Court Opinion

ID: 4766016
Source: CourtListenerOpinion
Date Created: 2021-08-16 15:01:45.204455+00
Date Added: 2024-06-11T08:09:14.256962
License: Public Domain

Case: 20-1747    Document: 79    Page: 1    Filed: 08/16/2021

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

   TEVA PHARMACEUTICALS INTERNATIONAL
                 GMBH,
                Appellant

                            v.

                ELI LILLY AND COMPANY,
                         Appellee

   ANDREW HIRSHFELD, PERFORMING THE
    FUNCTIONS AND DUTIES OF THE UNDER
       SECRETARY OF COMMERCE FOR
 INTELLECTUAL PROPERTY AND DIRECTOR OF
 THE UNITED STATES PATENT AND TRADEMARK
                   OFFICE,
                   Intervenor
             ______________________

            2020-1747, 2020-1748, 2020-1750
                ______________________

     Appeals from the United States Patent and Trademark
 Office, Patent Trial and Appeal Board in Nos. IPR2018-
 01422, IPR2018-01423, IPR2018-01425.
                  ______________________

                 Decided: August 16, 2021
                  ______________________

    WILLIAM M. JAY, Goodwin Procter LLP, Washington,
 DC, argued for appellant. Also represented by ELAINE
 BLAIS, EDWINA CLARKE, ALEXANDRA LU, Boston, MA;
Case: 20-1747     Document: 79     Page: 2     Filed: 08/16/2021

 2            TEVA PHARMACEUTICALS     v. ELI LILLY AND COMPANY

 NATASHA ELISE DAUGHTREY, Los Angeles, CA; WILLIAM
 MILLIKEN, DEBORAH STERLING, Sterne Kessler Goldstein &
 Fox, PLLC, Washington, DC.

     WILLIAM BARRETT RAICH, Finnegan, Henderson,
 Farabow, Garrett & Dunner, LLP, Washington, DC, ar-
 gued for appellee. Also represented by CHARLES COLLINS-
 CHASE, PIER DEROO, ERIN SOMMERS, YIEYIE YANG; SANJAY
 M. JIVRAJ, MARK STEWART, Eli Lilly and Company, Indian-
 apolis, IN.

     MONICA BARNES LATEEF, Office of the Solicitor, United
 States Patent and Trademark Office, Alexandria, VA, for
 intervenor. Also represented by THOMAS W. KRAUSE,
 BRIAN RACILLA, FARHEENA YASMEEN RASHEED.
                 ______________________

     Before LOURIE, BRYSON, and O’MALLEY, Circuit Judges.
 LOURIE, Circuit Judge.
     Teva Pharmaceuticals International GmbH (“Teva”)
 appeals from a combined final written decision of the U.S.
 Patent and Trademark Office (“PTO”) Patent Trial and Ap-
 peal Board (“Board”) holding that the claims of U.S. Pa-
 tents 9,340,614 (“’614 patent”), 9,266,951 (“’951 patent”),
 and 9,890,210 (“’210 patent”) are unpatentable because
 they would have been obvious over the cited prior art. Eli
 Lilly & Co. v. Teva Pharms. Int’l GmbH, Nos. IPR2018-
 01422, IPR2018-01423, IPR2018-01425, 2020 WL 806932
 (P.T.A.B. Feb. 18, 2020) (“Board Decision”). For the rea-
 sons provided below, we affirm.
                        BACKGROUND
                          I. Patents
     Teva owns the ’614, ’951, and ’210 patents (collectively,
 the “challenged patents”) directed to humanized antago-
 nist antibodies that target calcitonin gene-related peptide
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 TEVA PHARMACEUTICALS       v. ELI LILLY AND COMPANY          3

 (“CGRP”). CGRP is a 37-amino acid peptide that is “a neu-
 rotransmitter in the central nervous system, and has been
 shown to be a potent vasodilator in the periphery, where
 CGRP-containing neurons are closely associated with blood
 vessels.” ’614 patent, col. 1 ll. 49–53.
     The challenged patents explain that “CGRP has been
 noted for its possible connection to vasomotor symptoms,”
 id. at col. 1 ll. 57–58, such as “all forms of vascular head-
 ache, including migraines.” Id. at col 2 ll. 22–23. Although
 at the time of the challenged patents the pathophysiology
 of migraine was not well understood, dilation of blood ves-
 sels was associated with and thought to exacerbate the
 pain symptoms of migraine. Id. at col. 3 ll. 33–44. Thus,
 even before the challenged patents, the possible connection
 between CGRP as a vasodilator and the pathology of mi-
 graine informed the development of treatments for mi-
 graine that sought to restrict the activity of CGRP in the
 body. For example:
     Possible CGRP involvement in migraine has been
     the basis for the development and testing of a num-
     ber of compounds that inhibit release of CGRP
     (e.g., sumatriptan), antagonize at the CGRP recep-
     tor (e.g., dipeptide derivative BIBN4096BS
     (Boe[]hringer Ingelheim); CGRP(8-37)), or interact
     with one or more of receptor-associated proteins,
     such as, receptor activity membrane protein
     (RAMP) or receptor component protein (RCP), both
     of which affect binding of CGRP to its receptors.
 Id. at col. 2 ll. 32–40.
     The challenged patents are directed to humanized an-
 tibodies that antagonize CGRP and thus inhibit its activity
 in the body by targeting and binding to the CGRP ligand
 (as opposed to CGRP receptors). The written description
 describes “anti-CGRP antagonist antibodies and methods
 of using anti-CGRP antagonist antibodies for treating or
 preventing vasomotor symptoms, such as headaches, such
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 4           TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

 as migraine.” Id. at col. 3 ll. 55–63. For purposes of this
 appeal, however, the claims at issue are directed to the an-
 tibodies themselves. 1 Claim 1 in each patent is the only
 independent claim:
         1. A human or humanized monoclonal anti-
     CGRP antagonist antibody that preferentially
     binds to human α-CGRP as compared to amylin.
 ’614 patent, col. 101 ll. 32–34.
        1. A human or humanized monoclonal anti-
     CGRP antagonist antibody that (1) binds human α-
     CGRP and (2) inhibits cyclic adenosine monophos-
     phate (cAMP) activation in cells.
 ’951 patent, col. 99 ll. 21–23.
        1. A humanized monoclonal anti-Calcitonin
     Gene-Related Peptide (CGRP) antagonist anti-
     body, comprising:
         two human IgG heavy chains, each heavy
         chain comprising three complementarity
         determining regions (CDRs) and four
         framework regions, wherein portions of the
         two heavy chains together form an Fc re-
         gion; and
         two light chains, each light chain compris-
         ing three CDRs and four framework re-
         gions;

     1   In contrast to the claims at issue in this case, which
 are directed to the antibodies themselves, Teva also owns
 related patents with claims directed to methods of treat-
 ment comprising a step of administering such antibodies.
 Those claims are at issue in Appeal Nos. 2020-1876, 2020-
 1877, and 2020-1878.
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 TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY             5

         wherein the CDRs impart to the antibody
         specific binding to a CGRP consisting of
         amino acid residues 1 to 37 of SEQ ID
         NO:15 or SEQ ID NO:43.
 ’210 patent, col. 103 ll. 35–45. The differences between
 these claims have not been argued as significant to these
 appeals.
                II. IPR Petitions and Prior Art
     Eli Lilly and Company (“Lilly”) filed petitions for inter
 partes review (“IPR”) of claims 1–7 and 15–20 of the ’614
 patent, claims 1–6 and 14–19 of the ’951 patent, and claims
 1–5 of the ’210 patent. Lilly asserted that each of the chal-
 lenged claims would have been obvious over a combination
 of prior art references that includes Tan, 2 Wimalawansa, 3
 and Queen. 4
     Tan is a publication describing an in vivo study in rats
 using an anti-CGRP monoclonal antibody for immunob-
 lockade. 5 The study investigated the anti-CGRP activity of
 a full-length monoclonal antibody called “MAb C4.19” as

     2   K.K.C. Tan et al., Calcitonin gene-related peptide
 as an endogenous vasodilator: immunoblockade studies in
 vivo with an anti-calcitonin gene-related peptide monoclo-
 nal antibody and its Fab’ fragment, 89 CLINICAL SCI. 6,
 565–73 (1995).
     3   S.J. Wimalawansa, Calcitonin Gene-Related Pep-
 tide and its Receptors: Molecular Genetics, Physiology,
 Pathophysiology, and Therapeutic Potentials, 17
 ENDOCRINE REVIEWS 5, 533–85 (1996).
     4   U.S. Patent 6,180,370.
     5   Tan defines “immunoblockade” as “the blockade of
 the effects of a biological mediator by inhibition of its bind-
 ing to specific receptors with antibodies directed against
 the mediator.” J.A. 4996.
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 6           TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

 well as its Fab’ fragment. 6 See J.A. 4995–5003. Tan de-
 scribes the results of one experiment demonstrating that
 both the full-length antibody and the Fab’ fragment suc-
 cessfully achieved immunoblockade by inhibiting the ef-
 fects of exogenously administered CGRP. See J.A. 4996–
 97. Tan also describes the results of a second experiment
 analyzing whether the antibody and its Fab’ fragment in-
 hibit endogenous CGRP-induced blood flow after a pre-
 scribed incubation period.      J.A. 4999.    The results
 demonstrated that the Fab’ fragment effectively blocked
 skin blood flow after a 30-minute incubation period. The
 full-length antibody did not block skin blood flow after a
 60-minute incubation, but a 2-hour incubation period and
 higher dose resulted in a 16% block in skin blood flow. Id.
 Tan posited that “much larger doses and longer distribu-
 tion times are required for successful immunoblockade”
 with the full-length antibody. J.A. 5001.
     Wimalawansa is a review article that describes CGRP,
 including the history of its discovery, its molecular genetics
 and structure, its biological actions, and its therapeutic po-
 tentials. See J.A. 6552–604. Most of Wimalawansa’s dis-
 cussion focuses on the therapeutic potential of activating
 CGRP in the body with CGRP agonists. See J.A. 6578–86.
 Wimalawansa also includes a brief discussion, however, of
 the therapeutic potential of CGRP antagonists, noting that
 “[e]vidence is accumulating that inappropriate release of
 CGRP is a potential causative factor in several diseases,
 including migraine.” J.A. 6586–87. To treat such diseases,
 Wimalawansa states that the “role of CGRP antagonists
 and humanized monoclonal antibodies should be explored.”
 See J.A. 6589.
     Queen “relates generally to the combination of recom-
 binant DNA and monoclonal antibody technologies for

     6   A “Fab’ fragment” is the portion of an antibody that
 binds to the target antigen.
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY           7

 developing novel therapeutic agents.” J.A. 5063 at col. 1
 ll. 19–21. Specifically, Queen discloses a method of human-
 izing antibodies to address traditional problems associated
 with injecting monoclonal antibodies from donors (e.g.,
 mice) into humans.
                     III. Board Decision
     After a combined oral hearing in the three IPR proceed-
 ings, the Board issued a combined final written decision
 holding that the challenged claims in all three patents are
 unpatentable as they would have been obvious over various
 cited references. The Board first found that the prior art
 disclosed or suggested each and every limitation of the
 challenged claims. See Board Decision, 2020 WL 806932,
 at *12–15. The Board then found that a skilled artisan
 would have been motivated to combine the teachings of the
 prior art, id. at *40–41, and would have had a reasonable
 expectation of successfully achieving the claimed inven-
 tion, id. at *43. Lastly, the Board addressed secondary con-
 siderations of nonobviousness. Id. at *43–61.
     Regarding the motivation to combine, the Board con-
 sidered Lilly’s asserted reasons why a skilled artisan would
 have been motivated to combine the teachings of the refer-
 ences to make a humanized anti-CGRP antibody. Id.
 at *16–27. The Board also considered Teva’s asserted
 safety and efficacy concerns as potential reasons not to
 make a humanized anti-CGRP antibody. Id. at *27–40. Af-
 ter weighing the evidence, the Board found “that anti-
 CGRP antagonist antibodies were well known in the art,
 and that the art encouraged the development of humanized
 anti-CGRP antibodies.” Id. at *40. The Board also found
 “no evidence that making a humanized anti-CGRP antago-
 nist antibody would raise any safety concerns sufficient to
 discourage a person of ordinary skill in the art from making
 a human or humanized anti-CGRP antagonist antibody.”
 Id.
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 8           TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY

      In considering whether a skilled artisan would have
 had a reasonable expectation of success, the Board specifi-
 cally noted that the challenged claims in this case are di-
 rected to humanized antibodies and do not recite any safety
 or efficacy limitations. 7 Id. at *43. Accordingly, the Board
 rejected Teva’s argument that Lilly was required to make
 a showing that a skilled artisan would have had a reason-
 able expectation of successfully using the claimed antibod-
 ies in the treatment of any disease or condition. Id.
     Finally, the Board found that Teva failed to establish
 either a presumption of nexus or a direct showing of nexus
 between the claims and the asserted secondary considera-
 tions based on objective indicia of nonobviousness. Id.
 at *49. For completeness, the Board also considered Teva’s
 evidence relating to the secondary considerations but found
 that it was entitled to little weight. Id. at *49–61.
                      IV. Teva’s Appeal
     Teva appealed from the Board’s combined final written
 decision with respect to each of the three challenged pa-
 tents, and we consolidated the appeals. We have jurisdic-
 tion under 28 U.S.C. § 1295(a)(4)(A).
     Teva primarily challenged the Board’s decision on the
 merits, including the legal and factual issues underlying
 the Board’s decision regarding unpatentability. Addition-
 ally, Teva summarily argued that the panel that issued the
 Board’s final written decision in this case consisted of mem-
 bers who were unconstitutionally appointed in violation of
 the Appointments Clause. Teva purported to preserve that
 challenge based on this court’s decision in Arthrex, Inc. v.
 Smith & Nephew, Inc., 941 F.3d 1320 (Fed. Cir. 2019),

     7   Notably, in contrast to the claims at issue here, the
 claims at issue in Appeal Nos. 2020-1876, 2020-1877, and
 2020-1878 recite methods of treatment using humanized
 anti-CGRP antagonist antibodies.
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 TEVA PHARMACEUTICALS     v. ELI LILLY AND COMPANY             9

 vacated, 141 S. Ct. 1970 (2021), as well as the arguments
 presented to the Supreme Court in the then-pending peti-
 tion for a writ of certiorari in that case.
      While Teva’s appeal was pending, the Supreme Court
 decided United States v. Arthrex, Inc., 141 S. Ct. 1970
 (2021). We stayed all deadlines and proceedings in this
 case and ordered the parties to file supplemental briefs ex-
 plaining how the case should proceed in light of the Su-
 preme Court’s decision in Arthrex. On July 7, 2021, Teva
 filed its supplemental brief, proposing that we should first
 decide the merits of the appeal, and if we do not otherwise
 reverse or remand we should then issue a limited remand
 under Arthrex. On July 21, 2021, Lilly and the PTO filed
 their supplemental briefs. The PTO argued that, because
 Teva’s supplemental brief included a request for a limited
 remand under Arthrex, we should immediately remand the
 case without deciding the merits. In contrast, Lilly argued
 that by asking us to decide the merits of the appeal, Teva
 waived its opportunity for a limited remand under Arthrex.
      We rejected Teva’s proposal and instead ordered Teva
 to elect one of two options: (i) a request that we issue a re-
 mand for the limited purpose of allowing Teva the oppor-
 tunity to request Director rehearing of the final written
 decision; or (ii) a waiver of its right to seek Director rehear-
 ing of the final written decision. On July 28, 2021, Teva
 filed its response indicating that it waives its right to a lim-
 ited remand to seek rehearing by the Director. Accord-
 ingly, we lifted the stay, and we now proceed to decide the
 appeal on the merits.
                          DISCUSSION
     We review the Board’s legal determinations de novo, In
 re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), but we re-
 view the Board’s factual findings underlying those deter-
 minations for substantial evidence, In re Gartside, 203 F.3d
 1305, 1316 (Fed. Cir. 2000). A finding is supported by sub-
 stantial evidence if a reasonable mind might accept the
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 10         TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

 evidence as adequate to support the finding. Consol. Edi-
 son Co. v. NLRB, 305 U.S. 197, 229 (1938).
      We begin by briefly addressing the Board’s finding that
 each limitation of the challenged claims was individually
 taught by the prior art. See Board Decision, 2020 WL
 806932, at *12–15. The challenged patents’ written de-
 scription concedes that “[a]nti-CGRP antagonist antibodies
 [we]re known in the art” and commercially available. See,
 e.g., ’614 patent col. 26 ll. 13–17. Additionally, Tan dis-
 closed and described use of an anti-CGRP antagonist anti-
 body, see J.A. 4996, Wimalawansa proposed the use of
 humanized anti-CGRP antibodies, see J.A. 6586, and
 Queen described methods of humanizing monoclonal anti-
 bodies, see J.A. 5004. The Board also noted that Teva did
 not contest Lilly’s evidence regarding the additional limi-
 tations in the independent claims, including that the prior
 art antibodies preferentially bind to CGRP as compared to
 amylin (’614 patent, claim 1), that blocking CGRP would
 inhibit cAMP activation (’951 patent, claim 1), and that the
 recited heavy and light chains are generic to IgG antibodies
 and the recited sequence IDs correspond to CGRP (’210 pa-
 tent, claim 1). Accordingly, the Board’s finding that the
 prior art taught every element of the challenged claims is
 supported by substantial evidence. Teva does not chal-
 lenge that finding on appeal.
      Teva raises three challenges to the Board’s decision.
 First, Teva contends that the Board erred as a matter of
 law in its motivation to combine analysis by deviating from
 the motivation asserted by Lilly in its petitions for inter
 partes review. Second, Teva contends that even under the
 motivation to combine that the Board did analyze, substan-
 tial evidence does not support the Board’s factual findings.
 And third, Teva contends that the Board erred in its anal-
 ysis of secondary considerations of nonobviousness. We ad-
 dress each challenge in turn.
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY          11

                              I
     Teva first contends that the Board erred by relying on
 a different motivation to combine from the one that Lilly
 asserted in its petitions for inter partes review. According
 to Teva, Lilly asserted that a skilled artisan would have
 been motivated to combine the teachings of the references
 to make a humanized anti-CGRP monoclonal antibody for
 therapeutic use in humans, but the Board instead consid-
 ered whether a skilled artisan would have been motivated
 to make the antibody merely to study or use it. Teva insists
 that by not requiring Lilly to support its therapeutic moti-
 vation, the Board incorrectly discounted important safety
 and efficacy concerns that would have been demotivating
 factors—i.e., reasons why a skilled artisan would have been
 motivated not to make a humanized anti-CGRP monoclo-
 nal antibody.
     Lilly responds that the Board relied on the same moti-
 vation that was asserted in the petitions, and that a moti-
 vation to study or use a humanized antibody to assess its
 therapeutic potential is not meaningfully different from
 what Teva has termed a “therapeutic motivation.” Lilly
 further contends that the Board extensively relied on prior
 art disclosures regarding the potential safety and efficacy
 of anti-CGRP antagonist antibodies for the treatment of
 migraines and other vasomotor symptoms. For example,
 Lilly notes that the Board agreed with Lilly’s contention
 that Wimalawansa suggests study of anti-CGRP antibod-
 ies in migraine, and that substantial evidence demon-
 strates that Tan’s use of anti-CGRP antibodies in
 connection with skin vasodilation has relevance to treating
 disease in humans. As further examples, Lilly points to the
 Board’s reliance on at least four other prior art references
 demonstrating the therapeutic potential of anti-CGRP an-
 tibodies.
     As an initial matter, we agree with Lilly that the Board
 properly analyzed the motivation to combine that Lilly
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 12          TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY

 asserted in its IPR petitions. To be sure, the Board may
 not “deviate from the grounds in the petition and raise its
 own obviousness theory.” Sirona Dental Sys. GmbH v. In-
 stitut Straumann AG, 892 F.3d 1349, 1356 (Fed. Cir. 2018).
 But here, the Board upheld its mandate to “base its deci-
 sion on arguments that were advanced by a party”—
 namely, Lilly—“and to which the opposing party”—
 namely, Teva—“was given a chance to respond.” In re Mag-
 num Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir.
 2016).
     Lilly argued in its petition that a skilled artisan would
 have been motivated to make the claimed humanized anti-
 body for therapeutic use in humans. See, e.g., J.A. 829
 (“Consequently, a POSA—with her ordinary creativity—
 would have been motivated to combine [the prior art] to ob-
 tain a humanized anti-CGRP antagonist antibody that
 would be suitable for administration to humans . . . .” (em-
 phasis added)). And that was precisely the motivation that
 the Board found. Common sense and scientific reality dic-
 tate that scientists do not “study or use” humanized anti-
 bodies with an end goal of treating diseases in test tubes or
 in rats. At bottom, the prior art supports a motivation to
 humanize antibodies with the goal of treating human dis-
 ease.
     Teva’s argument about the Board’s alleged failure to
 consider safety and efficacy concerns misses the mark. Be-
 cause the claims are directed to humanized antibodies, the
 question before the Board was whether a skilled artisan at
 the time of the invention would have been motivated to
 make the claimed humanized antibodies, not whether a
 skilled artisan would have been motivated to use those an-
 tibodies to treat human disease. Teva is, of course, correct
 that the analysis must account for “reasons not to com-
 bine,” which are facts relevant to the overall consideration
 of obviousness. See, e.g., Arctic Cat Inc. v. Bombardier Rec.
 Prods., 876 F.3d 1350, 1360 (Fed. Cir. 2017); see also id. at
 1363 (“Evidence suggesting reasons to combine cannot be
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY          13

 viewed in a vacuum apart from evidence suggesting rea-
 sons not to combine”). But, as it pertains to Teva’s argu-
 ment about safety and efficacy concerns, the relevant
 inquiry is not (as Teva suggests) whether the asserted con-
 cerns would have presented a reason not to use the claimed
 antibodies in human treatments. Rather, the relevant in-
 quiry—which the Board extensively analyzed—is whether
 those concerns would have dissuaded a skilled artisan from
 making the claimed antibodies to study their therapeutic
 potential in the first place.
     As a factual matter, Teva is not correct in asserting
 that the Board failed to consider whether a skilled artisan
 would have expected the treatment to be unsafe or unsuc-
 cessful. On the contrary, the Board extensively analyzed
 Teva’s asserted safety and efficacy concerns, including
 those associated with “blocking the CGRP pathway,” those
 raised by “Tan and Wimalawansa,” those related to “mi-
 graine and stroke,” and those based on “differences be-
 tween blocking a CGRP receptor and an antibody against
 the CGRP ligand.” See Board Decision, 2020 WL 806932,
 at *27–40. After weighing evidence based on expert testi-
 mony and numerous publications that the parties pre-
 sented, the Board reached a factual finding that the safety
 and efficacy concerns would not be “sufficient to discourage
 a person of ordinary skill in the art from making a human
 or humanized anti-CGRP antagonist antibody.” Id. at *40.
 The Board specifically noted that Teva relied “heavily on
 potential safety concerns based on the role of CGRP in the
 body and general characteristics of antibodies in vivo,” and
 that evidence was outweighed by Lilly’s reliance on “actual
 studies of CGRP antagonists, including antibodies.” Id.
 at *41. Thus, the Board concluded that “any alleged safety
 concerns would not have deterred or discouraged the com-
 bination of prior art teachings to achieve the invention of
 the challenged claims.” Id.
    For the foregoing reasons, we are not persuaded by
 Teva’s contention that the Board deviated from Lilly’s
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 14         TEVA PHARMACEUTICALS     v. ELI LILLY AND COMPANY

 asserted motivation to combine, and we disagree with
 Teva’s assertion that the Board improperly discounted po-
 tential safety and efficacy concerns associated with the
 claimed invention. The Board properly considered the evi-
 dence relevant to Lilly’s asserted motivation to combine.
                              II
      As an alternative to its argument that the Board devi-
 ated from Lilly’s asserted motivation to combine, Teva ar-
 gues that the Board relied on unsupported interpretations
 of isolated statements in the prior art to find a motivation
 to study or use humanized anti-CGRP antibodies. For ex-
 ample, Teva contends that the Board misinterpreted the
 phrase “CGRP antagonists and humanized monoclonal an-
 tibodies” in Wimalawansa as referring to antibodies that
 target the CGRP ligand, even though, Teva asserts, a
 skilled artisan would have understood that term as refer-
 ring to the extremely specific receptor antagonists that are
 the focus of Wimalawansa’s section on CGRP antagonism.
 At best, Teva argues, Wimalawansa cautions that further
 study is needed before CGRP antagonists could be evalu-
 ated in humans. Regarding Tan, Teva emphasizes that the
 full-length antibody was unsuccessful in achieving im-
 munoblockade in rats, and Teva contends that Tan’s ex-
 pression of optimism that its negative results could be
 overcome does not support a motivation to further explore
 the full-length antibody.
     In response, Lilly argues that substantial evidence
 supports a motivation to make the claimed antibody. Lilly
 focuses on the disclosures of the references themselves, as
 well as the interpretations of the references by expert wit-
 nesses and contemporaneous prior art publications. Lilly
 argues that the disclosures of Tan, Wimalawansa, and nu-
 merous other prior art references would have motivated a
 skilled artisan to make humanized anti-CGRP antibodies
 with the goal of treating human disease.
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY           15

      We agree with Lilly that substantial evidence supports
 a motivation to make a humanized anti-CGRP antibody to
 study its therapeutic potential for use in treatment of hu-
 man disease. Lilly identifies evidence that supports the
 Board’s reasonable readings of each reference. For exam-
 ple, Lilly points to the testimony of three separate experts
 supporting the Board’s interpretation of Tan’s 16% re-
 sponse as a trend toward anti-CGRP activity with the full-
 length antibody, including the experts’ interpretation of
 Tan’s optimism that longer distribution times and higher
 concentrations would improve the response. See, e.g.,
 J.A. 4716 (testimony of Dr. Alain Vasserot); J.A. 4605–07
 (testimony of Dr. Andrew Charles); J.A. 9874–80 (testi-
 mony of Dr. Joseph Balthasar). As for Wimalawansa, alt-
 hough the expert witnesses differed regarding the phrase
 “CGRP antagonists and humanized monoclonal antibod-
 ies,” Lilly points to evidence of a contemporaneous prior art
 publication that cited Wimalawansa to support the propo-
 sition that the CGRP ligand is a target in migraine treat-
 ment. See, e.g., J.A. 6429.
      Unsurprisingly, Teva disagrees with the Board’s inter-
 pretations of Tan and Wimalawansa. But what a piece of
 prior art teaches presents a question of fact that is re-
 viewed for substantial evidence. See, e.g., In re Warsaw
 Orthopedic, Inc., 832 F.3d 1327, 1332 (Fed. Cir. 2016) (“An
 examination of the scope and content of the prior art pro-
 duces factual findings reviewed for substantial evidence.”
 (citing Gartside, 203 F.3d at 1316)). When it comes to com-
 peting interpretations of the teachings of prior art refer-
 ences, we must uphold the principle that “[i]f two
 ‘inconsistent conclusions may reasonably be drawn from
 the evidence in record, the PTAB’s decision to favor one
 conclusion over the other is the epitome of a decision that
 must be sustained upon review for substantial evidence.’”
 Elbit Sys. of Am., LLC v. Thales Visionix, Inc., 881 F.3d
 1354, 1356 (Fed. Cir. 2018) (internal brackets omitted)
 (quoting In re Cree, Inc., 818 F.3d 694, 701 (Fed. Cir.
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 16         TEVA PHARMACEUTICALS     v. ELI LILLY AND COMPANY

 2016)). Under this deferential standard of review, we can-
 not replace the Board’s reasonable interpretation of refer-
 ences with Teva’s interpretation.       For the foregoing
 reasons, we are not persuaded that the Board committed
 reversible error with regard to its analysis of the motiva-
 tion to combine the teachings of the prior art references.
                             III
     Turning to the issue of secondary considerations of
 nonobviousness, Teva’s primary evidence was based on two
 commercial products—its own AJOVY® product and Lilly’s
 Emgality® product—both of which are antibodies within
 the scope of the challenged patent claims. Teva asserted
 that both products have received industry-wide acclaim,
 satisfied a long-felt need, achieved unexpected results,
 faced industry skepticism, and achieved commercial suc-
 cess. Teva also presented evidence of a license it entered
 into with third parties AlderBio Holdings, LLC and Alder
 Biopharmaceuticals, Inc. (collectively, “AlderBio”) that in-
 cluded the challenged patents. The Board found that the
 commercial products and the license lacked sufficient
 nexus to the challenged claims. See Board Decision, 2020
 WL 806932, at *49–50, 60–61.
     Teva argues that the Board made two legal errors.
 First, Teva argues that, in finding no presumption of nexus
 between the claims and the secondary considerations based
 on the commercial products, the Board misapplied this
 court’s holding in Fox Factory, Inc. v. SRAM, LLC, 944 F.3d
 1366 (Fed. Cir. 2019). Second, with regard to the AlderBio
 license, Teva argues that the Board erred by focusing on
 AlderBio’s products rather than the scope of the license.
 We address each of Teva’s arguments below.
                              A
    In considering the Board’s finding that Teva failed to
 show a nexus between the challenged claims and the com-
 mercial AJOVY® and Emgality® products, we begin with a
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY           17

 discussion of the nexus requirement. It is well-established
 law that in order to accord substantial weight to secondary
 considerations of nonobviousness, “the evidence of second-
 ary considerations must have a ‘nexus’ to the claims, i.e.,
 there must be ‘a legally and factually sufficient connection’
 between the evidence and the patented invention.” Henny
 Penny Corp. v. Frymaster LLC, 938 F.3d 1324, 1332 (Fed.
 Cir. 2019) (quoting Demaco Corp. v. F. Von Langsdorff Li-
 censing Ltd., 851 F.2d 1387, 1392 (Fed. Cir. 1988)). “The
 patentee bears the burden of showing that a nexus ex-
 ists . . . .” WMS Gaming Inc. v. Int’l Game Tech., 184 F.3d
 1339, 1359 (Fed. Cir. 1999) (citing Cable Elec. Prods., Inc.
 v. Genmark, Inc., 770 F.2d 1015, 1027 (Fed. Cir. 1985)). “To
 determine whether the patentee has met that burden, we
 consider the correspondence between the objective evi-
 dence and the claim scope.” Henny Penny, 938 F.3d at
 1332.
     It has long been recognized that “a patentee is entitled
 to a rebuttable presumption of nexus between the asserted
 evidence of secondary considerations and a patent claim if
 the patentee shows that the asserted evidence is tied to a
 specific product and that the product ‘is the invention dis-
 closed and claimed.’” Fox Factory, 944 F.3d at 1373 (quot-
 ing Demaco, 851 F.2d at 1392). The presumption applies
 “when the patentee shows that the asserted objective evi-
 dence is tied to a specific product and that product ‘embod-
 ies the claimed features, and is coextensive with them.’”
 Polaris Indus., Inc. v. Arctic Cat, Inc., 882 F.3d 1056, 1072
 (Fed. Cir. 2018) (quoting Brown & Williamson Tobacco
 Corp. v. Philip Morris Inc., 229 F.3d 1120, 1130 (Fed. Cir.
 2000)). “Conversely, ‘[w]hen the thing that is commercially
 successful is not coextensive with the patented invention—
 for example, if the patented invention is only a component
 of a commercially successful machine or process,’ the pa-
 tentee is not entitled to a presumption of nexus.” Fox Fac-
 tory, 944 F.3d at 1373 (quoting Demaco, 851 F.2d at 1392).
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 18          TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

      Much has been written discussing the “coextensive-
 ness” requirement for the presumption of nexus, and in Fox
 Factory we attempted to summarize the current state of
 the law. We rejected attempts “to reduce the coextensive-
 ness requirement to an inquiry into whether the patent
 claims broadly cover the product that is the subject of the
 evidence of secondary considerations.” Id. at 1377. Rather,
 we explained, “the degree of correspondence between a
 product and a patent claim falls along a spectrum.” Id.
 at 1374. At one end of the spectrum lies “perfect or near
 perfect correspondence,” and at the other end lies “no or
 very little correspondence.” Id. “Although we do not re-
 quire the patentee to prove perfect correspondence to meet
 the coextensiveness requirement, what we do require is
 that the patentee demonstrate that the product is essen-
 tially the claimed invention.” Id. “Whether a product is
 coextensive with the patented invention, and therefore
 whether a presumption of nexus is appropriate in a given
 case, is a question of fact.” Id. at 1373.
      Bound up with the coextensiveness requirement is the
 issue of “unclaimed features” in a commercial product,
 which we also addressed in Fox Factory. “[W]e have never
 held that the existence of one or more unclaimed features,
 standing alone, means nexus may not be presumed.” Id.
 at 1374. Indeed, like the coextensiveness requirement it-
 self, the concept of unclaimed features is best viewed as
 part of a spectrum. Toward one end of the spectrum, we
 have said that “if the unclaimed features amount to noth-
 ing more than additional insignificant features, presuming
 nexus may nevertheless be appropriate.” Id. Toward the
 other end of the spectrum, we have said that “[a] patent
 claim is not coextensive with a product that includes a ‘crit-
 ical’ unclaimed feature that is claimed by a different patent
 and that materially impacts the product’s functionality.”
 Id. at 1375.
    In applying our Fox Factory holding in this case, the
 Board stated that it “d[id] not understand Fox Factory to
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 TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY            19

 be making a distinction between features that are ‘critical’
 and features that ‘materially impact’ the functionality of
 the product.” Board Decision, 2020 WL 806932, at *48. Ac-
 cordingly, the Board concluded that in order to defeat a pre-
 sumption of nexus, a patent challenger need only show that
 an “unclaimed feature materially affects the functioning of
 the product that is alleged to be coextensive with the
 claim.” Id. Teva argues that this was a misinterpretation
 of Fox Factory, and to the extent the Board announced a
 bright-line rule that the presumption of nexus does not ap-
 ply if any unclaimed feature materially affects the func-
 tioning of a product that is alleged to be coextensive, we
 agree with Teva that the Board erred. As Teva argues, un-
 der such a rule the presumption of nexus would rarely, if
 ever, attach because virtually every innovative product in-
 evitably has some unclaimed feature that materially af-
 fects its functionality. Such a rule would be unsound. For
 example, a claim to a new and unobvious pharmaceutical
 compound would surely have a nexus to the marketed fin-
 ished product sold to consumers, although that finished
 product will almost always contain excipients such as sol-
 ubilizers, antioxidants, stabilizers, etc., that materially af-
 fect its functionality.      Such excipients should not
 reasonably be found to destroy the nexus between the claim
 and the product.
     Our conclusion that the Board erred in its articulation
 of the legal standard, however, does not end our inquiry
 into whether a presumption of nexus applies in this case.
 The presumption analysis requires the fact finder to con-
 sider the unclaimed features of the stated products to de-
 termine their level of significance and their impact on the
 correspondence between the claim and the products. Fox
 Factory, 944 F.3d at 1375. As we discuss further below,
 despite its incorrect articulation of the law, the Board con-
 ducted the necessary factual analysis of the unclaimed fea-
 tures of the AJOVY® and Emgality® products and reached
 the correct conclusion that no presumption of nexus applies
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 20          TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

 in this case. Therefore, the Board’s error in articulating
 the legal standard was harmless. See In re Watts, 354 F.3d
 1362, 1369 (Fed. Cir. 2004) (“[T]he harmless error rule ap-
 plies to appeals from the Board . . . .”).
      As we turn to the Board’s factual analysis of the un-
 claimed features, we emphasize that the question whether
 the presumption of nexus applies in each case turns on the
 nature of the claims and the specific facts. For example, in
 Fox Factory the relevant comparison was between a struc-
 turally claimed mechanical chainring and a product that
 included an unclaimed “gap filling” feature that was “criti-
 cal,” “claimed by a different patent,” “materially impact[ed]
 the product’s functionality,” and led “to a chainring that
 will retain a chain in even the worst conditions.” 944 F.3d
 at 1375. Based on those facts, we determined that “no rea-
 sonable fact finder could conclude, under the proper stand-
 ard, that the X-Sync chainrings are coextensive with the
 patent claims.” Id. at 1374–75.
     We have also considered the coextensiveness require-
 ment in chemical and biological cases that more closely re-
 semble the technology at issue here. For example, in
 Immunex Corp. v. Sandoz Inc., 964 F.3d 1049, 1067–68
 (Fed. Cir. 2020), the patent claims recited the molecular
 weight and amino acid sequence of the “protein” to which
 they were directed. See U.S. Patent 8,063,182. There, we
 held that “[n]exus is appropriately presumed in this case
 where the court concluded that the claims are directed to
 the active ingredient in Enbrel® and its method of manu-
 facture.” Immunex, 964 F.3d at 1067. More generally, it is
 hard not to imagine a presumption of nexus between a
 structurally claimed genus of chemical compounds and a
 commercial product that meets each claim limitation.
     In contrast to the claims in Fox Factory and Immunex,
 the antibodies in the claims at issue in this case are de-
 scribed, not in terms of their structure, but rather in terms
 of their function—in particular, their ability to bind to the
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 TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY           21

 CGRP ligand. See ’614 patent, col. 101 ll. 32–34 (“1. A hu-
 man or humanized monoclonal anti-CGRP antagonist an-
 tibody that preferentially binds to human α-CGRP as
 compared to amylin.”); see also ’951 patent, col. 99 ll. 21–23
 (“1. . . . antibody that (1) binds to human α-CGRP and (2)
 inhibits [cAMP] activation in cells”); ’210 patent, col. 103
 ll. 35–45 (“1. . . . wherein the CDRs impart to the antibody
 specific binding to a CGRP . . . .”). As we have recently
 noted, functional claim language can lead to broad claims,
 especially when there are no structural limitations to
 clearly define the scope. See, e.g., Amgen Inc. v. Sanofi, 987
 F.3d 1080, 1087 (Fed. Cir. 2021) (discussing claims with
 “broad functional language”). 8 A claim to “anything that
 works” hardly has a nexus to any particular product. Thus,
 we reject the strained comparisons that the parties and the
 Board have made between the facts of this case and the
 facts in other cases dealing with the presumption of nexus.
      Because the claims in this case have a broad scope due
 to their lack of structural limitations, the unclaimed fea-
 tures in the commercial products cited here are of particu-
 lar importance to the coextensiveness analysis. The Board
 considered how four such unclaimed features in the
 AJOVY® and Emgality® antibodies affect the functionality
 of the products—i.e., their ability to function as anti-CGRP
 antagonist antibodies. For example, the Board found that,
 although the claims do not recite amino acid sequences,
 AJOVY® and Emgality® have specific sequences that criti-
 cally affect binding affinity and inhibit the ability of the
 antibodies to kill cells. See Board Decision, 2020 WL
 806932, at *46–47. The Board also found that, although

     8   While our Amgen decision considered breadth in
 the context of the enablement requirement of 35 U.S.C.
 § 112, we see a similar problem here as we must consider
 the breadth of functional claims to determine whether they
 are coextensive with specific commercial products.
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 22          TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY

 the claims did not recite limitations regarding picomolar
 binding affinity, full-length antibodies versus fragments,
 or IgG antibody classes, all of those features are critical to
 the ability of the AJOVY® and Emgality® antibodies to
 function as humanized anti-CGRP antagonist antibodies.
 See id. at *47–49. The Board’s factual findings regarding
 unclaimed features are thus supported by substantial evi-
 dence, and Teva has not shown otherwise.
     Teva concedes that “at some point”—i.e., somewhere
 along the coextensiveness spectrum that we described in
 Fox Factory—“the differences between a product and a pa-
 tent claim become so significant that nexus cannot be pre-
 sumed.” See Teva Br. at 52. In view of the extremely broad
 scope of the functionally claimed antibodies of the chal-
 lenged claims and the unclaimed features that undisput-
 edly materially affect how AJOVY® and Emgality® function
 as humanized anti-CGRP antagonist antibodies, no rea-
 sonable fact finder could conclude that that point has not
 been crossed in this case. Thus, Teva has failed to show
 that a presumption of nexus applies in this case. As Teva
 does not appear to dispute the Board’s statement that the
 presumption was the sole basis for its assertion of nexus,
 see Board Decision, 2020 WL 806932, at *49, we conclude
 that there is no nexus between the challenged claims and
 the secondary considerations based on the AJOVY® and
 Emgality® products.
                               B
     We finally turn to Teva’s arguments based on the
 AlderBio license. Teva argues that, while the law requires
 a nexus between the challenged claims and the “licenses
 themselves,” see In re Antor Media Corp., 689 F.3d 1282,
 1293–94 (Fed. Cir. 2012) (citing In re GPAC Inc., 57 F.3d
 1573, 1580 (Fed. Cir. 1995)), the Board erred by requiring
 a direct nexus between the challenged claims and Alder-
 Bio’s products.
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 TEVA PHARMACEUTICALS    v. ELI LILLY AND COMPANY            23

     Lilly responds that substantial evidence supports the
 Board’s finding that Teva failed to show a connection be-
 tween the broad AlderBio license and the challenged
 claims. Lilly argues that Teva relied exclusively on the fact
 that the three challenged patents were included among 188
 licensed patents, without any meaningful analysis of the
 economic reasons motivating the licensee. Moreover, Lilly
 argues, because Teva’s witnesses conceded that the license
 and royalty payments would continue unabated regardless
 of the validity of the three challenged patents, the license
 is not probative of the nonobviousness of the challenged pa-
 tents.
      We agree with Lilly that the Board’s conclusion that
 the AlderBio license lacked nexus to the challenged claims
 was supported by substantial evidence. The significance of
 licensing a patent as a secondary consideration in enhanc-
 ing the nonobviousness of an invention is that an independ-
 ent party with an interest in being free of the patent has
 chosen to respect it and pay a royalty under it rather than
 litigate and invalidate it. Such action tends to support its
 validity. Here, given that 188 patents were licensed, the
 nexus between the license and the validity of any particu-
 lar claim is rather tenuous to say the least. Thus, the
 Board was correct to require that Teva show something
 more than the mere existence of the license. See Sibia Neu-
 rosciences, Inc. v. Cadus Pharm. Corp., 225 F.3d 1349, 1358
 (Fed. Cir. 2000) (“[T]he mere existence of these licenses is
 insufficient to overcome the conclusion of obvious-
 ness . . . .”); see also Merck & Cie v. Gnosis S.p.A., 808 F.3d
 829, 838 (Fed. Cir. 2015) (“It is therefore difficult to deter-
 mine the extent to which the licensing agreement was a
 result of the novel features in the [challenged] patent, as
 opposed to the other patents involved.”).
     Teva failed to show anything more than the existence
 of the license. Teva did not present direct evidence that
 AlderBio’s motivation for entering into the license was re-
 lated to the validity or enforceability of the three
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 24          TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY

 challenged patents. In the absence of such evidence, we
 cannot fault the Board for looking to the license’s “whereas”
 clause to identify the purpose of the license, namely, the
 development of AlderBio’s products. With that purpose in
 mind, the Board reasonably considered whether Teva had
 presented evidence of a relationship between the chal-
 lenged claims and the development of such products. See
 S. Ala. Med. Sci. Found. v. Gnosis, S.p.A., 808 F.3d 823,
 827–28 (Fed. Cir. 2015) (holding that “evidence that the li-
 censee ultimately manufactured a product that embodies
 the claimed invention may be probative of a nexus between
 the claimed invention and the licensing activity”). The
 Board expressly found that Teva did not show “that any of
 the challenged patents cover the Alder Product by a com-
 parison of the [] product to the challenged claims.” Board
 Decision, 2020 WL 806932, at *61.
      Teva’s argument loses sight of the true purpose of the
 nexus requirement, which is to consider whether “the fact-
 finder can infer that the licensing ‘arose out of recognition
 and acceptance of the subject matter claimed’ in the pa-
 tent.” See S. Ala. Med., 809 F.3d at 827 (quoting GPAC, 57
 F.3d at 1580). Teva instead hinges its arguments on subtle
 differences between terms that have been used in our case
 law—e.g., the “licensing activity” versus the licensee’s
 “products.”
     At bottom, the Board found that the relevant facts,
 which are supported by substantial evidence, “minimize[d]
 any nexus between the challenged claims and the AlderBio
 License.” Board Decision, 2020 WL 806932, at *61. Ac-
 cordingly, we hold that substantial evidence supports the
 Board’s decision that there is a lack of nexus between the
 challenged claims and the secondary consideration of li-
 censing.
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 TEVA PHARMACEUTICALS   v. ELI LILLY AND COMPANY        25

                        CONCLUSION
     We have considered Teva’s remaining arguments but
 we find them unpersuasive. Accordingly, the Board’s deci-
 sion is affirmed.
                        AFFIRMED