`
` Paper No. 82
`Trials@uspto.gov
`571.272.7822 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 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 IPR2016-01191, IPR2016-01337, and IPR2016-01343 have been
`joined with the instant proceeding.
`
`
`
`IPR2016-00240
`Patent 7,772,209 B2
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`
`INTRODUCTION
`I.
`Neptune Generics, LLC, 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 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 inter partes review in that case and
`granted joinder. IPR2016-01191, 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, Teva
`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
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`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 Sur-reply (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 (“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.
`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. Teva
`Parenteral Medicines, Inc., No. 1:10-cv-1376 (S.D. Ind.) (filed Oct. 29,
`2010). Pet. 2–3; Prelim. Resp. 2.
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`The ’209 patent also has been challenged in IPR2016-00237 by
`Neptune Generics, LLC, and in IPR2016-00318 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.
`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. 1024 ¶ 67. 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. 1024 ¶ 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
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`associated with the administration of antifolate drugs was unknown
`heretofore.” Id. at 2:50–54.
`The ’209 patent describes “[a] method of administering an antifolate
`to a mammal in need thereof.” Id., Abstract. The method is said to improve
`the therapeutic utility of antifolate drugs by administering a methylmalonic
`acid (“MMA”) lowering agent, such as vitamin B12, to the host undergoing
`treatment. Id. at 2:37–46. The ’209 patent also states that a combination of
`a MMA lowering agent, such as vitamin B12, and folic acid “synergistically
`reduces the toxic events associated with the administration of antifolate
`drugs.” Id. at 2:47–50.
`The term antifolate is said to encompass chemical compounds that
`inhibit at least one key folate-requiring enzyme of the thymidine or purine
`biosynthetic pathways. Id. at 4:28–34. Pemetrexed disodium is the most
`preferred antifolate for the ’209 patent. Id. at 4:28–43. Pemetrexed is also
`referred to in the art as the “multitargeted antifolate” (“MTA”). 2 Ex. 1022,
`1293, Abstract 620P.
`
`Illustrative Claims
`C.
`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.
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`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 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
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`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
`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
`
`
`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. 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 of the
`Multitargeted Antifolate (MTA, LY231514) with Folic Acid (FA), 9 ANNALS
`ONCOLOGY 129, Abstract 620P (Supp. 4 1998) (Ex. 1022) (“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. 2072
`(not filed, Paper 67, 9)) (“the ’974 patent”).
`
`7
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`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”).
`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. 2015) (“Niyikiza II”).
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`and vitamin B12 levels. Id. The court therefore found that the ordinary
`artisan would have concluded that vitamin B12 deficiency was not the
`problem in pemetrexed toxicity. Id. at *10.
`
`Also, the court was not persuaded by evidence indicating that vitamin
`B12 was routinely added to folic acid pretreatment to prevent “masking,” a
`problem in which a vitamin B12 deficiency was misdiagnosed as a folate
`deficiency. Id. at *9–10. The court found this evidence to be in the context
`of treating rheumatoid arthritis, where vitamin B12’s interference with the
`antiproliferative effects of the active drug was less of a concern than in
`treating cancer. Id. at *10. Likewise, the court described other evidence
`showing that in patients who were vitamin B12 deficient, folate became
`“trapped” in cells, and when patients were later administered vitamin B12,
`that administration released the folates from the trap, counteracting the
`efficacy of an antifolate drug. Id. at *11.
`
`In making the third 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
`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
`
`9
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`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 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,
`138:7–8).
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`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. 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 Challenge
`E.
`We instituted trial based on the following ground of unpatentability
`(Dec. Inst. 19):
`
`
`11 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. 1014) (“Calvert 1999”).
`
`11
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`References
`Rusthoven12 and EP 00513
`
`Basis
`§ 103(a)
`
`Claims Challenged
`1–22
`
`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’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);
`
`
`12 James J. Rusthoven et al., Multitargeted Antifolate LY231514 As First-
`Line Chemotherapy for Patients with Advanced Non-Small-Cell Lung
`Cancer: A Phase II Study, 17 J. CLINICAL ONCOLOGY 1194 (1999)
`(Ex. 1011) (“Rusthoven”).
`13 Willem Jacob Serfontein, EP 0 595 005 A1, published May 4, 1994
`(Ex. 1010) (“EP 005”).
`
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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
`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.
`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 IPR2016-00318.
`PO Resp. 16. For purposes of this Decision, we do not disagree with that
`claim construction, and, moreover, as that term is not in dispute in this
`proceeding, do not find a need to construe it here.
`
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`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
`M.D. 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 ¶ 20.) “A POSA may work as part of a
`multi-disciplinary team and draw upon not only his or her own
`skills, but also take advantage of certain specialized skills of
`others on the team, to solve a given problem. For example, an
`expert in nutrition, an expert in hematology, a basic scientist
`with expertise in biochemistry, and a clinician may be part of
`the team.” (Id. ¶ 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] ¶ 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. ¶ 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 ¶ 24; Ex. 2118 ¶ 17).
`
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`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.
`
`i.
`
`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
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`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, 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; Ex. 1025 ¶ 64.
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`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 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:
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`Id. at 8:14–51. As shown in the table above, a patient is to receive a daily
`dose of PL (pyridoxal, the preferred form of vitamin B6); folate; and vitamin
`B12. Id. at 6:12–17, 8:14–51.
`
`Example 1 of EP 005 reports that a successful treatment is considered
`to be a reduction in homocysteine plasma levels below 16.3µmol/l. Id. at
`13:28‒30. Example 8 reports the administration of vitamins B6 and B12, as
`well as folate, to patients with hyperhomocysteinemia. Id. at 17:25‒27.
`EP 005 defines “elevated plasma homocysteine” as greater than 16.3µmol/l.
`Id. at 17:28; see also id. at 12:42‒45 (same).
`c.
`Niyikiza (Ex. 1008)
`Niyikiza, a meeting abstract, states that MTA (pemetrexed) “is a novel
`multitargeted antifolate with inhibitory activity against multiple enzymes.”
`Ex. 1008, 126, Abstract 609P. According to Niyikiza, “[h]istorical data on
`other antifolates have suggested that a patient’s nutritional status may play a
`role in the likelihood of experiencing severe toxicity.” Id. Thus, Niyikiza
`states that the “purpose of th[e] study was to assess the relationship of
`vitamin metabolites, drug exposure, and other prespecified baseline patient
`characteristics to toxicity following retreatment with MTA.” Id.
`Niyikiza describes treating 139 patients with tumors in a Phase II
`study with MTA and monitoring the patients for homocysteine,
`cystathionine, and methylmalonic acid (“MMA”) levels. Id. Toxicities
`resulting from the MTA treatment were found to be predictable from
`pretreatment homocysteine levels. Id. at 127. In particular, Niyikiza found
`that “[e]levated baseline homocysteine levels (≥ 10µM) highly correlate
`with severe hematologic and nonhematologic toxicities following treatment
`with MTA,” and that “[h]omocysteine was found to be better than albumin
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`at predicting toxicity.” Id. Niyikiza states that further studies are underway
`in patients with renal impairment or patients who received prior cisplatin.
`Id.
`
`Niyikiza II (Ex. 2015)
`d.
`Niyikiza II, a meeting abstract, considers the relationship of
`
`metabolite profile in relation to the toxicity of pemetrexed. Ex. 2015, 558a,
`Abstract 2139. Specifically, Niyikiza II teaches that of 246 patients being
`treated with pemetrexed in Phase II trials, 118 also had the vitamin
`metabolites homocysteine, cystathionine, and methylmalonic acid measured
`at baseline and once each cycle thereafter. Id. Niyikiza II performed a
`statistical analysis to determine which among a set of prespecified
`predictors, including vitamin metabolites, might correlate with toxicity. Id.
`Niyikiza II found a strong correlation between baseline homocysteine levels
`and the development of certain toxicities, with toxicity being seen in all
`patients with homocysteine levels over 10 µM. Id. Niyikiza II, however,
`found no correlation between toxicity and the remaining prespecified
`predictors. Id. Furthermore, according to Niyikiza II, “[m]aximum
`homocysteine levels did not appear to change from baseline during treatment
`with [pemetrexed].” Id.
`Calvert 1999 (Ex. 1014)
`e.
`Calvert 1999 provides an overview of folate metabolism and describes
`features relevant to the action and toxicities of antifolate cancer agents.
`Ex. 1014, 3. According to Calvert 1999, the development of cancer
`therapeutics
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