Uniqure Biopharma B.v. v. Pfizer Inc.

N OTE: This disposition is nonprecedential.
United States Court of Appeals
for the Federal Circuit
______________________
UNIQURE BIOPHARMA B.V.,
Appellant
v.
PFIZER INC.,
Appellee
______________________
2023-1404, 2023-1405, 2023-1406
______________________
Appeals from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2021-
00925, IPR2021-00926, IPR2021-00928.
______________________
Decided: May 22, 2025
______________________
MARK CHRISTOPHER F LEMING, Wilmer Cutler Pickering
Hale and Dorr LLP, Boston, MA, argued for appellant.
Also represented by EMILY R. WHELAN; J OSHUA L LOYD
STERN, Washington, DC.
D OV P HILIP G ROSSMAN, Williams & Connolly LLP,
Washington, DC, argued for appellee. Also represented by
D AVID I. BERL , K ATHRYN SCHLECKSER K AYALI, XUN L IU,
SHAUN P ATRICK M AHAFFY .
______________________
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 2
Before D YK, CHEN, and STARK, Circuit Judges.
STARK, Circuit Judge.
Appellant uniQure Biopharma B.V. (“uniQure”) ap-
peals from Final Written Decisions (“FWD”) of the Patent
Trademark and Appeal Board (“Board”) finding that all
challenged claims of uniQure’s U.S. Patent Nos. 9,982,248
(“’248 patent”) and 10,465,180 (“’180 patent”) are unpatent-
able. Because the Board did not commit any legal error
and its factual findings are supported by substantial evi-
dence, we affirm.
I
A
Hemophilia B is a serious bleeding disorder caused by
a single-gene mutation that leads to decreased or absent
production of Factor IX (“FIX”), a protein critical to the
body’s blood coagulation process. Traditional treatment for
hemophilia B involves protein replacement therapy, by
which recombinantly (artificially) made FIX is adminis-
tered to a patient through frequent infusions. Given that
hemophilia B is caused by a single genetic mutation, the
disease is an ideal candidate for treatment via gene ther-
apy. In this context, gene therapy involves dosing a patient
with a viral vector containing genetic information coding
for the production of FIX. Gene therapy thereby allows the
patient to continuously produce her own FIX protein, re-
ducing or even eliminating reliance on protein replacement
therapy for treatment.
Gene therapy requires the use of a viral vector to de-
liver genetic material into a patient’s cells. These viral vec-
tors elicit an immune response – a response that in this
context is undesirable – which may be exacerbated by
higher viral vector doses. This presented an obstacle to the
development of successful hemophilia B gene therapy,
since the high viral vector doses that may be necessary to
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 3
achieve efficacious results may also cause patients to expe-
rience serious adverse immune responses.
uniQure’s ’248 and ’180 patents purport to tackle this
problem by utilizing a mutated version of the wild-type FIX
gene1 in gene therapy. The specific mutation utilized by
the uniQure process is called “FIX-R338L” and consists of
an amino acid substitution of leucine for the wild-type ar-
ginine at position 338 of the FIX protein. FIX-R338L is
eight to nine times more active than wild-type FIX. This
higher activity of the FIX protein allows for lower viral vec-
tor dosing and, thus, reduced patient immune activation in
the context of gene therapy. Utilizing FIX-R338L, uniQure
developed HEMGENIX®, an FDA-approved gene therapy
for the treatment of hemophilia B.
Representative claims 1 of uniQure’s ’248 and ’180 pa-
tents are reproduced below:
A method of treating a coagulopathy in a human
patient, comprising administering a vector to the
human patient, wherein:
a. the vector is an adeno-associated virus;
b. the vector comprises a nucleic acid encoding a
modified FIX polypeptide, the modified FIX pol-
ypeptide comprising at least 70% identity to
SEQ ID NO: 2 and a leucine in position 338 of
SEQ ID NO:2; and
c. the vector comprises promoter sequences and
transcription termination and control elements;
thereby treating the coagulopathy.
1 “Wild-type FIX” is also known as “non-mutant”
FIX. A wild-type protein is one that is naturally occurring,
commonly found in a population, and can be used as a
standard against which mutations are measured.
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 4
J.A. 186.
An adeno-associated virus vector comprising:
a. a nucleic acid encoding a modified FIX polypep-
tide, the modified FIX polypeptide comprising at
least 70% identity to SEQ ID NO: 2 and a leucine
in position 338 of SEQ ID NO: 2; and
b. promoter sequences, transcription termination,
and control elements.
J.A. 212.
B
Pfizer, Inc. (“Pfizer”) filed three petitions for inter
partes review (“IPR”) of the ’248 and ’180 patents and the
Board instituted IPR for all three. As pertinent to this ap-
peal, the petitions set out the following grounds for un-
patentability: (i) all claims of the ’248 patent are
unpatentable as obvious over Stafford and Manno or, alter-
natively, over Stafford, Manno, and Schuettrumpf; and (ii)
all claims of the ’180 patent are invalid as anticipated by
Stafford.2
WO 99/03496 (“Stafford”) is an international patent ap-
plication published on January 28, 1999, entitled “Factor
IX Antihemophilic Factor with Increased Clotting Activ-
ity.” J.A. 1283. Stafford discloses a “recombinant FIX ar-
ginine 338 alanine mutant” (“FIX-R338A”) “which result[s]
in a gain-of-function whose activity levels are 2-3 folds
2 Specifically, IPR2021-00925 determined claims 1,
3, 7-10, 14-16, 19, and 20 of the ’248 patent unpatentable
as obvious; IPR2021-00926 determined claims 2, 5, 6, 11-
13, 17, and 18 of the ’248 patent unpatentable as obvious;
and IPR 2021-00928 determined claims 1-6 of the ’180 pa-
tent unpatentable as anticipated and obvious. uniQure’s
appeals from the three FWDs were consolidated.
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 5
higher than that found in wild type FIX.” J.A. 5; see also
J.A. 1286. Stafford claims all non-naturally occurring
mammalian FIX proteins having an amino acid substitu-
tion at position 338, including dependent claims directed to
preferred embodiments: “said substitution is a substitution
of an arginine residue for an amino acid residue selected
from the group consisting of alanine, leucine, and valine.”
J.A. 1302 ¶ 3 (emphasis added). Stafford further narrows
its three preferred embodiments by specifically claiming a
FIX protein in which the arginine at position 338 is substi-
tuted with leucine, i.e., FIX-R338L, see J.A. 1302 ¶5, and
explains that this variant had improved clotting activity,
see J.A. 1286. Stafford teaches that the mutations it dis-
closes “advantageously have increased clotting activity,” by
as much as two to three times “as compared to the corre-
sponding wild-type molecule.” J.A. 1286.
Manno is an article published in Nature Medicine in
2006. See Catherine S. Manno et al., Successful Transduc-
tion of Liver in Hemophilia AAV-Factor IX and Limitations
Imposed by the Host Immune Response, 12 N ATURE MED.
342 (2006). Manno reports the results of a clinical trial that
involved treating seven patients with severe hemophilia B
by delivering wild-type FIX with an adeno-associated virus
vector (“AAV”). Manno reported that this “AAV-FIX-wild
type” gene therapy was “[s]uccessful,” resulting in “thera-
peutic levels” of FIX over a period of approximately eight
weeks. J.A. 1570-1573. Manno acknowledges that “thera-
peutic levels [of FIX] in humans [were] short lived,” due to
immune responses triggered by and against the AAV vector
she used, but nonetheless discloses short-term treatment
of hemophilia B utilizing AAV-FIX-wild type. J.A. 1570.
Schuettrumpf is a 2004 academic article. See Joerg
Schuettrumpf et al., Factor IX Variants Improve Gene
Therapy Efficacy for Hemophilia B, 105 BLOOD 2316 (2005).
Schuettrumpf “constructed AAV vectors encoding FI.X var-
iants for . . . hemophilia B mice.” J.A. 1321. Schuettrumpf
noted that “[p]revious studies demonstrated that the
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 6
substitution R338A in [FIX] result[s] in a molecule with 3-
fold higher” activity than wild-type FIX. J.A. 1321.
Schuettrumpf found that intramuscular injection of AAV-
FIX-R338A3 in mice results in two-to-six-fold greater activ-
ity than that resulting from FIX-wild type.
II
“Obviousness is a question of law that we review de
novo,” although it is based on “underlying findings of fact”
that we review for substantial evidence. Liqwd, Inc.
v. L’Oreal USA, Inc., 941 F.3d 1133, 1136 (Fed. Cir. 2019).
“An obviousness determination requires finding that a per-
son of ordinary skill in the art would have been motivated
to combine or modify the teachings in the prior art and
would have had a reasonable expectation of success in do-
ing so.” Regents of Univ. of Cal. v. Broad Inst., Inc., 903
F.3d 1286, 1291 (Fed. Cir. 2018). “Whether a person of or-
dinary skill in the art would have been motivated to modify
or combine teachings in the prior art, and whether he
would have had a reasonable expectation of success, are
questions of fact.” Id. “Anticipation is a question of fact
reviewed for substantial evidence in an appeal from the
Board.” In re Antor Media Corp., 689 F.3d 1282, 1287
(Fed. Cir. 2012). “A finding is supported by substantial ev-
idence if a reasonable mind might accept the evidence as
adequate to support the finding.” Pfizer Inc. v. Sanofi Pas-
teur Inc., 94 F.4th 1341, 1347 (Fed. Cir. 2024) (citing Con-
sol. Edison Co. v. NLRB, 35 U.S. 197, 229 (1938)).
3 “AAV-FIX-R338A” is the scientific shorthand for a
gene therapy system that delivers, via an adeno-associated
virus vector, a mutated form of the FIX protein wherein the
naturally-occurring arginine at position 338 of the protein
is replaced with an alanine.
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 7
III
uniQure raises a number of challenges to the Board’s
decisions and we have carefully considered them all. Given
the Board’s thorough analysis, stretched out across three
opinions comprising more than 150 pages, and our deter-
mination that the Board committed no legal error and had
substantial evidence for its findings, we confine our discus-
sion to the most significant of uniQure’s concerns: (i) the
Board’s determination that the claims of the ’248 patent
were obvious over Stafford, Manno, and/or Schuettrumpf;
(ii) the Board’s treatment of uniQure’s objective evidence of
nonobviousness; and (iii) the Board’s finding that Stafford
anticipates the claims of the ’180 patent.
A
With respect to the Board’s conclusion that Pfizer suc-
ceeded in proving the challenged claims of the ’248 patent
would have been obvious, uniQure first attacks the Board’s
findings that a person of ordinary skill in the art (“POSA”)
would have had a reasonable expectation of success in uti-
lizing an AAV-FIX-R338L vector to treat hemophilia B via
gene therapy. It is undisputed that the prior art cited in
the petitions collectively discloses each of the limitations of
the challenged independent claim (claim 1): Stafford
teaches leucine is a preferred substitution for arginine at
position 338 in FIX-R338A, see J.A. 1302, Manno teaches
gene therapy “treatment” (as construed here) of hemophilia
B by generating therapeutic FIX levels, see J.A. 1321, and
Schuettrumpf teaches AAV-FIX-R338A produces proteins
with six-fold greater activity than wildtype-FIX when ad-
ministered to mice and that FIX-R338L is a “promising”
variant, see J.A. 1573. On appeal, uniQure further con-
cedes that a POSA would have had a motivation to combine
these references. uniQure’s principal dispute is with the
Board’s findings that a POSA would have had a reasonable
expectation of success in doing so.
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 8
The ’248 patent’s independent claims require (among
other components not relevant to this appeal) “treating a
coagulopathy” by “administering a vector to the human pa-
tient,” wherein such vector “is an adeno-associated virus,”
comprising “a nucleic acid encoding a modified FIX poly-
peptide” with “a leucine in position 338.” ’248 patent at
45:20-29. The Board construed “treating” as requiring at
least “a partial alleviation of symptoms, for any duration of
therapeutic efficacy.” J.A. 11. Applying this construction,
substantial evidence supports the Board’s finding that a
POSA would have had a reasonable expectation of success
in combining the references to achieve the claimed allevia-
tion of a coagulopathy, for some duration of therapeutic ef-
ficacy, by administering an AAV-FIX-R338L vector.
The Board read Stafford as demonstrating to a POSA
that the results achieved by use of FIX-R338A can also be
expected to be achieved by use of FIX-R338L. J.A. 40-43.
It noted: “FIX-R338L is one of three expressly preferred
variants, and only one of two individually claimed in Staf-
ford, and Stafford teaches that specific point mutations at
position 338 of the FIX polypeptide provide increased clot-
ting activity as compared to the corresponding wild-type
molecule for treating hemophilia B.” J.A. 31 (internal quo-
tation marks omitted). The Board further read Manno and
Schuettrumpf as establishing successful AAV vector gene
therapy for treating hemophilia B. To the Board, then, the
combination of either Stafford and Manno or Stafford,
Manno, and Schuettrumpf would have given a POSA a rea-
sonable expectation of success that hemophilia B could be
treated utilizing an AAV-FIX-R338L vector.
The Board was also persuaded that uniQure’s own ’248
patent would have contributed to a skilled artisan’s expec-
tation of success, as the patent indicated a POSA would un-
derstand that alanine and leucine are “homologous amino
acids” and that substitutions between them “would not
change the phenotype of the proteins.” J.A. 41. The Board
considered “Patent Owner’s argument concerning the
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 9
unpredictability of gene therapy, and a lack of efficacy data
specifically for AAV-FIX-R338L,” and after evaluating “ev-
idence submitted by both parties” found Pfizer had met its
burden. J.A. 42. We have not required such data as a pre-
requisite to a finding of reasonable expectation of success,
even in an unpredictable art. See Eli Lilly & Co. v. Teva
Pharms. Int’l GmBH, 8 F.4th 1331, 1346 (Fed. Cir. 2021)
(“[O]ur case law makes clear that a showing of a reasonable
expectation of success in a method of treatment claim need
not rely on clinical data . . . nor must it include a demon-
stration of certainty that the treatment would be successful
in every instance.”). Moreover, while the Board
“acknowledge[d] that [uniQure’s expert witness] Dr.
Doering present[ed] credible testimony concerning the un-
predictability of certain aspects of gene therapy,” it was (as
is permissible) more persuaded by Pfizer’s expert, Dr.
Wang, who “credibly testifie[d] [that] FIX levels correlate
well with clinical symptomology.” J.A. 42 (citing J.A.
11084).
The Board was likewise persuaded by another Pfizer
expert, Dr. Pedersen, who expressed the view that a POSA
would have expected to be able to substitute leucine for al-
anine at FIX-R338, without losing clotting activity, based
on structural similarities between the two amino acids.
J.A. 38. The Board credited Dr. Pedersen’s testimony that
a POSA would have viewed the substitution of leucine for
alanine to be “conservative” and, hence, likely to “improve
clotting activity relative to arginine at position 338 of FIX.”
Id.; see also J.A. 10580 (Dr. Pedersen testifying that: “[A]
POSA would . . . have expected that substituting leucine
for arginine at position 338 of FIX would have had a similar
effect on the resulting protein’s clotting activity as substi-
tuting alanine for arginine did”). Further, as the Board ob-
served, J.A. 48, the ’248 patent itself characterizes alanine
and leucine as conservative substitutions for one another,
based on their structural similarities. J.A. 165 (’248 patent
at 4:51-58) (“It is expected that substitutions between
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 10
[leucine and alanine,] homologous amino acids[,] would not
change the phenotype of the proteins.”).
We find no merit in uniQure’s contention that the evi-
dence on which the Board relied is tainted by impermissi-
ble hindsight. uniQure emphasizes that Stafford provides
no explanation for its featuring of three embodiments as
preferred and for dependently claiming just two of those,
including the leucine embodiment. The Board considered
this point and credited Dr. Pedersen’s opinion that a POSA
“would have understood that alanine and leucine are both
uncharged, non-polar, aliphatic, and hydrophobic amino
acids” and, further, that “detailed structural information
about FIX was available in 2008, including the effect of a
substitution at position 38.” J.A. 38 (citing J.A. 11196-97).
uniQure additionally contends that the Board violated
the Administrative Procedure Act (“APA”) by crediting Dr.
Pedersen without, purportedly, fully considering contrary
evidence from its expert, Dr. Spiegel. Dr. Spiegel testified,
for instance, that “no two amino acids are so similar that
the substitution of one for another protein produces a mu-
tant with predictable structure and function,” J.A. 13360 ¶
118, such that “there is no such thing as ‘conservative
amino acid substitutions,’” J.A. 13335 ¶ 72. In finding that
Dr. Spiegel’s “opinions do not account for the knowledge of
a person of ordinary skill in the art,” J.A. 39, the Board
credited Dr. Pedersen’s reply to Dr. Spiegel, J.A. 38 (citing
J.A. 11196-200), which was reasonable to do. See also J.A.
38 (“We also find Dr. Pedersen’s opinion with regard to a
leucine substitution in FIX-R338 more credible than Dr.
Spiegel’s . . .”). While “the Board may not short-cut its con-
sideration of the factual record before it,” there is no indi-
cation that this is what happened here. Princeton
Vanguard, LLC v. Frito-Lay N. Am., Inc., 786 F.3d 960, 970
(Fed. Cir. 2015).
uniQure’s citation to OSI Pharmaceuticals, LLC v.
Apotex Inc., 939 F.3d 1375 (Fed. Cir. 2019), does not lead
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 11
to a different conclusion. We agree with the Board that
whereas OSI involved evidence that “in vitro . . . effective-
ness of a drug . . . [is] a poor proxy for how effective that
drug actually was in treating cancer in vivo,” 939 F.3d at
1377, here the Board credited testimony from Pfizer’s ex-
pert, Dr. Wang, that “FIX levels correlate well with clinical
symptomology,” making such levels adequate proxies for
effectiveness. J.A. 42. It is also worth noting that in OSI,
939 F.3d at 1385, we explained that efficacy data is not al-
ways required in order to prove a reasonable expectation of
success.
uniQure directs additional criticisms at the Board’s
analyses of several of the dependent claims of the ’248 pa-
tent. Claim 14 depends from claim 1 and additionally re-
quires that “the modified FIX polypeptide is expressed at a
level that does not cause thrombotic complications.” J.A.
186. As the Board noted, the ’248 patent teaches that “risk
of thrombosis only increases when wild-type FIX levels ex-
ceed 120% of normal,” and Dr. Wang testified that
“Manno’s highest vector dose resulted in wild-type FIX ac-
tivity of 11.8%,” which is well below the danger level iden-
tified by the patent. J.A. 45. There is also no indication in
Manno that any patient participating in the study experi-
enced thrombotic complications. The Board’s finding that
a POSA would agree with Dr. Wang that mouse models
showing little risk of thrombotic complications are “predic-
tive of human response” is grounded in the record, includ-
ing expert declarations. J.A. 45 (citing declarations of Drs.
Wang and Doering).
Claim 15, too, depends from claim 1 and further re-
quires that the “modified FIX polypeptide is expressed at a
level that does not lead to neutralizing antibody genera-
tion.” J.A. 186. The Board found that, given the results
reported in Manno and Schuettrumpf – showing that par-
ticipants receiving FIX-wild type and FIX-R338A, respec-
tively, did not generate such antibodies – a POSA would
have understood that the structurally-similar FIX-R338L
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 12
would likewise not lead to production of such antibodies.
The Board additionally credited testimony from Dr. Wang
that patients with a history of not producing such neutral-
izing antibodies would continue not to produce such anti-
bodies, while subjects with a history of antibody formation
would not receive the claimed gene therapy treatment.
B
uniQure’s other principal challenge to the Board’s ob-
viousness determinations relates to its handling of
uniQure’s objective evidence of nonobviousness, particu-
larly “long-felt need, praise and copying by others, and un-
expected results.” J.A. 19. The Board found that uniQure
failed to demonstrate the required nexus between its objec-
tive evidence and the challenged claims, and, alternatively,
that “even if there is some nexus, it is weak.” J.A. 27. “We
give deference to [the Board’s] factual findings regarding
evidence of secondary considerations.” Bristol-Myers
Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 978
(Fed. Cir. 2014).
uniQure argues that the Board committed legal error
by: (i) imposing too strenuous of a nexus requirement, es-
sentially requiring that the evidence be entirely commen-
surate with the claims; and (ii) failing to recognize that
uniQure’s evidence relates to AAV-FIX-R338L and not just
FIX-R338L.
“[T]here is no nexus unless the evidence presented is
reasonably commensurate with the scope of the claims.”
ClassCo, Inc. v. Apple, Inc., 838 F.3d 1214, 1220 (Fed. Cir.
2016) (internal quotation marks omitted). The Board
found that uniQure’s objective evidence of nonobviousness
lacked a sufficient nexus to the claims because that evi-
dence was directed to FIX-R338L, which was disclosed in
Stafford, while the purported innovation of uniQure’s
claims was AAV-FIX-R338L as a whole, to which none of
uniQure’s evidence was specifically directed. J.A. 24-26
(“Patent Owner’s evidence is broadly directed to FIX-
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 13
R338L, which was in the prior art and does not suggest
non-obviousness of the claimed invention as a whole.”).
uniQure makes much of the fact that the Board also
discussed the legal standard for obtaining a presumption of
nexus, which applies “when the patentee shows that the
asserted objective evidence is tied to a specific product and
that product embodies the claimed features, and is coex-
tensive with them,” J.A. 20 (internal quotation marks omit-
ted). But the Board did not hold uniQure to that
heightened standard. The Board’s discussion of presump-
tion of nexus appears to have been the result of the parties’
arguments about whether the presumption should apply.
The Board expressly found “the Patent Owner’s evidence of
long-felt need and failure of others, industry praise, and
unexpectedly superior efficacy is not coextensive or com-
mensurate in scope with claim 1,” thereby applying the
standards applicable to presumptive nexus and non-pre-
sumptive nexus disputes. J.A. 24 (emphasis added); see
also J.A. 25 (“Patent Owner’s objective evidence is not com-
mensurate in scope with claim 1.”). After finding uniQure
is not “entitled to a presumption of a nexus,” the Board con-
tinued by examining if uniQure proved a nexus, and then
found uniQure “presents insufficient evidence to establish
a nexus by this alternative route.” J.A. 26.
In sum, we discern no legal error in any aspect of the
Board’s obviousness analysis. The Board’s underlying fac-
tual findings are supported by substantial evidence.
C
Finally, uniQure argues that the Board erred in finding
that Stafford anticipated the claims of the ’180 patent. We
are not persuaded.
Substantial evidence supports the Board’s finding that
Stafford discloses an AAV vector encoding a FIX-R338L
polypeptide for use in gene therapy. See J.A. 131-33 (citing
J.A. 1285). Stafford expressly discloses a vector, which it
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 14
describes as “a replicable DNA or RNA construct” that “typ-
ically comprise[s] plasmids, viruses (e.g., papillomavirus,
adenovirus, adeno-associated virus, cytomegalovirus),
phage, retroviruses and integratable DNA fragments.”
J.A. 1291. Stafford further discloses that “vectors may be
used to produce recombinant Factor IX, or may be used in
gene therapy to . . . produce the Factor IX in the patient.”
J.A. 1291. As we have noted above, the Board also found
Stafford’s preferred embodiments of leucine and alanine,
combined with a viral vector (including AAV) in gene ther-
apy, disclosed all of the elements as they are arranged in
the claims of the ’180 patent. J.A. 130.
While “[a] prior art reference can only anticipate a
claim if it discloses all the claimed limitations arranged or
combined in the same way as the claim . . . a reference can
anticipate even if it d[oes] not expressly spell out all the
limitations arranged or combined as in the claim, if a per-
son of skill in the art, reading the reference, would at once
envisage the claimed invention or arrangement or combi-
nation.” Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
780 F.3d 1376, 1381 (Fed. Cir. 2015) (cleaned up). The
Board reasonably relied on Stafford’s preferred embodi-
ments and dependent claims as evidence that a POSA
would know of the similarities between leucine and ala-
nine. J.A. 131 (finding POSA would understand Stafford
discloses a “limited class of two or three preferred substi-
tutions at R338 – at most, alanine, leucine and valine”).
uniQure counters the Board’s findings by arguing that
Stafford is not enabled. “[E]nablement is ultimately a
question of law subject to de novo review, [that] is based on
underlying factual findings . . . reviewed for clear error.”
Bruning v. Hirose, 161 F.3d 681, 686 (Fed. Cir. 1998).
While “[a] prior art reference cannot anticipate a claimed
invention ‘if the allegedly anticipatory disclosures cited by
the prior art are not enabled,” “claimed and unclaimed ma-
terials disclosed in a patent” and “prior art publications”
“are presumptively enabled.” In re Antor Media Corp., 689
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UNIQURE BIOPHARMA B. V. v. PFIZER INC. 15
F.3d 1282, 1287 (Fed. Cir. 2012). Thus, Stafford’s AAV-
FIX-R338L embodiment, despite not being claimed, is pre-
sumed enabled. The Board had substantial evidence for
finding that this presumption has not been rebutted, in-
cluding uniQure’s concession that Stafford discloses only
“eight categories of vectors,” Open. Br. at 67, and three pre-
ferred mutation embodiments, resulting in at most 24 po-
tential embodiments, a number consistent with what we
have previously presumed may be enabled in an anticipa-
tory reference. See Kennametal, 780 F.3d at 1382-83 (find-
ing enablement of class of five metals in combination with
one of three potential coatings); see also Antor Media, 689
F.3d at 1289 (“[A]n examiner is entitled to reject claims as
anticipated by a prior art publication or patent without
conducting an inquiry into whether or not that prior art
reference is enabling. As long as an examiner makes a
proper prima facie case of anticipation . . . the burden shifts
to the applicant to submit rebuttal evidence of nonenable-
ment.”).
uniQure additionally argues that Stafford does not dis-
close a pharmaceutical composition, as claimed in claim 2
of the ’180 patent. The Board had substantial evidence for
its contrary finding. The Board found that a pharmaceuti-
cal composition is inherent in Stafford’s disclosure of “vec-
tors . . . used in gene therapy to administer the expression
cassette,” citing testimony from Pfizer’s expert, Dr. Wang,
that a POSA would understand such vectors must be ad-
ministered in a pharmaceutical composition. J.A. 135-38.
IV
We have considered uniQure’s remaining arguments
and find they lack merit. Accordingly, we affirm the
Board’s judgments that the challenged claims are un-
patentable.
AFFIRMED
Case: 23-1404 Document: 65 Page: 15 Filed: 05/22/2025

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