  United States Court of Appeals
      for the Federal Circuit
                ______________________

 GENZYME THERAPEUTIC PRODUCTS LIMITED
             PARTNERSHIP,
                Appellant

                          v.

       BIOMARIN PHARMACEUTICAL INC.,
                    Appellee
             ______________________

                 2015-1720, 2015-1721
                ______________________

   Appeals from the United States Patent and Trade-
mark Office, Patent Trial and Appeal Board, in Nos.
IPR2013-00534, IPR2013-00537.
                ______________________

                Decided: June 14, 2016
                ______________________

    FILKO PRUGO, O’Melveny & Myers LLP, New York,
NY, argued for appellant. Also represented by ANTON
METLITSKY, MARGARET O’BOYLE, EBERLE SCHULTZ;
DEANNA MARIE RICE, Washington, DC; CHRISTINA A. L.
SCHWARZ, Fitzpatrick, Cella, Harper & Scinto, 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              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                       PHARMACEUTICAL




    BENJAMIN T. HICKMAN, Office of the Solicitor, United
States Patent and Trademark Office, Alexandria, VA,
argued for intervenor Michelle K. Lee. Also represented
by THOMAS W. KRAUSE, SCOTT WEIDENFELLER, FARHEENA
YASMEEN RASHEED.
                 ______________________

     Before MOORE, BRYSON, and REYNA, Circuit Judges.
BRYSON, Circuit Judge.
     This is an appeal from decisions of the Patent Trial
and Appeal Board in two inter partes review proceedings.
At the behest of petitioner Biomarin Pharmaceutical Inc.
(“Biomarin”), the Board held various claims of two patents
owned by Genzyme Therapeutics Products Limited Part-
nership (“Genzyme”) to be unpatentable as obvious. We
affirm.
                            I
                            A
    The patents at issue in this case, U.S. Patent   Nos.
7,351,410 (“the ’410 patent”) and 7,655,226 (“the    ’226
patent”), are both entitled “Treatment of Pompe’s    Dis-
ease” and are directed to treating Pompe’s disease   with
injections of human acid α-glucosidase.
    Pompe’s disease (also known as “Pompe disease”) is a
genetic condition associated with a deficiency or absence
of the lysosomal enzyme acid α-glucosidase (“GAA”). In a
healthy individual, GAA breaks down glycogen, a larger
molecule, into glucose. A person with Pompe’s disease
has significantly reduced levels of GAA, or no GAA at all,
and so is unable to break down glycogen into glucose.
That inability results in glycogen accumulating in the
muscles of affected patients in excessive amounts.
GENZYME THERAPEUTIC PRODUCTS    v. BIOMARIN              3
PHARMACEUTICAL


    Pompe’s disease is found in two forms—early-onset
and late-onset. Early-onset or infantile Pompe’s disease
presents shortly after birth and is associated with the
patient having no measurable GAA activity. Glycogen
accumulates in the patient’s heart and skeletal muscles,
causing a progressive deterioration of the heart muscles.
Without treatment, a patient with early-onset Pompe’s
disease will die from cardiac or respiratory failure before
reaching one year of age.
    Patients who have some degree of GAA activity, but
less than normal, first develop symptoms after infancy.
That condition is referred to as late-onset or juvenile
Pompe’s disease. Those patients develop progressive
muscle weakness and respiratory symptoms due to glyco-
gen buildup in the skeletal muscles, but only rarely do
they develop the cardiac symptoms associated with early-
onset Pompe’s disease.
    Following the discovery that Pompe’s disease is asso-
ciated with GAA deficiency, research efforts were focused
on treating the disease through enzyme replacement
therapy. Experts hoped that by injecting patients with
GAA from other sources they could counteract the effects
of harmful glycogen buildup. Early efforts failed, howev-
er, because the injected enzyme was predominantly taken
up by the patient’s liver, reducing glycogen levels there
but not in the skeletal or heart muscles where the excess
glycogen does the most harm.
    Later researchers theorized that the failure of early
experiments could be overcome by modifying the injected
GAA to include mannose-6-phosphate (“M-6-P”), which
promotes GAA uptake in heart and skeletal muscle cells
containing M-6-P receptors, including the cells that failed
to take up GAA in prior treatment attempts.
    Research along that pathway led to in vitro studies on
extracted cells. Those studies were very promising and
showed that GAA modified with M-6-P would be taken up
4              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                       PHARMACEUTICAL


by skeletal and heart muscle cells much more efficiently
than in the case of prior enzyme replacement therapies.
     Another problem that needed to be solved was how to
manufacture human GAA for injection into patients with
Pompe’s disease. Work on that problem led to the devel-
opment of a means to manufacture human GAA modified
to include M-6-P. Animals such as mice and other mam-
mals could have their genomes altered so that they would
produce human GAA that could be extracted by research-
ers.
    Finally, researchers faced the challenge of developing
a dosing schedule for the enzyme replacement therapy.
Gaucher disease, a lysosomal protein deficiency condition
like Pompe’s disease, had been successfully treated with
enzyme replacement therapy. Typical dosing schedules
for Gaucher disease enzyme treatments were once every
two weeks, or once a week if needed. Another known
factor bearing on the dosing schedule was the half-life for
GAA, which was known to be 6-9 days, suggesting a
relatively long dosage interval for recombinant GAA of
once per week or once every other week.
    By 1997, research had progressed far enough that the
Food and Drug Administration approved Duke Universi-
ty’s application for Orphan Drug Designation for a new
therapy for Pompe’s disease based on the injection of a
recombinant form of GAA. The University announced in
a press release that it would begin testing that treatment
on human patients suffering with Pompe’s disease.
                            B
    In 2013, Biomarin filed petitions requesting inter
partes review of the ’410 and ’226 patents. For the single
claim of the ’410 patent, Biomarin sought review on four
grounds. The Board instituted review on two of those
grounds: the combination of the Duke press release and
two references known as Barton and van der Ploeg ’88;
GENZYME THERAPEUTIC PRODUCTS    v. BIOMARIN               5
PHARMACEUTICAL


and the combination of a reference known as Reuser with
Barton and van der Ploeg ’88. The Board declined to
institute review on two other grounds as redundant. For
the ’226 patent, the Board instituted review of claims 1
and 3 for obviousness based on the Duke press release,
Reuser, and a reference known as van Hove. It declined
to institute review for anticipation on the basis of the
Duke press release alone and for obviousness based on the
Duke press release and Reuser. The Board instituted
review on claims 4-6 of the ’226 patent for obviousness
based on the Duke press release, Reuser, Barton, and van
der Ploeg ’88.
    In patent owner responses filed in both inter partes
reviews, Genzyme argued that because all of the combina-
tions of references described in vitro experiments, a
person of ordinary skill would not find those experiments
predictive of results in a human patient. Because the
Board did not institute review based on any references
that included in vivo data from studies on live animals,
Genzyme argued that Biomarin should not be permitted
to use any of the prior art showing successful in vivo tests
to demonstrate obviousness.
    In its reply, Biomarin responded to Genzyme’s argu-
ments by citing two in vivo studies, referred to as van der
Ploeg ’91 and Kikuchi. Van der Ploeg ’91 found that the
addition of M-6-P to GAA led to significantly increased
uptake of GAA in mouse heart and skeletal muscle tissue.
A. T. van der Ploeg et al., Intravenous Administration of
Phosphorylated Acid α-Glucosidase Leads to Uptake of
Enzyme in Heart and Skeletal Muscle of Mice, 87 J. Clini-
cal Investigation 513 (1991). Kikuchi found that GAA
deficiencies in Japanese quail suffering from symptoms
similar to the symptoms of Pompe’s disease could be
successfully treated with intravenous injections of GAA
modified with M-6-P. Kikuchi et al., Clinical and Meta-
bolic Correction of Pompe Disease by Enzyme Therapy in
6              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                       PHARMACEUTICAL


Acid Maltase-Deficient Quail, 101 J. Clinical Investigation
827 (1998).
    In its final written decisions, the Board found by a
preponderance of the evidence that the challenged claims
of the ’410 and ’226 patents would have been obvious. In
its analysis of the two patents, the Board noted that
Reuser disclosed every claim limitation other than a bi-
weekly dosing schedule, and that the claimed dosing
schedule would have been arrived at by routine optimiza-
tion. For claim 6 of the ’226 patent, which is directed to
reducing heart muscle symptoms, the Board found that a
person of ordinary skill would have understood that an
effective treatment for Pompe’s disease would treat that
condition as well.
    Although clinical trials had not been conducted as of
December 7, 1998, the priority date of the patents, the
Board found that a person of ordinary skill would have
been motivated to pursue the clinical development of the
therapy disclosed in Reuser. In response to Genzyme’s
arguments that there would have been no reasonable
expectation that the treatment would succeed, the Board
said that by December 7, 1998, “all that remained to be
achieved over the prior art was the determination that a
specific dose within a previously suggested dose range,
and its corresponding dosing schedule, would have been
safe and effective for the treatment of human patients.”
    By the 1998 priority date, the Board found, the field
related to the development of an enzyme replacement
therapy for Pompe’s disease had matured to the point that
it was recognized that GAA had to be translationally
modified with M-6-P; in vivo studies had been performed
in which GAA containing M-6-P had been intravenously
administered to mice and Japanese Quail; it was known
that human GAA containing M-6-P could be produced in
the milk of transgenic animals; and the FDA was grant-
ing applications for orphan drug designation for enzyme
GENZYME THERAPEUTIC PRODUCTS       v. BIOMARIN              7
PHARMACEUTICAL


replacement therapy for Pompe’s disease. The Board
referred to the Kikuchi and van der Ploeg ’91 references
as support for its findings as to the state of the art regard-
ing the in vivo studies. Based on the evidence before it,
the Board concluded that “a person of ordinary skill in the
art would have had a reasonable expectation of success at
the time the invention was made,” and “no more than
routine processes were needed” to achieve the results
recited in the disputed claims.
                              II
                              A
     On appeal, Genzyme first argues that the Board vio-
lated the requirements of notice and an opportunity to
respond found in the Administrative Procedure Act
(“APA”). Genzyme argues that in finding that the claims
at issue were unpatentable, the Board relied on “facts and
legal arguments” that were not set forth in the institution
decisions. Therefore, according to Genzyme, it was denied
notice “of the issues to be considered by the Board and an
opportunity to address the facts and legal arguments on
which the Board’s patentability determination [would]
rest.”
    In a formal adjudication, such as inter partes review,
the APA imposes certain procedural requirements on the
agency. The Patent and Trademark Office must provide
the patent owner with timely notice of “the matters of fact
and law asserted,” and an opportunity to submit facts and
argument. 5 U.S.C. §§ 554(b)-(c), 557(c); Dell Inc. v.
Acceleron, LLC, 818 F.3d 1293, 1301 (Fed. Cir. 2016). The
notice and opportunity to be heard provisions of the APA
have been applied “to mean that ‘an agency may not
change theories in midstream without giving respondents
reasonable notice of the change’ and ‘the opportunity to
present argument under the new theory.’” Belden v. Berk-
Tek LLC, 805 F.3d 1064, 1080 (Fed. Cir. 2015) (quoting
8              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                       PHARMACEUTICAL


Rodale Press, Inc. v. FTC, 407 F.2d 1252, 1256-57 (D.C.
Cir. 1968)).
    In this case, the Board did not “change theories in
midstream,” much less deny Genzyme notice of any such
change. The Board’s final written decisions were based
on the same combinations of references that were set
forth in its institution decisions. The Board instituted
trial on two grounds of unpatentability with respect to the
’410 patent and two grounds of unpatentability with
respect to the ’226 patent. In its final written decisions,
the Board found the claims at issue unpatentable based
on those same grounds and no others. Genzyme therefore
cannot argue that it lacked notice of the specific combina-
tions of references that the Board relied on in finding the
claims invalid. 1
    The principal thrust of Genzyme’s APA challenge is
that the Board cited references in its final written deci-
sions that were not specifically included in the combina-


    1   Genzyme relies on a series of cases involving the
“new ground of rejection” doctrine, as applied to examina-
tion and reexamination decisions appealed to the Board.
See In re Biedermann, 733 F.3d 329 (Fed. Cir. 2013);
Rambus Inc. v. Rea, 731 F.3d 1248 (Fed. Cir. 2013); In re
Leithem, 661 F.3d 1316 (Fed. Cir. 2011); In re Stepan Co.,
660 F.3d 1341 (Fed. Cir. 2011). The inter partes review
proceeding at issue in this case is not an appeal from an
examiner’s decision, but is a unitary trial proceeding
before the Board, so those cases are not directly applicable
here. Even if the “new ground of rejection” doctrine is
applicable by analogy to trial proceedings before the
Board, the Board did not adopt a new ground of rejection
or its equivalent in this case because, as noted, the
grounds on which the Board invalidated the disputed
claims in its final written decisions were the same as
those set forth in its institution decisions.
GENZYME THERAPEUTIC PRODUCTS    v. BIOMARIN               9
PHARMACEUTICAL


tions of prior art on which the Board instituted review. In
particular, Genzyme objects to the Board’s citation of two
references dealing with in vivo testing, the Kikuchi and
van der Ploeg ’91 references. 2 However, the introduction
of new evidence in the course of the trial is to be expected
in inter partes review trial proceedings and, as long as the
opposing party is given notice of the evidence and an
opportunity to respond to it, the introduction of such
evidence is perfectly permissible under the APA.
    Genzyme’s argument that the institution decision
must refer to every bit of evidence that is relied on by the
Board in its final written decision reflects a misunder-
standing of the role of the institution decision in inter
partes review proceedings before the Board. There is no
requirement, either in the Board’s regulations, in the
APA, or as a matter of due process, for the institution
decision to anticipate and set forth every legal or factual
issue that might arise in the course of the trial. See
Boston Carrier, Inc. v. ICC, 746 F.2d 1555, 1560 (D.C. Cir.
1984) (even when adjudicating charges of misconduct, an
agency “is not burdened with the obligation to give every
applicant a complete bill of particulars as to every allega-
tion that carrier will confront”). Because the institution
decision comes at the outset of the proceedings and the
patentee is not obligated to respond before the Board
makes its institution decision, it is hardly surprising that
the Board cannot predict all the legal or factual questions
that the parties may raise during the litigation.
    The development of evidence in the course of the trial
is in keeping with the oppositional nature of an inter
partes review proceeding. “The parties present their
evidence up front, the patent owner offers any amend-


   2     Kukuchi was referred to in the institution decision
on the ’410 patent, but only in the portion of the decision
citing the prior art relied upon by the petitioner.
10               GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                         PHARMACEUTICAL


ments, and the PTO simply decides whether the challeng-
er has met his burden of proving invalidity.” S. Rep.
No. 111-18, at 57 (2009) (views of Sens. Kyl, Feingold, and
Coburn). The purpose of the trial in an inter partes
review proceeding is to give the parties an opportunity to
build a record by introducing evidence—not simply to
weigh evidence of which the Board is already aware.
    The critical question for compliance with the APA and
due process is whether Genzyme received “adequate
notice of the issues that would be considered, and ulti-
mately resolved, at that hearing.” Pub. Serv. Comm’n of
Ky. v. FERC, 397 F.3d 1004, 1012 (D.C. Cir. 2005) (Rob-
erts, J.). As to that question, Genzyme has not shown
that the Board’s decisions rested on any factual or legal
issues as to which Genzyme was denied notice or an
opportunity to be heard at a meaningful point in the
proceedings.
    Genzyme cannot plausibly argue that it lacked notice
that the Board might cite Kikuchi and van der Ploeg ’91
in its final written decisions. Genzyme itself raised the
issue of the in vivo studies in its patent owner responses,
where it argued that Kikuchi and other in vivo studies
that the petitioner had cited in its petitions should not be
considered as rebuttal evidence. Genzyme argued:
     In fact, permitting Petitioner to rely on in vivo da-
     ta with GAA here would require Genzyme to ana-
     lyze prior art and prior art combinations involving
     references both (1) not included in this Board’s
     grounds (and for Kikuchi, in particular, already
     denied as redundant); and (2) upon which Peti-
     tioner itself did not include in its own suggested
     grounds.
    Biomarin then addressed both of the in vivo refer-
ences in its replies, arguing that the in vivo references
were relevant to show the state of the art at the time of
the inventions. With both parties addressing the rele-
GENZYME THERAPEUTIC PRODUCTS    v. BIOMARIN                11
PHARMACEUTICAL


vance of the in vivo references, Genzyme had ample notice
that the references were in play as potentially relevant
evidence and that the Board might well address the
parties’ arguments regarding those references in its final
written decisions.
    At the oral hearing before the Board, the parties dis-
puted what use the Board could make of the in vivo
references, but even Genzyme conceded that the in vivo
references could be used for some purposes. In the course
of the hearing, the judges questioned Genzyme’s counsel
about Kikuchi, van der Ploeg ’91, and one other in vivo
reference. Counsel contended that because those refer-
ences were not among the combinations of references on
which the Board granted review, they could not be used to
show “a reasonable expectation of success.” Counsel
acknowledged, however, that the “prior art as a whole”
could be used “in order to figure out what’s common
knowledge.” 3 The pertinent portion of the argument is
reproduced below:
   [Genzyme’s Counsel:] [Van der Ploeg is] advocat-
   ing for testing in in vivo models, and, Judge
   Green, I think that goes in part to what you were
   asking me earlier, well, what is it you would need?
   Well, if we look at the prior art, people are talking
   about testing in animal models.



   3     Genzyme argues that the Board must have used
the in vivo references to establish a reasonable expecta-
tion of success, and that it was improper for the Board to
use the references for that purpose. But the Board itself
cited those references as indicators of how far “the field
related to the development of an enzyme replacement
therapy for the treatment of Pompe disease had devel-
oped” at the time of the inventions, which is exactly what
Genzyme’s counsel conceded the Board could properly do.
12               GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                         PHARMACEUTICAL


     JUDGE GREEN: But then I’m still unsure why
     Grabowski or the Japanese quail doesn’t meet
     that.
     [Genzyme’s Counsel]: The—so the Bijvoet refer-
     ence or Kikuchi, which is the Japanese quail, we
     submit, Your Honors, cannot, absolutely cannot be
     part of the reasonable expectation of success anal-
     ysis.
     JUDGE GREEN: So they’re not—so we have to
     ignore that this is what would have been known to
     the ordinary artisan.
     [Genzyme’s Counsel]: I think when you—when we
     talk about using the prior art as a whole, you can
     use the prior art as a whole in order to figure out
     what’s common knowledge, but you can’t, after in-
     stituting trial on certain references, bring in addi-
     tional evidence that’s required, that’s required to
     show a reasonable expectation of success.
    From the record as a whole, it is clear that Genzyme
had actual notice of the in vivo references and an oppor-
tunity to respond to them—an opportunity that Genzyme
took advantage of in arguing that those references could
be used only for limited purposes.
    Beyond that, the regulations governing inter partes
review proceedings provide patent owners with procedur-
al mechanisms either to respond to evidence raised in the
petitioner’s reply or to move to exclude it. Biomarin
raised the in vivo data issue in its reply, stating that the
fact that Biomarin’s expert, Dr. Gregory M. Pastores,
“testified that in vitro data was sufficient and was con-
firmed by in vivo data . . . should not allow Genzyme to
hide behind an improper redundancy argument to prevent
the Board from considering relevant references.”
    If Genzyme had wanted the Board to disregard those
references, it could have filed a motion to exclude them.
GENZYME THERAPEUTIC PRODUCTS    v. BIOMARIN             13
PHARMACEUTICAL


See 37 C.F.R. § 42.64(c); Belden, 805 F.3d at 1081. If it
had wished to submit a further substantive response to
those references, it could have asked for leave to file a
surreply, as longstanding Board practice allows. See
Belden, 805 F.3d at 1081. But despite having actual
notice that Biomarin was relying on the in vivo references
to rebut Genzyme’s arguments, Genzyme failed to take
advantage of its procedural options to seek to exclude that
evidence or to respond to Biomarin’s arguments.
    Although Genzyme characterizes this case as being
about the sufficiency of notice and an opportunity to be
heard, the substance of Genzyme’s argument is to chal-
lenge the propriety of the Board’s use, for any purpose, of
a reference that was not part of the combinations set forth
in the institution decisions. 4 It is in that context that
Genzyme focuses on the Board’s references in its final



   4    Genzyme’s argument is actually even broader
than that. Genzyme contends that it was denied proper
notice when the Board referred in its final written deci-
sions to a portion of the Reuser reference that it did not
specifically cite in the institution decisions, even though
the Board cited the Reuser reference generally. Genzyme
also complains that the Board referred to the Duke press
release as relating to an FDA orphan drug designation,
even though the orphan drug designation was not men-
tioned in the institution decisions when those decisions
cited the Duke press release. There is no force to those
arguments. Under the regime imagined by Genzyme, the
Board would not only be prohibited from discussing any
references not cited in its institution decisions, but it
would be confined strictly to the quoted or cited portions
of even those references that were included in the institu-
tion decisions, requiring something approaching word-for-
word parity between the institution and final written
decisions.
14              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                        PHARMACEUTICAL


written decisions to Kikuchi and van der Ploeg ’91. But
those brief references by the Board merely served to
describe the state of the art as of December 7, 1998; they
were not among the prior art references that the Board
relied upon to establish any claim limitations.
    This court has made clear that the Board may consid-
er a prior art reference to show the state of the art at the
time of the invention, regardless of whether that reference
was cited in the Board’s institution decision. In Ariosa
Diagnostics v. Verinata Health, Inc., 805 F.3d 1359 (Fed.
Cir. 2015), this court vacated the Board’s decision because
it appeared that the Board had declined to consider a
reference simply because the reference “had not been
identified at the petition stage as one of the pieces of prior
art defining a combination for obviousness.” Id. at 1365.
The court in Ariosa held that such references “can legiti-
mately serve to document the knowledge that skilled
artisans would bring to bear in reading the prior art
identified as producing obviousness.” Id. That is exactly
how the Board used the Kikuchi and van der Ploeg ’91
references—as part of the Board’s survey of “the field
related to the development of an enzyme replacement
therapy for the treatment of Pompe disease” as of the
priority date of the patents.
    In sum, Genzyme was not denied notice of the in vivo
references or an opportunity to respond to them. And to
the extent it contends that the Board used those refer-
ences for an improper purpose, it is wrong.
                              B
    Genzyme next argues that the Board erred in its
claim construction in two respects. Genzyme’s first claim
construction argument is that the Board changed its
construction of the “whereby” clause in the ’226 and ’410
patents between the institution decisions and the final
written decisions. We see no merit in that argument.
GENZYME THERAPEUTIC PRODUCTS   v. BIOMARIN                15
PHARMACEUTICAL


   Claim 1 of the ’410 patent reads as follows, with the
whereby clause in italics:
   A method of treating a human patient with Pom-
   pe’s disease, comprising intravenously administer-
   ing biweekly to the patient a therapeutically
   effective amount of human acid alpha glucosidase,
   whereby the concentration of accumulated glyco-
   gen in the patient is reduced and/or further accu-
   mulation of glycogen is arrested.
Claim 1 of the ’226 patent contains the same whereby
clause.
    In the institution decisions, the Board construed the
whereby clause as describing the result achieved when a
patient is given a therapeutically effective dose of GAA:
   The claim feature of “whereby the concentration of
   accumulated glycogen in the patient is reduced
   and/or further accumulation of glycogen is arrest-
   ed” is not a separate step, but rather a result of
   administering a therapeutically effective amount
   of human acid alpha glucosidase according to the
   claimed method. Such results are not generally
   considered a patentable feature separate from the
   expressly recited steps of the claimed method.
In the final written decisions, the Board construed the
whereby clause in the same way, as describing the result
of administering an effective dose of GAA:
   The claimed method comprises a single step: “in-
   travenously administering biweekly to the patient
   a therapeutically effective amount of human acid
   alpha glucosidase.” Claim 1 further recites the
   result achieved from the practice of the method
   recited in claim 1. Specifically, the step of intra-
   venously administering biweekly to the patient a
   therapeutically effective amount of human GAA
   results in the reduction in the concentration of ac-
16              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                        PHARMACEUTICAL


     cumulated glycogen in the patient and/or the ar-
     rest of further accumulation of glycogen. Thus,
     the recited whereby clause defines what is
     achieved from the administration of “a therapeu-
     tically effective amount of human acid alpha glu-
     cosidase” to a human patient with Pompe disease.
The Board’s construction of the claim language did not
change between the institution decisions and the final
written decisions. In both instances the Board explained
that the whereby clause defines the result of administer-
ing an effective amount of GAA rather than constituting a
separate step of a method.
    Genzyme’s second claim construction argument is
that the whereby clause should be construed to require
that the reduction of glycogen occur in the patient’s
skeletal muscles, rather than occurring anywhere in the
patient’s body, including the heart, skeletal muscles, or
liver.
    In an inter partes review, the Board accords unexpired
claims their broadest reasonable interpretation consistent
with the specification. In re Cuozzo Speed Techs., LLC,
793 F.3d 1268, 1278 (Fed. Cir. 2015), cert. granted, 136 S.
Ct. 890 (2016). The broadest reasonable construction of
the whereby clause encompasses a reduction of accumu-
lated glycogen anywhere in the patient, rather than
necessarily in the skeletal muscles, as Genzyme argues.
    As the Board noted in its final written decisions, “the
claim does not recite specific organs or tissue, does not
recite any specific form of Pompe disease, and does not
require, for example, the patient to experience an in-
creased life-span. The whereby clause merely requires
the reduction or arrest of glycogen in the patient.” Be-
cause the claim language does not expressly or implicitly
require that the administration of GAA reduce glycogen in
any particular organ of the body, the Board was correct to
reject Genzyme’s narrower construction.
GENZYME THERAPEUTIC PRODUCTS       v. BIOMARIN                17
PHARMACEUTICAL


     Genzyme’s references to portions of the common speci-
fication of the two patents that describe the reduction of
glycogen buildup in the skeletal muscles do not support
its proposed construction. Rather than limiting “glycogen
in the patient” to the skeletal muscles, the specification
describes how GAA is taken up by the heart, liver, and
skeletal muscles, supporting the broader interpretation.
See ’410 patent, col. 13, ll. 41-46 (“These methods [of
treating Pompe’s disease] are premised in part on the
availability of large amounts of human acid alpha gluco-
sidase in a form that is catalytically active and in a form
that can be taken up by tissues, particularly, liver, heart
and muscle (e.g., smooth muscle, striated muscle, and
cardiac muscle), of a patient being treated.”); ’226 patent,
col. 13, ll. 27-32 (same).
    The prosecution history confirms the Board’s con-
struction. In support of the amendment that added the
whereby clause to the application that matured into the
’410 patent, Genzyme relied, for written description
support, on the following passages, which are now found
in the ’410 patent at col. 22, ll. 46-48, and col. 23, ll. 18-21,
and in the ’226 patent at col. 21, ll. 48-50, and col. 22, ll.
60-63:
    When two KO mice were injected 4 times every 6
    days (experiment B), a marked decrease of total
    cellular glycogen was observed in both heart and
    liver. . . .
    The results showed that mice treated 13 weeks
    with 0.5 mg/mouse (Group A, 3 animals/Group)
    had an increase of activity in the liver and spleen
    and decreased levels of glycogen in liver and per-
    haps in heart.
    Neither passage includes any suggestion that a de-
crease in skeletal muscle glycogen is required to satisfy
the whereby clause. In addition, immediately following
the first cited passage, the specification stated that “[n]o
18              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                        PHARMACEUTICAL


effects were observed in skeletal muscle tissues with
regard to total glycogen.” ’410 patent, col. 22, ll. 48-50;
’226 patent, col. 21, ll. 50-52.
    Although it was understood at the time of the inven-
tion that the claimed therapeutic effect of the patented
methods would typically result in a reduction in the
glycogen level in either the heart or the skeletal muscles,
the evidence before the Board suggests that the patentees
chose not to restrict the whereby clause in that fashion,
but instead elected to describe the effects of the therapy in
a more general manner, claiming any effective GAA
therapy.
    Based on the indications in the specification and the
prosecution history that some of the experimental results
did not show a reduction in the glycogen levels in skeletal
muscle tissue in in vivo testing, it was reasonable for the
Board to conclude that the patentees elected to describe
the result of their method as reducing (or arresting the
accumulation of) the concentration of glycogen anywhere
in the patient’s body. Accordingly, we conclude that the
Board was correct that the broadest reasonable interpre-
tation of the clause “whereby the concentration of accu-
mulated glycogen in the patient is reduced” does not
require a showing of a reduction in the glycogen level in
the skeletal muscles, or any other particular organ, of
patients treated according to the patented method.
    Genzyme argues that the Board’s construction cannot
be correct because “reduction of glycogen in liver alone
does not treat Pompe Disease, as everyone at the time of
the invention fully understood.” But the claims already
required that the method include the administration of “a
therapeutically effective amount” of GAA, so it was not
necessary for the whereby clause to specify the particular
organ or organs where the glycogen level was affected.
Regardless of the specificity of the whereby clause, the
method was required to be therapeutically effective. The
GENZYME THERAPEUTIC PRODUCTS      v. BIOMARIN              19
PHARMACEUTICAL


Board’s construction is therefore consistent with the
patentees’ apparent choice to draft their claims broadly to
reach any method of GAA administration that had thera-
peutic effects and reduced glycogen concentrations some-
where in the body.
                              C
    Genzyme’s third argument is that the Board erred by
not making an explicit finding as to the level of skill of a
person of ordinary skill as part of its obviousness analy-
sis. This court has explained that the failure to make
explicit findings regarding the level of skill in the art does
not constitute reversible error when “the prior art itself
reflects an appropriate level and a need for testimony is
not shown.” Okajima v. Bourdeau, 261 F.3d 1350, 1354-
55 (Fed. Cir. 2001) (quoting Litton Indus. Prods., Inc. v.
Solid State Sys. Corp., 755 F.2d 158, 163-64 (Fed. Cir.
1985)).
     Here the Board’s failure to make an explicit finding as
to the level of skill is not reversible error because both
parties proposed nearly identical language to describe a
person of ordinary skill. Both proposed that such a per-
son is a medical doctor or a Ph.D. in a biology-related
field, has experience in lysosomal diseases, and has
experience developing drugs and treatments for patients.
Genzyme has not shown that there are any meaningful
differences between its proposed definition of a person of
ordinary skill and Biomarin’s, or that the outcome of this
case would have been different based on which definition
the Board used. The Board’s failure to make a specific
finding as to the level of skill is therefore not reversible
error.
                              D
    Finally, Genzyme argues that substantial evidence
does not support the Board’s finding of a likelihood of
success from the combination of the prior art references.
20              GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                        PHARMACEUTICAL


Genzyme claims in particular that the testimony of Bio-
marin’s expert, Dr. Pastores, did not provide evidence as
to the knowledge of a person of ordinary skill in the art at
the time of the invention. Genzyme bases that argument
on Dr. Pastores’s use of the word “I” in several instances
in his declaration rather than referring to “a person of
ordinary skill in the art.” Because he used the word “I,”
Genzyme argues, it is clear that Dr. Pastores was testify-
ing to his own subjective view of the prior art rather than
providing evidence of how a person of ordinary skill at the
relevant date would have viewed the art.
    There is no merit to Genzyme’s argument. Dr. Pas-
tores described “how someone knowledgeable and skilled
in the field of enzyme replacement therapy of lysosomal
storage diseases would approach the task of developing a
treatment for Pompe disease using enzyme replacement
therapy as of December 6, 1997.” He then referred to
various facts that were “well-known,” were “known at the
time,” were “clear,” were “well-appreciated,” “would have
been recognized,” “would have been readily known,” and
“would have been further appreciated.”
    It is clear that the Board understood Dr. Pastores’s
testimony as being directed to the knowledge of persons of
skill in the art, even though some of his statements about
the prior art were prefaced with the word “I” rather than
with repeated incantations of the “person of ordinary skill
in the art” formulation. (“[W]e are persuaded by Dr.
Pastores’s testimony that the knowledge in the art re-
garding the treatment of Pompe disease with human GAA
would have provided the motivation to select a suitable
dose and dosing schedule . . . would have been informed
by the clinical experience with Gaucher disease . . . and
that, because ‘it was well known that any enzyme re-
placement therapy for Pompe disease would be required
for the rest of a patient’s life, . . . repeated spaced admin-
GENZYME THERAPEUTIC PRODUCTS   v. BIOMARIN             21
PHARMACEUTICAL


istration of GAA to patients would be immediately under-
stood upon reading [Reuser].”). 5
    Finally, contrary to Genzyme’s contention, Dr. Pas-
tores’s testimony was sufficient to support the Board’s
conclusion that a person of ordinary skill would have had
a reasonable expectation of success in arresting or reduc-
ing the accumulation of glycogen through the injection of
GAA. As he explained, the prior art disclosed that GAA
modified to include M-6-P was effectively taken up by
muscle cells and that it reduced the concentration of
glycogen in those cases. And the dosage experience with
Gaucher disease, in conjunction with the known half-life
of GAA in the body, provided a sound basis for belief that



   5     Genzyme argues in passing that Dr. Pastores’s
testimony was “hindsight-infected,” based on an answer
he gave in the course of his deposition. We do not discern
any hindsight bias in his testimony. He testified that he
was asked to review the state of the art in the early to
mid-1990s, and in particular “what I understood was
available in the general medical literature. And I looked
at it also within the context of what I would have under-
stood then the body of literature was telling me based on
my knowledge and experience at that time.” He was then
asked, “Did you apply all of the knowledge you have
obtained up to the present day in conducting that analy-
sis?” to which he answered, “I would think so. I don’t
know how one would separate your current body of
knowledge from what your knowledge was way back in
time.” In context, it appears that in answering that
question, Dr. Pastores was simply saying that in seeking
to determine what was known in the mid-1990s, he
brought to that inquiry his current knowledge and experi-
ence. That is not hindsight; it is simply the use of one’s
current knowledge to determine, as well as possible, what
the state of the art was at some point in the past.
22             GENZYME THERAPEUTIC PRODUCTS v. BIOMARIN
                                       PHARMACEUTICAL


a dosage interval of one to two weeks would be effective.
In sum, there was little left to do but to confirm that the
strategy suggested by the various prior art references
would work. Substantial evidence therefore supports the
Board’s finding that a person of ordinary skill would have
had a reasonable expectation of success based on the
combinations of references set forth in the institution
decisions.
                      AFFIRMED
