Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-15-01720/USCOURTS-ca13-15-01720-0/pdf.json

Parties Involved:
Biomarin Pharmaceutical Inc.
Appellee
Genzyme Therapeutic Products Limited Partnership
Appellant

Document Text:

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 Trademark 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. 

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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 Partnership (“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 Disease” 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. 

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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 glycogen buildup in the skeletal muscles, but only rarely do 

they develop the cardiac symptoms associated with earlyonset Pompe’s disease.

Following the discovery that Pompe’s disease is associated 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, however, 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 

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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 development of a means to manufacture human GAA modified 

to include M-6-P. Animals such as mice and other mammals could have their genomes altered so that they would 

produce human GAA that could be extracted by researchers.

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 University’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; 

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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 combinations 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 arguments 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. Clinical 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 Metabolic Correction of Pompe Disease by Enzyme Therapy in 

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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 biweekly dosing schedule, and that the claimed dosing 

schedule would have been arrived at by routine optimization. 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 granting applications for orphan drug designation for enzyme 

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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 regarding 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 violated 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. BerkTek LLC, 805 F.3d 1064, 1080 (Fed. Cir. 2015) (quoting 

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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 combinations 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 decisions 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 examination 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.

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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 misunderstanding 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 allegation 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.

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ments, and the PTO simply decides whether the challenger 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 ultimately resolved, at that hearing.” Pub. Serv. Comm’n of 

Ky. v. FERC, 397 F.3d 1004, 1012 (D.C. Cir. 2005) (Roberts, 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 data with GAA here would require Genzyme to analyze 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 Petitioner itself did not include in its own suggested 

grounds.

Biomarin then addressed both of the in vivo references 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 releCase: 15-1720 Document: 67-2 Page: 10 Filed: 06/14/2016
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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 disputed 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 references 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] advocating 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 expectation 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 developed” at the time of the inventions, which is exactly what 

Genzyme’s counsel conceded the Board could properly do. 

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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 reference or Kikuchi, which is the Japanese quail, we 

submit, Your Honors, cannot, absolutely cannot be 

part of the reasonable expectation of success analysis. 

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 instituting trial on certain references, bring in additional 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 opportunity 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 procedural 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 confirmed 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. 

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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 challenge 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 decisions 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 mentioned 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 institution decisions, requiring something approaching word-forword parity between the institution and final written 

decisions. 

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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 consider 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 legitimately 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 references 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.

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Claim 1 of the ’410 patent reads as follows, with the 

whereby clause in italics: 

A method of treating a human patient with Pompe’s disease, comprising intravenously administering biweekly to the patient a therapeutically 

effective amount of human acid alpha glucosidase, 

whereby the concentration of accumulated glycogen in the patient is reduced and/or further accumulation 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 arrested” 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: “intravenously 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 intravenously administering biweekly to the patient a 

therapeutically effective amount of human GAA 

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cumulated glycogen in the patient and/or the arrest of further accumulation of glycogen. Thus, 

the recited whereby clause defines what is 

achieved from the administration of “a therapeutically effective amount of human acid alpha glucosidase” 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 administering 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 accumulated 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 increased life-span. The whereby clause merely requires 

the reduction or arrest of glycogen in the patient.” Because 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.

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Genzyme’s references to portions of the common specification 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 glucosidase 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 construction. 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 perhaps in heart.

Neither passage includes any suggestion that a decrease 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 

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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 invention 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 interpretation of the clause “whereby the concentration of accumulated 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 

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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 therapeutic effects and reduced glycogen concentrations somewhere 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 analysis. 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 person 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. 

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Genzyme claims in particular that the testimony of Biomarin’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 testifying 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. Pastores 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 regarding 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 replacement therapy for Pompe disease would be required 

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istration of GAA to patients would be immediately understood upon reading [Reuser].”).5

Finally, contrary to Genzyme’s contention, Dr. Pastores’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 reducing 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 understood 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 analysis?” 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 experience. 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. 

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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

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