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 represented 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 Biotherapeutics, Inc., IPR2019-00554, 2020 WL 4237232 (July 

23, 2020) (“Board Decision”). For the reasons provided below, we affirm.

BACKGROUND

I. The ’069 Patent

Arbutus owns the ’069 patent directed to “stable nucleic 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 administering 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 double-stranded RNA “leads to posttranscriptional suppression 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 potential new approach to downregulate or silence the transcription and translation of a gene of interest.” Id. at col. 1 

ll. 41–43.

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A “safe and effective nucleic acid delivery system is required 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 period of time in order to achieve delivery to affected tissues.” 

Id. at col. 2 ll. 27–31. This requires a “highly stable, serumresistant nucleic acid-containing particle that does not interact with cells and other components of the vascular compartment.” 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, serum-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 present invention is based, in part, upon the surprising discovery 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 advantages when used for the in vitro or in vivo delivery of an 

active agent, such as a therapeutic nucleic acid (e.g., an interfering 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 encapsulated nucleic acid (e.g., an interfering RNA such as siRNA) 

and improved tolerability of the formulations in vivo, resulting 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 compositions. 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 mixture 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 derivative thereof comprises from 30 

mol % to 40 mol % of the total lipid present in the particle; and

(d) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 

mol % to 2 mol % of the total lipid present in the particle.

Id. at col. 91 ll. 24–35. The dependent claims, which contain all of these same limitations, do not raise separate issues. 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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ground, Moderna alleged that all claims of the ’069 patent 

would have been anticipated by and/or obvious over International 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 publication.

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 cholesterol 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 Liposome-DNA Complexes, 84 Biophysical J. 3307–16 (2003).

2 Ayesha Ahmad, et al., New Multivalent Cationic 

Lipids Reveal Bell Curve for Transfection Efficiency Versus 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-cationic 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 phospholipid 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 calculated 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 burden with respect to its challenges based on the ’196 PCT 

and the ’189 publication. Specifically, the Board determined that:

the teachings of the ’196 PCT and ’189 Publication 

do not anticipate or otherwise render obvious a nucleic acid-lipid particle containing each of the recited lipid components within the claimed ranges, 

including specifically a phospholipid range of 4–

10%.

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Board Decision, 2020 WL 4237232, at *11. The Board 

noted that Moderna had “derive[d] an overlapping phospholipid range by making certain assumptions about the 

other lipid components of the particle.” Id. at *12. Therefore, 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 necessarily disclosed based on broader ranges for other components disclosed in the prior art.” Id.

The Board proceeded to list the unfounded assumptions 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 cationic 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 identify the phospholipid as an optional example of a non-cationic 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 efficiency were general considerations when designing a nucleic 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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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 arrive at the claimed ranges. While Moderna had identified 

“reasons to adjust each of the lipid components individually,” the Board found that the optimization argument 

“does not take into account the interdependence of the 

claimed lipid components or how the adjustments would affect 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 pursuant 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 patent, we must first determine whether Moderna has standing 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 federalcourt jurisdiction to actual cases or controversies.” DaimlerChrysler 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 decade ago, we have had a number of occasions to consider the 

question of standing in appeals from Board decisions in 

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IPR proceedings.3 Our precedent generally makes clear 

that, as in all appeals before this court, an appellant seeking 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 requirement 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 redressability 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 decision 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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court.”). Accordingly, even when an appellant is “sharply 

opposed to the Board’s decision and the existence of [a] patent, that is not enough to make th[e] dispute justiciable.” 

Consumer Watchdog, 753 F.3d at 1263. As the party seeking judicial review, Moderna “has the burden of establishing 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 vaccine.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 technology, 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 emergency use authorization as of December 2020, and its subsequent 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 “substantial risk that Arbutus may bring an infringement action 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 Arbutus 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 affiliates “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 asserted, “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 specific threat of infringement litigation by the patentee’ to establish 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 sufficient 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 demonstrated enough of a risk that it will be faced with an infringement suit based on the combination of its own 

activities in developing the COVID-19 vaccine, Arbutus’s 

broad public statements about its extensive patent coverage 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 appeal 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 patent owner to remain silent regarding its intentions during 

the pendency of an appeal and wait to sue for infringement 

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until after the appeal has been dismissed for lack of standing.

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 appeal.

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 obviousness based on overlapping ranges in the prior art. Based 

on this first challenge, Moderna also raises a number of ancillary arguments about the Board’s misplacement of various evidentiary burdens. Second, Moderna argues that the 

Board erred in finding that Moderna had not shown a motivation 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 invention. 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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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 presumption should apply because the prior art does not disclose a range for the phospholipid component.

We have held that a presumption of obviousness typically exists “when the ranges of a claimed composition 

overlap the ranges disclosed in the prior art.” In re Peterson, 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 presumption of obviousness.” (emphasis added)). Here, it is undisputed 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 derived or calculated from the disclosures of the prior art.

The Board correctly recognized that we have never before applied the presumption of obviousness for overlapping 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, however, 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 issue, specifically, Moderna’s failure to show that the overlapping range is actually taught by the prior art.

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Before the presumption of obviousness could be applied, 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 lipid, cholesterol, phospholipid, conjugated lipid. Each reference 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 assumptions. 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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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 rather than acknowledge that selecting the maximums for 

cholesterol and conjugated lipid would result in a nonsensical 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 minimums 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 nucleic acid-lipid particle extends from a minimum 

value -40 mol % (which is a meaningless negative number)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 plethora of evidence, including evidence from the prior art references as well as expert testimony, demonstrating that the 

properties of nucleic acid-lipid particles depend on the particle as a whole, rather than on any one component. See, 

e.g., J.A. 1710–14 (expert declaration citing prior art references to demonstrate the effects of varying the amounts of 

the lipid components on toxicity and efficacy). Thus, substantial 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 adding up the amounts of the other three components and subtracting from 100%.

Even in cases with overlapping ranges involving multiple components, we have held that evidence that the components “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 assumption necessary to derive the implicit overlapping 

range is itself undermined by the unpredictable interactivity between the components.

It is telling that even Moderna has been unable to remain consistent in its contentions about the allegedly implied 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 references 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 obviousness 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 components 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 presumption 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 presumption of obviousness and the improper placement of the burdens, 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 evidence. 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 general 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 parameter 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-effective 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 recited 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 cholesterol 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 increase the amount of cationic lipid to increase transfection 

efficiency. See Moderna Opening Br. at 47–48 (citing expert testimony, Lin, and Ahmad). Moderna also argues 

that it was well known that phospholipids help stabilize 

the particles, but too much phospholipid can inhibit transfection. Id. at 48 (citing expert testimony). Cholesterol was 

known to stabilize lipid bilayers, but keeping the cholesterol level low would be necessary to prevent it from precipitating out of the lipid layer. Id. at 49 (citing prior art 

and expert testimony). And conjugated lipid prevents particles 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 argument that the phospholipid range is a result-effective variable, we would have to conclude based on the record that 

the other lipid components in the prior art nucleic acid-lipid particles are result-effective variables. Then the question would be whether Moderna showed that reaching the 

claimed ranges for these result-effective variables would 

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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 evidence that high cationic lipid amounts and low phospholipid 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 cationic lipids and higher amounts of phospholipid would be 

acceptable. See id. Ultimately, substantial evidence—including the prior art and expert testimony—supports the 

Board’s finding that optimizing the four interdependent lipid components in the prior art nucleic acid-lipid particles 

would not have been routine, and Moderna’s proposed adjustments 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

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