Court Opinion

ID: 5132196
Source: CourtListenerOpinion
Date Created: 2021-12-07 00:00:48.71281+00
Date Added: 2024-06-11T08:23:28.774383
License: Public Domain

Case: 20-2329   Document: 66     Page: 1    Filed: 12/01/2021

   United States Court of Appeals
       for the Federal Circuit
                 ______________________

         MODERNATX, INC., FKA MODERNA
             THERAPEUTICS, INC.,
                  Appellant

                            v.

      ARBUTUS BIOPHARMA CORPORATION,
                    Appellee
             ______________________

                       2020-2329
                 ______________________

     Appeal from the United States Patent and Trademark
 Office, Patent Trial and Appeal Board in No. IPR2019-
 00554.
                  ______________________

                Decided: December 1, 2021
                 ______________________

     AMY K. WIGMORE, Wilmer Cutler Pickering Hale and
 Dorr LLP, Washington, DC, argued for appellant. Also rep-
 resented by MARK CHRISTOPHER FLEMING, ANASTASIA
 GREENBERG, KATHERINE P. KIECKHAFER, MADELEINE C.
 LAUPHEIMER, EMILY R. WHELAN, Boston, MA.

    DAVID I. BERL, Williams & Connolly LLP, Washington,
 DC, argued for appellee. Also represented by THOMAS S.
 FLETCHER, JESSICA PALMER RYEN; SONJA ROCHELLE
 GERRARD, STEVEN WILLIAM PARMELEE, MICHAEL T.
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 2       MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 ROSATO, Wilson Sonsini Goodrich & Rosati, Seattle, WA;
 LORA MARIE GREEN, RICHARD TORCZON, Washington, DC.
                ______________________

     Before LOURIE, O’MALLEY, and STOLL, Circuit Judges.
 LOURIE, Circuit Judge.
     ModernaTx, Inc. (“Moderna”) appeals from the decision
 of the U.S. Patent and Trademark Office Patent Trial and
 Appeal Board (the “Board”) holding that the claims of U.S.
 Patent 8,058,069 (“’069 patent”) are not unpatentable as
 obvious. See Moderna Therapeutics, Inc. v. Protiva Bio-
 therapeutics, Inc., IPR2019-00554, 2020 WL 4237232 (July
 23, 2020) (“Board Decision”). For the reasons provided be-
 low, we affirm.
                         BACKGROUND
                      I. The ’069 Patent
     Arbutus owns the ’069 patent directed to “stable nu-
 cleic acid-lipid particles (SNALP) comprising a nucleic acid
 (such as one or more interfering RNA), methods of making
 the SNALP, and methods of delivering and/or administer-
 ing the SNALP.” ’069 patent at Abstract. The ’069 patent,
 which issued on November 15, 2011, claims priority from a
 provisional application filed on April 15, 2008.
      As described in the ’069 patent, RNA interference
 (“RNAi”) is a biological process in which recognition of dou-
 ble-stranded RNA “leads to posttranscriptional suppres-
 sion of gene expression.” Id. at col. 1 ll. 28–31. That
 biological process is mediated by small interfering RNA
 (“siRNA”), “which induces specific degradation of mRNA
 through complementary base pairing.” Id. at col. 1 ll. 31–
 34. The ’069 patent recognized that RNAi provided “a po-
 tential new approach to downregulate or silence the tran-
 scription and translation of a gene of interest.” Id. at col. 1
 ll. 41–43.
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION           3

      A “safe and effective nucleic acid delivery system is re-
 quired for RNAi to be therapeutically useful.” Id. at col. 1
 ll. 52–53. The delivery system “should be small” and
 “should remain intact in the circulation for an extended pe-
 riod of time in order to achieve delivery to affected tissues.”
 Id. at col. 2 ll. 27–31. This requires a “highly stable, serum-
 resistant nucleic acid-containing particle that does not in-
 teract with cells and other components of the vascular com-
 partment.” Id. at col. 2 ll. 31–34. The particle should also
 “readily interact with target cells at a disease site in order
 to facilitate intracellular delivery of a desired nucleic acid.”
 Id. at col. 2 ll. 34–36. The ’069 patent thus recognized that
 there remained “a strong need in the art for novel and more
 efficient methods and compositions for introducing nucleic
 acids such as siRNA into cells.” Id. at col. 2 ll. 55–57.
      The ’069 patent describes the invention as “novel, se-
 rum-stable lipid particles comprising one or more active
 agents or therapeutic agents, methods of making the lipid
 particles, and methods of delivering and/or administering
 the lipid particles (e.g., for the treatment of a disease or
 disorder).” Id. at col. 2 l. 65–col. 3 l. 2. The lipid particles
 are comprised of one or more cationic lipids, one or more
 non-cationic lipids, and one or more conjugated lipids. See
 id. at col. 3 ll. 11–20. As described in the patent, “[t]he pre-
 sent invention is based, in part, upon the surprising discov-
 ery that lipid particles comprising from about 50 mol % to
 about 85 mol % of a cationic lipid, from about 13 mol % to
 about 49.5 mol % of a non-cationic lipid, and from about 0.5
 mol % to about 2 mol % of a lipid conjugate provide ad-
 vantages when used for the in vitro or in vivo delivery of an
 active agent, such as a therapeutic nucleic acid (e.g., an in-
 terfering RNA).” Id. at col. 5 ll. 44–51. The ’069 patent
 further states that the stable nucleic acid-lipid particles
 “advantageously impart increased activity of the encapsu-
 lated nucleic acid (e.g., an interfering RNA such as siRNA)
 and improved tolerability of the formulations in vivo, re-
 sulting in a significant increase in the therapeutic index”
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 4      MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 as compared to prior art nucleic acid-lipid particle compo-
 sitions. Id. at col. 5 ll. 51–58. And the particles are “stable
 in circulation, e.g., resistant to degradation by nucleases in
 serum and are substantially non-toxic” to humans. Id. at
 col. 5 ll. 58–61.
     The ’069 patent contains 22 claims. Claim 1, the only
 independent claim, recites:
     1. A nucleic acid-lipid particle comprising:
         (a) nucleic acid;
         (b) a cationic lipid comprising from 50 mol
             % to 65 mol % of the total lipid present
             in the particle;
         (c) a non-cationic lipid comprising a mix-
             ture of a phospholipid and cholesterol
             or a derivative thereof, wherein the
             phospholipid comprises from 4 mol %
             to 10 mol % of the total lipid present in
             the particle and the cholesterol or de-
             rivative thereof comprises from 30
             mol % to 40 mol % of the total lipid pre-
             sent in the particle; and
         (d) a conjugated lipid that inhibits aggre-
             gation of particles comprising from 0.5
             mol % to 2 mol % of the total lipid pre-
             sent in the particle.
 Id. at col. 91 ll. 24–35. The dependent claims, which con-
 tain all of these same limitations, do not raise separate is-
 sues. As the parties have not argued them separately, we
 will not deal with them separately.
          II. Inter Partes Review of the ’069 Patent
     Moderna petitioned for inter partes review of the ’069
 patent. In its petition, Moderna asserted three grounds
 challenging all claims of the ’069 patent. In the first
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION      5

 ground, Moderna alleged that all claims of the ’069 patent
 would have been anticipated by and/or obvious over Inter-
 national Pat. Publ. WO 2005/007196 (“the ’196 PCT”) or
 U.S. Pat. Publ. 2006/0134189 (“the ’189 publication”). In
 the second ground, Moderna alleged that all claims of the
 ’069 patent would have been obvious over a combination of
 the ’196 PCT, the ’189 publication, Lin, 1 and Ahmad. 2 In
 the third ground, Moderna alleged that all claims of the
 ’069 patent were anticipated by U.S. Pat. Publ.
 2006/0240554 (“the ’554 publication”), and alternatively
 that the claims would have been obvious over the ’554 pub-
 lication.
     Relevant to this appeal, Moderna’s arguments based on
 the ’196 PCT and the ’189 publication centered on alleged
 overlapping ranges of components. Moderna contended
 that all of the ranges for the components in the claimed
 nucleic acid-lipid particle were disclosed or taught by the
 prior art, and that a presumption of obviousness should
 therefore apply under our precedent.
     For three of the four lipid components in the claimed
 nucleic acid-lipid particle—the cationic lipid, the choles-
 terol portion of the non-cationic lipid, and the conjugated
 lipid—Moderna pointed to expressly disclosed ranges in
 the prior art. For example, the prior art discloses a range
 of 2–60 mol % for the cationic lipid, see ’196 PCT at ¶ 88;
 ’189 publication at ¶ 152, which overlaps with the claimed
 range “from 50 mol % to 65 mol % of the total lipid present

    1   Alison J. Lin, et al., Three-Dimensional Imaging of
 Lipid Gene-Carriers: Membrane Charge Density Controls
 Universal Transfection Behavior in Lamellar Cationic Lip-
 osome-DNA Complexes, 84 Biophysical J. 3307–16 (2003).
     2  Ayesha Ahmad, et al., New Multivalent Cationic
 Lipids Reveal Bell Curve for Transfection Efficiency Ver-
 sus Membrane Charge Density: Lipid-DNA Complexes for
 Gene Delivery, 7 J. Gene Med. 739–48 (2005).
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 6      MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 in the particle.” ’069 patent at col. 91 ll. 26–27. Similarly,
 the prior art discloses ranges of 0.5–25 mol % and 0.5–20
 mol % for the conjugated lipid, see ’196 PCT at ¶¶ 92–93;
 ’189 publication at ¶ 152, which overlap with the claimed
 range “from 0.5 mol % to 2 mol %.” ’069 patent at col. 91
 ll. 33–35. And for the cholesterol portion of the non-cati-
 onic lipid, the prior art discloses ranges of 20–45 mol % and
 20–55 mol %, see ’196 PCT at ¶ 91; ’189 publication at
 ¶ 152, which overlap with the claimed range “from 30
 mol % to 40 mol %.” ’069 patent at col. 91 ll. 31–32.
     The parties’ dispute focused mainly on the phospho-
 lipid portion of the non-cationic lipid, for which the claims
 require a range “from 4 mol % to 10 mol % of the total lipid
 present in the particle.” ’069 patent at col. 91 ll. 29–31.
 Moderna acknowledged that the prior art does not contain
 any express disclosure of a range for the phospholipid in
 the particle. But Moderna argued that, because the total
 mol % of all lipids in the particle must equal 100%, based
 on the ranges of the other lipid components, the maximum
 amount and minimum amount of phospholipid can be cal-
 culated to form a range of 0–19.5 mol %. See, e.g., J.A. 134.
 Moderna also argued that the phospholipid range would
 have been obtainable through routine optimization using
 disclosed prior art formulations as starting points. See J.A.
 4808–09.
    The Board found that Moderna failed to meet its bur-
 den with respect to its challenges based on the ’196 PCT
 and the ’189 publication. Specifically, the Board deter-
 mined that:
     the teachings of the ’196 PCT and ’189 Publication
     do not anticipate or otherwise render obvious a nu-
     cleic acid-lipid particle containing each of the re-
     cited lipid components within the claimed ranges,
     including specifically a phospholipid range of 4–
     10%.
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION       7

 Board Decision, 2020 WL 4237232, at *11. The Board
 noted that Moderna had “derive[d] an overlapping phos-
 pholipid range by making certain assumptions about the
 other lipid components of the particle.” Id. at *12. There-
 fore, the Board concluded, a presumption of obviousness
 due to overlapping ranges did not apply in this case when
 “one of the claimed ranges for one of the expressly claimed
 sub-components of the claimed composition is not neces-
 sarily disclosed based on broader ranges for other compo-
 nents disclosed in the prior art.” Id.
      The Board proceeded to list the unfounded assump-
 tions upon which Moderna’s calculation of the phospholipid
 range was based. The Board specifically noted that
 Moderna arrived at the phospholipid range of 0–19.5% by
 assuming that a “skilled artisan would have selected a cat-
 ionic lipid amount of 60%, cholesterol in the amount 20–
 40%, and PEG in the amount of 0.5–20%,” but Moderna
 failed to explain why a skilled artisan would have chosen
 those particular amounts. Id. at *13. Moreover, the Board
 found that the ’196 PCT and the ’189 publication only iden-
 tify the phospholipid as an optional example of a non-cati-
 onic lipid and nothing in the references suggested that the
 entirety of the “broadly disclosed ranges could apply if all
 four claimed lipid components were to be included as part
 of the nucleic-acid lipid[sic] particle.” Id.
     The Board also rejected Moderna’s argument that the
 claimed phospholipid range would have been obtainable
 through routine optimization based on knowledge that
 some phospholipid would provide structural stability but
 too much would inhibit release of the nucleic acid payload.
 Id. The evidence showed that stability and delivery effi-
 ciency were general considerations when designing a nu-
 cleic acid-lipid particle, but these considerations were not
 connected with phospholipid amounts. Id. Thus, the Board
 found, the evidence was “insufficient to establish that the
 claimed phospholipid range in particular was a recognized
 result-effective variable subject to routine optimization.”
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 8      MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 Id. at *14 (citing E.I. Dupont De Nemours & Co. v. Synvina
 C.V. , 904 F.3d 996, 1008 (Fed. Cir. 2018)).
      Finally, the Board rejected Moderna’s argument that
 certain formulations in the prior art—namely, the “2:30”
 and “2:40” formulations—would have served as starting
 points for routine optimization. The Board found that
 Moderna failed to sufficiently explain how or why a skilled
 artisan would have upwardly and downwardly adjusted
 the amounts of the components in those formulations to ar-
 rive at the claimed ranges. While Moderna had identified
 “reasons to adjust each of the lipid components individu-
 ally,” the Board found that the optimization argument
 “does not take into account the interdependence of the
 claimed lipid components or how the adjustments would af-
 fect the nucleic acid-lipid particle as a whole.” Id. *15.
      Moderna appealed from the Board’s decision that it
 failed to show that the claims of the ’069 patent would have
 been obvious over the cited prior art. Subject to the parties’
 dispute about Moderna’s standing to pursue its appeal,
 which we discuss further below, we have jurisdiction pur-
 suant to 28 U.S.C. § 1295(a)(4).
                           DISCUSSION
                           I. Standing
      Before we consider Moderna’s argument on the merits
 of the Board’s decision upholding the claims of the ’069 pa-
 tent, we must first determine whether Moderna has stand-
 ing to pursue its appeal. After all, “no principle is more
 fundamental to the judiciary’s proper role in our system of
 government than the constitutional limitation of federal-
 court jurisdiction to actual cases or controversies.” Daim-
 lerChrysler Corp. v. Cuno, 547 U.S. 332, 341–42 (2006)
 (quoting Raines v. Byrd, 521 U.S. 811, 818 (1997)).
     Since the America Invents Act took effect nearly a dec-
 ade ago, we have had a number of occasions to consider the
 question of standing in appeals from Board decisions in
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION          9

 IPR proceedings. 3 Our precedent generally makes clear
 that, as in all appeals before this court, an appellant seek-
 ing review of a Board decision in an IPR must have “(1)
 suffered an injury in fact, (2) that is fairly traceable to the
 challenged conduct of the [appellee], (3) that is likely to be
 redressed by a favorable judicial decision.” Phigenix, 845
 F.3d at 1171–72 (Fed. Cir. 2017).
     Under the IPR statute, there is no standing require-
 ment for petitioners to request institution of IPR by the
 Board. See Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct.
 2131, 2143–44 (2016) (“Parties that initiate [IPRs] need not
 have a concrete stake in the outcome; indeed, they may lack
 constitutional standing.”). And we recognize that where a
 statute grants judicial review, as the IPR statute does, see
 35 U.S.C. § 319, the criteria of immediacy and redressabil-
 ity may be “relaxed.” See Momenta, 915 F.3d at 768. But
 we have always maintained that a party’s participation in
 the underlying IPR before the Board is insufficient by itself
 to confer standing on that party to appeal the Board’s deci-
 sion to this Article III court. See Phigenix, 845 F.3d at
 1175; see also Momenta, 915 F.3d at 768 (“Although the
 statutory grant of judicial review may ‘relax’ the Article III
 criteria, judicial review of agency action remains subject to
 the constitutional foundation of injury-in-fact, lest the
 court occupy only an advisory role.”); JTEKT, 898 F.3d at
 1219 (“[T]he statute cannot be read to dispense with the
 Article III injury-in-fact requirement for appeal to this

     3   See, e.g., Apple Inc. v. Qualcomm Inc., 992 F.3d
 1378 (Fed. Cir. 2021); Samsung Elecs. Co. v. Infobridge Pte.
 Ltd., 929 F.3d 1363 (Fed. Cir. 2019); Momenta Pharms.,
 Inc. v. Bristol-Myers Squibb Co., 915 F.3d 764 (Fed. Cir.
 2019); JTEKT Corp. v. GKN Auto. Ltd., 898 F.3d 1217 (Fed.
 Cir. 2018); Phigenix, Inc. v. Immunogen, Inc., 845 F.3d
 1168 (Fed. Cir. 2017); Consumer Watchdog v. Wis. Alumni
 Research Found., 753 F.3d 1258 (Fed. Cir. 2014).
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 10       MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 court.”). Accordingly, even when an appellant is “sharply
 opposed to the Board’s decision and the existence of [a] pa-
 tent, that is not enough to make th[e] dispute justiciable.”
 Consumer Watchdog, 753 F.3d at 1263. As the party seek-
 ing judicial review, Moderna “has the burden of establish-
 ing that it possesses the requisite injury.” See JTEKT, 898
 F.3d at 1220.
     Moderna asserts as a basis for standing that there is a
 substantial risk that Arbutus will assert the ’069 patent in
 an infringement suit targeting Moderna’s COVID-19 vac-
 cine. 4 In connection with its burden to show standing,
 Moderna supplemented the record with a declaration from
 Shaun Ryan, Moderna’s Senior Vice President and Deputy
 General Counsel. See J.A. 5737–47. Mr. Ryan described
 Moderna’s work to harness its “proprietary mRNA technol-
 ogy, delivery technologies, and manufacturing processes to
 develop its COVID-19 vaccine, mRNA-1273.” J.A. 5738.
 Mr. Ryan further described Moderna’s concrete plans as of
 September 2020 to release a COVID-19 vaccine, its emer-
 gency use authorization as of December 2020, and its sub-
 sequent commercial shipments of the vaccine. J.A. 5739–
 41.
     Mr. Ryan also described, from Moderna’s perspective,
 how Arbutus’s statements and actions have created a “sub-
 stantial risk that Arbutus may bring an infringement ac-
 tion relating to Moderna’s COVID-19 vaccine.” J.A. 5741.
 Specifically, Mr. Ryan listed a series of public statements
 made by Arbutus in 2017 regarding the alleged extensive
 scope of its patent coverage over virtually all lipid

      4   Moderna also asserts a second basis for standing
 based on its current status as a licensee of the ’069 patent
 with monetary obligations affected by the validity of the
 patent. For the reasons discussed in our opinion in Appeal
 No. 20-1184, issued today, we reject Moderna’s argument
 that it has standing on this basis.
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 nanoparticle (“LNP”) delivery systems. Id. For example,
 Mr. Ryan quoted a May 2017 statement from former Arbu-
 tus CEO Mark Murray in Forbes Magazine that Arbutus
 “invented, developed and dominate[s] the field of LNP.” Id.
 Furthermore, Mr. Ryan attested that Arbutus and its affil-
 iates “have consistently taken the position with Moderna
 that [Moderna] requires a license to [Arbutus’s] patents,
 including the ’069 patent.” J.A. 5742. And, Mr. Ryan as-
 serted, “Arbutus has not granted Moderna a covenant not
 to sue on the ’069 patent.” Id.
      We have held that an appellant “need not face ‘a spe-
 cific threat of infringement litigation by the patentee’ to es-
 tablish the requisite injury in an appeal from a final
 written decision in an inter partes review.” Adidas AG v.
 Nike, Inc., 963 F.3d 1355, 1357 (Fed. Cir. 2020) (quoting
 DuPont, 904 F.3d at 1004). Instead, “it is generally suffi-
 cient for the appellant to show that it has engaged in, is
 engaging in, or will likely engage in ‘activity that would
 give rise to a possible infringement suit.’” Grit Energy
 Sols., LLC v. Oren Techs., LLC, 957 F.3d 1309, 1319 (Fed.
 Cir. 2020) (quoting Consumer Watchdog, 753 F.3d at 1262).
 Accordingly, on the record before us, Moderna has demon-
 strated enough of a risk that it will be faced with an in-
 fringement suit based on the combination of its own
 activities in developing the COVID-19 vaccine, Arbutus’s
 broad public statements about its extensive patent cover-
 age in this area, and Arbutus’s refusal to grant a covenant
 not to sue.
     It also bears noting that, if we were to dismiss this ap-
 peal for lack of standing, Arbutus could sue Moderna for
 infringement immediately thereafter. That possibility is
 easy to envision based on the record, and Arbutus has done
 nothing to dispel it. We seek to avoid such a result, which
 would perversely incentivize a future similarly situated pa-
 tent owner to remain silent regarding its intentions during
 the pendency of an appeal and wait to sue for infringement
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 12     MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 until after the appeal has been dismissed for lack of stand-
 ing.
     For the foregoing reasons, we conclude that Moderna
 has standing to pursue its appeal based on the risk of an
 infringement suit, and we proceed to the merits of this ap-
 peal.
                      II. Nonobviousness
      Moderna raises two primary challenges to the Board’s
 obviousness analysis. First, Moderna contends that the
 Board erred by failing to apply a presumption of obvious-
 ness based on overlapping ranges in the prior art. Based
 on this first challenge, Moderna also raises a number of an-
 cillary arguments about the Board’s misplacement of vari-
 ous evidentiary burdens. Second, Moderna argues that the
 Board erred in finding that Moderna had not shown a mo-
 tivation to optimize the lipid components of the prior art
 nucleic acid-lipid particles and that the phospholipid is a
 result-effective variable. We address these two challenges
 in turn.
     Obviousness is a question of law that “lends itself to
 several basic factual inquiries,” including the scope and
 content of the prior art, the level of ordinary skill in the art,
 and differences between the prior art and the claimed in-
 vention. Graham v. John Deere Co., 383 U.S. 1, 17–18
 (1966) (citing Great Atl. & Pac. Tea Co. v. Supermarket
 Equip. Corp., 340 U.S. 147, 155 (1950)). We review the
 Board’s legal determinations de novo, In re Elsner, 381
 F.3d 1125, 1127 (Fed. Cir. 2004), and the Board’s factual
 findings underlying those determinations for substantial
 evidence, In re Gartside, 203 F.3d 1305, 1316 (Fed. Cir.
 2000). A finding is supported by substantial evidence if a
 reasonable mind might accept the evidence to support the
 finding. See Consol. Edison Co. of New York v. NLRB, 305
 U.S. 197, 229 (1938).
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION       13

                              A.
     Moderna contends that the Board erred when it held
 that Moderna had not established that a presumption of
 obviousness should apply based on the overlapping ranges
 in the prior art. Arbutus responds that the Board correctly
 found that Moderna had not demonstrated that the pre-
 sumption should apply because the prior art does not dis-
 close a range for the phospholipid component.
     We have held that a presumption of obviousness typi-
 cally exists “when the ranges of a claimed composition
 overlap the ranges disclosed in the prior art.” In re Peter-
 son, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (emphasis added);
 see also Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299,
 1311 (Fed. Cir. 2006) (“Where a claimed range overlaps
 with a range disclosed in the prior art, there is a presump-
 tion of obviousness.” (emphasis added)). Here, it is undis-
 puted that a range for the phospholipid is not expressly
 “disclosed” in the prior art. Yet, Moderna argues that the
 Board should have applied the presumption anyway based
 on Moderna’s theory that a phospholipid range can be de-
 rived or calculated from the disclosures of the prior art.
     The Board correctly recognized that we have never be-
 fore applied the presumption of obviousness for overlap-
 ping ranges in a case in which the prior art does not contain
 an express disclosure of a range. Board Decision, 2020 WL
 4237232, at *12 (“[T]he Federal Circuit has only applied
 the presumption where the overlapping range is expressly
 disclosed, not where an overlap might be assumed based on
 other motivating factors.” (citations omitted)). It is, how-
 ever, also true that we have never affirmatively decided
 whether or not the presumption ever could apply in such a
 case. Though the parties would have us make that decision
 here, it is not necessary or appropriate for us to reach that
 general question because this case turns on a narrower is-
 sue, specifically, Moderna’s failure to show that the over-
 lapping range is actually taught by the prior art.
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 14     MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

     Before the presumption of obviousness could be ap-
 plied, Moderna would have to first show that, despite the
 lack of an express disclosure in the references, a person of
 ordinary skill would have nevertheless understood that the
 ’196 PCT and the ’189 publication teach or suggest a range
 for the phospholipid component that overlaps with the
 claimed range. Moderna has failed to make that threshold
 showing.
     Moderna’s theory essentially proceeds as follows. The
 ’196 PCT and the ’189 publication each disclose a nucleic
 acid-lipid particle with four lipid components—cationic li-
 pid, cholesterol, phospholipid, conjugated lipid. Each ref-
 erence discloses a range for three out of the four lipids. It
 is axiomatic that the amounts of the four lipids must add
 to 100 mol %. Therefore, Moderna posits, it would have
 been a matter of simple subtraction for a person of ordinary
 skill in the art to derive a range for the phospholipid.
      We agree with the Board and Arbutus that Moderna’s
 theory is an oversimplification based on unfounded as-
 sumptions. One of the key flawed assumptions that
 Moderna makes is that the amount of each individual lipid
 component in the prior art nucleic acid-lipid particles can
 be freely manipulated and adjusted across the full scope of
 the disclosed ranges. As a corollary to that assumption,
 Moderna assumes that any lipid component of the particle
 can be increased as long as any other lipid component of
 the particle is decreased by a corresponding amount to
 maintain a total of 100%. These assumptions are contrary
 to logic and the evidence in the record.
     In its petition, Moderna presented one hypothetical
 “scenario” in which it assumed that the prior art particle
 contains the maximum 60 mol % of cationic lipid and the
 ranges of cholesterol and conjugated lipid are selected from
 the range of 20–40 mol % and 0.5–25 mol %, respectively.
 See J.A. 134 (Moderna’s petition for IPR, presenting a table
 showing a scenario in which the cationic lipid in the prior
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION        15

 art nucleic acid-lipid particle is set to maximum). But even
 that one scenario illustrates the problem with Moderna’s
 assumptions. Moderna focuses on the minimum selection
 for cholesterol and conjugated lipid, which would, in fact,
 result in a phospholipid maximum of 19.5 mol %. But ra-
 ther than acknowledge that selecting the maximums for
 cholesterol and conjugated lipid would result in a nonsen-
 sical negative value for the phospholipid, Moderna simply
 sets the phospholipid minimum to 0. Indeed, if this case
 were as simple as arbitrarily setting maximums and mini-
 mums for each individual component in the prior art and
 subtracting from 100%, it would seem that the possible
 range for the phospholipid component in the prior art nu-
 cleic acid-lipid particle extends from a minimum
 value -40 mol % (which is a meaningless negative num-
 ber) 5 to a maximum value of 77.5 mol % (which is an
 amount inconsistent with the teachings of the prior art). 6
      As Arbutus demonstrated to the Board, this case is not
 that simple because the lipid components of the nucleic
 acid-lipid particle are interdependent, and they interact
 with each other unpredictably. Arbutus put forth a pleth-
 ora of evidence, including evidence from the prior art refer-
 ences as well as expert testimony, demonstrating that the
 properties of nucleic acid-lipid particles depend on the par-
 ticle as a whole, rather than on any one component. See,
 e.g., J.A. 1710–14 (expert declaration citing prior art refer-
 ences to demonstrate the effects of varying the amounts of
 the lipid components on toxicity and efficacy). Thus, sub-
 stantial evidence supports the Board’s rejection of

     5   -40% phospholipid =
             [100% total]–[60% cationic]–[55%
             cholesterol]–[25% conjugated]
     6   77.5% phospholipid =
             [100% total]–[2% cationic]–[20%
             cholesterol]–[0.5% conjugated]
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 16     MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 Moderna’s premise that one could obtain a value for the
 amount of any one lipid component in the particle by add-
 ing up the amounts of the other three components and sub-
 tracting from 100%.
     Even in cases with overlapping ranges involving mul-
 tiple components, we have held that evidence that the com-
 ponents “interacted in an unpredictable or unexpected way
 could render the combination nonobvious.” In re Applied
 Materials, Inc., 692 F.3d 1289, 1298 (Fed. Cir. 2012). That
 holding applies even more strongly here, where the as-
 sumption necessary to derive the implicit overlapping
 range is itself undermined by the unpredictable interactiv-
 ity between the components.
     It is telling that even Moderna has been unable to re-
 main consistent in its contentions about the allegedly im-
 plied phospholipid range in the prior art. For example,
 Moderna argued in its petition that the phospholipid range
 in the ’196 PCT and the ’189 publication can be calculated
 as 0–19.5 mol %. See J.A. 134. In its opening brief in this
 court, however, Moderna acknowledged that performing its
 arithmetic using different inputs from the prior art refer-
 ences could result in ranges of 0–30 mol % or 0–80 mol %.
 See Moderna Opening Br. at 38. Although we recognize
 that both of those ranges would still overlap with the 4–10
 mol % phospholipid range in claim 1 of the ’069 patent, the
 possibility of calculating multiple different ranges for the
 phospholipid cuts against Moderna’s argument that there
 is a clearly taught overlapping phospholipid range that
 compels the application of a presumption of obviousness.
     For the foregoing reasons, the Board correctly held that
 Moderna had not established that a presumption of obvi-
 ousness applies based on overlapping ranges. As noted
 above, Moderna raises a number of ancillary arguments
 that are contingent on its argument that a presumption of
 obviousness should have applied. For example, Moderna
 argues that the Board improperly placed the burden on
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION          17

 Moderna to show a motivation to optimize the lipid compo-
 nents as well as to demonstrate that the phospholipid
 range is a result effective variable, but that those showings
 should have been considered subsumed within the pre-
 sumption of obviousness. Because we hold that the Board
 did not err in its analysis of the overlapping range issue,
 we reject these ancillary arguments as essentially moot.
 Furthermore, as indicated above, all of the dependent
 claims are subject to this same resolution.
                               B.
     Beyond its legal arguments contingent on the presump-
 tion of obviousness and the improper placement of the bur-
 dens, Moderna argues that, even if it did bear the burden
 of proof on the fact questions that underlie obviousness, it
 presented sufficient evidence to meet those burdens. This
 argument pertains, in particular, to the Board’s findings
 with respect to the motivation to optimize result-effective
 variables in the prior art. Importantly, as these are fact
 issues, we review the Board’s findings for substantial evi-
 dence. See St. Jude Med., LLC v. Snyders Heart Valve
 LLC, 977 F.3d 1232, 1238 (Fed. Cir. 2020).
     It has long been established law that “where the gen-
 eral conditions of a claim are disclosed in the prior art, it is
 not inventive to discover the optimum or workable ranges
 by routine experimentation.” In re Aller, 220 F.2d 454, 456
 (C.C.P.A. 1955). It is also well-established that “the pa-
 rameter to be optimized must have been recognized by
 those skilled in the art to be a ‘result-effective variable.’”
 In re Antoine, 559 F.2d 618, 620 (C.C.P.A. 1977). But, more
 recently, we clarified that in cases with multiple result-ef-
 fective variables, “[e]vidence that the variables interacted
 in an unpredictable or unexpected way could render the
 combination nonobvious.” Applied Materials, 692 F.3d at
 1298.
    It cannot be disputed that the general conditions for a
 nucleic acid-lipid particle were disclosed in the prior art.
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 18     MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION

 Specifically, the ’196 PCT and the ’189 publication disclose
 particles that contain all four of the lipid components re-
 cited in the claims of the ’069 patent. Moderna argues that
 it presented sufficient evidence that the disclosures in
 those references presented a starting point that would have
 allowed a person of ordinary skill in the art to arrive at the
 claimed invention through routine optimization.
      Moderna relies on the previously discussed ranges as
 well as the 2:30 and 2:40 formulations as starting points
 for optimization. Those formulations have cationic lipid
 amounts slightly below the claimed 50–65% range and cho-
 lesterol amounts slightly above the claimed 30–40% range.
 According to Moderna, it presented evidence to the Board
 regarding the motivating factors for optimizing each lipid
 component in the prior art particles. For example, Lin and
 Ahmad would have taught a person of ordinary skill to in-
 crease the amount of cationic lipid to increase transfection
 efficiency. See Moderna Opening Br. at 47–48 (citing ex-
 pert testimony, Lin, and Ahmad). Moderna also argues
 that it was well known that phospholipids help stabilize
 the particles, but too much phospholipid can inhibit trans-
 fection. Id. at 48 (citing expert testimony). Cholesterol was
 known to stabilize lipid bilayers, but keeping the choles-
 terol level low would be necessary to prevent it from pre-
 cipitating out of the lipid layer. Id. at 49 (citing prior art
 and expert testimony). And conjugated lipid prevents par-
 ticles from aggregating, but it is used in small amounts to
 avoid inhibiting particles from fusing with cells. Id.
     The Board found that the evidence was insufficient to
 establish that the phospholipid range was a result-effective
 variable. However, even if we accepted Moderna’s argu-
 ment that the phospholipid range is a result-effective vari-
 able, we would have to conclude based on the record that
 the other lipid components in the prior art nucleic acid-li-
 pid particles are result-effective variables. Then the ques-
 tion would be whether Moderna showed that reaching the
 claimed ranges for these result-effective variables would
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 MODERNA TX, INC.   v. ARBUTUS BIOPHARMA CORPORATION      19

 have been achievable through routine optimization.
 Moderna failed to make that showing.
     Moderna provided evidence of general considerations
 to be taken into account with respect to each individual
 component. But Moderna’s evidence failed to address the
 interdependence of the claimed lipid components and how
 adjustments would affect the nucleic acid-lipid particle as
 a whole. See Board Decision, 2020 WL 4237232, at *15. As
 one example, the Board considered Moderna’s general evi-
 dence that high cationic lipid amounts and low phospho-
 lipid amounts would be desirable, but the Board was
 unpersuaded in part because the ’196 PCT and the
 ’189 publication also suggested that lower amounts of cati-
 onic lipids and higher amounts of phospholipid would be
 acceptable. See id. Ultimately, substantial evidence—in-
 cluding the prior art and expert testimony—supports the
 Board’s finding that optimizing the four interdependent li-
 pid components in the prior art nucleic acid-lipid particles
 would not have been routine, and Moderna’s proposed ad-
 justments to the various lipid components are hindsight
 driven. See id. The unpredictable interactivity between
 the various lipid components renders the claims of the ’069
 nonobvious. See Applied Materials, 692 F.3d at 1298.
                         CONCLUSION
     We have considered Moderna’s remaining arguments
 but we find them unpersuasive. Accordingly, the decision
 of the Board is affirmed.
                         AFFIRMED