Court Opinion

ID: 4162958
Source: CourtListenerOpinion
Date Created: 2017-04-25 15:04:37.67142+00
Date Added: 2024-06-11T14:23:55.650900
License: Public Domain

NOTE: This disposition is nonprecedential.

  United States Court of Appeals
      for the Federal Circuit
                ______________________

                DUKE UNIVERSITY,
                    Appellant

                           v

       BIOMARIN PHARMACEUTICAL INC.,
                    Appellee
             ______________________

                      2016-1106
                ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2013-
00535.
                 ______________________

                Decided: April 25, 2017
                ______________________

    STEVEN A. ZALESIN, Patterson Belknap Webb & Tyler
LLP, New York, NY, argued for appellant. Also repre-
sented by CHARLENE CHOI, EUGENE M. GELERNTER,
ZHIQIANG LIU, IRENA ROYZMAN; JOHN P. WHITE, Cooper &
Dunham, LLP, New York, NY.

    GERALD MYERS MURPHY, JR., Birch Stewart Kolasch &
Birch, LLP, Falls Church, VA, argued for appellee. Also
represented by MARYANNE ARMSTRONG, LYNDE FAUN
HERZBACH, EUGENE PEREZ.
2         DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

                  ______________________

       Before LOURIE, O’MALLEY, and TARANTO, Circuit
                        Judges.
LOURIE, Circuit Judge.
    Duke University (“Duke”) appeals from the decision of
the U.S. Patent and Trademark Office (“PTO”) Patent
Trial and Appeal Board (“Board”) in an inter partes review
(“IPR”) holding claims 1–9, 11, 12, 15, and 18–21 of U.S.
Patent 7,056,712 (the “’712 patent”) unpatentable. See
BioMarin Pharm. Inc. v. Duke Univ., No. IPR2013-00535,
2015 WL 1009196 (P.T.A.B. Feb. 23, 2015) (“Board Deci-
sion”), aff’d on reh’g, 2015 WL 4467381 (P.T.A.B. July 14,
2015) (“Rehearing Decision”). Because the Board erred in
holding claims 9 and 19 unpatentable, but did not other-
wise err, we affirm in part, reverse in part, vacate in part,
and remand.
                       BACKGROUND
                    I. The ’712 Patent
    Duke owns the ’712 patent, directed to methods for
treating glycogen storage disease type II (“GSD-II” or
“Pompe disease”) using enzyme replacement therapy.
’712 patent col. 2 ll. 45–50. Pompe disease is a genetic
disorder affecting muscles caused by a deficiency of acid α-
glucosidase (“GAA”), a lysosomal enzyme that breaks
down glycogen. Id. col. 1 ll. 12–15. The deficiency results
in the accumulation of lysosomal glycogen in most of the
body’s tissues and most seriously affects the cardiac and
skeletal muscles. Id. col. 1 ll. 20–22.
    Pompe disease has multiple forms. Id. col. 1 ll. 28–44.
The most severe form is infantile, which is characterized
by less than 1% of normal GAA activity. Id. Affected
individuals with the infantile form usually die of cardiac
failure by one year of age. Id.
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.          3

    The ’712 patent describes the successful treatment of
three infants suffering from infantile Pompe disease by
administering recombinant human GAA (“rhGAA”) twice
weekly to the infants. Id. col. 2 ll. 50–55, col. 6 l. 59–col.
12 l. 26. The patent discloses that the “rhGAA was puri-
fied primarily as the 110-kD precursor protein” and was
produced in Chinese hamster ovary (“CHO”) cell cultures.
Id. col. 8 ll. 48–55. The patent explains that administra-
tion in “precursor form” is a “preferred embodiment”
because “the precursor contains motifs which allow effi-
cient receptor-mediated update of GAA.” Id. col. 3 ll. 60–
63; see also id. col. 2 ll. 4–9. Additionally, rhGAA pro-
duced in CHO cells is “a particularly preferred embodi-
ment.” Id. col. 4 ll. 1–4.
    The treated “infants demonstrated improvement of
cardiac status, pulmonary function, and neurodevelop-
ment, as well as reduction of glycogen levels in tissue.”
Id. col. 2 ll. 53–55; see also id. col. 9 l. 64–col. 12 l. 14.
Two of the three infants developed anti-rhGAA antibodies
after the initiation of enzyme replacement therapy. Id.
col. 9 ll. 54–59, Figs. 1A–1C. As the amount of anti-
rhGAA antibodies increased in the two infants, the “clini-
cal improvements (noted early during therapy . . . ) were
no longer advancing.” Id. col. 9 ll. 59–61.
    The ’712 patent teaches that GAA can be adminis-
tered in conjunction with other agents, e.g., “immunosup-
pressants or other immunotherapeutic agents which
counteract anti-GAA antibodies.” Id. col. 5 ll. 29–33. It
states that “[i]n a particularly preferred embodiment, the
immunosuppressive or immunotherapeutic regime is
begun prior to the first administration of GAA, in order to
minimize the possibility of production of anti-GAA anti-
bodies.” Id. col. 5 ll. 55–59.
     Claims 1 and 20 are the only independent claims, are
illustrative of what is claimed, and read as follows:
4         DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

    1. A method of treating glycogen storage disease
    type II in a human individual having glycogen
    storage disease type II, comprising administering
    to the individual a therapeutically effective
    amount of human acid α-glucosidase periodically
    at an administration interval, wherein the human
    acid α-glucosidase was produced in chinese [sic]
    hamster ovary cell cultures.
Id. col. 12 ll. 45–51.
    20. A method of treating cardiomyopathy associ-
    ated with glycogen storage disease type II in an
    human individual having glycogen storage disease
    type II, comprising administering to the individu-
    al a therapeutically effective amount of human ac-
    id α-glucosidase periodically at an administration
    interval, wherein the human acid α-glucosidase
    was produced in chinese [sic] hamster ovary cell
    culture.
Id. col. 14 ll. 13–19.
    Claims 9 and 18 depend from claim 1. Claim 9 con-
tains the additional limitation “wherein the human acid
α-glucosidase is a precursor of recombinant human acid α-
glucosidase that has been produced in chinese [sic] ham-
ster ovary cell cultures.” Id. col. 13 ll. 9–12 (emphasis
added). Claim 18 adds “wherein the human acid α-
glucosidase is administered in conjunction with an immu-
nosuppressant.” Id. col. 14 ll. 7–9. Claim 19 depends
from claim 18 and further adds “wherein the immunosup-
pressant is administered prior to any administration of
human acid α-glucosidase to the individual.” Id. col. 14 ll.
10–12 (emphasis added).
          II. The Board’s Final Written Decision
     BioMarin Pharmaceutical Inc. (“BioMarin”) filed a pe-
tition for IPR of claims 1–9, 11, 12, 15, and 18–21 of the
’712 patent. The Board instituted review and ultimately
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.            5

held that all of the challenged claims are unpatentable as
anticipated by U.S. Patent 7,351,410 (“van Bree”) and/or
as obvious over PCT Publication WO 97/05771 (“Reuser”)
in view of Johan L.K. Van Hove et al., Purification of
Recombinant Human Precursor Acid α-Glucosidase, 43(3)
BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL
613–23 (1997) (“Van Hove”) either alone or in combination
with other references, including Roscoe O. Brady et al.,
Management of Neutralizing Antibody to Ceredase in a
Patient with Type 3 Gaucher Disease, 100(6) PEDIATRICS
e11 (1997) (“Brady”).
     The Board construed certain claim limitations, includ-
ing “precursor” in claim 9 and “administered prior to any
administration” in claim 19. The Board noted that Duke
“proposes that the term ‘precursor’ in claim 9 means ‘any
precursor of recombinant hGAA (e.g. a 110-kD form)’ that
is ‘exclusively . . . produced in CHO cell cultures.’” Board
Decision, 2015 WL 1009196, at *4 (alteration in original).
The Board “agree[d]” with this construction, but clarified
that “[n]either claim 1 nor claim 9 precludes administer-
ing a non-precursor form of hGAA or rhGAA . . . .” Id.
The Board construed “administered prior to any admin-
istration” in claim 19 “to refer to administering an immu-
nosuppressant prior to the first administration of hGAA
to the individual.” Id.
                      A. The Prior Art
     van Bree and Reuser disclose methods of producing
rhGAA in transgenic mammals and its use in enzyme
replacement therapy to treat Pompe disease. van Bree
col. 2 ll. 33–36, col. 4 ll. 54–55; Reuser p. 4 ll. 14–37, p. 18
ll. 12–14. They both disclose that the main species of
hGAA are a 110/100 kD precursor, a 95kD intermediate,
and 76 kD and 70 kD mature forms. van Bree col. 6 ll. 6–
8; Reuser p. 9 ll. 24–26. van Bree states that administra-
tion of GAA “is preferably predominantly (i.e., >50%) in
the precursor form of about 100-110 kD.” van Bree col. 13
6         DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

ll. 48–50. van Bree and Reuser state that CHO cells are
an alternative way to produce hGAA, but note disad-
vantages—labor and expense, respectively—with this
approach. van Bree col. 13 ll. 58–64; Reuser p. 3 ll. 15–22.
    Both references describe the post-translational pro-
cessing of GAA, including glycosylation and phosphoryla-
tion. They recognize the function of GAA mannose 6-
phosphate in mediating transport of lysosomal proteins.
van Bree col. 5 ll. 54–57, col. 6 ll. 17–24; Reuser p. 9 ll. 6–
9, p. 9 l. 35–p. 10 l. 3. Both explain that “post transla-
tional processing of natural [hGAA] and of recombinant
forms of [hGAA] as expressed in cultured mammalian
cells like . . . CHO cells is similar.” van Bree col. 6 ll. 11–
15; Reuser p. 9 ll. 30–33. Both state that “restoration of
the endogenous [GAA] activity by [GAA] isolated from
mouse milk was as efficient as restoration by [GAA]
purified from bovine testis, human urine and medium of
transfected CHO cells.” van Bree col. 20 ll. 32–36; Reuser
p. 28 ll. 11–14.
     Van Hove teaches a method for purifying large quan-
tities of rhGAA expressed in CHO cells for use in Pompe
disease enzyme replacement therapy. J.A. 491. Van
Hove states that “precursor 110 kD [GAA] isolated from
tissue culture medium is endocytosed efficiently via the
mannose-6-phosphate receptor, and corrects patient cells
in vitro.” J.A. 491–92.
    Brady discloses administering an immunosuppressant
to treat an immune response to enzyme replacement
therapy in the treatment of Gaucher disease with
Ceredase. J.A. 526. Gaucher disease is a genetic disorder
caused by a deficiency of the lysosomal enzyme gluco-
cerebrosidase. Id.; Reuser p. 1 l. 37–p. 2 l. 9.
                     B. The Rejections
    The Board found that van Bree anticipates claims 1–
9, 12, 15, 20, and 21. It rejected Duke’s argument that an
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.        7

ordinary artisan would have understood that the admin-
istration amounts and intervals disclosed in van Bree for
transgenic mice would not have been applicable to hGAA
produced in CHO cell cultures because of the difference in
properties, e.g., glycosylation and phosphorylation pat-
terns, of hGAA produced in transgenic animals and CHO
cells. Board Decision, 2015 WL 1009196, at *10. The
Board explained that “van Bree ’410 itself indicates hGAA
produced in CHO cells would have similar characteristics
as hGAA produced in transgenic mice, including glycosyl-
ation and phosphorylation patterns.” Id. It ultimately
found that van Bree “describes administering hGAA
produced in CHO cell cultures to patients in the same
manner, i.e., using the same amounts and dosage inter-
vals, as described for hGAA produced in transgenic ani-
mals.” Id. at *11.
    Regarding claim 9, the Board reiterated that its con-
struction of “precursor” “encompass[es] administering
both precursor and non-precursor forms of rhGAA at the
same time, and [is] not limited to administering exclusive-
ly a precursor form and no other form.” Id. at *12. The
Board found that “van Bree ’410 describes administering
a precursor of recombinant hGAA produced in CHO cell
cultures, even assuming that the reference [only] teaches
administering a mixture which is preferably predomi-
nantly (i.e., >50%) in the precursor form of about 100-110
kD.” Id. (internal quotations omitted).
    The Board also concluded that claims 1–9, 11, 12, 15,
and 18–21 were unpatentable as obvious over Reuser in
view of Van Hove, either alone or in combination with
other references, including Brady. The Board found that
a skilled artisan would have had reason to combine the
teachings of Reuser and Van Hove because “both discuss[]
rhGAA produced in CHO cells and methods of treating
Pompe disease.” Id. at *18. The Board explained that
“Reuser ’771 identified rhGAA produced in CHO cells, in
particular, and, especially in view of Van Hove 1997,
8        DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

provided ‘good reason to pursue the known options within
his or her technical grasp’ using such rhGAA for the
treatment of Pompe disease, as taught by Reuser ’771,
including at the administration doses and intervals
disclosed in Reuser ’771.” Id. (quoting KSR Int’l Co. v.
Teleflex, Inc., 550 U.S. 398, 402–03 (2007)).
    The Board rejected Duke’s contention that a skilled
artisan would have understood CHO cells to be a relative-
ly inferior source of GAA based on the amounts of GAA
disclosed as being produced in Van Hove (90 µg/ml) and
Reuser (“at least . . . 10,000 µg/ml”). Id. at *19 (quoting
Patent Owner Response at 33). The Board found that
Van Hove did not “describe[] production in concentrations
of up to only 90 µg/ml.” Id. The Board again rejected
Duke’s arguments premised on the alleged differences
between hGAA produced in transgenic mammals and
hGAA produced in CHO cell cultures and found that a
skilled artisan would have had a reasonable expectation
of success in combining Reuser and Van Hove. Id. at *20.
    Regarding claim 9, the Board found that Reuser re-
cites a precursor form of rhGAA and teaches that the
main species of GAA include a 110/100 kDa precursor. Id.
at *16. The Board did not discuss whether Reuser dis-
closes administering exclusively a precursor of rhGAA.
    As for claim 19, the Board found that “Brady teaches
administering both enzyme and immunosuppressant on
‘Day 1,’ i.e., the first day of treatment in the individual”
and “again prior to subsequent administrations of the
enzyme.” Id. at *26. The Board explained that “Brady
teaches administering the immunosuppressant in this
fashion in an ‘effort to immunosuppress the patient’ and
reduce neutralizing antibodies in the individual.” Id.
(quoting Brady 3). Thus, the Board concluded that claims
18 and 19 would have been obvious over Reuser in view of
Van Hove and Brady.
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.        9

    The Board also considered Duke’s evidence relating to
objective indicia of nonobviousness, but found that none of
it was persuasive. Id. at *27. Duke alleged that long-felt
need, failure of others, unexpected results, licensing,
commercial success, praise, and industry acceptance
evidenced the nonobviousness of the claims, but the Board
found that Duke failed to establish a nexus between the
claims and the proffered objective indicia. Id.
           III. The Board’s Rehearing Decision
    The Board granted Duke’s request for rehearing to re-
consider the teachings of Brady in relation to the subject
matter of claim 19, and modified its analysis. On rehear-
ing, all three administrative patent judges (“APJs”)
agreed that “Brady does not disclose administering im-
munosuppressant prior to any and all administration of
hGAA, as required by claim 19.” Rehearing Decision,
2015 WL 4467381, at *4 (majority opinion), *9 (APJ
Bonilla, dissenting). Despite this modification to its
previous factual findings, a split panel still held that
claim 19 would have been obvious over Reuser in view of
Van Hove and Brady.
    The majority explained that “[t]he choice of adminis-
tering immunosuppressant before an adverse immune
response develops in a patient, or after a patient has
experienced an adverse immune response, are predictable
variations producing the same result—prevention of an
adverse immune response to foreign protein.” Id. at *8.
The majority relied on the testimony of Dr. Pastores, one
of BioMarin’s experts, in reaching its obviousness conclu-
sion.
     The dissenting APJ would have held that BioMarin
failed to meet its burden with respect to claim 19. The
APJ concluded that “[n]either [BioMarin] in its Petition or
Reply, nor Dr. Pastores in his cited testimony adequately
explains, however, how Brady (or Grabowski) teaches or
suggests administering an immunosuppressant to a
10        DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

patient before the patient has exhibited any sign of an
adverse reaction to the enzyme therapy.” Id. at *11 (APJ
Bonilla, dissenting). The APJ explained that “[w]hile Dr.
Pastores’ conclusory statements may indicate what ‘could
be’ done if ‘there is a high incidence’ of antibody response,
he does not explain, nor provide evidence showing, what
an ordinary artisan would have done in this regard prior
to the filing date of the ’712 patent, or what one would
have understood in relation to incidents of ‘high antibody
titers’ in response to exogenous enzyme therapy.” Id.
(APJ Bonilla, dissenting) (emphases in original).
    Duke timely appealed. We have jurisdiction pursuant
to 28 U.S.C. § 1295(a)(4)(A).
                        DISCUSSION
    We review the Board’s legal determinations de novo,
In re Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), but we
review 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 sup-
ported by substantial evidence if a reasonable mind might
accept the evidence to support the finding. Consol. Edi-
son Co. of New York v. NLRB, 305 U.S. 197, 229 (1938).
                      I. Anticipation
    We first address Duke’s argument that the Board
erred in finding that van Bree anticipated claims 1–9, 12,
15, 20, and 21 of the ’712 patent. Anticipation is a ques-
tion of fact that we review for substantial evidence. In re
Rambus, Inc., 753 F.3d 1253, 1256 (Fed. Cir. 2014). A
prior art document may anticipate a claim if it describes
every element of the claimed invention, either expressly
or inherently. Husky Injection Molding Sys. Ltd. v. Athe-
na Automation Ltd., 838 F.3d 1236, 1248 (Fed. Cir. 2016).
An anticipatory reference must be enabled, but “no ‘actual
creation or reduction to practice’ is required.” In re
Gleave, 560 F.3d 1331, 1334 (Fed. Cir. 2009) (quoting
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.        11

Schering Corp. v. Geneva Pharm., Inc., 339 F.3d 1373,
1380–81 (Fed. Cir. 2003)).
    Because Duke does not argue dependent claims 2–8,
12, 15, and 21 “separately or attempt to distinguish them
from the prior art,” these “dependent claims stand or fall
with their attendant independent claim.” In re Warsaw
Orthopedic, Inc., 832 F.3d 1327, 1330 n.3 (Fed. Cir. 2016);
see also In re Margolis, 785 F.2d 1029, 1030 (Fed. Cir.
1986) (stating that where dependent claims “were not
argued separately, [they] need not be separately consid-
ered”).
            A. Independent Claims 1 and 20
     Duke argues that the Board’s anticipation findings
were not supported by substantial evidence. Duke con-
tends that van Bree does not disclose administering
hGAA derived from CHO cells to human patients with
Pompe disease in a therapeutically effective amount,
periodically at administration intervals, as required by
the independent claims. Duke challenges the applicabil-
ity of teachings “focus[ed]” on hGAA produced in “the milk
of transgenic nonhuman animals” to hGAA produced in
CHO cell cultures. Appellant’s Br. 41. Duke asserts that
no expert opined that van Bree disclosed all the limita-
tions of any claim.
    BioMarin responds that substantial evidence does
support the Board’s findings. BioMarin contends that van
Bree discloses all of the limitations in the independent
claims and that actual reduction to practice of the claimed
methods is not required for there to be an anticipation.
BioMarin asserts that the Board was free to independent-
ly assess the teachings of van Bree and was not required
to rely on expert testimony.
    We agree with BioMarin that the Board’s anticipation
findings with respect to claims 1 and 20 were supported
by substantial evidence. van Bree states that “the inven-
12        DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

tion provides methods of treating a patient with Pompe’s
disease” that “entail administering to the patient a thera-
peutically effective amount of [hGAA].” van Bree col. 2 ll.
33–36. van Bree provides dosage amounts and periodic
administration intervals for administering hGAA. See,
e.g., id. col. 2 ll. 36–42, col. 14 ll. 1–29. van Bree states
that the “[hGAA] is preferably obtained in the milk of a
nonhuman transgenic mammal,” id. col. 2 ll. 43–45, and
provides examples of producing and testing hGAA from
transgenic mice and rabbits, id. col. 16 l. 20–col. 24 l. 7.
van Bree also contains examples discussing human clini-
cal trials in which hGAA was or would be administered
that do not specify the source of the hGAA. Id. col. 24 l.
10–col. 26 l. 67. The question thus is whether the Board
correctly found that van Bree’s teachings, which focus on
hGAA produced by transgenic mammals, are applicable to
hGAA produced in CHO cells, as required by the inde-
pendent claims. 1
    We conclude that the disclosure in van Bree supports
the Board’s finding that its teachings applied to GAA
produced in CHO cell cultures. van Bree links its teach-
ings to CHO cell cultures with respect to structure and
post translational processing, including glycosylation and
phosphorylation. See id. col. 5 l. 35–col. 6 l. 24. It ex-
plains that “post translational processing of natural
[hGAA] and of recombinant forms of [hGAA] as expressed

     1We note that Duke has not raised an enablement
challenge to van Bree and that, in any event, proof of
efficacy or an actual reduction to practice using CHO cell
cultures is not required for a reference to be an anticipa-
tion of the challenged method of treatment claims. In re
Gleave, 560 F.3d at 1334; Rasmusson v. SmithKline
Beecham Corp., 413 F.3d 1318, 1326 (Fed. Cir. 2005)
(explaining “proof of efficacy is not required in order for a
reference to be enabled for purposes of anticipation”).
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.         13

in . . . CHO cells is similar.” Id. col. 6 ll. 11–15. In the
“Therapeutic Methods” section, van Bree teaches that a
CHO cell line is “an alternative way to produce [hGAA].”
Id. col. 13 ll. 58–60. In an example, van Bree reports that
“restoration of the endogenous [GAA] activity by [GAA]
isolated from mouse milk was as efficient as restoration
by [GAA] purified from . . . CHO cells.” Id. col. 20 ll. 32–
36. Those statements constitute substantial evidence
supporting the Board’s finding that van Bree “describes
administering hGAA produced in CHO cell cultures to
patients in the same manner, i.e., using the same
amounts and dosage intervals, as described for hGAA
produced in transgenic animals.” Board Decision, 2015
WL 1009196, at *11.
     Expert testimony was not necessary to support the
Board’s anticipation determination. Here, the disclosures
of van Bree alone were sufficiently clear and on point to
constitute substantial evidence to support the Board’s
anticipation findings. Thus, the Board “could permissibly
‘rely on its own reading of [van Bree]—supported by the
Petition’s observations about it’—to find that the [limita-
tions] were disclosed.” In re NuVasive, Inc., 841 F.3d 966,
973 (Fed. Cir. 2016) (quoting Belden Inc. v. Berk-Tek LLC,
805 F.3d 1064, 1074 (Fed. Cir. 2015)).
    Duke also argues that the Board “acted outside its
statutory authority in instituting an IPR and in its Final
Decision by adopting anticipation theories that BioMarin
never raised.” Appellant’s Br. 46. We reject this argu-
ment on its merits insofar as it challenges the Board’s
final decision.
    BioMarin argued in the petition that van Bree antici-
pates the relevant claims and did not limit its arguments
to the claim construction position rejected by the Board.
See J.A. 146–50 (BioMarin’s Petition). Duke had an
opportunity to, and did in fact, respond to those argu-
ments. See J.A. 263–75 (Duke’s Patent Owner Response).
14       DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

Thus, the Board properly “base[d] its decision on argu-
ments that were advanced by a party, and to which the
opposing party was given a chance to respond.” In re
Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed.
Cir. 2016). That conclusion leaves no live issue as to
Duke’s challenge to the institution decision on the very
same ground: that challenge is either unreviewable or, if
reviewed, incorrect (for the reason just stated), and so
could not benefit Duke.
                 B. Dependent Claim 9
    Duke argues that under a correct construction of “pre-
cursor” van Bree does not anticipate claim 9 and that the
correct construction is “exclusively a precursor of recom-
binant hGAA that has been produced in CHO cell cul-
tures.” Appellant’s Br. 46. Duke asserts that this
construction is supported by the written description and
the closed transitional term “is” preceding “precursor” in
claim 9. Duke contends that the Board properly adopted
this construction, but then improperly applied it. Specifi-
cally, Duke asserts that the Board erred by applying “a
scope for claim 9 that ‘encompass[es] administering both
precursor and non-precursor forms of rhGAA at the same
time, and [is] not limited to administering exclusively a
precursor form and no other form.’” Id. at 47 (quoting
Board Decision, 2015 WL 1009196, at *12). Duke also
argues that BioMarin waived any challenge to Duke’s
construction by not proposing an alternative during the
IPR.
    Applying its proposed construction of “precursor,”
Duke argues that van Bree does not anticipate claim 9
because van Bree does not disclose administering rhGAA
produced from CHO cells exclusively in precursor form.
Duke contends that van Bree describes a mixture of
precursor and non-precursor forms.
    BioMarin responds that the Board properly construed
“precursor” as “any precursor of recombinant hGAA (e.g.,
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.          15

a 110-kD form) that is exclusively produced in CHO cell
cultures,” and that under that construction van Bree
anticipates claim 9. Appellee’s Br. 56. BioMarin contends
that the Board cited “part of” Duke’s proposed construc-
tion, but “did not adopt the entirety” of it as “made clear
by the use of ellipses and reinforced” by the Board’s
statements about the scope of the language. Id. (empha-
sis in original). BioMarin asserts that the record does not
support limiting claim 9 to the administration of exclu-
sively precursor and no other form of GAA.
    We begin with Duke’s argument relating to the proper
construction of the term “precursor” in claim 9. In an
IPR, a patent claim is given “its broadest reasonable
construction in light of the specification of the patent in
which it appears.” Cuozzo Speed Techs., LLC v. Lee, 136
S. Ct. 2131, 2142 (2016) (quoting 37 C.F.R. § 42.100(b)).
“[W]e review the Board’s ultimate claim constructions de
novo and its underlying factual determinations involving
extrinsic evidence for substantial evidence.” Microsoft
Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1297 (Fed. Cir.
2015) (citing Teva Pharm. USA Inc. v. Sandoz, Inc., 135 S.
Ct. 831, 841–42 (2015)). Here, because the intrinsic
record alone determines the proper construction of “pre-
cursor,” we review the Board’s construction de novo. See
Shire Dev., LLC v. Watson Pharm., Inc., 787 F.3d 1359,
1364, 1368 (Fed. Cir. 2015) (citing Teva, 135 S. Ct. at
840–42).
      As an initial matter, we agree with BioMarin that the
Board construed “precursor” to mean any precursor of
recombinant hGAA (e.g., a 110-kD form) that is exclusive-
ly produced in CHO cell cultures. The Board made clear
that its construction was not limited to administration of
exclusively precursor rhGAA, Board Decision, 2015 WL
1009196, at *4 (“Neither claim 1 nor claim 9 precludes
administering a non-precursor form of hGAA or rhGAA
. . . .”), *12 (“[W]e construe ‘precursor’ in claim 9 . . . as
encompassing administering both precursor and non-
16        DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

precursor forms of rhGAA at the same time, and not
limited to administering exclusively a precursor form and
no other form.”).
    However, our agreement with BioMarin as to what
the Board held is not the same as agreeing with the
Board’s holding. On this point, we disagree with the
Board’s construction and agree with Duke that the proper
construction of “precursor” in claim 9 is “exclusively a
precursor of recombinant hGAA that has been produced
in CHO cell cultures.” Claim 9 requires that “the [hGAA]
is a precursor” and refers to claim 1 for the antecedent
basis of “the [hGAA].” ’712 patent col. 13 ll. 9–12 (empha-
ses added). That sentence structure makes clear that the
“is a precursor” phrase limits the form of hGAA to a
precursor form. The claim language and structure thus
support the conclusion that “the [hGAA]” in claim 9 is
exclusively a precursor of hGAA.
      The written description also supports Duke’s proposed
construction. The patent repeatedly refers to “precursor”
as a “form” of GAA. See id. col. 2 ll. 4–9, col. 3 ll. 58–67,
col. 12 ll. 20–22. The patent teaches administering a
particular form of hGAA, e.g., precursor form, with cer-
tain characteristics, i.e., “a form that . . . targets tissues
. . . affected by the disease.” Id. col. 3 ll. 57–67. When
referring to particular forms of GAA, it does not describe
administering a mixture of those forms. Specifically, it
states:
     In the methods of the invention, human acid α-
     glucosidase (GAA) is administered to the individ-
     ual. The GAA is in a form that, when adminis-
     tered, targets tissues such as the tissues affected
     by the disease (e.g., heart, muscle). In one pre-
     ferred embodiment, the human GAA is adminis-
     tered in its precursor form, as the precursor
     contains motifs which allow efficient receptor-
     mediated uptake of GAA. Alternatively, a mature
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.        17

   form of human GAA that has been modified to
   contain motifs to allow efficient uptake of GAA,
   can be administered. In a particularly preferred
   embodiment, the GAA is the precursor form of re-
   combinant human GAA.
Id. (emphases added). Thus, the written description also
supports a conclusion that “precursor” in claim 9 refers to
exclusively a precursor form of hGAA. The Board erred in
concluding otherwise.
    Applying the correct construction, we agree with Duke
that van Bree does not disclose a “precursor.” The Board
did not find that van Bree discloses administering exclu-
sively a precursor of rhGAA produced in CHO cell cul-
tures. See Board Decision, 2015 WL 1009196, at *12.
And BioMarin does not argue on appeal that van Bree’s
disclosure teaches the “precursor” limitation of claim 9
under the correct construction. Thus, we reverse the
Board’s finding that claim 9 was anticipated.
                      II. Obviousness
    We now turn to Duke’s arguments that the Board
erred in concluding that claims 1–9, 11, 12, 15, and 18–21
were unpatentable as obvious over Reuser in view of Van
Hove, either alone or in combination with other refer-
ences, including Brady.      Because addressing Duke’s
arguments relating to whether van Bree anticipates
claims 1 and 20 resolves this appeal, except with respect
to claims 9 and 19, we need not address Duke’s argu-
ments relating to the Board’s conclusion that claims 1 and
20 were unpatentable as obvious. Duke does not argue
dependent claims 2–8, 11, 12, 15, 18, and 21 “separately
or attempt to distinguish them from the prior art,” so
these “dependent claims stand or fall with their attendant
independent claim.” In re Warsaw Orthopedic, 832 F.3d at
1330 n.3; see also In re Margolis, 785 F.2d at 1030.
18        DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

    However, we need to address the obviousness ques-
tion with respect to claims 9 and 19. Obviousness is a
question of law, based on underlying factual findings,
including what a reference teaches, whether a person of
ordinary skill in the art would have been motivated to
combine references, and any relevant objective indicia of
nonobviousness. Apple Inc. v. Samsung Elecs. Co., 839
F.3d 1034, 1047–48, 1051 (Fed. Cir. 2016) (en banc).
                  A. Dependent Claim 9
    Duke argues that under the correct construction of
“precursor,” Reuser in view of Van Hove does not render
claim 9 unpatentable as obvious. Duke contends that
neither reference teaches or suggests administering
rhGAA produced from CHO cells exclusively in precursor
form.
    BioMarin responds that, even under Duke’s construc-
tion of “precursor,” Reuser in view of Van Hove would
have rendered claim 9 obvious. BioMarin contends that
both of its experts testified that the highly purified active
precursor form should be administered to patients, and
the art disclosed purification of the 110 kD precursor form
of hGAA. Thus, it would have been obvious to use only
the active precursor form.
    Because we have modified the construction of “precur-
sor,” we do not have the benefit of the Board’s considered
analysis whether claim 9 would have been obvious under
the correct construction. Although the Board found that
both Reuser and Van Hove disclose precursor rhGAA,
Board Decision, 2015 WL 1009196, at *15–16, the Board
did not determine whether they teach or suggest adminis-
tering exclusively a precursor of rhGAA produced in CHO
cell cultures. Before the Board, the parties certainly
disputed whether claim 9 would have been obvious. For
example, BioMarin offered expert testimony to support its
contention that Reuser teaches or suggests administra-
tion of exclusively a precursor of rhGAA that has been
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.         19

produced in CHO cell cultures. See, e.g., J.A. 561 (Reuser
“confirms what was already reported in the literature, i.e.,
that when GAA is produced for a therapeutic use, either
in CHO cells or in the milk of a recombinant mammal, the
enzyme should be produced in the precursor form with
proper glycosylation/phosphorylation of mannose resi-
dues.”); J.A. 641 (“[T]he rhGAA described by [Reuser] for
therapeutic use would be the 110kd precursor form.”).
Thus, we vacate the Board’s obviousness conclusion with
respect to claim 9 and remand for the Board to apply our
claim construction of “precursor.”
    Duke also argues that there was no motivation to
combine Reuser and Van Hove, there was no reasonable
expectation of success from that combination, and its
proffered objective indicia support a conclusion of nonob-
viousness. On remand, the Board is to consider these
arguments and provide a meaningful discussion of its
analysis of them. 2
                  B. Dependent Claim 19
     Duke argues that the Board’s claim 19 obviousness
determination is legally deficient and the underlying fact-
finding is not supported by substantial evidence because
it rests on cursory and conclusory expert testimony. Duke
contends that combining Reuser, Van Hove, and Brady
would not have yielded the invention of claim 19 because
none of the references discloses prophylactically adminis-
tering an immunosuppressant prior to any administration
of enzyme replacement therapy. Duke asserts that the
Board’s finding that “prophylactically administering an
immunosuppressant would have been a ‘predictable

   2  Notably, Duke’s objections to the Board’s treatment
of its evidence of objective indicia of non-obviousness—
including its failure to apply a presumption of nexus—
appear well taken.
20         DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

variation of the [after-the-fact] use of immunosuppressant
disclosed in Brady’” was neither supported by any record
evidence nor argued by BioMarin. Appellant’s Br. 64
(quoting Rehearing Decision, 2015 WL 4467381, at *8).
Duke also contends that the record lacks a motivation to
combine these references and that a skilled artisan would
not have had a reasonable expectation of success. Duke
further argues that BioMarin’s common-sense theory
lacks record support and ignores known risks and side
effects.
    BioMarin responds that prophylactic administration
of immunosuppressants was a common sense solution to
expected immune responses, informed by experience with
other therapeutic proteins, e.g., Gaucher disease, dis-
cussed in Brady. BioMarin asserts that the Board proper-
ly relied on BioMarin’s expert’s testimony that a skilled
artisan would reasonably have predicted that an adverse
immune reaction may occur and would have been moti-
vated to prevent that adverse immune reaction.
    We agree with Duke that the Board erred in conclud-
ing that claim 19 was unpatentable as obvious. Substan-
tial evidence does not support the Board’s finding that
“the prophylactic administration of an immunosuppres-
sant would have been a predictable variation of the use of
immunosuppressant disclosed in Brady.” Id. at *8. It is
undisputed that the Board correctly found that “Brady
does not disclose administering immunosuppressant prior
to any and all administration of hGAA, as required by
claim 19.” Rehearing Decision, 2015 WL 4467381, at *4.
The expert testimony relied on by the Board to bridge the
gap between the disclosure in Brady and claim 19 falls
short of what would have rendered the subject matter of
claim 9 obvious.
     BioMarin’s expert testified, inter alia, that:
     [I]t would not be surprising if a proportion of pa-
     tients treated with recombinant GAA protein de-
DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.         21

   veloped an immune response to the recombinant
   enzyme. In patients with high titers of antibodies
   against the enzyme, particularly those with neu-
   tralizing antibodies, administering an immuno-
   suppressant prior to, with or immediately after
   the therapeutic enzyme would be considered to
   mitigate the presence of antibodies and its nega-
   tive impact. For example, Brady et al. discuss . . .
   efforts to “immunosuppress” the patient. . . . If
   there is a high incidence of patients developing
   high antibody titers, an immunosuppressant could
   be administered prophylactically prior to any ad-
   ministration of the recombinant enzyme begins to
   minimize the potential adverse effects of such.
J.A. 575–76 (internal citations omitted) (emphasis added).
    That testimony falls short because it does not address
what an ordinary artisan would have done or understood
regarding prophylactic administration of immunosuppres-
sants in the context of GAA enzyme replacement therapy
prior to the priority date of the ’712 patent. It merely
suggests what “could be” done “if there is a high inci-
dence” of antibody response. Id.
    Moreover, there was no evidence that “a high inci-
dence of patients” developed, or were expected to develop,
“high antibody titers” to GAA enzyme replacement thera-
py. BioMarin submitted no evidence regarding the inci-
dence of high antibody titers in patients receiving GAA
before the ’712 patent. Furthermore, Brady teaches that
“[v]ery few patients with Gaucher disease who are treated
with [enzyme replacement therapy] develop a neutraliz-
ing antibody to the exogenous enzyme” and refers to this
phenomenon as “rare.” J.A. 526. Brady suggests that its
“technique may be helpful when enzyme replacement
therapy is attempted in patients with other disorders in
which the genetic mutation abrogates the production of
the protein (CRIM-negative individuals),” id., but Brady’s
22          DUKE UNIVERSITY   v. BIOMARIN PHARMACEUTICAL INC.

technique did not involve prophylactic administration of
immunosuppressants, Rehearing Decision, 2015 WL
4467381, at *4, *9 (APJ Bonilla, dissenting). Thus, the
evidence of record does not establish the conditions prece-
dent (a high incidence of patients with high antibody
titers to the enzyme) to the prophylactic administration of
immunosuppressants according to the expert’s testimony.
Such conclusory expert testimony cannot support an
obviousness conclusion. See In re Magnum Oil Tools, 829
F.3d at 1380 (“To satisfy its burden of proving obvious-
ness, a petitioner cannot employ mere conclusory state-
ments. The petitioner must instead articulate specific
reasoning, based on evidence of record, to support the
legal conclusion of obviousness.”). The evidence thus fails
to render claim 19 obvious.
                        CONCLUSION
     We have considered the parties’ remaining argu-
ments, but conclude that they are without merit. For the
reasons set forth above, we reverse the Board’s obvious-
ness determination with respect to claim 19, vacate its
obviousness determination with respect to claim 9, re-
verse its anticipation finding with respect to claim 9, and
affirm in all other respects. We remand for proceedings
consistent with this opinion.
     AFFIRMED IN PART, REVERSED IN PART,
       VACATED IN PART, AND REMANDED
                              COSTS
No costs.