Court Opinion

ID: 9554896
Source: CourtListenerOpinion
Date Created: 2023-08-10 15:01:45.17878+00
Date Added: 2024-06-11T15:37:28.425595
License: Public Domain

Case: 22-1346    Document: 40   Page: 1     Filed: 08/10/2023

        NOTE: This disposition is nonprecedential.

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

                IN RE: THERIPION, INC.,
                         Appellant
                  ______________________

                        2022-1346
                  ______________________

     Appeal from the United States Patent and Trademark
 Office, Patent Trial and Appeal Board in No. 15/909,314.
                   ______________________

                 Decided: August 10, 2023
                  ______________________

    JILL BROWNING, Greenblum & Bernstein, P.L.C.,
 Reston, VA, argued for appellant. Also represented by
 NICHOLAS V. SHERBINA, Sherbina Intellectual Property
 Law, PLLC, Everett, WA.

    MARY L. KELLY, Office of the Solicitor, United States
 Patent and Trademark Office, Alexandria, VA, argued for
 appellee Katherine K. Vidal. Also represented by THOMAS
 W. KRAUSE, ROBERT MCBRIDE, AMY J. NELSON, FARHEENA
 YASMEEN RASHEED.
                 ______________________

 Before HUGHES, CUNNINGHAM, and STARK, Circuit Judges.
    STARK, Circuit Judge.
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 2                                       IN RE: THERIPION, INC.

     Theripion, Inc. (“Theripion”) appeals the results of the
 Patent Trial and Appeal Board’s (“Board”) ex parte exami-
 nation of U.S. Patent Application No. 15/909,314 (the “’314
 application”). The Board affirmed a patent examiner’s fi-
 nal rejection of claims 1-13, 16, 22-24, and 27 of the ’314
 application as obvious over numerous prior-art references.
 For the following reasons, we vacate and remand. On re-
 mand, the Board must reassess its affirmance of the exam-
 iner’s rejection of the claims and must provide further
 explanation of its reasoning for whatever conclusions it
 reaches.
                               I
     Low levels of high-density lipoprotein (“HDL”) have
 long been associated with an increased risk of myocardial
 infarction. (J.A. 23) (Specification ¶ 4) Along with stroke,
 myocardial infarction is often a consequence of cardiovas-
 cular disease, and these two conditions share “a common
 underlying etiology of atherosclerosis.” 1 (J.A. 23) (Specifi-
 cation ¶ 3) Therefore, therapeutic strategies developed to
 promote atheroprotection – that is, protecting patients
 from cardiovascular disease and, thereby, reducing the risk
 of stroke and myocardial infarction – have focused on in-
 creasing a patient’s HDL levels. (J.A. 1416 (“It is hypothe-
 sized that high levels of plasma HDL are not only
 protective against coronary artery disease, but may actu-
 ally induce regression of atherosclerotic plaques.”); J.A.
 2902 (“HDL infusion therapies may induce both acute and
 chronic mechanisms that mediate atheroprotection.”))
     Apolipoprotein A-1 (“ApoA1”) is “the principal protein
 component of HDL.” (J.A. 24) (Specification ¶ 5) Introduc-
 ing ApoA1 into the body can, thus, be a mechanism for in-
 creasing HDL levels. (J.A. 24) (Specification ¶¶ 6-7)

     1   Atherosclerosis is the “thickening or hardening of
 the arteries caused by plaque buildup.” Appellant’s Br. 3.
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 IN RE: THERIPION, INC.                                         3

 However, ApoA1 has a relatively short half-life, meaning it
 only remains intact in the human body for a short time.
 (J.A. 75 (Specification ¶ 169) (discussing “circulating half-
 life of the resulting molecule”); J.A. 1418 (“ApoA-I mole-
 cules of the invention may retain all or most of their biolog-
 ical activities and the following properties may result:
 altered pharmacokinetics and pharmacodynamics leading
 to increased half-life and alterations in tissue distribution
 (e.g[.], ability to stay in the vasculature for longer periods of
 time) . . . .”) (emphasis added)) The half-life of ApoA1 can
 be improved by joining it to another protein, forming what
 is referred to in the art as a fusion protein. (J.A. 6) (“[I]t
 was known that the Fc portion in the fusion protein in-
 creases the plasma half-life of the fused ApoA-1.”) ApoA1
 can be connected to another protein either directly or by
 using a linker molecule, creating an ApoA1 fusion protein.
 (J.A. 25) (Specification ¶ 10)
      Immunoglobulins, a different kind of protein than
 ApoA1 (J.A. 43) (Specification ¶ 76), have remarkably long
 half-lives. (J.A. 602) (“The half-life of [a certain class of
 immunoglobulins] in circulation is the longest among all
 five types of immunoglobulin and may reach 21 days.”)
 Portions of immunoglobulins that “bind[] to antibody recep-
 tors on cells” are referred to as “Fc regions” or “Fc frag-
 ments.” (J.A. 43-44) (Specification ¶ 78) Prior to the ’314
 application, it was known in the art that fusion proteins
 could achieve longer half-lives when one protein was an Fc
 fragment of an immunoglobulin. (J.A. 2182) (“Fusion pro-
 teins comprising an Fc portion of an immunoglobulin can
 bestow several desirable properties on a fusion protein in-
 cluding . . . increased serum half-life . . . .”) At the time the
 ’314 application was filed, there was already a commer-
 cially available fusion protein, the Sino Biological ApoA1-
 Fc fusion protein, which contained ApoA1 directly bound
 (i.e., without a linker) to an Fc region of an immunoglobu-
 lin. (J.A. 105) (Specification ¶ 248)
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 4                                        IN RE: THERIPION, INC.

     Raising HDL levels does not, by itself, provide suffi-
 cient atheroprotection. (J.A. 23 (Specification ¶ 4) (refer-
 ring to “consensus view that the process of reverse
 cholesterol transport [i.e., RCT] . . . is central to beneficial
 HDL activity rather than simply an increase in HDL with-
 out RCT”); J.A. 2904 (“[C]holesterol efflux relates to ather-
 osclerotic severity to a greater degree than HDL cholesterol
 concentration.”)) Scientists have come to understand that
 RCT, the process by which the human body removes free
 cholesterol, is also important for atheroprotection – and,
 further, that RCT is mediated by ApoA1 and HDL. (J.A.
 2904) (“The removal of free cholesterol . . . within athero-
 sclerotic plaques by HDL and [ApoA1] is thought to be piv-
 otal to atheroprotection.”) The first, and critical, step in
 RCT is cholesterol efflux. (Id.)
     Theripion observed that the Sino Biological ApoAl-Fc
 fusion protein, wherein ApoA1 and the Fc fragment are di-
 rectly bound to each other without a linker, exhibits disap-
 pointing cholesterol efflux activity relative to ApoA1-Fc
 fusion proteins having linkers consisting of a large number
 of amino acids. (J.A. 49) (Specification ¶ 95) As the speci-
 fication of the ’314 application states:
        ApoA-1-Fc fusion protein containing a 26
        amino acid linker between ApoA-1 and the Fc
        region (ApoA-1(26)Fc) demonstrated in-
        creased cholesterol efflux as compared to ei-
        ther an ApoA-1-Fc fusion protein with a two
        amino acid linker (ApoA-1(2)Fc (Theripion))
        or an ApoA-1-Fc fusion protein without a
        linker (ApoA-1(0)Fc ([Sino Biological ApoA1-
        Fc fusion protein])) and had activity similar to
        wild-type human ApoA-1 (Control ApoA-1).”)
 (Id.) Theripion discovered that using a linker composed of
 10 to 40 amino acids between ApoA1 and the Fc region in-
 creases cholesterol efflux activity. (Id.) The claims of the
 ’314 application purport to cover this alleged invention.
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 IN RE: THERIPION, INC.                                    5

     Independent claim 1, which is illustrative of the issues
 presented in this appeal, reads:
        1. A fusion polypeptide comprising, from an
           amino-terminal position to a carboxyl-ter-
           minal position, ApoA1-L1-D, wherein:
        ApoA1 is a first polypeptide segment compris-
           ing an amino acid sequence having at
           least 95% identity with amino acid resi-
           dues 19-267 or 25-267 of SEQ ID NO:2,
           wherein said first polypeptide segment
           has cholesterol efflux activity;
        L1 is a first polypeptide linker consisting of
            from 10 to 40 amino acid residues; and
        D is an immunoglobulin Fc region,
        wherein the fusion polypeptide has increased
           cholesterol efflux activity as compared to
           the ApoA1-L1-D fusion polypeptide in
           which L1 is a two amino acid linker or is
           absent.
 (J.A. 17) Claims 2-13, 16, 22-24, and 27 depend from claim
 1. (J.A. 17-19)
     In a January 24, 2020 office action, an examiner with
 the Patent and Trademark Office (“PTO”) rejected claims
 1-13 and 27 as obvious in view of a combination of
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 6                                        IN RE: THERIPION, INC.

 references including Knudsen, 2 Ledbetter, 3 Bacus, 4 and/or
 Lagerstedt. 5 (J.A. 634-35, 637) The examiner also rejected
 claims 16 and 22-24 as obvious in view of Knudsen, Bacus,
 and Lagerstedt, but not Ledbetter, in addition to other ref-
 erences that are not relevant to this appeal. (J.A. 648)
     Theripion appealed to the Board, which affirmed the
 rejections. 6 (J.A. 2) Theripion then timely appealed to us.
 We have jurisdiction under 28 U.S.C. § 1295(a)(4)(A).

     2  Knudsen et al., U.S. Patent App. Pub. No.
 2011/0178029 A1, published July 21, 2011. (J.A. 1409-
 1533)

     3  Ledbetter et al., U.S. Patent No. 8,937,157 B2, is-
 sued January 20, 2015. (J.A. 1757-1897)

     4  Bacus et al., U.S. Patent App. Pub. No.
 2009/0318346 A1, published December 24, 2009. (J.A.
 2114-51)

     5  Lagerstedt et al., U.S. Patent App. Pub. No.
 2015/0353626 A1, published December 10, 2015. (J.A.
 2152-2390)

     6   The examiner specifically rejected claims 1-13 and
 27 based on Knudsen in view of Benoit, Igawa, Ledbetter,
 Heusser, Nezu, Bacus, Lagerstedt, and Wu. On appeal, the
 Board affirmed, focusing on the teachings of Knudsen,
 Ledbetter, Bacus, and Lagerstedt. (J.A. 8-12) At the
 Board, Theripion “did not separately argue the Examiner’s
 rejection of claims 16 and 22-24,” so the Board affirmed as
 to claims 1-13, 16, 22-24, and 27. (J.A. 12) On appeal to
 us, Theripion challenges only the Board’s findings with re-
 gards to Knudsen, Ledbetter, Bacus, and Lagerstedt, see,
 e.g., Appellant’s Br. 2, so we limit our analysis to these ref-
 erences.
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 IN RE: THERIPION, INC.                                        7

                                II
     Obviousness presents a question of law based on sub-
 sidiary factual findings. See In re Kubin, 561 F.3d 1351,
 1355 (Fed. Cir. 2009). A proposed patent claim is obvious,
 and should not be issued, “if the differences between the
 claimed invention and the prior art are such that the
 claimed invention as a whole would have been obvious be-
 fore the effective filing date of the claimed invention to a
 person having ordinary skill in the art to which the claimed
 invention pertains.” 35 U.S.C. § 103(a). In determining
 whether a claim is obvious, we – like the patent examiner
 and the Board – assess “(1) ‘the scope and content of the
 prior art,’ (2) ‘differences between the prior art and the
 claims at issue,’ (3) ‘the level of ordinary skill in the perti-
 nent art,’ and (4) the presence of objective indicia of nonob-
 viousness such ‘as commercial success, long felt but
 unsolved needs, failure of others,’ and unexpected results.”
 Elbit Sys. of Am., LLC v. Thales Visionix, Inc., 881 F.3d
 1354, 1357 (Fed. Cir. 2018) (quoting Graham v. John Deere
 Co. of Kansas City, 383 U.S. 1, 17 (1966)).
      On appeal, we review the Board’s legal determination
 of obviousness de novo and its factual findings for substan-
 tial evidence. See, e.g., Almirall, LLC v. Amneal Pharms.
 LLC, 28 F.4th 265, 271 (Fed. Cir. 2022). “[A] fact finder
 must consider all evidence of obviousness and nonobvious-
 ness before reaching a determination” as to whether a par-
 ticular claim would have been obvious to a person of
 ordinary skill in the art at the priority date of the proposed
 claim. In re Cyclobenzaprine Hydrochloride Extended-Re-
 lease Capsule Patent Litig., 676 F.3d 1063, 1077 (Fed. Cir.
 2012). Among the evidence that must be considered is any
 objective evidence of non-obviousness (if presented), such
 as commercial success or satisfaction of a long-felt but un-
 met need, as such evidence “serve[s] to guard against slip-
 ping into use of hindsight” and, thereby, help courts avoid
 “the temptation to read into the prior art the teachings of
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 8                                       IN RE: THERIPION, INC.

 the invention in issue.” Graham, 383 U.S. at 36 (internal
 quotation marks omitted).
     The Board “must make the necessary findings and
 have an adequate evidentiary basis for its findings,” includ-
 ing those made in connection with an obviousness determi-
 nation. In re Nuvasive, Inc., 842 F.3d 1376, 1382 (Fed. Cir.
 2016) (internal quotation marks omitted). Moreover, the
 Board “‘must examine the relevant data and articulate a
 satisfactory explanation for its action including a rational
 connection between the facts found and the choice made.’”
 Id. (quoting Motor Vehicle Mfrs. Ass’n v. State Farm Mut.
 Auto. Ins. Co., 463 U.S. 29, 43 (1983)). “[T]he amount of
 explanation needed will vary from case to case, depending
 on the complexity of the matter and the issues raised in the
 record.” Pers. Web Techs., LLC v. Apple, Inc., 848 F.3d 987,
 992 (Fed. Cir. 2017). “A brief explanation may do all that
 is needed if, for example, the technology is simple and fa-
 miliar and the prior art is clear in its language and easily
 understood.” Id. at 994.
                              III
      On appeal, Theripion argues that the Board erred in its
 analysis of unexpected results and motivation to combine.
 We agree with Theripion – though only to the extent that
 we find the Board failed to adequately explain how it de-
 termined the ’314 application’s claims are obvious in light
 of the totality of the record before it. We vacate the Board’s
 judgment of obviousness and remand for it to reassess the
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 IN RE: THERIPION, INC.                                        9

 evidence and provide a more fulsome explanation for what-
 ever conclusions it reaches.
                                 A7
     Theripion insists that, at the time it filed the ’314 ap-
 plication, a person of ordinary skill in the art would not
 have expected that the addition or extension of a linker be-
 tween fusion components would improve protein functions.
 The Board, by contrast, found that this relationship would
 have been expected – but for reasons that we are unable to
 discern from its written decision. (J.A. 11) (“Thus, one of
 ordinary skill in the art would similarly expect that use of
 a peptide linker, such as Gly4Ser4, would increase the bio-
 logical activity (i.e., cholesterol efflux activity) of a Fc fu-
 sion protein with ApoA1.”) Given the complexity of the
 technology involved here, we vacate and remand for the
 Board to look again at the evidence before it and to provide
 a better explanation of how it evaluated Theripion’s evi-
 dence regarding unexpected results.
     According to Theripion, at the time of its alleged inven-
 tion, an ordinarily skilled artisan would have thought that
 the addition or extension of a linker between fusion-protein
 components would not necessarily improve, and could even
 decrease, desired protein function. Theripion’s expert, Dr.
 Jeffrey A. Ledbetter – who is also the lead author on the
 Ledbetter prior-art reference (J.A. 1757) as well as the sec-
 ond named inventor on the ’314 application (J.A. 2) –

     7   We reject Theripion’s argument that the Board
 erred in waiting to consider objective indicia of nonobvious-
 ness until after concluding the claims were prima facie ob-
 vious. So long as the Board considers all evidence before
 reaching an ultimate conclusion as to obviousness, “there
 is nothing inherently wrong” with proceeding in the order
 the Board did here. Adapt Pharma Ops. Ltd. v. Teva
 Pharms. USA, Inc., 25 F.4th 1354, 1372-73 (Fed. Cir. 2022).
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 10                                     IN RE: THERIPION, INC.

 declared it was “common practice in the art of Fc fusion
 protein engineering to not include a peptide linker, or to
 include only a short, one or two amino acid linker, between
 the N-terminus of an Fc region and the C-terminus of a fu-
 sion partner.” (J.A. 579) Theripion presented the Board
 with examples of prior-art fusion-protein studies seemingly
 supporting the contention that the addition or extension of
 a linker between fusion components might decrease, and
 certainly does not necessarily increase, protein function, a
 view further endorsed by Dr. Ledbetter. (See, e.g., J.A. 417-
 18 (Dr. Ledbetter discussing Mack (J.A. 435-39) as example
 of fusion-protein activity being insensitive to linker
 length); J.A. 418 (discussing Hu (J.A. 440-49) as example
 of increased fusion-protein linker length resulting in de-
 creased fusion-protein efficacy)) Theripion also referenced
 Dwyer (J.A. 748), 8 a prior-art reference teaching that a
 DNase-Fc fusion protein was significantly less active than
 wild type DNase (J.A. 428), regardless of linker length,
 which again suggests that increasing linker length in a fu-
 sion protein does not necessarily improve activity. 9 (J.A.

      8  Mary A. Dwyer et al., Expression and Characteri-
 zation of a DNase I-Fc Fusion Enzyme, 274 J. BIOLOGICAL
 CHEMISTRY 9738 (1999) (J.A. 428-33).

      9  The Director argues that Theripion forfeited the ar-
 guments it makes to us regarding Dwyer and unpredicta-
 bility in the art. We disagree. The Board clearly
 understood that Theripion was arguing “the Examiner did
 not properly consider evidence of unexpected results.” (J.A.
 7; see also J.A. 10-11 (citing Theripion’s appeal brief to
 Board); J.A. 748 (portion of Theripion’s brief before Board
 which cited to Dwyer and Second Ledbetter Declaration, as
 “demonstrat[ing] that the addition or extension of a linker
 between fusion components does not necessarily improve
 and can even decrease protein function”); J.A. 765 (listing
 Dwyer as “evidence relied upon in this Brief” filed with
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 IN RE: THERIPION, INC.                                      11

 431-32) ( “[T]he DNase I-Fc fusion was ~10-fold less active
 in the plasmid nicking assay than wild type DNase I. This
 was independent of the linker length between the Fc and
 DNase I.”) Therefore, the relationship between linker
 length and protein function was, in Theripion’s view, un-
 predictable, at the pertinent date.
      Theripion also relied on Example 1 in the ’314 applica-
 tion which showed, seemingly surprisingly, increased cho-
 lesterol efflux activity with ApoA1 fused to the N-terminus
 of an Fc fragment using a linker of 26 amino-acid residues,
 as compared to the amount of cholesterol efflux activity
 when ApoA1 was fused to the N-terminus of Fc with no
 linker or with a two amino acid linker. (J.A. 105-06) (Spec-
 ification ¶ 248) (“Cholesterol efflux was increased in cul-
 tures containing ApoA-1-Fc with a 26 amino acid linker
 (ApoA-1(26)Fc), compared to either ApoA-1-Fc with a two
 amino acid linker (ApoA-1(2)Fc (Theripion)) or ApoA-1-Fc
 without a linker (ApoA-l(0)Fc (Sino Biol)).”)
     It appears the Board was not persuaded by Theripion’s
 evidence of unexpected results. However, we cannot dis-
 cern from its opinion the reasons for such a conclusion. Nor
 can we determine whether the Board adequately consid-
 ered the totality of Theripion’s evidence.
     The Board found that “one of ordinary skill in the art
 would . . . expect that use of a peptide linker, such as
 Gly4Ser4, would increase the biological activity (i.e., choles-
 terol efflux activity) of a Fc fusion protein with ApoA1.”
 (J.A. 11) In making this finding, the Board relied heavily

 Board); J.A. 405-06 (Theripion citing Second Ledbetter
 Declaration to examiner for its argument that “fusion pro-
 tein studies demonstrate that the addition or extension of
 a linker between fusion components does not necessarily
 improve and can even decrease protein function” and, fur-
 ther, discussing Dwyer))
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 12                                     IN RE: THERIPION, INC.

 on Bacus and Ledbetter. (J.A. 10-11) The Board does not
 explain, however, why a skilled artisan would look to Ba-
 cus’ ErbB-based fusion proteins for linkers to use in a sys-
 tem based on ApoA1, an entirely different type of protein.
 Ledbetter teaches that increasing linker length, using a
 (Gly4Ser)4 linker, increased DNase activity in an RNase-
 (Gly4Ser)4-Fc-NLG-DNase fusion protein, but DNase is a
 different protein than ApoA1, and NLG is yet another kind
 of linker. (J.A. 428 (Dwyer discussing DNase); J.A. 1812
 (Ledbetter observing “robust DNase enzymatic activity” for
 this fusion protein); J.A. 1771 (Ledbetter figure 11b demon-
 strating these results)) The Board did not provide any ra-
 tionale for why a skilled artisan would have expected
 Ledbetter’s data relating to DNase fusion protein activity
 to be predictive of ApoA1 activity in the fusion proteins
 claimed in the ’314 application. After all, ApoA1 is an en-
 tirely different kind of protein than Bacus’ ErbB or Ledbet-
 ter’s DNase.
     Then there is Dwyer, which appears to support The-
 ripion’s argument that linker length does not predictably
 impact the activity of adjacent proteins. In particular,
 Dwyer at least suggests that even among DNase fusion
 proteins like those used in Ledbetter, linker length does
 not predictably impact DNase activity. (J.A. 431-32) Yet
 the Board does not even mention Dwyer, much less grapple
 with how Theripion’s results could have been expected in
 view of it. 10
     The Board’s failure to “explicitly discuss every issue or
 every piece of evidence does not alone establish that [the
 Board] did not consider it.” Novartis AG v. Torrent

      10At oral argument, the Director acknowledged that
 the Board did not specifically address Dwyer. Oral Arg. at
 14:21-32,       available        at       https://oralargu-
 ments.cafc.uscourts.gov/default.aspx?fl=22-1346_0504202
 3.mp3.
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 IN RE: THERIPION, INC.                                     13

 Pharms. Ltd., 853 F.3d 1316, 1328 (Fed. Cir. 2017). At the
 same time, however, the Board “must examine the relevant
 data and articulate a satisfactory explanation for its ac-
 tion[,] including a rational connection between the facts
 found and the choice made.” Motor Vehicle Mfrs. Ass’n, 463
 U.S. at 43 (internal quotation marks omitted). Here, with-
 out more from the Board, we are concerned that the Board
 may have improperly used the claims of the ’314 applica-
 tion “as a template for its own reconstruction,” Sensonics,
 Inc. v. Aerosonic Corp., 81 F.3d 1566, 1570 (Fed. Cir. 1996),
 just as Theripion alleges, see Appellant’s Br. 45.
      Theripion further contends that the Board erred in an-
 alyzing unexpected results relative to Bacus and Ledbet-
 ter, which teach structurally and functionally distinct
 fusion proteins, rather than relative to Knudsen, which
 Theripion argued was the closest prior art because it
 teaches ApoA1-Fc fusion proteins with peptide linkers.
 “This court has held that when unexpected results are used
 as evidence of nonobviousness, the results must be shown
 to be unexpected compared with the closest prior art.” Kao
 Corp. v. Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir.
 2006) (internal quotation marks omitted); see also Adapt
 Pharma Ops., 25 F.4th at 1373 (“To be particularly proba-
 tive, evidence of unexpected results must establish that
 there is a difference between the results obtained and those
 of the closest prior art, and that the difference would not
 have been expected by one of ordinary skill in the art at the
 time of the invention.”) (internal quotation marks omitted).
 By seeming to focus on whether Theripion’s results were
 unexpected based on Bacus’ and Ledbetter’s teachings (see
 J.A. 11), it appears that the Board believed Bacus and
 Ledbetter were the closest prior art, although the Board
 never says so expressly. On remand, the Board must de-
 termine which prior art is the closest prior art and explain
 why that is, and then consider and explain whether The-
 ripion’s results are unexpected relative to that closest prior
 art.
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 14                                       IN RE: THERIPION, INC.

     Yet another difficulty we have in reviewing the Board’s
 analysis arises from Theripion’s contention that, at the
 time it filed the ’314 application, a person of skill in the art
 would not even have known of the problem of poor choles-
 terol efflux being associated with ApoA1-Fc fusion proteins
 with shorter linkers or no linker. See Appellant’s Br. 15-
 18, 46. That the ’314 application solves a problem that was
 not recognized in the prior art, if true, could support a find-
 ing of nonobviousness, as it would support Theripion’s con-
 tention that its results were unexpected. See, e.g., In re
 Gruskin, 234 F.2d 493, 498 (C.C.P.A. 1956) (“Therefore,
 since the cited prior art does not appear to have been cog-
 nizant of the problem . . . it can hardly be said that the
 references would have suggested [a resolution to the un-
 known problem].”). Where a patent applicant “has recog-
 nized, attacked, and successfully solved a problem,” that
 applicant may have “achiev[ed] unobvious and unexpected
 results.” Id. at 499. As the Board did not address this ar-
 gument, we have no analysis of it to review.
     In short, we must remand so the Board can reconsider
 the totality of Theripion’s evidence of unexpected results
 and for it to explain, for itself, 11 how it reaches its recon-
 sidered conclusion as to whether Theripion has proven un-
 expected results.

      11  On appeal, the Director supplies reasoning she
 speculates the Board adopted. For instance, the Director
 insists that “the Board necessarily considered Theripion’s
 alleged superior results in comparison to Knudsen as part
 of its secondary considerations analysis.” Appellee Br. at
 46-47. “[C]ourts may not accept appellate counsel’s post
 hoc rationalizations for agency action.” Burlington Truck
 Lines, Inc. v. United States, 371 U.S. 156, 168-69 (1962).
 Instead, we must remand so the Board can better explain
 its own analysis.
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 IN RE: THERIPION, INC.                                    15

                              B
     With respect to motivation to combine prior-art refer-
 ences, Theripion again contends that the Board failed to
 adequately explain itself. We again agree.
      The Board found that a person of ordinary skill in the
 art would have been motivated to modify Knudsen in view
 of Bacus, Ledbetter, and Lagerstedt, among other refer-
 ences not relevant on appeal. (J.A. 7-8) (“[O]ne of ordinary
 skill in the art would have been motivated to include a
 linker from 10 to 40 amino acids (such as the Gly4Ser4
 linker) [taught in Ledbetter (J.A. 1799)] in the fusion pep-
 tide taught in Knudsen . . . .”)) Theripion argued to the
 Board that the examiner failed to identify a reason that one
 of ordinary skill in the art would have selected an extended
 linker (10 to 40 amino acids) to join ApoA1 to the N-termi-
 nus of an immunoglobulin Fc region. (J.A. 732) Theripion
 further contended that the “art fails to teach or suggest any
 functional relationship between linker length and protein
 function in the context of an ApoA1-Fc fusion.” (J.A. 732;
 see also J.A. 7 (Board referencing this argument)) Addi-
 tionally, Dr. Ledbetter declared that “the immunoglobulin
 hinge region . . . which constitutes the N-terminal end of
 the Fc region, has generally been viewed in the art as a
 natural linker region that does not require further exten-
 sion when constructing an Fc fusion protein,” which may
 discourage a skilled artisan from investigating linker
 length. (J.A. 581) Therefore, according to Theripion, a
 skilled artisan would have had no motivation to combine
 the teachings of Knudsen, Bacus, Ledbetter, and Lager-
 stedt.
     In finding the requisite motivation to combine, the
 Board evidently rejected Theripion’s arguments, but in do-
 ing so it provided little more than the conclusory statement
 that “the Examiner has the better position.” (J.A. 7) The
 Board made findings regarding what each prior art refer-
 ence taught in isolation (J.A. 7-8) and failed to articulate
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 16                                       IN RE: THERIPION, INC.

 any reason why a skilled artisan would have modified
 Knudsen’s system with Ledbetter’s linker – other than the
 unexplained assertion that “incorporation of such a linker
 increases biological activity of the fusion partner” (J.A. 8),
 for which there is little, if any, support in the record, espe-
 cially in view of Dwyer, which the Board fails to address.
 The Board did not identify any evidence for its conclusion
 that a person of ordinary skill in the art would have viewed
 Ledbetter’s DNase fusion-protein data as instructive with
 respect to the biological activity of ApoA1-Fc, an entirely
 different fusion protein.
     “[I]t is not adequate to summarize and reject argu-
 ments without explaining why the [Board] accepts the pre-
 vailing argument.” In re Nuvasive, Inc., 842 F.3d at 1383.
 The Board “must articulate a reason why” a person of skill
 would be motivated to combine references. Id. at 1382.
 “Conclusory statements alone are insufficient” to permit us
 to review the Board’s motivation analysis. Id. at 1383 (in-
 ternal quotation marks omitted). Therefore, we must re-
 mand. On remand, the Board is free to reach the same
 conclusions it previously reached with respect to motiva-
 tion to combine, but it must provide further explanation for
 whatever conclusion it reaches.
                               C
      While Theripion contends that the record is so clear as
 to warrant reversal – that is, the evidence of unexpected
 results is so compelling as to overwhelm any prima facie
 case of obviousness and, in any event, there is no prima
 facie showing of obviousness because there was no motiva-
 tion to combine the prior art references – we are unable to
 reach that conclusion. Given that we are presently unsure
 of the bases on which the Board reached its subsidiary fac-
 tual findings supporting its ultimate legal conclusion of ob-
 viousness, we are not in a position to determine whether
 there is substantial evidence to support the Board’s deter-
 mination. See Alacritech, Inc. v. Intel Corp., 966 F.3d 1367,
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 IN RE: THERIPION, INC.                                  17

 1370-73 (Fed. Cir. 2020) (vacating and remanding for fur-
 ther consideration where we could not “reasonably discern
 whether the Board followed a proper path in determining”
 challenged claims were obvious). Instead, we will remand
 for further proceedings before the Board.
                             IV
     In sum, we vacate and remand for the Board to provide
 a more thorough explanation of its obviousness findings,
 particularly its findings on unexpected results and motiva-
 tion to combine, and to reassess whether to affirm the ex-
 aminer’s rejection of the claims once more. We take no
 position on whether the prior art renders the claims of the
 ’314 application obvious.
                VACATED AND REMANDED
                           COSTS
 No Costs.