Case: 18—1257
`
`Document: 91
`
`Page: 1
`
`Filed: 04/26/2019
`
`@Hniteh games (Enurt of appeals
`
`for the jfeheral QEirwit
`
`NEPTUNE GENERICS, LLC, FRESENIUS KABI
`USA, LLC,
`Appellants
`
`V.
`
`ELI LILLY & COMPANY,
`Appellee
`
`2018-1257, 2018-1258
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00237, IPR2016-00240, IPR2016-01190, IPR2016-01191,
`IPR2016-01335,
`IPR2016-01337,
`IPR2016-01341,
`IPR2016-01343.
`
`MYLAN LABORATORIES LIMITED, FRESENIUS
`KABI USA, LLC,
`Appellants
`
`V.
`
`E-LI LILLY & COMPANY,
`Appellee
`
`2018-1288, 2018-1290
`
`

`

`Case: 18—1257
`
`Document: 91
`
`Page: 2
`
`Filed: 04/26/2019
`
`2
`
`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00818, IPR2016-01340, IPR2016-01393, IPR2016-01429.
`
`Decided: April 26, 2019
`
`SARAH ELIZABETH SPIRES, Skiermont Derby LLP, Dal-
`las, TX, argued for all appellants. Appellant Neptune Ge-
`nerics, LLC also represented by PAUL SKIERMONT; MIEKE
`K. MALMBERG, Los Angeles, CA; JOSHUA HARLAN HARRIS,
`Neptune Generics, LLC, Chicago, IL.
`
`MICHAEL B. COTTLER, Goodwin Procter LLP, New York,
`NY, for appellant Fresenius Kabi USA, LLC.
`
`THOMAS J. PARKER, Alston & Bird LLP, New York, NY,
`for appellant Mylan Laboratories Limited. Also repre-
`sented by CHARLES ABRAHAM NAGGAR, STEPHEN YANG.
`
`ADAM LAWRENCE PERLMAN, Williams & Connolly LLP,
`Washington, DC, argued for appellee. Also represented by
`GALINA I. FOMENKOVA, DOV PHILIP GROSSMAN, DAVID M.
`KRINSKY, ANDREW P. LEMENS, CHARLES McCLOUD; JAMES
`PATRICK LEEDS, Eli Lilly and Company, Indianapolis, IN.
`
`Before MOORE, WALLACH, and HUGHES, Circuit Judges.
`
`MOORE, Circuit Judge.
`
`Neptune Generics, LLC, Fresenius Kabi USA, LLC,
`and Mylan Laboratories Ltd. (“Petitioners”) appeal the Pa-
`tent Trial and Appeals Board’s inter partes review (“IPR”)
`decisions holding Petitioners did not establish that claims
`1—22 of US. Patent No. 7,772,209 are unpatentable for
`
`

`

`Case: 18-1257
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`Document: 91
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`Page: 3
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`Filed: 04/26/2019
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`3
`
`obviousness. Because the Board did not err in its obvious-
`
`ness analysis, substantial evidence supports its underlying
`fact findings, and subject matter eligibility is not properly
`before the court in an appeal from an IPR decision, we af-
`firm.
`
`BACKGROUND
`
`The ’209 patent is owned by Eli Lilly & Co. and relates
`to administering folic acid and a methylmalonic I acid
`(“MMA”) lowering agent, such as vitamin B12, before ad-
`ministering pemetrexed disodium, a chemotherapy agent,
`in order to reduce the toxic effects of pemetrexed, an anti-
`folate.
`’209 patent at 1:19—21, 57—61. Antifolates inhibit
`enzymes used in making the components of DNA and RNA,
`slowing the ability of cells to divide. Id. at 1:36—38. How-
`ever, antifolates have toxic effects, which can be life threat-
`ening. E.g., id. at 1:11—12; 1:62—2z4.
`
`The two independent claims in the patent are method
`of treatment claims. They recite:
`
`1. A method for administering pemetrexed diso-
`dium to a patient in need thereof comprising ad-
`ministering 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 vita-
`min B12, hydroxycobalamin,
`cyano-IO-
`chlorocobalamin, aquocobalamin perchlo-
`rate, aquo-lO-cobalamin perchlorate, az-
`idocobalamin, cobalamin, cyanocobalamin,
`or chlorocobalamin.
`
`administering
`12. An improved method for
`pemetrexed disodium to a patient in need of chemo-
`therapeutic treatment, Wherein the improvement
`comprises:
`
`

`

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`Document191
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`4
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
`
`a) administration of between about 350 pg
`and about 1000 pg of folic acid prior to the
`first administration of pemetrexed diso-
`dium;
`
`b) administration of about 500 pg to about
`1500 pg of Vitamin B12, prior to the first
`administration of pemetrexed disodium;
`and
`
`c) administration of pemetrexed disodium.
`
`The Board considered three petitions for IPR, each of
`which alleged the claims would have been obvious.
`In
`IPR2016-00318, Petitioners alleged claims 1—22 would
`have been obvious over a 1999 article by Hilary Calvert,
`titled “An Overview of Folate Metabolism: Features Rele-
`
`vant to the Actions and Toxicities of Antifolate Anticancer
`
`Agents”; a 1998 abstract by C. Niyikiza, et. al., titled “MTA
`(LY231514): Relationship of vitamin metabolite profile,
`drug exposure, and other patient characteristics to tox-
`icity” (“Niyikiza I”); a 1998 article by John F. Worzalla, et
`al., titled “Role of Folic Acid in Modulating the Toxicity and
`Efficacy of the Multitargeted Antifolate, LY231514”; Euro-
`pean Patent Application 0 595 005 A1 (“EP005”); and US.
`Patent No. 5,217,974.
`In IPR2016-00237, Petitioner al-
`leged the claims would have been obvious over Niyikiza I,
`the ’974 patent, and EP005. In IPR2016-00240, Petitioners
`alleged the claims would have been obvious over a 1999 ar-
`ticle by James J. Rusthoven, et al., titled “Multitargeted
`Antifolate LY281514 As First-Line Chemotherapy for Pa-
`tients with Advanced Non-Small—Cell Lung Cancer: A
`Phase II Study,” and EP005.
`
`The Board concluded in each case that the claims were
`
`It
`not established to be unpatentable for obviousness.
`found that it was known in the prior art that pretreatment
`with folic acid reduces the toxicity associated with admin-
`istration of an antifolate, like pemetrexed, but there was
`not a reason to pre‘treat with vitamin B12 along with folic
`
`

`

`Case: 18-1257
`
`Document: 91
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`Page: 5
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`Filed: 04/26/2019
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`5
`
`It
`acid before administering pemetrexed to treat cancer.
`also found that the skepticism of others, particularly the
`FDA, supported a conclusion of nonobviousness. Because
`the Board concluded the independent claims would not
`have been obvious, it did not consider the additional limi-
`tations of the dependent claims.
`
`Petitioners appeal. We have jurisdiction under
`28 U.S.C. § 1295(a)(4)(A).
`
`DISCUSSION
`
`We review the Board’s legal determinations de novo
`and its underlying factual findings for substantial evi-
`. dence. Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073
`(Fed. Cir. 2015). Obviousness is a question oflaw based on
`underlying facts. Id. Motivation to combine is a question
`of fact.
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge
`Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016).
`
`On appeal, the parties focus on three references: Ni-
`yikiza I, EP005, and another abstract by C. Niyikiza, et al.,
`titled “Relationship of Vitamin Metabolite Profile to Tox-
`icity,” (“Niyikiza II”). The lead author on Niyikiza I and II
`is also the sole named inventor of the ’209 patent.
`
`Pretreatment with Vitamin B12
`
`The Board found that that a skilled artisan would not
`
`have been motivated to administer an MMA lowering
`agent, such as vitamin B12, in addition to folic acid. On
`appeal, Petitioners argue that in making this finding, the
`Board did not consider EP005 for all that it teaches. Spe-
`cifically, PetitiOners point to EPOO5’S disclosure of the ad-
`ministration of
`folic acid and vitamin B12 to lower
`
`homocysteine levels for all purposes. We disagree and hold
`that substantial evidence supports the Board’s findings.
`
`The Board’s findings are based on the prior art’s disclo-
`sure of the relationships between various biochemicals and
`toxicity. The Board found that deficiencies in both vitamin
`
`

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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`B12 and folate can lead to elevated levels of the biomarker
`
`homocysteine. In contrast, it found that elevated levels of
`MMA are correlated only with vitamin B 12 deficiencies and
`not folate deficiencies. J .A. 61. Therefore, in patients with
`a vitamin B12 deficiency, but not a folate deficiency, both
`MMA levels and homocysteine levels would be elevated,
`while in patients with just a folate deficiency homocysteine
`levels would be elevated, but MMA levels would not be el-
`evated. The Board further found that while elevated levels
`
`of homocysteine were known to be predictive of pemetrexed
`toxicity, elevated levels of MMA were understood to not be
`a predictor of pemetrexed toxicity. Because elevated MMA
`levels are not predictive of toxicity, but do correlate with
`vitamin B12 deficiency, the Board credited the testimony
`of Lilly’s expert Dr. Bruce Chabner that a skilled artisan
`would have understood that there was no observed correla-
`
`tion between vitamin B12 deficiency and pemetrexed-in-
`duced toxicity. J .A. 62—63.
`
`Each step of the Board’s analysis is supported by sub-
`stantial evidence. In finding that elevated MMA levels cor-
`related with vitamin B12 deficiency but not
`folate
`deficiency, the Board considered the disclosures in a prior
`art article by David G. Savage, et al., which found that in
`patients with vitamin B12 deficiency 94.8% of MMA levels
`and 95.9% of homocysteine levels were elevated, but in pa-
`tients with folate deficiencies, only 12.2% of MMA levels
`were elevated while 91% of homocysteine levels were.
`J .A. 61 (citing J .A. 7698). These findings are further sup-
`ported by additional prior art and are consistent with the
`testimony of Petitioner’s expert Dr. Ron Schiff. J .A. 60—61
`(citing J .A. 4404).
`
`The Board’s finding that while elevated levels of homo-
`cysteine were known to be predictive of pemetrexed tox-
`icity, elevated levels of MMA were understood to not be a
`predictor of pemetrexed toxicity is also supported by sub-
`stantial evidence. Niyikiza I discloses that elevated levels
`of homocysteine are predictive of pemetrexed toxicity,
`
`

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`Document: 91
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`Page: 7
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`J .A. 4148, and the Board credited Dr. Chabner’s testimony
`that a skilled artisan would have read Niyikiza II to mean
`that elevated MMA levels were not a predictor of
`pemetrexed-induced toxicity, J.A. 62—63 (citing J .A. 9084).
`The Board further credited Dr. Chabner’s testimony that
`given the link between vitamin B12 deficiency and elevated
`MMA levels, and the lack of a correlation between elevated
`MMA levels and pemetrexed-induced toxicity, a skilled ar-
`tisan would have understood “there was no correlation ob-
`
`served between vitamin B12 deficiency and pemetrexed-
`induced toxicity.” J .A. 62 (quoting J .A. 9084). Because vit-
`amin B12 deficiencies are linked to both elevated levels of
`
`MMA and homocysteine, the mere fact that homocysteine
`is correlated'with toxicity does not mean that vitamin B12
`levels are linked with toxicity. In short, this evidence indi-
`cates that pemetrexed-inducted toxicity correlated with fo-
`late deficiencies, but not vitamin B12 deficiencies.
`
`,
`
`Collectively, this constitutes substantial evidence in
`support of the Board’s finding that the art did not provide
`a motivation for a skilled artisan to administer an MMA
`
`lowering agent, such as vitamin B12, in addition to folic
`acid.
`In contrast, the Board found that there would have
`been a motivation to pretreat with folate, which was a
`known way to reduce the toxicity associated with admin-
`istration of an antifolate, like pemetrexed. J .A. 50.
`
`Petitioners argue that EPOO5 teaches the administra-
`tion of folic acid and vitamin B12 to lower homocysteine
`levels for all purposes. Therefore, they argue, a skilled ar-
`tisan would have been motivated to pretreat with vitamin
`B12. This is, at heart, a challenge to the Board’s factual
`findings, and the Board’s position is supported by substan-
`tial evidence. Admittedly, EPOO5 states that it “is applica-
`ble to the lowering of total homocysteine blood levels if
`elevated by any known cause.” J .A. 4409. However, as the
`Board found, EP005 is concerned with the cardiovascular
`effects associated with elevated homocysteine levels, does
`not discuss antifolates generally, and only generally
`
`

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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`mentions certain cancers. J .A. 67 (citing J .A. 4407). More-
`over, the Board found that the levels of homocysteine asso-
`ciated with elevated pemetrexed toxicity risk were not
`“elevated” as that term is defined in EPOO5. J .A. 68—69.
`
`This is consistent with the plain language of EPOO5 and the
`testimony of Dr. Schiff.
`J.A. 4417, 7308—09. Likewise,
`while EPOO5 also states that methotrexate, an antifolate
`drug like pemetrexed, “induce [s] elevated homocysteine
`levels,” J .A. 4409, the Board noted that, in contrast, Ni-
`yikiza II explained that pemetrexed did not increase homo-
`cysteine levels, J .A. 67, 4148. Given the contrast between
`the specific, directly applicable teachings of Niyikiza II and
`the tangential, general statements of EPOO5, substantial
`evidence supports the Board’s finding that EPOO5 did not
`provide information as to how pretreatment with folic acid
`and vitamin B12 would impact toxicity effects. J .A. 69.
`
`Petitioners attempt to evade the substantial evidence
`standard of review by manufacturing legal error. Among
`other things, they argue the Board legally erred in its treat-
`ment of EP005 and in requiring the art to directly link vit-
`amin B12 deficiency with pemetrexed toxicity. The Board
`extensively discussed EPOO5 both individually and in the
`context of the prior art, and we see no error in its analysis.
`Likewise, we see nothing in the Board’s opinion that re-
`quired the art directly link vitamin B12 deficiency with
`pemetrexed toxicity.
`
`Lilly’s Statements to the FDA
`
`During clinical trials of pemetrexed, Lilly engaged in
`various communications with the FDA. Petitioners argue
`that the Board erred in not considering these statements
`and precluding Lilly from taking contrary positions in the
`IPR. In particular, they argue that in its communications
`with the FDA, Lilly “inform[ed] the FDA that the prior art
`suggested that pretreating with folic acid and B12 was a
`no-risk, predictable way to lower pemetrexed-induced fa-
`talities by lowering pretreatment homocysteine levels.”
`
`

`

`Case: 18-1257
`
`Document: 91
`
`Page: 9
`
`Filed: 04/26/2019
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`.
`
`9
`
`Appellants’ Br. 33. It argues that even if these communi-
`cations are not in the prior art, they reflect the background
`knowledge of a skilled artisan and are indicators of the
`level of ordinary skill in the art.
`
`The level of skill in the art and the scope and content
`of the prior art are fact questions we review for substantial
`evidence. Arctic Cat Inc. v. Bombardier Recreational
`
`Prods. Inc, 876 F.3d 1350, 1358 (Fed. Cir. 2017). While, a
`patent owner’s own disclosures to the FDA may be consid-
`ered in assessing the state of the prior art, In re Copaxone
`Consol. Cases, 906 F.3d 1013, 1030 (Fed. Cir. 2018), a fact
`finder must not allow its analysis to be distorted by hind-
`sight bias, KSR Int’l Co. v. Teleflex, 550 US. 398, 421
`(2007).
`
`Here, the statements Petitioners argue established the
`state of the art were made in December 1999, more than
`five months after the critical date. As the Board found, the
`views Lilly expressed about the prior art references in its
`communications are made through the lens of what they
`had invented. J .A. 81. Therefore, it declined to read the
`other prior art references in View of these communications.
`In doing so, the Board did not err.
`
`Skepticism
`
`Evidence of industry skepticism is a question of fact
`that weighs in favor of non-obviousness. WBIP, LLC v.
`Kohler Co., 829 F.3d 1317, 1335 (Fed. Cir. 2016). The
`Board found that evidence of skepticism of others, particu-
`larly the FDA, supported a conclusion of nonobviousness.
`J .A. 87. During Lilly’s clinical trials for pemetrexed, a
`number of fatalities occurred.
`In response, Lilly recom-
`mended supplementation with folic acid and vitamin B12.
`The FDA responded that the “medical officer does not sup-
`port adding vitamins to the ongoing .
`.
`. trial.” J .A. 8748
`(capitalization changed).
`In other communications with
`Lilly it stated that the information provided to it “does not
`
`

`

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`Document: 91
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
`
`appear to support the addition of vitamins,” J .A. 8750, and
`“the addition of vitamins .
`.
`. is risky,” J .A. 8687.
`
`Petitioners argue that the Board legally erred in hold-
`ing this evidence sufficient to support a finding of skepti-
`cism because, despite the FDA’s concerns, it allowed the
`trial to continue.
`It argues skepticism must be premised
`on whether it is “technically infeasible,” “unworkable,” or
`“impossible” that the claimed subject matter would work
`for its intended purpose. Appellants’ Br. 51. This position
`is not consistent with our caselaw, which recognizes a
`range of third-party opinion that can constitute skepticism.
`See, e.g., Circuit Check Inc. v. QXQ Inc, 795 F.3d 1331,
`1337 (Fed. Cir. 2015) (holding testimony that third parties
`were “worried” or “surprised” was sufficient to establish
`skepticism). The FDA’s concerns in this case fall well
`within that range. While evidence that third parties
`thought the invention was impossible might be entitled to
`more weight, that does not mean the Board erred in giving
`weight to the skepticism evidence here. Accordingly, the
`Board did not err in finding that skepticism supported a
`conclusion of nonobviousness.
`
`Dependent Claims
`
`Petitioners argue the nonobviousness determination
`should be reversed for the dependent claims as well. Given
`our affirmance as to the independent claims, we likewise
`affirm as to the dependent claims.
`
`Patent Eligibility
`
`Finally, Petitioners argue the claims are not directed
`to patentable subject matter.
`It argues this issue is
`properly raised because eligibility is a question of law and
`in this appeal there are no factual issues that must be de-
`cided. We do not agree. Congress expressly limited the
`scope of inter partes review to a subset of grounds that can
`be raised under 35 U.S.C. §§ 102 & 103. 35 U.S.C. § 311(b)
`(stating that in an “inter partes review,” a petitioner is
`
`

`

`Case: 18-1257
`
`Document: 91
`
`Page: 11
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`Filed: 04/26/2019
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`NEPTUNE GENERICS, LLC V. ELI LILLY & COMPANY
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`11
`
`limited to only grounds that “could be raised under section
`102 or 103”). The ground of patent eligibility arises under
`§ 101. Accordingly, we may not address it on appeal of an
`IPR.
`
`CONCLUSION
`
`We have considered Petitioners’ remaining arguments
`and find them unpersuasive. Accordingly, we affirm.
`
`AFFIRMED
`
`

`

`Case: 18-1257
`
`Document: 92
`
`Page: 1
`
`Filed: 04/26/2019
`
`UHntteiJ étates @Znurt of gppealg
`
`for the feheral Qtirtuit
`
`NEPTUNE GENERICS, LLC, FRESENIUS KABI
`USA, LLC,
`Appellants
`
`V.
`
`ELI LILLY & COMPANY,
`Appellee
`
`2018- 1257, 2018-1258
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00237, IPR2016-00240, IPR2016-01190, IPR2016-01191,
`IPR2016-01335,
`IPR2016-01837,
`IPR2016-01341,
`IPR2016-01343.
`
`MYLAN LABORATORIES LIMITED, FRESENIUS
`KABI USA, LLC,
`Appellants
`
`V.
`
`ELI LILLY & COMPANY,
`Appellee
`
`20 18- 1288, 2018- 1290
`
`

`

`Case:18-—1257
`
`Document: 92
`
`Page:2
`
`Filed:04/26/2019
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00318, IPR2016-01340, IPR2016-01393, IPR2016-01429.
`
`JUDGMENT
`
`THIS CAUSE having been considered, it is
`
`ORDERED AND ADJUDGED:
`
`AFFIRMED
`
`ENTERED BY ORDER OF THE COURT
`
`April 26, 2019
`
`/s/ Peter R. Marksteiner
`Peter R. Marksteiner
`
`Clerk of Court
`
`

`

`Casez18-1257
`
`Document: 93
`
`Page:1
`
`Filed:06/O4/2019
`
`Uflntteh étates (Enurt of gppeals
`
`£017th jfeberal QEirtuit
`
`NEPTUNE GENERICS, LLC, FRESENIUS KABI
`USA, LLC,
`Appellants
`
`V.
`
`ELI LILLY & COMPANY,
`Appellee
`
`2018—1257, 2018- 1258
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00237, IPR2016-00240, IPR2016-01190, IPR2016-01191,
`IPR2016-01335,
`IPR2016-01337,
`IPR2016-01341,
`IPR2016-01343.
`
`MYLAN LABORATORIES LIMITED, FRESENIUS
`KABI USA, LLC,
`Appellants
`
`V.
`
`ELI LILLY & COMPANY,
`Appellee
`
`2018-1288, 2018- 1290
`
`

`

`Case:18—1257
`
`Document: 93
`
`Page:2
`
`Filed:O6/O4/2019
`
`Appeals from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in Nos. IPR2016-
`00318, lPR2016-01340, IPR2016-01393, IPR2016-01429.
`
`MANDATE
`
`In accordance with the judgment of this Court, entered
`April 26, 2019, and pursuant to Rule 41 of the Federal
`Rules of Appellate Procedure,
`the formal mandate is
`hereby issued.
`
`June 04, 2019
`
`FOR THE COURT
`
`/s/ Peter‘R. Marksteiner
`Peter R. Marksteiner
`Clerk of Court
`
`