UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN LABORATORIES LIMITED,
`
`PETITIONER,
`
`v.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`Case IPR2016-003181
`
`Patent 7,772,209
`
`;
`
`PETITIONER’S NOTICE OF APPEAL
`
`‘: “
`
`:3.
`
`1 IPR2016-01340, IPR2016-01393, and IPR2016-01429 were joined with this
`proceeding.
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN LABORATORIES LIMITED,
`
`PETITIONER,
`
`v.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`Case IPR2016-003181
`
`Patent 7,772,209
`
`;
`
`PETITIONER’S NOTICE OF APPEAL
`
`‘: “
`
`:3.
`
`1 IPR2016-01340, IPR2016-01393, and IPR2016-01429 were joined with this
`proceeding.
`
`
`
`On October 4, 2016, the Patent Trial and Appeal Board (“PTAB”) instituted
`
`inter partes review on claims 1-22 of US. Patent No. 7,772,209 (“the ’209 patent”)
`
`in IPR2016-01429, in which Mylan Laboratories Limited (“Petitioner” or “Mylan”)
`
`is a petitioner. IPR2016—01429, Paper 10. Concurrently, the PTAB terminated this
`
`proceeding under 37 CPR. § 42.72, joined it with IPR2016-003 18, and directed that
`
`“all further filings in the joined proceeding shall be made only in 1PR2016-00318.”
`
`Id. at 11. The PTAB entered a Final Written Decision in IPR2016—003 18 on October
`
`5, 2017, concluding that the petitioners failed to show by a preponderance of the
`
`evidence that claims 1-22 of the ’209 patent are unpatentable (the “Final Written
`
`Decision”). IPR2016-00318, Paper 88.2
`
`Notice is hereby given, pursuant to 35 U.S.C. §§ 141—144 and 319, and 37
`
`C.F.R. §§ 90.2(a) and 90.3, that Mylan appeals to the United States Court of Appeals
`
`for the Federal Circuit from the Final Written Decision and from all underlying
`
`findings, orders, decisions, rulings, and opinions adverse to Mylan. A copy of the
`
`Final Written Decision is attached.
`
`In accordance with 37 C.F.R. § 90.2(a)(3)(ii), Mylan further anticipates that
`
`the issues on appeal may include, but are not limited to, the PTAB’s determination
`
`that petitioners failed to show by a preponderance of the evidence that claims 1-22
`
`of the ’209 patent are unpatentable under 35 U.S.C. § 103, the PTAB’s failure to
`
`2 The Final Written Decision was also entered as Paper 13 in IPR2016-01429.
`
`2
`
`
`
`properly consider evidence of record, the PTAB’s findings with respect to objective
`
`indicia of non-obviousness, and any finding or determination supporting or relating
`
`to those issues, as well as all other issues decided adversely to Mylan in any findings,
`
`orders, determinations, rulings, decisions, and opinions, including but not limited to
`
`any adverse evidentiary orders, decisions, rulings, and opinions.
`
`Dated: December 7, 2017
`
`Respectfully Submitted,
`
`/Thomas J. Parker/
`
`Thomas J. Parker, Reg. No.- 42,062
`ALSTON & BIRD LLP
`
`90 Park Avenue
`
`New York, NY 10016
`thomas.parker@alston.com
`212-210—9529
`
`Counselfor Petitioner Mylan
`Laboratories Limited
`
`
`
`CERTIFICATE OF FILING
`
`I hereby certify that a true and correct copy of the foregoing “Petitioner’s
`
`Notice of Appeal” was filed electronically through the Patent Trial and Appeal
`
`Board’s E2E and delivered by hand to the Director of the United States Patent and
`
`Trademark Office on December 7, 2017 at the following address:
`
`Director of the United States Patent and Trademark Office
`
`c/o Office of the General Counsel
`
`United States Patent and Trademark Office
`
`10B20, Madison Building East
`600 Dulany Street
`Alexandria, VA 22314
`
`I also hereby certify that a true and correct copy of the foregoing “Petitioner’s
`
`Notice of Appeal” was filed electronically through CM/ECF and delivered by hand
`
`to the Clerk’s Office of the United States Court of Appeals for the Federal Circuit
`
`on December 7, 2017, along with the required $500 filing fee.
`
`Dated: December 7, 2017
`
`Respectfully Submitted,
`
`/Thomas J. Parker/
`
`Thomas J. Parker, Reg. No. 42,062
`ALSTON & BIRD LLP
`
`90 Park Avenue
`
`New York, NY 10016
`thomas.parker@alston.com
`212-210—9529
`
`Counselfor Petitioner Mylarz
`Laboratories Limited
`
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 CPR. § 42.6(e), I hereby certify that I caused to be served on
`
`counsel for Patent Owner a true and correct copy of the foregoing “Petitioner’s
`
`Notice of Appeal” by Express Mail and electronic mail on December 7, 2017:
`
`James P. Leeds
`
`John C. Demeter
`ELI LILLY AND COMPANY
`
`Lilly Corporate Center
`Indianapolis, IN 46285
`leeds_james@lilly.com
`demeter_j ohn_c@lilly.com
`
`Dov P. Grossman
`
`David M. Krinsky
`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 Eli Lilly &
`Company
`
`Dated: December 7, 2017
`
`Respectfully Submitted,
`
`/Thomas J. Parker/
`
`Thomas J. Parker, Reg. No. 42,062
`ALSTON & BIRD LLP
`
`90 Park Avenue
`
`New York, NY 10016
`thomas.parker@alston.com
`212-210—9529
`
`Counselfor Petitioner Mylan
`Laboratories Limited
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`.
`
`
`
`:7
`0;,
`
`.L; S
`
`NN
`
`7‘."
`
`FRESENIUS KABI USA, LLC,
`
`PETITIONER,
`
`V.
`
`ELI LILLY & COMPANY,
`
`PATENT OWNER.
`
`'
`
`CaseIPR2016—OO3181
`Patent 7,772,209
`
`PETITIONER’S NOTICE OF APPEAL
`
`1 IPR2016—01340, IPR2016-01393, and IPR2016-01429 were joined with this
`proceeding.
`
`
`
`Office of the General Counsel
`
`Patent and Trademark Office
`Madison East
`10B2O 600 Dulany Street
`Alexandria, VA 22314
`
`Notice is hereby given, pursuant to 37 C.F.R. § 90.-2(a), that Petitioner
`
`.‘ Fresenius Kabi USA, LLC (“Petitioner”) appeals under 35 U.S.C. §§ 139, 141 and
`i 142 to the United States Court (ofAppeals for the Federal Circuit from the Final
`Written Decision entered on October 5, 2017 (Paper No. 88 in1PR2016-003 1 82)
`
`(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
`
`supporting or related to that issue, including the weight the Board
`
`2 The same decision was entered in IPR2016-01429 (Paper No. 13). This IPR was
`joined with IPR2016—003 18 and terminated under 37 C.F.R. § 42.72 on October 4,
`2016 (IPR2016—01429 at Paper No. 10) with an Order that “all further filings in the
`joined proceeding shall be made only in IPR2016-00318” (see, e. g., IPR2016- '
`01429, Paper No. 10 at 11).‘
`
`2
`
`
`
`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 AppealBoard, and the Clerk of the United
`
`States Court of Appeals for the Federal Circuit.
`
`Dated: December 7, 2017
`
`Respectfully Submitted,
`
`/Cynthia Lambert Hardman/
`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 “Petitioner’s
`
`Notice of Appeal,” was filed electronically through the Patent Trial and Appeal
`
`Board’s E2E on this 7th day of December, 2017 and deposited with Federal
`
`Express on December 7, 2017 to the Director of the United States Patent and
`
`Trademark Office at the following address:
`
`Director of the United States Patent and Trademark Office
`c/o Office of the General Counsel
`
`United States Patent and Trademark Office ‘
`
`lOB20, Madison Building East
`600 Dulany Street
`Alexandria, VA 22314
`
`I also hereby certify that a true and correct copy of the foregoing .
`
`“Petitioner’s Notice of Appeal,” was filed electronically by CM/ECF on this 7th
`
`day of December, 2017, with the United States Court of Appeals for the Federal
`
`' Circuit,
`
`Dated: December 7, 2017
`
`Respectfully Submitted,
`
`/Cynthia Lambert Hardman/
`Cynthia Lambert Hardman (53,179)
`
`,
`
`
`
`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 “Petitioner’s
`
`Notice of Appeal,”on December 7th, 2017, by Federal Express to counsel for
`
`Patent Owner at the follbwing addresses of record:
`
`Thomas J. Parker
`
`Reg. No. 42,062
`thomas.parker@alston.com
`Alston & Bird LLP
`
`90 Park Avenue, 15th Floor
`
`New York, NY 10016
`P: 212—210-9529/F: 212—210—9444
`Counselfor Mylar; Laboratories Limited
`
`Dov P. Grossman (72,525)
`David M'. Krinsky (72,339)
`. Adam L. Perlman
`
`WILLIAMS & CONNOLLY LLP
`
`725 Twelfth St. NW
`
`Washington, DC 20005
`dgro‘ssman@wc.com
`dkrinsky@wc.com
`aperlman@wc.com
`Counselfor Patent Owner
`
`James P. Leeds (3 5,241)
`John C. Demeter (30,167)
`ELI LILLY AND COMPANY
`
`Lilly Corporate Center
`Indianapolis, IN 46285
`1eeds_j ames@lilly.com
`demeter_.j ohn_c@lilly.com
`Counselfor Patent Owner ‘
`
`Datcd: December 7, 2017
`
`Respectfully Submitted,
`
`/Cynthia Lambert Hardman/
`Cynthia Lambert Hardman (53,179)
`
`-
`
`
`
`Exhibit 1
`
`
`
`Trials@uspto.gov
`571.272.7822
`
`Paper No. 88
`Entered: October 5, 2017
`
`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, FRESENIUS KABI USA, LLC, and
`
`WOCKHARDT BIO AG,
`
`Petitioner,
`
`V.
`
`ELI LILLY & COMPANY,
`Patent Owner.
`
`Case IPR2016-00318I
`
`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
`3b U.S.C. § 318(a) and 37 CFR. § 42.73
`
`' Cases IPR2016-01340, IPR2016-01393, and IPR2016-01429 have been
`joined with the instant proceeding.
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`I.
`
`INTRODUCTION
`
`Sandoz Inc. 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
`
`2 (“Pet”). Eli Lilly & Company (“Patent Owner” or “Lilly”) filed a
`
`Preliminary Response to the Petition. Paper 11 (“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 16, 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., Apotex Corp., Emcure
`
`Pharmaceuticals Ltd., Heritage Pharma Labs Inc., Heritage Pharmaceuticals
`
`Inc., Glenmark Pharmaceuticals Inc., USA, Glenmark Holding SA,
`
`Glenmark Pharmaceuticals Ltd., and Mylan Laboratories Limited requested
`
`inter partes review of claims 1—22 of the ’209 patent in IPR2016-01429, and
`
`joinder to the instant proceeding. IPR2016-01429, Papers 2 and 3. On
`
`October 6, 2016, the Board instituted inter partes review in that case, and
`
`granted joinder. IPR2016-01429, Paper 11. Teva Pharmaceuticals USA, Inc.
`
`and Frcscnius Kabi USA, LLC requested inter partes review of claims 1—22
`
`of the ’209 patent in IPR2016-01340, as well as joinder to the instant
`
`proceeding. IPR2016—01340, Papers 2 and 3. Inter partes review was
`
`instituted in that case and joinder granted on October 6, 2016. IPR2016-
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`01340, Paper 9. Finally, Wockhardt Bio AG also requested inter partes
`
`review of claims 1—22 ofthe ’209 patent in IPR2016-01393, andjoinder to
`
`the instant proceeding. IPR2016-01393, Papers 1 and 3. Inter partes review
`
`was instituted and joinder granted on November 21, 2016. IPR2016-01393,
`
`Paper 9. We collectively refer to all enjoined Petitioners in this Final
`
`Written Decision as “Petitioner.”
`
`Patent Owner filed a Response (Paper 36, “PO Resp”), Petitioner
`
`filed a Reply (Paper 49), and Patent Owner filed a Sur-reply (Paper 68). In
`
`addition, Petitioner filed a Motion to Exclude (Paper 64, “Mot. Exclude”), to
`
`which Patent Owner filed an Opposition (Paper 72, “Opp. Mot. Exclude”),
`
`and Petitioner filed a Reply (Paper 77). Oral hearing was held on March 16,
`
`2017, and a transcript of that hearing has been entered into the record. Paper
`
`81 (“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 CPR. § 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 'uupalentable. We also deny Petitioner’s Motion to Exclude.
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`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. Sandoz Inc,
`
`No. 1:14-cv-2008 (S.D. Ind.) (filed Dec. 5, 2014). Pet. 2—3; Paper 5, 2—3.
`
`The ’209 patent also has been challenged in IPR2016-00237 and in
`
`IPR2016-00240 by Neptune Generics, LLC. IPR2016-01190, IPR2016-
`
`01335, and IPR2016—0134l have been joined with IPR2016-00237, and
`
`proceedings IPR2016-01 191, IPR2016-01337, and IPR2016-01343 have
`
`been joined with IPR2016—00240.
`
`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. 1047, 35. 2 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. Because antifolates interfere with DNA and RNA
`
`synthesis, antifolates are used as chemotherapeutic drugs to treat certain
`
`types of cancer. Ex. 1004 1111 28—29, 31.
`
`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
`
`2 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.
`
`4
`
`
`
`IPR2016-003l8
`
`Patent 7,772,209 B2
`
`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
`
`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”). 3 Ex. 1015,
`
`129, Abstract 620P.
`
`C.
`
`Illustrative Claims
`
`Petitioner challenges claims 1—22 of the ’209 patent. Claims 1 and 12
`
`are independent, and are reproduced below:
`
`3 We use “pemetrexed” and “MTA” interchangeably throughout this
`Decision.
`
`
`
`IPR2016—00318
`
`Patent 7,772,209 B2
`
`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-lO-chlorocobalamin,
`aquocobalamin perchlorate, aquo—10-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—12z4.
`
`D.
`
`Prior Litigation
`
`On March 31, 2014, the US. District Court for the Southern District
`
`ofIndiana 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 coadministering folic acid and vitamin B12 with pemetrexed,
`
`which is an antifolate and chemotherapy drug marketed under the trade
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`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
`
`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 1,6
`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
`
`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. 1013) (“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. 1015) (“Hammond I”).
`
`7 DA. Rinaldi et al., A Phase [Evaluation ofLY231514, A Novel ll/Iulti-
`Targeted Antifolate, Administered Every 2] 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. 1005)
`(“the ’974 patent”).
`
`
`
`IPR2016—00318
`
`Patent 7,772,209 B2
`
`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
`
`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 1’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 IIlo (collectively, the “Niyikiza Abstracts”). Id. at * 10. Niyikiza
`
`and Niyikiza 11 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
`
`M1V1A levels were necessary to establish a vitamin B12 deficiency. Id. at *4.
`
`9 C. Niyikiza et al., MTA (Ll/231514): Relationship of Vitamin Metabolite
`Profile, Drug Exposure, and Other Patient Characteristics To Toxicity, 9
`ANNALS ONCOLOGY 126, Abstract 609P (Supp. 4 1998) (Ex. 1006)
`(“Niyikiza” or “Niyikiza1”).
`
`‘0 C. Niyikiza et al., LY231514 (MTA): Relationship of Vitamin Metabolite
`Profile To Toxicity, PROC. AM. Soc’v CLINICAL ONCOLOGY, May 16—19,
`1998, at 558a, Abstract 2139 (Ex. 1016) (“Niyikiza II”).
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`The court further explained that in Niyikiza and Niyikiza 11, there was no
`
`correlation between toxicity and other measured variables, including MMA,
`
`which suggested at the time that there was no correlation between toxicity
`
`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 folate from the trap, counteracting the
`
`efficacy of an antifolate drug. Id. at *1 1.
`
`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 prctrcatment for use with an antifolat‘e 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
`
`
`
`lPR2016-00318
`
`Patent 7,772,209 B2
`
`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
`
`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 ‘concern[] 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 indicated a vitamin B12
`
`deficiency—instead, MMA levels specifically indicate a vitamin B12
`
`deficiency. Id. at 1373. The Federal Circuit then quoted from Niyikiza II,
`
`that “no correlation between toxicity .
`
`.
`
`. and [WA 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
`
`10
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`have viewed as “a problem.” Id. (alteration in original) (quoting Ex. 1064,ll
`
`13827—8).
`
`The Federal Circuit found that two prior art references, one of them
`
`being Calvert 1999, '2 which Petitioner relies on in its challenges in this
`
`proceeding, “merely note in passing that vitamin B12 can be related to
`
`homocysteine levels and folate biochemical pathways.” Id. at 1375; Tr.
`
`147: 14—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 Challenges
`
`We instituted trial based on the following grounds of unpatentability
`
`(Dec. Inst. 21):
`
`
`
`Calvert, Niyikiza I, Worzalla,
`EP 005, ‘3 and the ’974 atent
`
`
`
`§ 103(a)
`
`1—22
`
`
`
`" Petitioner did not file Exhibit 1064 in this proceeding. Paper 75, 9. The
`same exhibit is filed as Exhibit 1051 in IPR2016—00237.
`
`‘2 Hilary Calvert, An Overview ofFolate Metabolism: Features Relevant to
`the Action and Toxicities ofAntifolate Anticancer Agents, SEMINARS
`ONCOLOGY, Apr. 1999, at 3 (Ex. 1007) (“Calvert 1999” or “Calvert”).
`
`'3 Willem Jacob Serfontein, EP 0 595 005 A1, published May 4, 1994
`(Ex. 1033) (“EP 005”).
`
`11
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`
`
`__m
`Calvert, Niyikiza 1, Hammond 1,
`EP 005, and the ’974 patent
`
`
`
`
`
`Petitioner relies also on the Declaration of Ron D. Schiff, M.D., Ph.D.
`
`(EX. 1004), as well as the Reply Declarations of Dr. Schiff (Ex. 1075),
`
`David B. Ross, MD, Ph.D., M.B.I. (Ex. 1093) and Patrick J. Stover, Ph.D.
`
`(Ex. 1091).
`
`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 shifis 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(e); 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
`
`12
`
`
`
`IPR2016-00318
`
`Patent 7,772,209 B2
`
`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
`
`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.
`
`9—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)). For purposes of this Decision, we determine that the only
`
`claim term that is in controversy is the term “patient.”
`
`Petitioner argues that the claim term “patient” should be construed as
`
`encompassing mammals. Pet. 18—21. Specifically, Petitioner notes that the
`
`Specification of the ’209 patent does not define the term “patient,” and uses
`
`the terms “mammal” and “patient” interchangeably. Id. at 19 (citing (Ex.
`
`1001, 4:4—27; 6:35—54). Petitioner asserts further that the prosecution
`
`history supports construing “patient as mammal,” asserting that Patent
`
`Owner “knew how to limit the scope of the claims to treatment of a ‘human’
`
`when that was the intention.” Id. at 19—20 (citing Ex. 1024, 38; Ex. 1002,
`
`3).
`
`Patent Owner responds that the claim term “patient” should be
`
`construed in accordance with “its ordinary and customary meaning” as
`
`would be understood by the ordinary artisan of “a human undergoing
`
`medical treatment.” PO Resp. 14—1 5 (citing Ex. 2120 W 28—29). Patent
`
`13
`
`
`
`1PR2016-00318
`
`Patent 7,772,209 B2
`
`Owner asserts that construction has been adopted by Petitioner’s expert, and
`
`is supported by the Specification of the ’209 patent. Id. at 15—16 (citing Ex.
`
`2026, 345—347, 349; Ex. 1001, 6257—67, 7:1, 7:41—42, 7:46—47, 7:66, 8:15,
`
`8:39, 8:42—45, 8:49, 8:55—58, 9:14—17, 9:21—55, 9:21—55, 10:17—28 (noting
`
`that laboratory mice in the test examples are referred to as “animals,”
`
`whereas, when discussing clinical studies, the Specification refers to
`
`“patients”)).
`
`We conclude14 that the ordinary artisan, in view of the Specification
`
`of the ’209 patent, would understand that when referring to a “patient” in the
`
`claims, that patient include mammals, and is not limited to human patients.
`
`In that regard, we agree with Petitioner that the Specification uses
`
`“mammal” and “patient” interchangeably. See BX. 100], 424—27; 6:35—54.
`
`We acknowledge that the Specification refers to the test mice as animals, see
`
`id. at 6:57—7: 1, and refers to humans as patients when discussing clinical
`
`trials, see id. at 10:43—52. We, however, may not limit the claims to a
`
`particular embodiment, but instead we must apply the broadest reasonable
`
`interpretation consistent with the Specification’s interchangeable use of the
`
`terms “ma
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