Court Opinion

ID: 4766018
Source: CourtListenerOpinion
Date Created: 2021-08-16 15:01:46.864068+00
Date Added: 2024-06-11T09:02:09.064952
License: Public Domain

Case: 20-1876    Document: 50    Page: 1    Filed: 08/16/2021

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

                ELI LILLY AND COMPANY,
                        Appellant

                            v.

   TEVA PHARMACEUTICALS INTERNATIONAL
                   GMBH,
                   Appellee
            ______________________

            2020-1876, 2020-1877, 2020-1878
                ______________________

     Appeals from the United States Patent and Trademark
 Office, Patent Trial and Appeal Board in Nos. IPR2018-
 01710, IPR2018-01711, IPR2018-01712.
                  ______________________

                 Decided: August 16, 2021
                  ______________________

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

    WILLIAM M. JAY, Goodwin Procter LLP, Washington,
 DC, argued for appellee. Also represented by ELAINE
 BLAIS, EDWINA CLARKE, ALEXANDRA LU, Boston, MA;
 NATASHA ELISE DAUGHTREY, Los Angeles, CA; WILLIAM
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 2            ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 MILLIKEN, DEBORAH STERLING, Sterne Kessler Goldstein &
 Fox, PLLC, Washington, DC.
                ______________________

     Before LOURIE, BRYSON, and O’MALLEY, Circuit Judges.
 LOURIE, Circuit Judge.
      Eli Lilly and Company (“Lilly”) appeals from a com-
 bined final written decision of the U.S. Patent and Trade-
 mark Office (“PTO”) Patent Trial and Appeal Board
 (“Board”) holding that the claims of U.S. Patents 8,586,045
 (“’045 patent”), 9,884,907 (“’907 patent”), and 9,884,908
 (“’908 patent”) are not unpatentable as obvious. Eli Lilly
 & Co. v. Teva Pharms. Int’l GmbH, Nos. IPR2018-01710,
 IPR2018-01711, IPR2018-01712, 2020 WL 1540364
 (P.T.A.B. Mar. 31, 2020) (“Board Decision”). For the rea-
 sons provided below, we affirm.
                         BACKGROUND
                           I. Patents
      Teva Pharmaceuticals International GmbH (“Teva”)
 owns the ’045, ’907, and ’908 patents (collectively, the “chal-
 lenged patents”) directed to methods of using humanized
 antagonist antibodies that target calcitonin gene-related
 peptide (“CGRP”). CGRP is a 37-amino acid peptide that
 is “a neurotransmitter 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.” ’045 patent, col. 1 ll. 31–35.
     The challenged patents explain that “CGRP has been
 noted for its possible connection to vasomotor symptoms,”
 id. at col. 1 ll. 39–40, such as “all forms of vascular head-
 ache, including migraines,” id. at col 2 ll. 3–6. Although at
 the time of the challenged patents the pathophysiology of
 migraine was not well understood, dilation of blood vessels
 was associated with and thought to exacerbate the pain
 symptoms of migraine. Id. at col. 3 ll. 14–26. Thus, even
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 ELI LILLY AND COMPANY      v. TEVA PHARMACEUTICALS          3

 before the challenged patents, the possible connection be-
 tween CGRP as a vasodilator and the pathology of mi-
 graine informed the development of treatments for
 migraine 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
     number 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. 14–22.
     The challenged patents are directed to methods of
 treatment using humanized antibodies that antagonize
 CGRP and thus inhibit its activity in the body by targeting
 and binding to the CGRP ligand (as opposed to CGRP re-
 ceptors). The challenged patents’ written description de-
 scribes “anti-CGRP antagonist antibodies and methods of
 using anti-CGRP antagonist antibodies for treating or pre-
 venting vasomotor symptoms, such as headaches, such as
 migraine.” Id. at col. 3 ll. 37–45. The claims at issue are
 directed to methods of treatment comprising the step of ad-
 ministering a humanized anti-CGRP antagonist antibody. 1
 Claim 1 in each patent is representative:

     1   In contrast with the claims at issue in this case,
 which are directed to methods of using anti-CGRP antibod-
 ies in treatment, Teva also owns related patents with
 claims directed to the antibodies themselves. Those claims
 are at issue in Appeal Nos. 2020-1747, 2020-1748, 2020-
 1749, 2020-1750, 2020-1751, and 2020-1752.
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 4           ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

         1. A method for reducing incidence of or treat-
     ing at least one vasomotor symptom in an individ-
     ual, comprising administering to the individual an
     effective amount of an anti-CGRP antagonist anti-
     body, wherein said anti-CGRP antagonist antibody
     is a human monoclonal antibody or a humanized
     monoclonal antibody.
 ’045 patent, col. 99 ll. 2–7.
         1. A method for treating headache in an indi-
     vidual, comprising:
         administering to the individual an effective
         amount of a humanized monoclonal anti-
         Calcitonin Gene-Related Peptide (CGRP)
         antagonist antibody, 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;
         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.
 ’907 patent, col. 103 ll. 21–35.
         1. A method for treating headache in an indi-
     vidual, comprising:
         administering to the individual an effective
         amount of a humanized monoclonal anti-
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS             5

         Calcitonin Gene-Related Peptide (CGRP)
         antagonist antibody, 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;
         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, and wherein the
         antibody binds to the CGRP with a binding
         affinity (KD) of about 10 nM or less as meas-
         ured by surface plasmon resonance at 37o
         C.
 ’908 patent, col. 99 l. 55–col. 100 l. 57. The differences be-
 tween these claims have not been argued as significant to
 these appeals.
                II. IPR Petitions and Prior Art
     Lilly filed petitions for inter partes review of claims 1,
 3, 4, 8–17, 19, 20, and 24–31 of the ’045 patent, claims 1–
 18 of the ’907 patent, and claims 1–18 of the ’908 patent.
 Lilly asserted that each of the challenged claims would
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 6           ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 have been obvious over a combination of prior art refer-
 ences that includes Olesen, 2 Tan, 3 and Queen. 4
     Olesen describes a clinical trial proving the efficacy of
 BIBN4096BS (“BIBN”), a nonpeptide CGRP-receptor an-
 tagonist, in the treatment of migraine. In Olesen’s study,
 patients receiving 2.5 mg of BIBN intravenously over a pe-
 riod of 10 minutes had a 66% response rate, with a pain-
 free rate of 44% after two hours and a recurrence rate of
 19%. See Board Decision, 2020 WL 1540364, at *11 (citing
 Olesen). In short, Olesen teaches that BIBN was effective
 and safe in treating acute attacks of migraine. Olesen also
 discusses past studies and discloses that CGRP may have
 a role in initiating and mediating migraine attacks.
 J.A. 3741.
     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
 well as its Fab’ fragment. 6 See J.A. 3708–18. Tan describes
 the results of one experiment demonstrating that both the

     2   J. Olesen et al., Calcitonin Gene-Related Peptide
 Receptor Antagonist BIBN 4096 BS for the Acute Treatment
 of Migraine, N. ENG. J. MED. 350, 1104–10 (2004).
     3   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).
     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. 3711.
     6   A “Fab’ fragment” is the portion of an antibody that
 binds to the target antigen.
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS            7

 full-length antibody and the Fab’ fragment successfully
 achieved immunoblockade by inhibiting the effects of exog-
 enously administered CGRP. See J.A. 3711–12. Tan also
 describes the results of a second experiment analyzing
 whether the antibody and its Fab’ fragment inhibit endog-
 enous CGRP-induced blood flow after a prescribed incuba-
 tion period. J.A. 3714. The results demonstrated that the
 Fab’ fragment effectively blocked skin blood flow after a 30-
 minute incubation period. Id. 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 distribution times are required for
 successful immunoblockade” with the full-length antibody.
 J.A. 3716.
      Queen “relates generally to the combination of recom-
 binant DNA and monoclonal antibody technologies for de-
 veloping novel therapeutic agents.” J.A. 27230 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, the Board issued a com-
 bined final written decision in the three IPRs. The Board
 first construed the claims, including the preambles and the
 term “effective amount.” The Board then analyzed the as-
 serted prior art and concluded that Lilly failed to prove
 that the challenged claims in the three patents would have
 been obvious over the stated references.
     For the constructions of the claim preambles, the Board
 noted that “[t]he parties do not dispute that the preamble
 claim language is a statement of intended purpose.” Board
 Decision, 2020 WL 1540364, at *7. The Board thus deter-
 mined that the preambles are “limiting to the extent that
 they require that the recited method must be performed
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 8            ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 with the intentional purpose of ‘reducing incidence of or
 treating’ at least one vasomotor symptom . . . or headache.”
 Id. The Board also discussed how the claim construction
 affected Lilly’s burden to demonstrate that a skilled arti-
 san would have had a reasonable expectation of success in
 combining the teachings of the prior art to achieve the
 claimed invention:
         [W]e determine here that to prove a reasonable
     expectation of success with respect to a limitation
     that recites achieving a particular result as the in-
     tended purpose for which a recited method must be
     performed, what is required is not proof that the
     recited method would actually bring about the re-
     cited result, but rather proof that a person of ordi-
     nary skill in the art would have had a reasonable
     expectation that performing the recited method
     would bring about the recited result.
 Id. at *8.
     For the term “effective amount,” the Board determined
 that the written descriptions defined the term to mean “an
 amount sufficient to effect beneficial or desired results.”
 Id. at *10. The Board specifically addressed the relation-
 ship between an “effective amount” under the claims, and
 potential clinical results demonstrating efficacy:
          Although the term “effective amount” may en-
     compass a clinical result, we do not interpret the
     term “effective amount” as requiring a clinical re-
     sult because, as defined in the Specification, the
     term “effective amount” refers only to “beneficial or
     desired results” without the qualifier “clinical.”
     That is, the term “effective amount” requires a ben-
     eficial or desired result, but it need not be a “clini-
     cal” result.
 Id. at *9.
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS             9

     After construing the claims, the Board considered the
 evidence pertaining to obviousness. The Board first found
 that Lilly had shown by a preponderance of the evidence
 that the asserted prior art discloses or suggests each and
 every element of the challenged claims. Id. at *18. Next,
 the Board found that a skilled artisan would have been mo-
 tivated to combine the teachings of the prior art:
         [T]here are clearly reasons that a person of or-
     dinary skill in the art would have been motivated
     to combine the teachings of Olesen, Tan, and
     Queen to pursue a method to reduce incidence of or
     treat a vasomotor symptom, such as a migraine
     headache, by administering a human or human-
     ized monoclonal anti-CGRP antagonist antibody.
 Id. at *43. Moreover, the Board found that “any alleged
 safety concerns would not have deterred, discouraged, or
 taught away from pursuing” the patented methods of treat-
 ment. Id.
      After finding a motivation to combine the teachings of
 the prior art, the Board next considered whether a skilled
 artisan would have had a reasonable expectation of suc-
 cess. The Board first addressed Lilly’s arguments based on
 the asserted prior art references, namely, Olesen and Tan.
 Regarding Olesen, the Board found that “the data provided
 by Olesen only relate[] to a small molecule (BIBN) and to
 blocking a CGRP receptor” and “Olesen does not provide a
 reasonable expectation of success of administering an anti-
 CGRP antibody (a different compound) that binds to the
 CGRP ligand rather than the CGRP receptor (a different
 site upstream of the receptor) to treat migraine.” Id. at *44.
 Regarding Tan, the Board found that “Tan did not provide
 data showing that a full length anti-CGRP antibody could
 reach the synaptic cleft, the site of action for immunoblock-
 ade, to thereby achieve inhibition of endogenous CGRP in
 vivo” and “Tan provides no information or data regarding
 the use of a full-length anti-CGRP antibody to reduce
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 10           ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 incidence of or treat a vasomotor symptom such as mi-
 graine headache.” Id. at *45–46.
      Having found no reasonable expectation of success
 based on the asserted prior art references, the Board next
 addressed the evidence relied on by each party and its ex-
 perts pertaining to “whether migraine drugs would have
 been required to cross the blood brain barrier (BBB).” Id.
 at *47–59. The Board noted that the blood-brain barrier
 “raised uncertainty, unpredictability, and skepticism in us-
 ing full-length anti-CGRP antibodies to reduce incidence of
 or treat headache such as migraine.” Id. at *57. The Board
 determined that “in 2005, a [skilled artisan] would have
 been aware of the differences of opinion among key opinion
 leaders as to the pathogenesis of migraine and that it was
 largely unresolved.” Id. at *58. Thus, the Board found
 that:
           [I]t was unknown as of November 14, 2005,
      whether anti-CGRP antibodies needed to cross the
      blood-brain barrier to reduce incidence of or treat
      headache such as migraine. Although absolute
      predictability in the art is not required to establish
      a reasonable expectation of success, the uncer-
      tainty and unpredictability about this basic
      knowledge and the pathogenesis of migraine head-
      ache, as well as the skepticism around whether
      full-length anti-CGRP antibodies would be effec-
      tive, counsel against finding a reasonable expecta-
      tion of success.
      Id.
     The Board also relied on precedent from this court to
 support its finding that a skilled artisan would not have
 had a reasonable expectation of success. For example, the
 Board cited Honeywell International Inc. v. Mexichem
 Amanco Holdings S.A. DE C.V., 865 F.3d 1348, 1356 (Fed.
 Cir. 2017), for the proposition that “when there is a high
 enough quantum of unpredictability, . . . a proponent of
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 ELI LILLY AND COMPANY     v. TEVA PHARMACEUTICALS               11

 unpatentability may not have met its burden of showing a
 reasonable expectation of success.” Board Decision, 2020
 WL 1540364, at *59. Based on Honeywell, the Board
 stated:
            [Lilly] is arguing that a person of ordinary skill
       would have taken the leap from a small molecule
       antagonist such as BIBN to a large molecule anti-
       CGRP antagonist antibody. We determine that
       [Lilly] has not demonstrated that a person of ordi-
       nary skill in the art would have had a reasonable
       expectation of success in using an antibody treat-
       ment in view of the level of unpredictability in
       whether the blood brain barrier would have been
       an obstacle, i.e., the uncertainty in whether anti-
       CGRP antibodies needed to cross the blood-brain
       barrier to reduce incidence of or treat headache
       such as migraine.
 Id.
     The Board also found that the facts in this case resem-
 bled the fact pattern in Novartis Pharmaceuticals Corp. v.
 West-Ward Pharmaceuticals International Ltd., 923 F.3d
 1051 (Fed. Cir. 2019), where this court held that the as-
 serted art would not have given a skilled artisan a reason-
 able expectation of success. See Board Decision, 2020 WL
 1540364, at *60. The Board found:
           Similar to West-Ward where clinical results
       had been obtained with temsirolimus but not with
       everolimus, clinical results had been obtained with
       BIBN (e.g., Olesen []) but not with anti-CGRP an-
       tagonist antibodies. Indeed, the anti-CGRP anti-
       bodies are pharmacologically different from BIBN
       because anti-CGRP antibodies have different half-
       lives and different sizes than BIBN. . . . Further, as
       above, the mechanisms of migraine and its treat-
       ment were still uncertain in 2005.
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 12         ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 Id. Thus, the Board concluded that “West-Ward illustrates
 how a jump from one molecule to another may result in a
 lack of a reasonable expectation of success in an area with
 uncertainty.” Id. at *61.
     In summary, the Board found that Lilly failed to prove
 by a preponderance of the evidence that a skilled artisan
 would have had a reasonable expectation of success as to
 any of the challenged claims. Id. at *62–64. Accordingly,
 the Board concluded that Lilly failed to satisfy its burden
 of demonstrating that the challenged claims would have
 been obvious over the combination of Olesen, Tan, and
 Queen. Id. at *64.
     Lilly 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).
                        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 ev-
 idence as adequate to support the finding. Consol. Edison
 Co. v. NLRB, 305 U.S. 197, 229 (1938).
     While Lilly makes a number of interrelated arguments
 in its briefing, Lilly’s appeal can be broadly broken down
 into two primary challenges. In its first challenge, Lilly
 contends that the Board erred by reading a result into the
 constructions of the preambles and the term “effective
 amount,” which led the Board to erroneously require Lilly
 to prove that a skilled artisan would have expected to
 achieve results that are unclaimed. In its second chal-
 lenge, Lilly contends that even if the preambles are limit-
 ing and the claims thus require administration of an
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS           13

 antibody with an expectation of results, the Board erred by
 applying too high a standard when weighing the evidence
 to determine whether a skilled artisan would have had a
 reasonable expectation of success. We address each chal-
 lenge in turn.
                               I
      We first consider Lilly’s challenge that the Board im-
 properly required proof that a skilled artisan would have
 had a reasonable expectation of achieving a result that was
 not claimed. In considering this challenge, we think it is
 helpful to break down the challenge into two parts. In the
 first part, we discuss the aspects of the challenge that
 sound in claim construction. In the second part, we discuss
 the aspects of the challenge that relate more directly to the
 impact of the Board’s constructions on its analysis of the
 reasonable expectation of success.
                              A
     Claim construction is a matter of law that we review de
 novo. See Poly-America, L.P. v. API Indus., Inc., 839 F.3d
 1131, 1135–36 (Fed. Cir. 2016). Because the challenged
 patents are unexpired and the IPR petitions in this case
 were filed before November 13, 2018, the claims are to be
 given their broadest reasonable interpretation. See 37
 C.F.R. § 42.100(b) (2018); Cuozzo Speed Techs., LLC v. Lee,
 136 S. Ct. 2131, 2142 (2016).
     Lilly challenges the Board’s construction of the claim
 preambles as limiting to the extent that they require that
 the recited methods be performed with an intentional pur-
 pose. According to Lilly, a preamble that contains only a
 statement of purpose cannot as a matter of law be a claim
 limitation. Lilly argues that a proper construction would
 attribute no weight to the claim preambles, and thus ren-
 der them irrelevant to the obviousness analysis. And Lilly
 argues that the Board erred in its construction of the term
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 14          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 “effective amount,” which compounded the Board’s errors
 in imposing required results from the preambles.
     Teva responds that Lilly’s argument is based on a false
 dichotomy between limiting preambles as contrasted with
 preambles that are merely statements of intended purpose.
 Teva further argues that the preambles here are limiting
 because they are central to the invention, they provide an-
 tecedent basis for later claim limitations, and they give
 meaning to the substantive claim requirement of adminis-
 tering an “effective amount,” which, Teva argues, the
 Board construed correctly.
     First, we agree with Teva that our case law does not
 support Lilly’s proposed binary distinction between state-
 ments of mere intended purpose on the one hand and lim-
 iting preambles on the other. On the contrary, we have
 stressed that there is no “litmus test” for determining
 whether a preamble is limiting. See Bicon, Inc. v. Strau-
 mann Co., 441 F.3d 945, 952 (Fed. Cir. 2006) (citing Cata-
 lina Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,
 808 (Fed. Cir. 2002)). Rather, “[w]hether to treat a pream-
 ble as a claim limitation is determined on the facts of each
 case in light of the claim as a whole and the invention de-
 scribed in the patent.” Storage Tech. Corp. v. Cisco Sys.,
 Inc., 329 F.3d 823, 831 (Fed. Cir. 2003).
     The claims in this case are directed to methods, and
 more specifically to methods of using a composition for a
 specific purpose. Each claim is directed to a method for
 treating or reducing the incidence of vasomotor symptoms,
 and the method comprises a single step of administering
 an effective amount of a composition, namely, a humanized
 anti-CGRP antagonist antibody. This claim format is par-
 ticularly relevant in our consideration of the claim as a
 whole because, while there is no bright-line rule for deter-
 mining whether a preamble is limiting, we have generally
 construed statements of intended purpose in such method
 claims as limiting.
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS           15

     To illustrate the significance of methods of using appa-
 ratuses and compositions for specific purposes, we start by
 contrasting them with more general claims directed to ap-
 paratuses or compositions of matter, which are governed
 by the well-established principle that “[a]pparatus claims
 cover what a device is, not what a device does.” Hewlett-
 Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1468
 (Fed. Cir 1990). With regard to claims directed to apparat-
 uses or compositions, we have often relied on the proposi-
 tion that “[p]reamble language that merely states the
 purpose or intended use of an invention is generally not
 treated as limiting the scope of the claim.” Bicon, 441 F.3d
 at 952. For example, in Cochlear Bone Anchored Solutions
 AB v. Oticon Med. AB, we held that a statement of intended
 purpose in the preamble—“for rehabilitation of unilateral
 hearing loss”—was not limiting because the claimed appa-
 ratus was fully structurally claimed in the body of the
 claim, and its structure would allow it to function identi-
 cally whether or not used for its stated intended purpose.
 See 958 F.3d 1348, 1355 (Fed. Cir. 2020).
      Even with respect to apparatus or composition claims,
 however, we have, when warranted by the facts, found
 statements of intended purpose to be limiting. For exam-
 ple, in Bicon, we considered a claim in which the preamble
 recited an apparatus and its intended use: “[a]n emergence
 cuff member for use in preserving the interdental papilla
 during the procedure of placing an abutment on a root
 member implanted in the alveolar bone of a patient.” 441
 F.3d at 948. We held that the preamble’s statement of in-
 tended use was limiting because it “recites essential ele-
 ments of the invention pertaining to the structure of the
 abutment that is used with the claimed emergence cuff.”
 Id. at 952. We further noted that the body of the claim
 “refers back to the features of the abutment described in
 the preamble”—i.e., the preamble provided antecedent ba-
 sis for the structural terms in the body of the claim. Id. at
 952–53. Similarly, in Pacing Technologies, LLC v. Garmin
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 16          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 International, Inc., we held that a statement of intended
 use—“[a] repetitive motion pacing system for pacing a
 user”—was limiting because the term “user” in the pream-
 ble provided antecedent basis for that term later in the
 body of the claim. 778 F.3d 1021, 1023–24 (Fed. Cir. 2015).
     In contrast to apparatus and composition claims,
 claims to methods of using such apparatuses or composi-
 tions are not directed to what the method “is,” but rather
 they typically rely entirely on what the method “does.” And
 what a method does is usually recited in its preamble. Ac-
 cordingly, our claim construction analysis of statements of
 intended purpose in methods of using apparatuses or com-
 positions has tended to result in a conclusion that such pre-
 amble language is limiting. See, e.g., Boehringer Ingelheim
 Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339,
 1345 (Fed. Cir. 2003); Jansen v. Rexall Sundown, Inc., 342
 F.3d 1329, 1333 (Fed. Cir. 2003); but cf. Bristol-Myers
 Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375–
 76 (Fed. Cir. 2001) (holding preamble language non-limit-
 ing in method of treatment claims containing two steps, the
 second of which was administering a compound).
     For example, in Boehringer Ingelheim Vetmedica, we
 considered a claim directed to “[a] method of growing and
 isolating swine infertility and respiratory syndrome virus,
 ATCC-VR2332.” 320 F.3d at 1344. In holding the pream-
 ble language limiting, we explained that:
          [P]reamble language will limit the claim if it
      recites not merely a context in which the invention
      may be used, but the essence of the invention with-
      out which performance of the recited steps is noth-
      ing but an academic exercise. . . . This principle
      holds true here, as it frequently does for method
      claims: “growing” and “isolating” are not merely
      circumstances in which the method may be useful,
      but instead are the raison d’etre of the claimed
      method itself.
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS               17

 Id. at 1345 (emphasis added). Similarly, in Jansen, we
 held that the preamble of a method “for treating or prevent-
 ing macrocytic-megaloblastic anemia” was limiting be-
 cause it “set[] forth the objective of the method, and the
 body of the claim directs that the method be performed on
 someone ‘in need.’” 342 F.3d at 1332–33. We elaborated
 that the preamble “is therefore not merely a statement of
 effect that may or may not be desired or appreciated. Ra-
 ther, it is a statement of the intentional purpose for which
 the method must be performed.” Id. Again, while there is
 no bright-line rule, it is instructive that this court has not
 hesitated to hold preambles limiting when they state an
 intended purpose for methods of using a compound.
      Here, like in Boehringer Ingelheim and Jansen, the
 preambles are not merely statements of effect but rather
 statements of the intentional purpose for which the meth-
 ods must be performed. First and foremost, the treatment
 of vasomotor symptoms such as migraine is central to the
 inventions of the challenged patents. That reality is re-
 flected in the extensive discussions of such treatment in
 every section of the patents’ written description. For ex-
 ample, the Abstract states that the invention “features
 methods for preventing or treating CGRP associated disor-
 ders such as vasomotor symptoms, including headaches.”
 ’045 patent at Abstract. The “Field of the Invention” de-
 scribes the invention as relating to “the use of anti-CGRP
 antagonist antibodies for the prevention, amelioration, or
 treatment of vasomotor symptoms, such as CGRP related
 headaches (e.g., migraine).” Id. at col. 1 ll. 15–21. The
 “Background of the Invention” section is largely devoted to
 discussions of the connection between CGRP and vasomo-
 tor symptoms. See id. at col. 1 l. 39–col. 3 l. 29. The “Brief
 Summary of the Invention” describes a number of aspects
 of the invention, all of which are directed to “methods of
 using anti-CGRP antagonist antibodies for treating or pre-
 venting vasomotor symptoms, such as headaches, such as
 migraine.” Id. at col. 3 ll. 38–40; see also id. at col. 3 l. 46–
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 18          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 col. 4 l. 3. And the “Detailed Description of the Invention”
 begins by stating that “[t]he invention disclosed herein pro-
 vides methods for treating and/or preventing vasomotor
 symptoms such as headache (e.g., migraine, cluster head-
 ache, chronic headache, and tension headache).” Id. at
 col. 11 ll. 36–39.
     After this heavy emphasis on the treatment of vasomo-
 tor symptoms throughout the written description, the
 claims also reference such treatment, but only in the pre-
 ambles. Thus, the preambles are the portions of the claims
 that embody the essence of the claimed invention—meth-
 ods for treating vasomotor symptoms. Under these circum-
 stances, we reject Lilly’s suggestion that the preambles
 merely state an intended purpose that need not be per-
 formed to practice the claims. The preambles limit the
 scope of the claims because these claims would not read on,
 for example, the performance of the same method step to
 treat other conditions.
     Building on this idea, the claim language provides fur-
 ther support for the limiting nature of the preambles by
 including in each independent claim a step of administer-
 ing an “effective amount” of an anti-CGRP antibody. The
 preambles provide the only metric by which one practicing
 the claim could determine whether the amount adminis-
 tered is an “effective amount.” For this reason, Lilly is in-
 correct when it argues that the methods would be
 “performed ‘in the same way’ regardless of the preamble,”
 see Lilly Br. at 32–33, because an “amount” of anti-CGRP
 antagonist antibodies that is “effective” for treatment of
 vasomotor symptoms may not be—and likely is not—the
 same amount that would be effective for treatment of other
 conditions. This case is, therefore, not like cases in which
 the administration of a specified amount is the same re-
 gardless of the purpose. See, e.g., Bristol-Myers Squibb,
 246 F.3d at 1375 (noting that the method step of adminis-
 tering “135–175 mg/m2 taxol over about three hours”
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS            19

 would be performed in the same way regardless of the in-
 tended purpose).
      Lilly takes issue with the Board’s construction of the
 term “effective amount” and argues that “effective amount”
 cannot support treating the preambles as limiting because
 that term must encompass administering clinically ineffec-
 tive doses as low as “3 µg/kg” claimed in the dependent
 claims. But the Board derived the construction of “effective
 amount” directly from the definition provided by the pa-
 tents’ written description: “an amount sufficient to effect
 beneficial or desired results.” Board Decision, 2020 WL
 1540364, at *9 (citing ’045 patent, col. 18 ll. 38–40). The
 Board further noted that the written description provides
 examples of beneficial or desired results in the context of
 prophylactic or therapeutic uses. Id. (citing ’045 patent,
 col. 18 ll. 41–57). And the Board found that while the
 claims encompass a clinical result, they do not require such
 a result. Id. Thus, Lilly’s argument about whether the
 3 µg/kg in the dependent claims would achieve a “clinical”
 result is irrelevant, and it does not dissuade us from our
 conclusion that the preambles give life and meaning to the
 “effective amount” recited in the lone method step of each
 challenged claim.
     In addition to giving life and meaning to the method
 step of each claim, the preambles also provide antecedent
 basis for at least one later claim term in the independent
 claims, namely, the term “administering to the individual,”
 which refers back to the preamble term “treating . . . in an
 individual.” See, e.g., ’045 patent, col. 99 ll. 2–4 (emphases
 added). Lilly cites Cochlear Bone for the proposition that a
 statement of intended purpose in a preamble can be non-
 limiting even if a different term in the preamble provides
 antecedent basis for later claim terms. See 958 F.3d at
 1355 (“A conclusion that some preamble language is limit-
 ing does not imply that other preamble language, or the
 entire preamble, is limiting.”). But Cochlear involved an
 apparatus claim in which the statement of intended
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 20          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 purpose in the preamble provided no structure to the fully
 claimed structural apparatus described in the body of the
 claim. Id. In Cochlear, although the preamble term “pa-
 tient” provided antecedent basis for the later claim terms
 that specifically referenced “the patient’s” skull bone, the
 claimed apparatus would function identically whether or
 not it was used for the stated intended purpose—“for reha-
 bilitation of unilateral hearing loss.” See id. Here, in con-
 trast, the preamble notes that the claim is a method for
 treating symptoms “in an individual”—i.e., an individual
 who is suffering from those symptoms—by administering
 “to the individual” an “effective amount” to treat those
 symptoms. Axiomatically, without an individual experi-
 encing vasomotor symptoms, there would be no effective
 amount that could be used to treat the nonexistent symp-
 toms. Thus, the “individual” is part of the statement of in-
 tended purpose—for “treating at least one vasomotor
 symptom in an individual”—the entirety of which provides
 antecedent basis for the later claim term “administering to
 the individual.”
     In view of our case law regarding statements of in-
 tended purpose in claims directed to methods of using com-
 positions, and in view of the intrinsic evidence, including
 the claim language and the written description of the chal-
 lenged patents, we find no error in the Board’s conclusion
 that the preambles are limiting.
                              B
     Having found no error in the Board’s claim construc-
 tions, we turn to Lilly’s related argument regarding the im-
 pact of those constructions on the burden to prove a
 reasonable expectation of success. Before addressing
 Lilly’s specific arguments, however, we must first empha-
 size the clear distinction in our case law between a patent
 challenger’s burden to prove that a skilled artisan would
 have been motivated to combine prior art references and
 the additional requirement that the patent challenger also
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS           21

 prove that the skilled artisan would have had a reasonable
 expectation of successfully achieving the claimed invention
 from the combination. See, e.g., Procter & Gamble Co. v.
 Teva Pharms. USA, Inc., 566 F.3d 989, 994 (Fed. Cir. 2009)
 (“A party seeking to invalidate a patent based on obvious-
 ness must demonstrate ‘by clear and convincing evidence
 that a skilled artisan would have been motivated to com-
 bine the teachings of the prior art references to achieve the
 claimed invention, and that the skilled artisan would have
 had a reasonable expectation of success in doing so.’” (quot-
 ing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed.
 Cir. 2007))). A finding by the Board that a patent chal-
 lenger has demonstrated a motivation to combine refer-
 ences does not necessarily imply that the challenger has
 also met its burden of showing a reasonable expectation of
 success in achieving a claimed method of treatment. See,
 e.g., West-Ward, 923 F.3d at 1062.
     Our analysis in West-Ward is particularly instructive
 here. In West-Ward, the claims at issue were directed to a
 method of treatment with a single step:
          A method for inhibiting growth of solid excre-
     tory system tumors in a subject, said method con-
     sisting of administering to said subject a
     therapeutically effective amount of a compound of
     formula I.
 Id. at 1054. Regarding the motivation to combine require-
 ment, we held that the appellant-defendant had met its
 burden of showing that a skilled artisan “would have been
 motivated to pursue everolimus as one of several potential
 treatment options for advanced solid tumors.” Id. at 1060.
 We then considered the reasonable expectation of success
 requirement, noting that the appellant-defendant “ar-
 gue[d] that the district court erred by imposing ‘a height-
 ened standard under which it found no reasonable
 expectation of success simply because there was not yet
 clinical proof that everolimus would successfully treat
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 22          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 advanced RCC.’” Id. (quoting the appellant-defendant’s
 brief). But we rejected that argument and concluded that
 the district court had not erred when, based on its review
 of the evidence, the court “determined that the molecular
 biology of advanced RCC was not fully understood, recog-
 nized the limitations in the temsirolimus phase I data, and
 found that such data did not provide a person of ordinary
 skill with a reasonable expectation of success.” Id. at 1062.
 Said differently, we held that it was not enough for the ap-
 pellant-defendant to have shown that a skilled artisan
 would have pursued the claimed method as a treatment op-
 tion, but the appellant-defendant also had to show that the
 skilled artisan would have reasonably expected to achieve
 success in the treatment.
      The claims in this case, which are written in a “method
 for treating” format and comprise a single step of adminis-
 tering an effective amount of a compound, are analogous to
 the claims at issue in West-Ward. Like the appellant-de-
 fendant in West-Ward, Lilly must not only prove that a
 skilled artisan would be motivated to combine Olesen, Tan,
 and Queen, but also that the skilled artisan would have
 reasonably expected success in administering a humanized
 anti-CGRP antagonist antibody for “treating at least one
 vasomotor symptom.”
     Because we reject Lilly’s claim construction argument
 that the preambles are non-limiting, we find Lilly’s reli-
 ance on case law regarding unclaimed limitations to be
 misplaced. For example, Lilly cites Intelligent Bio-Sys-
 tems, Inc. v. Illumina Cambridge, Ltd., where we clarified
 that the reasonable expectation of success requirement “re-
 fers to the likelihood of success in combining references to
 meet the limitations of the claimed invention.” 821 F.3d
 1359, 1367 (Fed. Cir. 2016). In that case, we rejected the
 Board’s approach of looking to “whether one would reason-
 ably expect the prior art references to operate as those ref-
 erences intended once combined.” Id. We determined that,
 although one prior art reference contained a “quantitative
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS             23

 deblocking” requirement that was not met by a different
 reference in the asserted obviousness combination, that
 fact was irrelevant to the reasonable expectation of success
 analysis because the challenged claim itself did not contain
 that requirement. Id. Here, in contrast, the claims do con-
 tain limitations related to their intended purpose for treat-
 ing vasomotor symptoms, and thus those limitations are
 undoubtedly relevant to the reasonable expectation of suc-
 cess.
      We are also unpersuaded by Lilly’s argument that the
 patents’ definitions of “treatment” and “reducing inci-
 dence” conflict with the notion that a skilled artisan must
 reasonably expect success from the claimed methods. On
 the contrary, we find that those definitions further support
 our conclusion as to what is required by the claims. As de-
 fined by the patents’ written description, a “‘treatment’ is
 an approach for obtaining beneficial or desired clinical re-
 sults” and “‘[r]educing incidence of headache means any of
 reducing severity . . . , duration, and/or frequency.” See ’045
 patent, col. 17 ll. 37–38, 52–58. But, included in those def-
 initions, the patents also expressly recognize that:
         As is understood by those skilled in the art, in-
     dividuals may vary in terms of their response to
     treatment, and, as such, for example, a “method of
     reducing incidence of headache in an individual”
     reflects administering the anti-CGRP antagonist
     antibody based on a reasonable expectation that
     such administration may likely cause such a reduc-
     tion in incidence in that particular individual.
 Id. at col. 17 ll. 58–65. This language from the written de-
 scription is consistent with our conclusion that, in order to
 prove that the claims would have been obvious, Lilly was
 required to show that a skilled artisan would have had a
 “reasonable expectation” of success in treating vasomotor
 symptoms, even if such success was not guaranteed in all
 cases.
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 24           ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

    At bottom, the Board’s conclusion on this issue was
 summed up as follows:
          [W]hat is required is not proof that the recited
      method would actually bring about the recited re-
      sult, but rather proof that a person of ordinary skill
      in the art would have had a reasonable expectation
      that performing the recited method would bring
      about the recited result.
 See Board Decision, 2020 WL 1540364, at *8. In view of
 our determination that the claim preambles are limiting in
 this case, and in view of our case law regarding the require-
 ment that a patent challenger prove only a reasonable ex-
 pectation of success, we find no error in this conclusion by
 the Board.
                                II
     We next turn to Lilly’s challenge that the Board im-
 posed a heightened standard regarding the reasonable ex-
 pectation of success. In this challenge, Lilly first contends
 that the Board erred by requiring that the prior art refer-
 ences include anticipatory data rather than the type of
 guidance in prior art references that is generally accepted
 for a showing of a reasonable expectation of success. And
 Lilly also contends that the Board erred by requiring a
 showing of certainty regarding the blood-brain barrier. We
 address each argument below.
                                A
     Lilly contends that the Board applied the wrong stand-
 ard to evaluate whether the asserted prior art references,
 specifically Tan and Olesen, would have given a skilled ar-
 tisan a reasonable expectation of success. According to
 Lilly, the Board erroneously focused on the fact that Olesen
 and Tan lacked clinical data regarding the efficacy of using
 anti-CGRP antibodies to treat vasomotor symptoms. Lilly
 argues that this error was particularly problematic be-
 cause the challenged patents themselves do not provide the
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS            25

 kind of data that the Board demanded from the prior art
 references. Had the Board not required efficacy data, Lilly
 argues, the Board would have credited the express guid-
 ance and instructions in Tan and Olesen that would have
 led to a reasonable expectation of success.
      Teva responds that the Board did not purport to re-
 quire efficacy data, clinical or otherwise. Rather, Teva ar-
 gues, the Board observed that both Olesen and Tan lacked
 efficacy data, which the Board then considered as part of
 the overall obviousness analysis. And Teva contends that
 substantial evidence supports the Board’s findings that
 neither Tan nor Olesen would have given a skilled artisan
 a reasonable expectation of success in treating vasomotor
 symptoms with an anti-CGRP antibody.
     We agree with Teva that Lilly’s argument misreads the
 Board’s decision. To be sure, our case law makes clear that
 a showing of a reasonable expectation of success in a
 method of treatment claim need not rely on clinical data
 (which might, in fact, lead to a finding of anticipation), nor
 must it include a demonstration of certainty that the treat-
 ment would be successful in every instance. Indeed, in OSI
 Pharmaceuticals, LLC v. Apotex Inc., we expressly stated
 that “we d[id] not hold . . . that efficacy data is always re-
 quired for a reasonable expectation of success,” and that
 the law does not require “absolute predictability of suc-
 cess.” 939 F.3d 1375, 1385 (Fed. Cir. 2019). But in this
 case, the Board followed our case law and did not demand
 that the prior art include efficacy data.
     Lilly directs its argument at isolated, out-of-context
 statements plucked from dozens of pages of the Board’s fac-
 tual findings regarding the reasonable expectation of suc-
 cess. Moreover, even those statements are not as limited
 to “data” as Lilly would have us believe. For example, as a
 summation of five paragraphs of analysis regarding
 Olesen, the Board stated:
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 26          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

          We find that Olesen provides no data or direc-
      tion regarding the administration of a humanized
      monoclonal anti-CGRP antagonist antibody in an
      amount effective to achieve a beneficial or desired
      result in reducing the incidence of or treating mi-
      graine or any other vasomotor symptom, or other-
      wise specifically suggest such use.
 Board Decision, 2020 WL 1540364, at *44 (emphases
 added). Similarly, after eight paragraphs of analysis of
 Tan’s disclosures—including analysis of Tan’s reported
 16% experimental result, analysis of the differences be-
 tween the full-length antibody and the Fab’ fragment, and
 analysis of whether an antibody could reach the synaptic
 cleft—the Board included the following statement about
 Tan:
          We also find that Tan provides no information
      or data regarding the use of a full-length anti-
      CGRP antibody to reduce incidence of or treat a
      vasomotor symptom such as migraine headache (or
      any other disease).
 Id. at *46 (emphases added).
      Far from demands for data, these statements reflect
 the Board’s recognition that if the prior art had included
 efficacy data regarding use of an anti-CGRP antibody to
 treat vasomotor symptoms, that fact would have been im-
 portant in the obviousness analysis, but no such data were
 disclosed. The statements also demonstrate that the Board
 considered whether the references included any other “in-
 formation,” “direction,” or “specific[] suggest[ion]” that
 would have led to a reasonable expectation of success. In
 Sanofi v. Watson Labs. Inc., we rejected the appellants’ ar-
 gument that the district court had “by necessary implica-
 tion demand[ed] known certainty” simply because it had
 used phrases like “not a ‘concrete’ factual assertion” and “in
 less than certain terms” to describe statements in the prior
 art. 875 F.3d 636, 647 (Fed. Cir. 2017). Similarly here, we
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS          27

 decline to infer a demand for data from the Board’s obser-
 vation that references did not include those data.
      Beyond its argument about the Board’s supposed de-
 mand for data, Lilly argues that the Board “omitt[ed]” from
 its analysis “express statements of expected success” in the
 prior art. Lilly Br. at 59. Lilly focuses on Tan’s statement
 that higher doses, longer distribution times, and repeated
 administration would achieve positive results. Lilly also
 emphasizes Olesen’s clinical trial demonstrating success in
 treating migraine with a CGRP-receptor antagonist. But
 the Board’s opinion includes an extensive section on the
 reasonable expectation of success, with subsections specif-
 ically dedicated to findings about Tan and Olesen. As a
 factual matter, the Board found that neither of those refer-
 ences contained disclosures sufficient to create a reasona-
 ble expectation of success in treating vasomotor symptoms
 with a humanized anti-CGRP antibody. For Olesen, that
 finding was based on the undisputed differences between
 Olesen’s small molecule CGRP-receptor antagonist as com-
 pared to the large ligand-targeting antibodies of the chal-
 lenged claims. See Board Decision, 2020 WL 1540364, at
 *44. For Tan, the Board’s finding was based on the com-
 peting expert interpretations of Tan’s results, the unre-
 solved dispute about whether the antibody could reach the
 synaptic cleft, and the fact that Tan studied skin vasodila-
 tion in rats rather than any condition in humans. Id. at
 *45–46.
      Lilly’s disagreement with the Board’s interpretations
 of Tan and Olesen does not amount to a demonstration that
 the Board somehow failed to use the proper analysis. Ulti-
 mately, what a piece of prior art teaches presents a ques-
 tion of fact that is reviewed 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 produces factual findings reviewed for sub-
 stantial evidence.”). When it comes to competing interpre-
 tations of the teachings of prior art references, we must
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 28          ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

 uphold the principle that “if 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 re-
 view for substantial evidence.’” Elbit Sys. of Am., LLC v.
 Thales Visionix, Inc., 881 F.3d 1354, 1356 (Fed. Cir. 2018)
 (quoting In re Cree, Inc., 818 F.3d 694, 701 (Fed. Cir. 2016)
 (internal brackets omitted)). Under this deferential stand-
 ard of review, we cannot replace the Board’s reasonable in-
 terpretation of references with a different interpretation
 that Lilly would prefer.
     For the foregoing reasons, we are not persuaded that
 the Board imposed a heightened standard, or otherwise
 erred, in its analysis of whether the prior art references
 would have given a skilled artisan a reasonable expectation
 of success.
                              B
     We finally consider Lilly’s argument that the Board
 erred in its analysis of the blood-brain barrier. For back-
 ground, large compounds like the anti-CGRP antibodies of
 the challenged claims have difficulty crossing the blood-
 brain barrier, as compared with, for example, small mole-
 cule receptor antagonists. See Board Decision, 2020 WL
 1540364, at *57–58. Thus, the issue before the Board per-
 tained to whether migraine treatment must cross the
 blood-brain barrier to be effective. Id. If migraine treat-
 ment does have to cross the blood-brain barrier, that fact
 would have detracted from an expectation of successfully
 treating migraine with a large anti-CGRP antibody. Id.
 Conversely, if migraine treatment does not have to cross
 the blood-brain barrier, then the large size of the anti-
 CGRP antibodies of the challenged claims would have been
 less relevant to whether a skilled artisan would have had
 a reasonable expectation of success.
     Lilly contends that the Board incorrectly credited gen-
 eralized assertions of uncertainty about the blood-brain
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 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS           29

 barrier and omitted the latest clinical prior art, “Petersen
 2005.” 7 Lilly argues that Petersen 2005 conclusively
 demonstrated that anti-CGRP drugs prevent headache
 without crossing the blood-brain barrier. Teva responds
 that substantial evidence supports the Board’s findings
 with respect to the blood-brain barrier. Fundamentally,
 Teva argues, the Board’s decision was based on the uncer-
 tainty about whether migraine treatment must cross the
 blood-brain barrier, and Lilly’s identification of one refer-
 ence among many is not sufficient to overturn the Board’s
 analysis.
      We again agree with Teva. In analyzing the blood-
 brain barrier issue, the Board first considered the evidence
 relied on by Teva and its expert as well as the evidence re-
 lied on by Lilly and its expert (including Petersen 2005).
 See Board Decision, 2020 WL 1540364, at *47–57. Based
 on all of the evidence, the Board determined that “in 2005,
 a [skilled artisan] would have been aware of the differences
 of opinion among key opinion leaders as to the pathogene-
 sis of migraine and that it was largely unresolved.” Id. at
 *58. In view of those different opinions, the Board stated
 its finding regarding the blood-brain barrier:
         We determine that it was unknown as of No-
     vember 14, 2005, whether anti-CGRP antibodies
     needed to cross the blood-brain barrier to reduce
     incidence of or treat headache such as migraine.
     Although absolute predictability in the art is not
     required to establish a reasonable expectation of
     success, the uncertainty and unpredictability
     about this basic knowledge and the pathogenesis of
     migraine headache, as well as the skepticism

     7  K. A. Petersen et al., BIBN4096BS antagonizes hu-
 man α-calcitonin gene related peptide-induced headache
 and extracerebral artery dilatation, 77 CLIN. PHARMACOL.
 THER. 202–13 (2005).
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 30           ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS

       around whether full-length anti-CGRP antibodies
       would be effective, counsel against finding a rea-
       sonable expectation of success.
 Id.
      As discussed above, the law does not require certainty;
 it requires a reasonable expectation of success. See OSI,
 939 F.3d at 1385 (“Nor are we requiring ‘absolute predict-
 ability of success.’”). But, in considering what constitutes
 a reasonable expectation of success, we must also consider
 that the law places the burden of proof on the petitioner to
 prove a proposition of unpatentability by a preponderance
 of the evidence. 35 U.S.C. § 316(e). Thus, in this case, it
 was, at all times, Lilly’s burden to show that the claims
 would have been obvious, including that a skilled artisan
 would have had a reasonable expectation of success in
 achieving the claimed invention. See Sinskey v. Pharmacia
 Ophthalmics, Inc., 982 F.2d 494, 498 (Fed. Cir. 1992) (“The
 statutory presumption of validity under 35 U.S.C. § 282
 puts the burden of proving invalidity on the party asserting
 it and the burden never shifts to the patentee.”); see also
 Honeywell, 865 F.3d at 1355 (“In an inter partes reexami-
 nation involving obviousness, the standard is not whether
 the patent owner can persuasively show that one of ordi-
 nary skill would have expected failure. Rather, the burden
 is on the Examiner to show that one of ordinary skill would
 have had a motivation to combine the references with a rea-
 sonable expectation of success.”).
     To the extent that the blood-brain barrier dispute was
 relevant to the expectation of success in this case, which
 neither party appears to dispute, it was Lilly’s burden to
 demonstrate that despite any unpredictability in the liter-
 ature, a skilled artisan nevertheless would have had a rea-
 sonable expectation of success. Both sides presented
 numerous pieces of evidence on the blood-brain barrier is-
 sue, including prior art references and expert testimony.
 The Board weighed the evidence supporting each side of
Case: 20-1876    Document: 50     Page: 31   Filed: 08/16/2021

 ELI LILLY AND COMPANY   v. TEVA PHARMACEUTICALS          31

 the factual dispute and found that sufficient uncertainty
 and unpredictability remained—i.e., that Lilly’s evidence
 failed to demonstrate enough certainty that migraine treat-
 ment does not have to cross the blood-brain barrier to give
 a skilled artisan a reasonable expectation of success. That
 finding is consistent with our past holdings that “[u]npre-
 dictability of results equates more with nonobviousness ra-
 ther than obviousness.” Honeywell, 865 F.3d at 1356.
     Unsurprisingly, Lilly would have preferred that the
 Board accept its expert’s opinion that Petersen 2005 settled
 the question regarding the blood-brain barrier. But in view
 of the Board’s extensive analysis of the evidence, it is im-
 possible for us to conclude that the Board’s finding on the
 blood-brain barrier issue is unsupported by substantial ev-
 idence. We are therefore not persuaded that the Board
 erred in analyzing the blood-brain barrier issue and its im-
 pact on whether a skilled artisan would have had a reason-
 able expectation of success in combining the prior art
 teachings to achieve the claimed invention.
                         CONCLUSION
     We have considered Lilly’s remaining arguments but
 we find them unpersuasive. Accordingly, we affirm the
 Board’s final written decision upholding the patentability
 of the claims of the challenged patents.
                         AFFIRMED