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 IPR2016-003181
`Patent 7,772,209 B2
`____________
`
`Before JACQUELINE WRIGHT BONILLA, MICHAEL P. TIERNEY,
`Vice Chief Administrative 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 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`1 Cases IPR2016-01340, IPR2016-01393, and IPR2016-01429 have been
`joined with the instant proceeding.
`
`
`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 IPR2016-003181
`Patent 7,772,209 B2
`____________
`
`Before JACQUELINE WRIGHT BONILLA, MICHAEL P. TIERNEY,
`Vice Chief Administrative 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 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`1 Cases IPR2016-01340, IPR2016-01393, and IPR2016-01429 have been
`joined with the instant proceeding.
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`INTRODUCTION
`I.
`Sandoz Inc. filed a Petition requesting an inter partes review of claims
`1–22 of U.S. 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 Fresenius 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-
`
`2
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`01340, Paper 9. Finally, Wockhardt Bio AG also requested inter partes
`review of claims 1‒22 of the ’209 patent in IPR2016-01393, and joinder 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 (“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.
`
`3
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`Related Proceedings
`A.
`The ’209 patent is the subject of litigation in the U.S. 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 IPR2016-01341 have been joined with IPR2016-00237, and
`proceedings IPR2016-01191, IPR2016-01337, and IPR2016-01343 have
`been joined with IPR2016-00240.
`The ’209 Patent
`B.
`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 ¶¶ 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
`
`
`
`IPR2016-00318
`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.
`
`Illustrative Claims
`C.
`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.
`
`5
`
`
`
`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-10-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 μg and about
`1000 μg of folic acid prior to the first administration of
`pemetrexed disodium;
`b) administration of about 500 μg to about 1500 μg of
`vitamin B12, prior to the first administration of
`pemetrexed disodium; and
`c) administration of pemetrexed disodium.
`Ex. 1001, 10:56‒65, 11:25‒12:4.
`Prior Litigation
`D.
`On March 31, 2014, the U.S. District Court for the Southern District
`of Indiana upheld claims 9, 10, 12, 14, 15, 18, 19, and 21 of the ’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 (S.D. Ind. Mar. 31, 2014), aff’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
`
`6
`
`
`
`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,4,5 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
`
`
`4 John F. Worzalla et al., Role of Folic Acid in Modulating the Toxicity and
`Efficacy 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 of the
`Multitargeted Antifolate (MTA, LY231514) with Folic Acid (FA), 9 ANNALS
`ONCOLOGY 129, Abstract 620P (Supp. 4 1998) (Ex. 1015) (“Hammond I”).
`7 D.A. Rinaldi et al., A Phase I Evaluation of LY231514, 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., U.S. Patent No. 5,217,974, issued June 8, 1993 (Ex. 1005)
`(“the ’974 patent”).
`
`7
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`Hammond I. 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 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. Niyikiza
`and Niyikiza II 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.
`
`
`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. 1006)
`(“Niyikiza” or “Niyikiza I”).
`10 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. 1016) (“Niyikiza II”).
`
`8
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`The court further explained that in Niyikiza and Niyikiza II, 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 *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 U.S. 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
`
`9
`
`
`
`IPR2016-00318
`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 [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
`
`10
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`have viewed as “a problem.” Id. (alteration in original) (quoting Ex. 1064,11
`138:7–8).
`The Federal Circuit found that two prior art references, one of them
`being Calvert 1999,12 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.
`Instituted Challenges
`E.
`We instituted trial based on the following grounds of unpatentability
`(Dec. Inst. 21):
`References
`Calvert, Niyikiza I, Worzalla,
`EP 005, 13 and the ’974 patent
`
`11 Petitioner did not file Exhibit 1064 in this proceeding. Paper 75, 9. The
`same exhibit is filed as Exhibit 1051 in IPR2016-00237.
`12 Hilary Calvert, An Overview of Folate Metabolism: Features Relevant to
`the Action and Toxicities of Antifolate Anticancer Agents, SEMINARS
`ONCOLOGY, Apr. 1999, at 3 (Ex. 1007) (“Calvert 1999” or “Calvert”).
`13 Willem Jacob Serfontein, EP 0 595 005 A1, published May 4, 1994
`(Ex. 1033) (“EP 005”).
`
`Claims Challenged
`1–22
`
`Basis
`§ 103(a)
`
`11
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`Basis
`§ 103(a)
`
`Claims Challenged
`1–22
`
`References
`Calvert, Niyikiza I, Hammond I,
`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, M.D, 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 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 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.
`Claim Construction
`A.
`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. 14‒15 (citing Ex. 2120 ¶¶ 28‒29). Patent
`
`13
`
`
`
`IPR2016-00318
`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, 6:57‒67, 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 Ex. 1001, 4:4‒27; 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 “mammal” and “patient.”
`Level of Ordinary Skill in the Art
`B.
`Petitioner contends:
`[T]he person of ordinary skill in the art (“POSA”) at the
`time of the alleged invention would have been a medical doctor
`experienced in oncology with knowledge and/or several years
`of experience regarding the use of antifolates in the treatment of
`
`
`14 We note that the analysis of the patentability of the claims, below, would
`be the same under either Petitioner’s or Patent Owner’s proposed
`construction.
`
`14
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`cancer and additional qualifications or experience in the field of
`nutritional sciences involving vitamin deficiencies.
`Pet. 18 (citing Ex. 1004 ¶ 13).
`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 ¶ 23. The
`[ordinary artisan] 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. ¶ 25.
`PO Resp. 13‒14.
`Patent Owner notes that the definition of the ordinary artisan as
`provided by Petitioner’s expert, Dr. Schiff, “is generally consistent with Dr.
`Chabner’s definition.” PO Resp. 14. Thus, we determine we need not
`distinguish between the two definitions provided. We note further 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, to the
`extent there may be minor differences, our analysis would be the same under
`either Petitioner’s or Patent Owner’s definition of the ordinary artisan.
`
`15
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`C. Obviousness over Calvert, Niyikiza I, and Worzalla or Hammond I,
`in addition to EP 005, and the ’974 patent15
`Petitioner contends that claims 1–22 are rendered obvious by the
`combination of over Calvert, Niyikiza I, Worzalla or Hammond I, EP 005,
`and the ’974 patent. Pet. 27–59. 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. 17–
`57.
`
`
`
`Overview of the Prior Art Relied Upon
`i.
`We find the following as to the teachings of the relevant prior art.
`a.
`Calvert (Ex. 1007)
`Calvert provides an overview of folate metabolism and describes
`features relevant to the action and toxicities of antifolate cancer agents.
`Ex. 1007, 3. According to Calvert, the development of cancer therapeutics
`has been linked intimately to the study of folic acid metabolism and the
`action of antifolate drugs. Id. Calvert depicts the chemical structures of
`various antifolates, including methotrexate, lometrexol, and MTA. Id. at 6.
`Folic acid supplementation is said to reduce the toxicity of antifolate drugs.
`Id. at 8. Calvert also discusses, however, how it had been difficult to
`correlate antifolate-induced toxicity with pretreatment folate levels. Id.
`Calvert teaches that intracellular homocysteine can be reduced by
`converting it to methionine through remethylation by methionine synthase.
`Id. at 8–9. Figure 8 of Calvert is reproduced below:
`
`
`15 We note that both Petitioner and Patent Owner addressed the two
`instituted grounds simultaneously, so we do the same in this Decision.
`
`16
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`
`
`
`Id. at 9. As depicted in Figure 8 of Calvert, methionine synthase requires
`folate (5-methyltetrahydrofolate) as a methyl donor and vitamin B12 as a
`cofactor for the remethylation reaction. According to Calvert, an increase in
`the plasma level of homocysteine occurs when there is a functional
`deficiency in either vitamin B12 or folate, and that the “measurement of
`pretreatment plasma homocysteine has proved to be a sensitive way of
`predicting the toxicity of MTA.” Id. at 8‒9.
`b.
`Niyikiza I (Ex. 1006)
`Niyikiza I, a meeting abstract, states that MTA (pemetrexed) “is a
`novel multitargeted antifolate with inhibitory activity against multiple
`enzymes.” Ex. 1006, 126, Abstract 609P. According to Niyikiza I,
`“[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 I states that the “purpose of th[e] study was to
`assess the relationship of vitamin metabolites, drug exposure, and other
`prespecified baseline patient characteristics to toxicity following retreatment
`with MTA.” Id.
`Niyikiza I 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
`
`17
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`resulting from the MTA treatment were found to be predictable from
`pretreatment homocysteine levels. Id. at 127. In particular, Niyikiza I found
`that “[e]levated baseline homocysteine levels (≥ 10µM) 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 I states that further studies are
`underway in patients with renal impairment or patients who received prior
`cisplatin. Id.
`
`EP 005 (Ex. 1033)
`c.
`EP 005 is drawn to pharmaceutical preparations for lowering blood
`
`and tissue levels of homocysteine and counteracting harmful effects
`associated with homocysteine. Ex. 1033, Abstract, 2:1–3. 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 2:4‒6. 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 2:25–30. 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. EP 005 teaches that
`
`18
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`other situations in which blood homocysteine may be elevated include
`leukemia and other cancers. Id. at 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 result in better control of
`blood homocysteine levels at lower dosages of each. Id. at 11:23‒26.
`A suitable daily dosage of the pharmaceutical preparation is described
`in the table reproduced below:
`
`
`
`19
`
`
`
`IPR2016-00318
`Patent 7,772,209 B2
`
`Id. at 8:14–51. As shown i
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
