’s efficacy by “having to increase the [antifolate] dose to
`
`get the same activity” of cancer treatment, which the ordinary artisan would
`
`have viewed as “a problem.” Id. (alteration in original) (quoting Ex. 1051,
`
`138:7—8).
`
`10
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`
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`IPR2016-00237
`
`Patent 7,772,209 B2
`
`The Federal Circuit found that two prior art references, one of them
`
`being Calvert 1999,11 which Petitioner cites as evidence as to the knowledge
`
`of the ordinary artisan in this proceeding, “merely note in passing that
`
`vitamin B12 can be related to homocysteine levels and folate biochemical
`
`pathways.” Id. at 1375; Tr. 147214—19. There was no testimony that those
`
`references would have provided a motivation to use vitamin B 12
`
`pretreatment with pemetrexed, when viewed with the evidence of the gaps
`
`and concerns in the prior art that were specifically identified by the Federal
`
`Circuit. 845 F.3d at 1375.
`
`The Federal Circuit also addressed the doses and schedules and
`
`determined that there was only evidence of vitamin B 12 doses and schedules
`
`that are “routine” in different medical contexts. Id. at 1374. The Federal
`Circuit found no evidence that the ordinary artisan would have applied those
`
`doses and schedules wholesale to the context of pemetrexed treatment. Id.
`
`E.
`
`Instituted Challenge
`
`We instituted trial based on the following ground of unpatentability
`
`(Dec. Inst. 19):
`
`
`
`§ 103(a)
`
`
`
`Niyikiza, the ’974 patent, and
`
`
`EP 00512
`
`
`1—22
`
`.
`
`
`
`1‘ Hilary Calvert, An Overview ofFolate Metabolism: Features Relevant to
`the Action and Toxicities ofAntifolate Anticancer Agents, SEMINARS
`ONCOLOGY, Apr. 1999, at 3 (Ex. 1014) (“Calvert 1999”).
`
`‘2 Willem Jacob Serfontein, EP 0 595 005 A1, published May 4, 1994
`(Ex. 1010) (“EP 005”).
`
`11
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`
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`IPR2016-00237
`Patent 7,772,209 B2
`
`Petitioner relies also on the Declaration of W. Archie Bleyer, M.D.,
`
`FRCP (Ex. 1025), the Supplemental Declaration of Dr. Bleyer (Ex. 1077), as
`
`well as the Reply Declarations of David W. Feigal, Jr., M.D., M.P.H.
`
`(Ex. 1080) and Joel B. Mason, M.D. (Ex. 1078).
`
`Patent Owner relies on the Declarations of Steven H. Zeisel, M.D.,
`
`Ph.D. (Ex. 2118), and Bruce A. Chabner, M.D. (Ex. 2120).
`
`II.
`
`ANALYSIS
`
`Petitioner bears the burden of proving unpatentability of the
`
`challenged claims, and the burden of persuasion never shifts to Patent
`
`Owner. Dynamic Drinkware, LLC v. Nat ’1 Graphics, Inc, 800 F.3d 1375,
`
`1378 (Fed. Cir. 2015). To prevail, Petitioner must establish the facts
`
`supporting its challenge by a preponderance of the evidence. 35 U.S.C.
`
`§ 316(c); 37 C.F.R. § 42.1(d). Below, we explain why Petitioner has failed
`
`to meet its burden with respect to the challenged claims.
`
`A.
`
`Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. See 37 C.F.R. § 42.100(b);
`
`Cuozzo Speed Techs, LLC v. Lee, 136 S. Ct. 2131, 2144—45 (2016)
`
`(upholding the use of the broadest reasonable interpretation standard).
`
`Under that standard, we presume that a claim term carries its “ordinary and
`
`customary meaning,” which “is the meaning that the term would have to a
`
`person of ordinary skill in the art in question” at the time of the invention.
`
`In re Translogic Tech, Inc, 504 F.3d 1249, 1257 (Fed. Cir. 2007); see also
`
`TriVascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`
`a broadest reasonable interpretation, words of the claim must be given their
`
`12
`
`
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`IPR2016-00237
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`Patent 7,772,209 B2
`
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history”). Any special definition for a claim term must be
`set forth in the specification with reasonable clarity, deliberateness, and
`
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`In the Institution Decision, we determined that none of the terms in
`
`the challenged claims required express construction at that time. Dec. Inst.
`
`10 (citing Vivid Techs., Inc. v. Am. Sci. & Eng ’g, 1110., 200 F.3d 795, 803
`
`(Fed. Cir. 1999) (noting that only claim terms that are in controversy need to
`
`be construed, and then only to the extent necessary to resolve the
`
`controversy)). In its Response, Patent Owner agrees that none of the claim
`
`terms require construction (PO Resp. 16),13 and Petitioner does not dispute
`
`that in its Reply. Thus, we again determine that none of the terms in the
`
`challenged claims require express construction.
`
`B. Level of Ordinary Skill in the Art
`
`Petitioner contends:
`
`A person of ordinary skill in the art (“POSA”) in
`oncology as of June 30, 1999—the earliest possible priority
`date for the ’209 Patent—would be “a medical doctor with an
`MD. 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.” (Ex. 1025 1] 20.) “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
`
`‘3 Patent Owner notes that both it and Petitioner agree that a “patient” is “a
`human undergoing medical treatment,” which is disputed in IPR2016-00318.
`PO Resp. 16. For purposes of this Decision, we do not disagree with that
`claim construction, and, moreover, as that term is not in dispute in this
`proceeding, do not find a need to construe it here.
`
`13
`
`
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`IPR2016-00237
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`Patent 7,772,209 B2
`
`with expertise in biochemistry, and a clinician may be part of
`the team.” (Id. 1[ 21; see also Ex. 1028 at 9.)
`
`Pet. 24—25.
`
`Patent Owner responds, relying on its expert, Dr. Chabner, that the
`
`ordinary artisan
`
`would be a “medical doctor who specializes in oncology,
`specifically medical oncology,” and “would have knowledge
`and experience concerning the use of chemotherapy agents,
`including antifolates, in the treatment of cancer, as well as
`knowledge and experience regarding the management of
`toxicities associated with such treatment.” [Ex. 2120] 11 23. Dr.
`Chabncr added that the POSA would have an “understanding of
`how nutritional issues relate to the use of chemotherapy
`agents,” as well as “an understanding of theinterrelationships
`between antifolates, the folic acid pathway, and pathways
`related to vitamin B12.” Id. 1] 25.
`
`PO Resp. 14—15. In particular, Patent Owner disagrees with Petitioner’s
`
`expert, Dr. Bleyer, that the ordinary artisan would defer to a nutritionist in
`
`determining whether to treat a cancer patient with vitamins, but asserts that
`
`such decisions would be made by the medical oncologist. Id. at 15 (citing
`
`Ex. 2120 1i 24;Ex.21181[17).
`
`We adopt Patent Owner’s statement of the level of ordinary skill in
`
`the art, as we find that the ordinary artisan would be an oncologist, and
`
`although that oncologist may have access to experts in nutrition, the
`
`oncologist would make final decisions as to treatment. Moreover, we note
`
`that, in this case, the level of ordinary skill in the art is reflected by the prior
`
`art ofrecord. Cf Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.
`
`2001); In re GPACInc., 57 F.3d 1573, 1579 (Fed. Cir. 1995). In addition,
`
`our analysis would be the same under either Petitioner’s or Patent Owner’s
`
`definition of the ordinary artisan.
`
`l4
`
`
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`IPR2016-00237
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`Patent 7,772,209 B2
`
`C.
`
`Obviousness over Niyikiza, the ’974 patent, and EP 005
`
`Petitioner contends that claims 1—22 are rendered obvious by the
`
`combination of Niyikiza, the ’974 patent, and EP 005. Pet. 25—51. Patent
`
`Owner disagrees with Petitioner’s contentions, asserting that the Petition
`
`fails to demonstrate the obviousness of the challenged claims by a
`
`preponderance of the evidence. PO Resp. 16—54.
`
`1'.
`
`Overview of the Prior Art Relied Upon
`
`We find the following as to the teachings of the relevant prior art.
`
`a.
`
`Niyikiza (Ex. 1008)
`
`Niyikiza, a meeting abstract, states that MTA (pemetrexed) “is a novel
`
`multitargeted antifolate with inhibitory activity against multiple enzymes.”
`
`Ex. 1008, 126, Abstract 609P. According to Niyikiza, “[h]istorical data on
`
`other antifolates have suggested that a patient’s nutritional status may play a
`
`role in the likelihood of experiencing severe toxicity.” Id. Thus, Niyikiza
`
`states that the “purpose of th[e] study was to assess the relationship of
`
`vitamin metabolites, drug exposure, and other prespecifled baseline patient
`
`characteristics to toxicity following retreatment with MTA.” Id
`
`Niyikiza describes treating 139 patients with tumors in a Phase II
`
`study with MTA and monitoring the patients for homocysteine,
`
`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. In particular, Niyikiza found
`
`that “[e]levated baseline homocysteine levels (2 IOuM) highly correlate
`
`with severe hematologic and nonhematologic toxicities following treatment
`
`with MTA,” and that “[h]omocysteine was found to be better than albumin
`
`at predicting toxicity.” Id. Niyikiza states that further studies are underway
`
`15
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`IPR2016-00237
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`Patent 7,772,209 B2
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`in patients with renal impairment or patients who received prior cisplatin.
`
`Id.
`
`b.
`
`The ’974 patent (Ex. 1009)
`
`The ’974 patent describes the administration of a folate binding
`
`protein binding agent in conjunction with the use of an antifolate. Ex. 1009,
`
`Abstract, l:54~58, 2:60—65. In particular, the ’974 patent teaches “a method
`
`for improving the therapeutic utility of [glycinamide ribonucleotide
`
`(“GAR”)]-transformylase inhibitors and other antifolates by co-
`
`administering a [folate binding protein (“FBP”)] binding agent to the host
`
`under going treatment.” Id. at 1:54—58. The preferred antifolate of the ’974
`
`patent is lometrexol, which is “a potent antitumor agent, especially against
`
`solid tumors such as colorectal, lung, breast, head and neck and pancreatic.”
`
`Id. at 1:34—37. The ’974 patent teaches, howevcr, that lomctrcxol has
`
`undesirable side effects, such as anorexia, weight loss, mucositis,
`
`leukopenia, anemia, hypoactivity, and dehydration. Id. at 1240—45.
`
`In the method of the ’974 patent, the FBP binding agent is
`
`administered to a mammal prior to treatment with an antifolate. Id. at 6:22—
`
`24. A preferred embodiment involves administering about 1 mg to about 5
`
`mg of folic acid as the FBP binding agent, with the folic acid administered
`
`orally about 1 to 24 hours prior to treatment with lometrexol. Id. at 6:37—42.
`
`Multiple doses of folic acid may be administered up to weeks before
`
`treatment to ensure that the folate binding protein is sufficiently bound. Id.
`
`at 6232—3 7. The 1974 patent teaches;
`
`It should be noted that the FBP binding agent is not an
`antitumor agent and that the pretreatment of a mammal with a FBP
`binding agent is not a synergistic or potentiating effect. Rather, by
`having substantially bound the folate binding protein with a FBP
`
`16
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`IPR2016-00237
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`Patent 7,772,209 B2
`
`binding agent prior to administration of the GAR-transformylase
`inhibitor or other antifolate, the toxic effects of such subsequent
`treatment are greatly reduced without aff
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