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 IPR2016-002401
`
`Patent 7,772,209
`
`PETITIONERS’ AMENDED JOINT NOTICE OF APPEAL
`
`1 IPR2016-01191, IPR2016-01337, and IPR2016—01343 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 IPR2016-002401
`
`Patent 7,772,209
`
`PETITIONERS’ AMENDED JOINT NOTICE OF APPEAL
`
`1 IPR2016-01191, IPR2016-01337, and IPR2016—01343 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. §§ 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. 82 in IPR2016-002402) (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 C.F.R. § 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 IPR2016-01191 (Paper No. 13) and IPR2016-
`01343 (Paper No. 12). These lPRs were joined with IPR2016-00240 and
`terminated under 37 C.F.R. § 42.72 on October 4, 2016 (IPR2016-01191 at Paper
`No. 10) and October 6, 2016 (IPR2016—01343 at Paper No. 11) with an Order that
`“all further filings in the joined proceeding shall be made only in IPR2016-00240”
`(see, e.g., IPR2016—01 191, 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. S ires/
`1
`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. Kil ore/
`/C nthia Lambert Hardman]
`11
`Cynthia Lambert Hardman (53,179)
`John D. Polivick (57,926)
`Michael B. Cottler
`Deanne M. Mazzochi (50,158)
`Goodwin Procter LLP
`Patrick C. Kilgore (69,131)
`The New York Times Building
`Rakoczy Molino
`620 Eighth Avenue
`Mazzochi Siwik LLP
`New York, NY 10018-1405
`6 West Hubbard Street, Suite 500
`mcottler@goodwinlaw.com
`Chicago, Illinois 60654
`chardman@goodwinlaw.com
`jpolivick@rmmslegal.com
`dmazzochi@rmmslegal.com
`pkilgore@rmmslegal.com
`
`Counselfor Fresenius Kabi USA, LLC
`
`Counselfor Apotex Inc. and
`Apotex Corp.
`
`
`
`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 6Lh 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),1 certify that I caused to be served on the
`
`counsel for Patent Owner a true and correct copy of the foregoing “Petitioners”
`
`Amended 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
`demeterJohn_c@lilly.com
`Counselfor Patent Owner
`
`Dated: December 6, 2017
`
`Respectfully Submitted,
`
`/Sarah 11'. Spires/
`Sarah E. Spires
`
`
`
`EXHIBIT A
`
`
`
`Trials@uspto.gov
`571.272.7822
`
`Paper No. 82
`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—002401
`
`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 USC. § 318(a) and 37 CFR. § 42.73
`
`1 Cases IPR2016-01191, IPR2016-01337, and IPR2016—01343 have been
`joined with the instant proceeding.
`
`
`
`IPR2016-00240
`
`Patent 7,772,209 B2
`
`1.
`
`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 9 (“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, we
`
`instituted trial on June 3, 2016, as to all of the challenged claims of the ’209
`
`patent. Paper 14 (“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. IPR2016-01191, Papers 2 and 3. On
`
`October 6, 2016, the Board instituted interpartes review in that case and
`
`granted joinder. IPR2016—01 191, Paper 11. Wockhardt Bio AG also
`
`requested inter partes review of claims 1—22 of the ’209 patent in IPR2016-
`
`01337, as well as joinder to the instant proceeding. IPR2016-01337, Papers
`
`1 and 3. Inter partes review was instituted in that case and joinder granted
`
`on November 18, 2016. IPR2016-01337, Paper 8. Finally, cha
`
`Pharmaceuticals USA, Inc., and Fresenius Kabi USA, LLC, also requested
`
`inter partes review of claims 1—22 of the ”209 patent in IPR2016-01343, and
`
`joinder to the instant proceeding. IPR2016—01343, Papers 2 and 4. Inter
`
`2
`
`
`
`IPR2016-00240
`
`Patent 7,772,209 B2
`
`partes review was instituted and joinder granted on October 6, 2016.
`
`IPR2016-01343, Paper 10. We collectively refer to all enjoined Petitioners
`
`in this Final Written Decision as “Petitioner.”
`
`Patent Owner filed a Response (Paper 32, “PO Resp”), Petitioner
`
`filed a Reply (Paper 47), and Patent Owner filed a Surtreply (Paper 62).
`
`Petitioner filed a Motion to Exclude (Paper 56, “Mot. Exclude”), to which
`
`Patent Owner filed an Opposition (Paper 66, “Opp. Mot. Exclude”), and
`
`Petitioner filed a Reply (Paper 72). Oral hearing was held on March 16,
`
`2017, and a transcript of that hearing has been entered into the record. Paper
`
`78 (“TL”).
`
`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 ’1
`
`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 (S.D. Ind.) (filed Oct. 29,
`
`2010). Pet. 2—3; Prelim. Resp. 2.
`
`
`
`IPR2016-00240
`
`Patent 7,772,209 B2
`
`The ’209 patent also has been challenged in IPR2016-00237 by
`
`Neptune Generics, LLC, and in IPR2016—003 18 by Sandoz Inc. Proceedings
`IPR2016-01190, IPR2016-01335, and IPR2016—01341 have been joined
`
`with IPR2016-00237, and proceedings IPR2016-01393, IPR2016-01340,
`
`and IPR2016-01429 have been joined with IPR2016-00318.
`
`B.
`
`The ’2 09 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. 1024 11 67. Antifolates are a well-studied
`class of antineoplastic agents that inhibit one or several key folate-requiring
`
`enzymes of the thymidine 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. 1024 1] 67.
`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
`
`
`
`IPR2016-00240
`
`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.” 1d,, Abstract. The method is said to improve
`
`the therapeutic utility of antifolate drugs by administering a methylmalonic
`
`acid (“MMA”) lowering agent, such as vitamin B 12, 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 4228—43. Pemetrexed is also
`referred to in the art as the “multitargeted antifolate” (“MTA”). 2 Ex. 1022,
`
`1293, 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—00240
`
`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-lO-chlorocobalamin,
`aquocobalamin perchlorate, aquo- 1 O—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 B 12, prior to the first administration of
`pemetrexed disodium; and
`
`c) administration of pemetrexed disodium.
`
`Ex. 1001,10256—65, 11225—1224.
`
`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 pemetrexed,
`
`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—00240
`
`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 finding—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 Antifolate (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 0fLY231514, 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. 2072
`(not filed, Paper 67, 9)) (“the ’974 patent”).
`
`7
`
`
`
`IPR2016-00240
`
`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 II10 (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., LY231514 (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
`
`
`
`IPR2016-00240
`
`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 B 12 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 finding—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 B 12 pretreatment with pemetrexed, let alone
`
`at the appropriate doses and schedules of vitamin B12 pretreatment. Id. at
`
`
`
`IPR2016-00240
`
`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 B12 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,
`
`13827—8).
`
`10
`
`
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`IPR2016-00240
`
`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 B12
`
`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 B12 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):
`
`‘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”).
`
`11
`
`
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`IPR2016-00240
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`Patent 7,772,209 B2
`
`‘\
`
`
`
`§ 103(a)
`Rusthoven12 and EP 00513
`
`
`
`
`Petitioner relies also on the Declaration of W. Archie Bleyer, M.D.,
`
`,FRCP (Ex. 1024), 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(6); 37 CPR. § 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);
`
`12 James J. Rusthoven et al., MultitargetedAntifoIate LY231514 As First—
`Line Chemotherapyfor Patients with Advanced Non-Small—Cell Lung
`Cancer: A Phase 11 Study, 17 J. CLINICAL ONCOLOGY 1194 (1999)
`(BX. 101 1) (“Rusthoven”).
`
`13 Willem Jacob Serfontein, EP 0 595 005 A1, published May 4, 1994
`(Ex. 1010) (“EP 005”).
`
`12
`
`
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`IPR2016-00240
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`Patent 7,772,209 B2
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`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
`
`Tri Vascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`
`a broadest reasonable interpretation, words of the claim must be given their
`
`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, Inc., 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),14 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.
`
`14 Patent Owner notes that both it and Petitioner agree that a “patient” is “a
`human undergoing medical treatment,” which is disputed in IPR2016—003 18.
`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
`
`
`
`IPR2016-00240
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`Patent 7,772,209 B2
`
`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. 1024 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 cxpcrt in hcmatology, a basic scientist
`with expertise in biochemistry, and a clinician may be part of
`the team.” (Id. 11 21; see also Ex. 1027 at 9.)
`
`Pet. 23—24.
`
`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. Chabner 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 the
`interrelationships 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 11 24; Ex. 2118 1117).
`
`14
`
`
`
`IPR2016—00240
`
`Patent 7,772,209 B2
`
`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, 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 of record. Cf
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001); In re GPAC
`
`Inc., 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.
`
`C.
`
`Obviousness over Rusthoven and EP 005
`
`Petitioner contends that claims 1—22 are rendered obvious by the
`
`combination of Rusthoven and EP 005. Pet. 24—48. 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.
`
`Rusthoven (Ex. 1011)
`
`Rusthoven describes a Phase II study evaluating the efficacy and
`
`safety of multitargeted antifolate LY231514 (“MTA”) in patients receiving
`
`initial chemotherapy for advanced non-small-cell lung cancer (“NSCLC”).
`
`Ex. 1011, Abstract. The study involved thirty-three patients, all of whom
`
`were assessed for toxicity. Id. Initial MTA dosages were reduced after three
`
`patients received MTA treatment because of toxicity seen in the study and
`
`another Canadian MTA trial in colorectal cancer. Id. Rusthoven states that
`
`earlier MTA studies suggested that “dietary supplementation with folic acid
`
`15
`
`
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`IPR2016—00240
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`Patent 7,772,209 B2
`
`may improve the therapeutic index by reducing toxicity in mice.” Id. at
`
`1195.
`
`Based on the results of the study, Rusthoven reported that MTA seems
`
`to have exhibited a clinically meaningful activity against NSCLC and
`
`toxicity was said to be “generally mild and tolerable,” although ten of the
`
`thirty-three patients stopped the protocol therapy due to toxicity. Id. at
`Abstract. Rusthoven states that their group is conducting a Phase II study of
`
`MTA in combination with cisplatin drugs for NSCLC. Id. at 1198.
`
`b.
`
`EP 005 (Ex. 1010)
`
`EP 005 is drawn to pharmaceutical preparations for lowering blood
`
`and tissue levels of homocysteine and counteracting harmful effects
`
`associated with homocysteine. Ex. 1010, Abstract, 221—3. According to
`
`EP 005, elevated homocysteine levels are correlated with “some of the
`
`princip[al] causes of morbidity and mortality in the Western world,” such as
`myocardial and cerebral infarction. Id. at 224—6. Elevated homocysteine
`levels are highly undesirable and normalization of elevated levels constitutes
`
`a therapeutic goal. Id. at 3:7—9.
`
`Three pathways are said to exist to control homocysteine including
`
`remethylation to methionine, which requires folate, as well as vitamin B12
`
`as a co-factor. Id. at 2225—30. EP 005 identifies a number of publications
`
`that are said to describe the relationship between vitamin B12 and folate
`
`levels individually and blood levels of homocysteine. Id. at 3:37—45. EP
`
`005 seeks to lower total homocysteine blood levels elevated by any known
`
`cause, including drugs that induce elevated homocysteine levels, such as
`
`methotrexate, a well—known antifolate. Id. at 4:43—48; Ex. 1025 fil 64.
`
`'16
`
`
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`IPR2016-00240
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`Patent 7,772,209 B2
`
`EP 005 teaches that other situations in which blood homocysteine may be
`
`elevated include leukemia and other cancers. Ex. 1010, 9:54—56.
`
`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
`
`folate, vitamin B12, and Vitamin B6 produces advantageous effects that go
`
`substantially beyond what would be expected from a simple additive effect
`
`of the action of these compounds. Id. at 11:20—23. In addition, EP 005
`
`teaches that “an unexpected synergism exists when vitamin B12, folate and
`
`[vitamin B6] are given concurrently,” which may res
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