BioMarin Pharmaceutical Inc.v.Genzyme Therapeutic Products Limited Partnership

Patent Trial and Appeal Board

Feb 23, 2015

12012003 (P.T.A.B. Feb. 23, 2015)

Trials@uspto.gov Paper 79
Tel: 571-272-7822 Entered: February 23, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
_______________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________
BIOMARIN PHARMACEUTICAL INC.,
Petitioner,
v.
GENZYME THERAPEUTIC PRODUCTS LIMITED PARTNERSHIP,
Patent Owner.
____________

Case IPR2013-00537
Patent 7,655,226
____________

Before LORA M. GREEN, JACQUELINE WRIGHT BONILLA, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

SNEDDEN, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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I. INTRODUCTION
BioMarin Pharmaceutical Inc. (“Petitioner”) filed a Petition to
institute an inter partes review of claims 1 and 36 (Paper 1, “Pet.”) of
Patent No. 7,655,226 B2 (Ex. 1065, “the ’226 patent”). We instituted trial
for the challenged claims on the following grounds of unpatentability
asserted by Petitioner:
Reference(s) Basis Claims challenged
Duke Press Release,
1
Reuser,
2

and Van Hove
3

§ 103(a) 1 and 3
Duke Press Release, Reuser,
Barton,
4
and Van der Ploeg
5

§ 103(a) 4–6
Decision to Institute (Paper 9, “Dec.”) 9.
After institution, the Board of Trustees of Genzyme Therapeutic
Products Limited Partnership (“Patent Owner”), filed its Patent Owner’s
Response (“Resp.”). Paper 40. Petitioner filed a Reply (Paper 49,
“Reply.”). Patent Owner did not file a motion to amend claims.
Petitioner relies upon the declarations of Dr. Gregory M. Pastores

1
Duke University, “Duke Obtains FDA Designation for Pompe Disease
Therapy”, press release dated September 2, 1997, 2 pages (Ex. 1002).
2
Reuser et al., WO 97/05771, published Feb. 20, 1997 (Ex. 1005).
3
Van Hove et al., “Purification of recombinant human precursor acid α-
glucosidase,” 43(3) BIOCHEM. MOL. BIOL. INT. 613-23 (1997) (Ex. 1012).
4
Barton et al., “Replacement Therapy for Inherited Enzyme Deficiency –
Macrophage-Targeted Glucocerebrosidase for Gaucher’s Disease,” 324 N.
ENG. J. MED. 1464-1470 (1991) (Ex. 1004).
5
Van der Ploeg et al., “Receptor-Mediated Uptake of Acid α-Glucosidase
Corrects Lysosomal Glycogen Storage in Cultured Skeletal Muscle,” 24(1)
PEDIATRIC RESEARCH 90-94 (1988) (Ex. 1032).
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(“Pastores Declaration”) (Ex. 1030) and Dr. Matthew Croughan (“Croughan
Declaration”) (Ex. 1033) in support of its Petition. Patent Owner relies upon
the declaration of William Canfield, M.D., Ph.D. (“Canfield Declaration”)
(Ex. 2041) in support of its Response.
Petitioner filed a Motion to Exclude certain of Patent Owner’s
evidence. Paper 53. Patent Owner filed an Opposition (Paper 62), and
Petitioner filed a Reply (Paper 64).
Patent Owner filed a Motion to Exclude certain of Petitioner’s
evidence. Paper 55. Petitioner filed an Opposition (Paper 58), and Patent
Owner filed a Reply (Paper 65).
Oral argument was conducted on October 3, 2014. A transcript is
entered as Paper 77 (“Tr.”).
This Final Written Decision addresses challenges to the patentability
of claims 1 and 3–6. Petitioner has shown by a preponderance of the
evidence that claims 1 and 3–6 of the ’226 patent are unpatentable.
Petitioner’s Motion to Exclude is dismissed as moot. Patent Owner’s
Motion to Exclude is denied-in-part and dismissed-in-part.
A. Related Matters
The parties represent that there are no related matters. Pet. 1; Paper 7;
Paper 35.
On the same day Petitioner filed its Petition in this proceeding,
however, it also filed two other Petitions seeking inter partes review of U.S.
Patent No. 7,056,712 (IPR2013-00535) and U.S. Patent No. 7,351,410
(IPR2013-00534), both of which are related to methods of treating Pompe
disease
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B. The ’226 patent (Ex. 1065)
The technology of the patent is enzyme-replacement therapy for
patients with Pompe disease, which is caused by deficiency of the lysosomal
enzyme acid α-glucosidase (“GAA”). Ex. 1065, 1:18–2:6. The patent
discloses a method for treating Pompe disease comprising administering to
the patient a therapeutically effective amount of human GAA. Id. at 2:30–
43. The amount is preferably at least 10 mg of enzyme per kilogram of body
weight, which may be administered weekly or two weeks apart. Id. at 14:1–
18. The claimed treatment results in the arrest or reduction of clinical and
biochemical characteristics of Pompe disease, which include, generally, an
accumulation of glycogen in various tissues such as heart and skeletal
muscle, and more specifically, hypertrophic cardiomyopathy. Id. at 13:50–
15:43.
C. The Claim
Claims 1 and 6 are the independent claims of the ’226 patent,
and are reproduced below:

1. A method of treating a human patient with Pompe’s disease,
comprising administering intravenously 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.

6. 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 hypertrophic cardiomyopathy in the
patient is reduced and/or arrested.

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Claims 3–5 depend from claim 1.
II. DISCUSSION
A. Claim Interpretation
In an inter partes review, claim terms in an unexpired patent are
interpreted according to their broadest reasonable construction in light of the
specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14,
2012). Claim terms are given their ordinary and customary meaning, as
would be understood by one of ordinary skill in the art in the context of the
entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed.
Cir. 2007). Any special definition for a claim term must be set forth in the
specification with reasonable clarity, deliberateness, and precision. In re
Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
We expressly interpret below only those claim terms that require
analysis to resolve arguments related to the patentability of the challenged
claims.
1. Construction of the phrase “whereby the concentration of
accumulated glycogen in the patient is reduced and/or
further accumulation of glycogen is arrested”
We construe claim 1 to be directed to a method of treating a human
patient with Pompe disease. 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 results in the reduction in
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the concentration of accumulated 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.
As to what is required in order to achieve the result defined by the
whereby clause, Patent Owner proposes a construction that would
necessarily include “lysosomal glycogen in the skeletal muscle” within the
meaning of the phrase “glycogen in a patient.” Resp. 12–16. Patent Owner
argues that such a construction is necessary because skeletal muscle must be
targeted in order to effectively treat Pompe disease. Id. (citing Ex 1162,
62:5–22). Patent Owner further directs our attention to a section of the ’226
patent that describes complications and treatment for both the infantile and
adult forms of Pompe disease. Id. (citing Ex 1065, 15:22–39). For the
infantile form, “lysosomal glycogen storage is observed in various tissues,
and is most pronounced in heart and skeletal muscle.” Ex. 1065, 15:26–28.
For the adult form, “skeletal muscle weakness is the major problem;
cardiomegaly, hepatomegaly, and macroglossia can be seen, but are rare.”
Id. at 15:48–50.
Petitioner notes that the whereby clause of claim 1 was added during
the prosecution of the claim in the parent application, which issued as U.S.
Patent No. 7,351,410 (Ex. 1001).
6
Reply, 1–2 (citing Ex. 1022, 3). The
paper that introduces the claim language directs the reader to where written
description support for the addition of the whereby clause may be found in

6
The ’226 patent is a continuation of US 7,351,410. The claim of US
7,351,410 is challenged by the Petitioner in IPR2013-000534.
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the Specification. Ex. 1022, 3. The passage of the Specification cited by the
inventor during prosecution for support of the amendment provides as
follows:
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. No effects were observed
in skeletal muscle tissues with regard to total glycogen. . . .
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. One animal showed increased
activity in muscles, although there was no significant decrease
of glycogen in muscle.
Ex. 1001, 35:1–3, 31–34. That passage of the Specification summarizes an
in vivo experiment that resulted in “a marked decrease of total cellular
glycogen was observed in both heart and liver,” but not in skeletal muscle
tissue.
After consideration of the arguments presented by the parties, we do
not find that the record supports Patent Owner’s construction that would
necessarily include “lysosomal glycogen in the skeletal muscle” within the
meaning of the phrase “glycogen in a patient.” We note that 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. In that regard, the evidence highlighted by
Petitioner supports a conclusion that the whereby clause is reasonably
interpreted to encompass the scenario where the reduction or arrest of
glycogen is observed solely in the heart or liver. Accordingly, we conclude
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that the broadest reasonable interpretation of the phrase “glycogen in a
patient” does not necessarily include “lysosomal glycogen in the skeletal
muscle.” Rather, the broadest reasonable interpretation of the phrase
“glycogen in a patient,” as would be understood by the ordinary artisan in
light of the Specification, encompasses lysosomal glycogen in the skeletal
muscle, heart, or liver.
B. The Prior Art
1. Summary of Duke Press Release (Ex. 1002)
The Duke Press Release reports the U.S. Food and Drug
Administration (FDA) approval of Duke University’s application for Orphan
Drug Designation for a new therapy for Pompe disease. Ex. 1002; Ex. 1182.
The Duke Press Release describes Pompe disease as an inherited deficiency
of the enzyme acid alpha glucosidase and provides a discussion of how the
therapy, developed at Duke, “will be tested in infants with the most severe
symptoms and for whom the disease is fatal.” Id. With regard to how the
therapy would be tested, the Duke Press Release provides as follows:
The Duke clinical trial will test a genetically engineered form of
the enzyme, expressed in a cell line developed in the laboratory
of Dr. Y. T. Chen, chief of the Division of Medical Genetics in
the department of pediatrics. Initially, the drug will be tested in
a small number of Pompe disease infants to evaluate the safety
and efficacy of the recombinant enzyme treatment. . . .
Chen, who will lead the clinical trial, anticipates that
recombinant enzyme injected into infants will be taken up by
their muscle cells and restore normal glycogen levels. This
treatment, known as an enzyme replacement therapy, would be
required for the rest of these patients’ lives.
He said he hopes to expand the treatment to additional Pompe
disease patients as safety and efficacy are demonstrated and
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supplies of the enzyme are available. Chen’s team at Duke has
spent more than five years developing the cell line that
produces the recombinant drug.
Id.
2. Summary of Reuser (Ex. 1005)
Reuser discloses the production of phosphorylated lysosomal proteins
using transgenic nonhuman mammals for use in enzyme replacement
therapy as treatment for lysosomal enzyme deficiencies. Ex. 1005, Abstract,
18:12–14. Reuser expressly discloses Pompe disease
7
as such a lysosomal
enzyme deficiency. Id. at 2:13–29. With regard to the treatment of Pompe
disease, Reuser discloses as follows:
For lysosomal diseases other than Gaucher disease the evidence
suggests that enzyme therapy is most effective when the
enzyme being administered is phosphorylated at the 6' position
of a mannose side chain group. For [Pompe disease] this has
been tested by intravenously administering purified acid α-
glucosidase in phosphorylated and unphosphorylated forms to
mice and analyzing uptake in muscle tissue. The highest uptake
was obtained when mannose 6-phosphate-containing enzyme
was used (Van der Ploeg et al., Pediat. Res. 28, 344-347 (1990);
J. Clin. Invest. 87, 513-518 (1991)).
8

Id. at 2:35–3:10 (emphasis added).
Reuser expressly identifies GAA as an enzyme useful for production
in the disclosed transgenic animal systems. Id. at 4:36–37.
9
Specific to

7
Also referred to as Glycogen Storage Disease Type II (GSD II).
8
Citations provided by Petitioner as Ex. 1051 and Ex. 1009, respectively.
9
Reuser also discloses the use of a stable eukaryotic cell line transfected
with the acid α-glucosidase gene for the purposes of producing the human
acid α-glucosidase protein. Id. at 3:15–18.
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human GAA, Reuser discloses a map of several transgenes containing GAA
cDNA
10
or genomic DNA,
11
and details experiments in which a mannose 6-
phosphate containing human GAA was produced in the milk of transgenic
mice. Id. at 21:14–28:24. Reuser discloses that the main forms of GAA are
the 110/100 kDa precursor, a 95 kDa intermediate, and 76 kDa and 70 kDa
mature forms. Id. at 9:15–17, 28:19–24.
Reuser contemplates pharmaceutical compositions for use in enzyme
replacement therapeutic procedures, and specifically pharmaceutical
compositions for intravenous administration. Id. at 18:36–20:28.
Furthermore, Reuser provides general guidance with regard to dosage and
dosage regimen. Specifically, Reuser provides as follows:
For individuals at risk of lysosomal enzyme deficiency disease,
the pharmaceutical composition [sic] are administered
prophylactically in an amount sufficient to either prevent or
inhibit accumulation of metabolite. An amount adequate to
accomplish this is defined as a “therapeutically-” or
“prophylactically-effective dose.” Such effective dosages will
depend on the severity of the condition and on the general state
of the patient’s health, but will generally range from about 0.1
to 10 mg of purified enzyme per kilogram of body weight.
Id. In the case of Pompe disease, glycogen is the metabolite. Id. at 2:13–29.
With regard to dose, Reuser discloses as follows:
For therapeutic applications, the pharmaceutical compositions
are administered to a patient suffering from established disease
in an amount sufficient to reduce the concentration of
accumulated metabolite and/or prevent or arrest further
accumulation of metabolite. For individuals at risk of
lysosomal enzyme deficiency disease, the pharmaceutical

10
Ex. 1005, Fig. 1.
11
Ex. 1005, Fig. 2.
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composition are administered prophylactically in an amount
sufficient to either prevent or inhibit accumulation of
metabolite. An amount adequate to accomplish this is defined
as a “therapeutically-” or “prophylactically-effective dose.”
Such effective dosages will depend on the severity of the
condition and on the general state of the patient's health, but
will generally range from about 0.1 to 10 mg of purified
enzyme per kilogram of body weight.
Id. at 20:15–28.
3. Summary of Van Hove (Ex. 1012)
Van Hove discloses a purification of large quantities of recombinant
precursor GAA for the purposes of enzyme replacement therapy in Pompe
disease. Ex. 1012, 613. In particular, Van Hove provides as follows:
Large quantities of recombinant enzyme are required for in vivo
experimentation in the animal model, and eventually for use in
medicine. A method amenable to scale up is now needed to
efficiently purify recombinant precursor enzyme from tissue
culture medium. The preferred method should result in a high
level of purification with a considerable yield, while preserving
the mannose-6-phosphorylation of the protein required for
efficient lysosomal targeting. It should be highly reproducible,
avoid toxic buffers, preferably use commercially available gels
on standard equipment. We aimed to develop such a
purification method as described below.
Id. at 614. Precursor GAA is the 110 kDa form of the enzyme. Id. at 617.
4. Summary of Barton (Ex. 1004)
Barton describes a clinical trial in which patients with Gaucher
Disease
12
were administered glucocerebrosidase for enzyme replacement

12
Gaucher disease is a lysosomal storage disorder caused by an
insufficiency of glucocerebrosidase. Ex. 1004, 1464.
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therapy on a biweekly intravenous administration schedule. Ex. 1004,
Abstract.
5. Summary of Van der Ploeg (Ex. 1032)
Van der Ploeg describes an in vitro study using cultured skeletal
muscle cells from a patient with Pompe disease. Ex 1032, Abstract.
Cultured skeletal muscle cells were incubated with GAA containing
mannose-6-phosphate purified from human urine. Id. Van der Ploeg reports
that the “[e]fficient uptake of acid α-glucosidase was achieved by using the
mannose-phosphate receptor on the cell surface as a target for an enzyme
precursor with phosphorylated high-mannose types carbohydrate chains
purified from human urine.” Id. The enzyme was reported to have a half-
life of 6–9 days. Id. at 91.
C. Obviousness of Original Claims
1. Obviousness of Claims 1 and 3 over the Combination of
Duke Press Release, Reuser, and Van Hove
Petitioner contends that claims 1 and 3 are obvious over the
combination of Duke Press Release 1997, Reuser, and Van Hove. Pet. 41–
44. In our Decision to Institute, we found that the combination of Duke
Press Release, Reuser, and Van Hove disclosed each element of claims 1
and 3. Dec. 7–8. Patent Owner does not contend that the combination of
references fail to address each element of the claims. Rather, Patent Owner
contends that a person of ordinary skill in the art would not have had a
reasonable expectation of successfully reducing or arresting further
accumulation of glycogen in a patient’s muscle cells. Resp. 35–40.
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We are not persuaded. First, Patent Owner’s argument is premised on
a claim construction that would require the phrase “glycogen in the patient”
in claim 1 necessarily to include lysosomal glycogen in skeletal muscle. Id.
at 14–16. As discussed above in Section II.A.1, however, we do not adopt
Patent Owner’s proposed claim construction in this regard. As such, we do
not understand Patent Owner’s arguments with regard to a reasonable
expectation of success to be applicable to the question of whether or not a
person of ordinary skill in the art would have had a reasonable expectation
of successfully reducing or arresting further accumulation of glycogen in a
patient’s other tissues such as heart and liver.
To the extent that Patent Owner’s arguments are applicable under our
claim construction, we note that a reasonable expectation of success does not
require absolute predictability. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir.
1988). The fact that a suggested dose (as taught in Reuser) and dosing
schedule had not been established yet as safe and effective in human clinical
trials at the time of invention does not demand a conclusion of
nonobviousness. While we recognize that there would have been some
degree of unpredictability for the successful treatment of Pompe disease
from the administration of GAA, the preponderance of evidence of record
indicates that 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 December 7, 1998, the field related to the development of an
enzyme replacement therapy for the treatment of Pompe disease had
developed to the point at which 1) it was recognized that GAA must be post-
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translationally modified with mannose-6-phosphate to promote cellular
uptake through a mannose-6-phosphate receptor in vitro;
13
2) in vivo studies
had been performed in which GAA containing mannose-6-phosphate was
intravenously administered to mice
14
and Japanese Quail;
15
3) it was known
that mannose 6-phosphate containing human GAA could be produced in the
milk of transgenic animals;
16
and 4) the FDA was granting applications for
orphan drug designation for enzyme replacement therapy for Pompe disease
using recombinant GAA.
17
Thus, this is not a case where the prior art
teaches merely to pursue a “general approach that seemed to be a promising
field of experimentation” or “gave only general guidance as to the particular
form of the claimed invention or how to achieve it.” O’Farrell, 853 F.2d at
903; Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1167 (Fed. Cir. 2006).

13
Ex. 1005 at 2:35–3:10.
14
Ex. 1009 presents data suggesting that GAA containing mannose 6-
phosphate is taken up in the skeletal muscle and heart of mice after
intravenous administration.
15
Ex. 1007 presents data suggesting that the intravenous administration of
human GAA to GAA-deficient Japanese reduced glycogen levels in the
heart, liver and muscle and produced muscle improvement. Ex. 1007,
Abstract. The authors conclude that “[t]hese data also suggest enzyme
replacement with recombinant human GAA is a promising therapy for
human Pompe disease.” Id.
16
Ex. 1005 at 21:14–28:24.
17
Ex. 1002; Ex. 1182. We further note that the FDA application process
requires an applicant to provide “enough information to establish a
medically plausible basis for expecting the drug to be effective in the rare
disease.” Ex. 1029. Furthermore, as stated by Dr. Canfield, “a [skilled
artisan] would know, and would understand from Ex 1002, that the purpose
of the proposed clinical trial would be to evaluate whether the administered
enzyme was safe and effective in humans and to determine the appropriate
dose.” Ex 2041 ¶ 81 (citing Ex 1002, 2).
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Finally, we note that the absence in the record of evidence identifying
a difference between the prior art and the subject matter of the claims further
persuades us that no more than routine processes were needed to achieve the
results recited in claim 1. For example, the absence of any discussion with
regard to unexpected or superior results associated with any feature of
claims 1 or 3 further persuades us that the claimed subject matter was a
product of routine clinical trial processes. That is, the prior art brought the
subject matter of the claims within the technical grasp of a person of
ordinary skill in the art rendering it obvious, absent objective evidence of
nonobviousness. Pfizer, 480 F.3d at 1344 (“[O]bviousness cannot be
avoided simply by a showing of some degree of unpredictability in the art so
long as there was a reasonable probability of success.”).
In view of the above, we conclude that a person of ordinary skill in
the art would have had a reasonable expectation of success at the time the
invention was made. What remained was the execution of human clinical
trials, arguably “routine” to a person of ordinary skill in the art, to verify the
expectation that a specific dosage (within a previously suggested dosage
range) and corresponding dosage regimen would have been safe and
effective. Cf. Pfizer, 480 F.3d at 1367 (“[E]xperiments used by Pfizer’s
scientists to verify the physicochemical characteristics of each salt are not
equivalent to the trial and error procedures often employed to discover a new
compound where the prior art gave no motivation or suggestion to make the
new compound nor a reasonable expectation of success.”); Velander v.
Garner, 348 F.3d 1359, 1368 (Fed. Cir. 2003) (stating that one skilled in the
art would view variability in producing fibrinogen in transgenic mammals as
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evidence that “expense, time and effort” would be involved did not equate to
a conclusion that success was unlikely).
2. Obviousness of Claims 4–6 over the Combination of
Duke Press Release, Reuser, Barton, and Van der Ploeg
a. Obviousness of the recited dose and dosing schedule
Claim 4 depends directly from claim 1 and requires weekly
administration of GAA. Independent claim 6 differs from claim 1, inter
alia, in that the method of claim 6 requires biweekly administration of the
enzyme. Petitioner relies on Barton (Ex. 1004) and Van der Ploeg (Ex.
1032) to reach the “weekly” and “biweekly” elements of claims 4 and 6.
Claim 5 depends from claim 4 and requires that the therapeutically
effective amount of human GAA is at least 10 mg/kg body weight of the
patient. Petitioner relies on Reuser to meet that limitation, as Reuser
discloses a dosage range from 0.1 to 10 mg/kg of purified enzyme per
kilogram of body weight. Pet. 47 (citing Ex. 1005, 20:27–28).
Petitioner argues that “[d]etermination of how much and how often to
administer the enzyme . . . is a matter of routine optimization” and that
“[t]he ’226 patent is claiming the result of a typical drug development
pathway based on previous testing, such as in vitro and in vivo animal model
studies.” Pet. 4–5; see also, id. at 9 (“All the inventors of the van Bree ’226
patent did was to follow a typical drug development pathway laid out in the
prior art, where the use of GAA to successfully treat Pompe disease in a
human patient was a predictable outcome based on previous in vitro and in
vivo studies.”).
Patent Owner makes several arguments related to the dose and dosing
schedule elements of the claims. First, Patent Owner contends that a person
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of ordinary skill in the art would not have had motivation to combine Barton
with Duke Press Release, Reuser, and Van der Ploeg due to the significant
differences between Gaucher disease and Pompe disease. Resp. 41.
Second, Patent Owner argues that reliance on Van der Ploeg is flawed
because “mere knowledge of the target receptor plus in vitro data indicating
uptake via that receptor” is insufficient to predict success and further notes
particular complications that arise when transitioning from an in vitro model
to an in vivo model. Id. at 23–24.
Patent Owners remaining arguments are directed to the predictability
of clinical trials in general. Id. at 44–46. Additionally, Patent Owner argues
that the grant of orphan drug designation disclosed in Duke Press Release
would not be understood by a person of ordinary skill in the art to mean that
the therapy had a reasonable expectation to be effective for its intended use.
Id. at 3235. Patent Owner adds that that the standards used by the FDA to
grant of orphan drug designation is low and ultimately “unrelated to the
standard regulatory requirements for marketing approval or authorization to
begin clinical trials.” Id. at 33–34 (citing Ex 2043 ¶¶ 24, 27–28, 42–43; Ex
2023; Ex 2027, 368; Ex 2006; Ex. 2036, 520 (Fig. 1a)).
After consideration of the evidence and arguments summarized above,
we find that Petitioner has the better position. We recognize that the record
shows that human clinical trials were not initiated prior to December 7,
1998, the priority date of the ’226 patent. The record shows also that an
ordinary artisan would have understood that to treat Pompe disease
effectively using GAA, sufficient quantities of enzyme would have to reach
the patient’s muscle cells, which could potentially require high doses that
could introduce safety and efficacy hurdles resolvable only with human
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clinical trials.
18
Resp. 55–57 (citing Ex 2041 ¶ 105; Ex 2042 ¶¶ 67-68, 86,
99, 121-122; Ex 1162, 63:14-64:13, 67:2-11; Ex. 1030 ¶ 75; Ex 1011).
Accordingly, a person of ordinary skill in the art could not have predicted
with absolute certainty that a safe and effective dosing regimen for using
GAA in a method of treating Pompe disease could be achieved.
19

Despite this recognized difficultly, however, we are persuaded that,
under the facts of this case, a person of ordinary skill would have been
motivated to pursue the clinical development of the therapy disclosed in
Reuser. See Section II.B.2 for summary of Rueser. Given that Reuser
discloses a pharmaceutical composition containing GAA, a dose range that
includes the recited dose range of 1–10 mg of enzyme per kilogram of body
weight of the individual, a method of making the composition using
transgenic animals, and a method of using the composition in an enzyme
replacement therapy for the treatment of Pompe disease, what remained to

18
As discussed in Section II.A.1, we do not interpret the claim to necessarily
require the reduction or arrest of stored glycogen in skeletal muscle, but
understand that achieving such a result is important for the complete
treatment of both forms of Pompe disease. Nonetheless, we include the
concept of reduction or arrest of stored glycogen in skeletal muscle in our
analysis as we do not find its inclusion to hinder our analysis. That is,
whether we include or exclude the result of reduction or arrest of stored
glycogen in skeletal muscle within the scope of the claims, our conclusions
remain the same, albeit achievement of the reduction of glycogen in the
heart and liver appear to be less controversial, and thus the evidence
suggests there was a greater expectation of success with regard to these
tissues.
19
We recognize that “absolute predictability of success” is not the criterion
“[f]or obviousness under § 103, all that is required is a reasonable
expectation of success.” O’Farrell, 853 F.2d at 903.
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be achieved to arrive at the claimed subject matter was the selection of a
specific dose and dosing schedule for a treatment regimen. Pet. 4–5.
For example, in 1973, an infant with Pompe disease was intravenously
administered GAA derived from human placenta. Resp. 1–2; Ex. 1010; Ex.
2041 ¶ 31. That patient died. Id. Since that time, however, it was
discovered that “mannose-6-phosphate receptors are present at the cell
surface of myotubes and mediate efficient uptake of lysosomal enzymes
containing carbohydrate chains with mannose-6-phosphate residues.” Ex.
1032, 90 (citations omitted). The record suggests that it was this discovery,
combined with the ability to produce large quantity of enzyme using
recombinant technology, which led the field toward human clinical trials.
Ex. 1030 ¶ 29 (citing Ex. 1006). Patent Owner does not direct us
sufficiently to hurdles that needed to be overcome by the inventors of the
’226 patent to achieve the claimed subject matter.
Thus, our decision rests on the answer to the question of whether the
dose and dosing schedule recited in the claims were nothing more than the
result of routine optimization that would have been obvious to one of
ordinary skill in the art. We conclude that a preponderance of the evidence
establishes that the selection of the dose and dosing schedule would have
been a routine optimization of the therapy outlined in Reuser (Ex. 1005,
18:36–20:28), which would have been achievable through the use of
standard clinical trial procedures (Ex. 1030 ¶¶ 7490). Stated differently,
the subject matter of the claims was disclosed in the prior art and the
experimentation needed to confirm the successful application of the method
disclosed in the prior art was “‘nothing more than the routine’ application of
a well-known problem-solving strategy, . . . ‘the work of a skilled [artisan],
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not of an inventor.’” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1368 (Fed.
Cir. 2007) (quoting Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809
(Fed. Cir. 1989); DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H.
Patrick Co., 464 F.3d 1356, 1371 (Fed. Cir. 2006); see also In re Aller, 220
F.2d 454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.”); In re Boesch, 617 F.2d 272,
276 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective
variable in a known process is ordinarily within the skill of the art.”). The
motivation to optimize the therapy disclosed in Reuser “flows from the
‘normal desire of scientists or artisans to improve upon what is already
generally known.’” Pfizer, 480 F.3d at 1348 (quoting In re Peterson, 315
F.3d 1325, 1330 (Fed. Cir. 2003)).
We further note that this is not a case where there were “numerous
parameters” to try. Pfizer, 480 F.3d at 1364 (citing Medichem, 437 F.3d at
1165 (“to have a reasonable expectation of success, one must be motivated
to do more than merely to vary all parameters or try each of numerous
possible choices until one possibly arrived at a successful result, where the
prior art gave either no indication of which parameters were critical or no
direction as to which of many possible choices is likely to be successful.”)
(internal quotations omitted)). Rather, we are persuaded by Dr. Pastores’
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 (Ex. 1030 ¶ 38), would have been
informed by the clinical experience with Gaucher disease (id. at ¶ 74 (citing
Ex. 1004, 1056, 1057)), and that, because “it was well known that any
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21
enzyme replacement therapy for Pompe disease would be required for the
rest of a patient’s life, . . . repeated spaced administration of GAA to patients
would be immediately understood upon reading [Reuser]” (id. at ¶ 58).
b. Reducing or Arresting Hypertrophic Cardiomyopathy
Independent claim 6 further differs from claim 1, inter alia, in that the
method of claim 6 requires hypertrophic cardiomyopathy in the patient to be
reduced and/or arrested, as oppose to the concentration of accumulated
glycogen in the patient to be reduced and/or arrested. The preponderance of
evidence shows that the concentration of accumulated glycogen in the
patient is related to the condition of hypertrophic cardiomyopathy. See also,
Ex 2041, ¶ 24 (“[Pompe disease] patients develop accumulation of glycogen
in the heart and skeletal muscle, which results in progressive deterioration of
the heart muscle (cardiomyopathy) and generalized muscle weakness”). As
such, we conclude that if the concentration of accumulated glycogen in the
patient is arrested, for example, then the condition caused by this
accumulation is also necessarily arrested, at least in some fashion.
Accordingly, we conclude that independent claim 6 is unpatentable for the
reasons set forth above with regard to claim 1.
3. Secondary Considerations
As to secondary considerations, we note that factual inquiries for an
obviousness determination include secondary considerations based on
evaluation and crediting of objective evidence of nonobviousness. Graham
v. John Deere Co., 383 U.S. 1, 17 (1966). Notwithstanding what the
teachings of the prior art would have suggested to one with ordinary skill in
the art at the time of the invention, the totality of the evidence submitted,
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including objective evidence of nonobviousness, may lead to a conclusion
that the claimed invention would not have been obvious to one with ordinary
skill in the art. In re Piasecki, 745 F.2d 1468, 1471–1472 (Fed. Cir. 1984).
However, such a conclusion requires the finding of a nexus to
establish that the evidence relied upon traces its basis to a novel element in
the claim and not to something in the prior art. Institut Pasteur & Universite
Pierre et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013).
All types of objective evidence of nonobviousness must be shown to have
nexus. In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (nexus
generally); In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (commercial
success); Rambus Inc. v. Rea, 731 F.3d 1248, 1256 (Fed. Cir. 2013) (long-
felt need); Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318, 1328 (Fed.
Cir. 2008) (praise); Stamps.com Inc. v. Endicia, Inc., 437 F. App’x 897, 905
(Fed. Cir. 2011) (skepticism).
Patent Owner argues that several lines of objective evidence (or
“secondary considerations”) demonstrate the non-obviousness of the
challenged claims. Resp. 56–60. In particular, Patent Owner argues long-
felt but unmet need, skepticism, praise, and commercial success. Id. Patent
Owner’s arguments with regard to each of the secondary considerations,
however, fail to establish a nexus between any feature of the claims and any
asserted objective evidence of non-obviousness. Rather, the discussion of
secondary considerations relates to the merits of the therapeutic
compositions of GAA brought to market by Patent Owner. Such
compositions, however, were known in the art. See discussion in Sections
II.C.1 and II.C.2. Accordingly, the objective evidence does not persuade us
that claim 1 and 36 are non-obvious.
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4. Conclusion
In view of the above, we conclude that Petitioner has demonstrated
the unpatentability of claims 1 and 36 by a preponderance of the evidence.
III. MOTIONS TO EXCLUDE
A. PETITIONER’S MOTION TO EXCLUDE
Petitioner seeks to exclude paragraphs 61, 62, 63, and 66 of the
Canfield Declaration, Ex. 2041, because the testimony allegedly is based on
insufficient facts or data. Paper 55. Because we do not rely on any of
paragraphs 61, 62, 63, and 66 of Ex. 2041 to reach the final decision, we
dismiss Petitioner’s motion as moot.
B. PATENT OWNER’S MOTION TO EXCLUDE
1. Ex. 1002
Patent Owner seeks to exclude Ex. 1002 as not properly authenticated
under Federal Rules of Evidence (“FRE”) 901–902. Paper 55, 2–5. Patent
Owner further seeks to exclude Ex. 1002 as inadmissible hearsay under FRE
802. Id. at 6–7. Patent Owner seeks also to exclude Ex. 1002 under FRE
402 and 403 because it cannot qualify as a printed publication and thus
“Exhibit 1002 is irrelevant (FRE 402), can serve only to prejudice Genzyme,
[and] is confusing in this context (FRE 403) as it cannot have any bearing on
the issue of validity.” Id. at 7–8.
Federal Rule of Evidence 901(a) states that the authentication
requirement is satisfied if the proponent presents “evidence sufficient to
support a finding that the item is what the proponent claims it is.” Here,
Petitioner has presented evidence to authenticate Ex. 1002. That evidence
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includes an article from the Herald-Sun (Durham, NC) (Ex. 1144)
20

published September 3, 1997,
21
discussing the content of the Duke Press
Release, and the affidavit of Ms. Beth Nichol, an Investigative Associate at
Nichol Investigative Services, LLC, who obtained a copy of the original
Duke Press Release from a Duke University library having a Duke
University trade inscription (Ex 1182, Ex C). Under FRE 902(6)(7),
22
Ex.
1144 and Ex. 1182, Ex. C are self-authenticating. Based on the evidence
before us, we determine that Ex. 1002 has been authenticated under FRE
901(b)(1), 901(b)(4), 902(6), and 902(7) to warrant its admissibility. The
fact that the Duke Press Release was reported in the Herald-Sun newspaper
establishes the Duke Press Release as a printed publication.
We further note that Patent Owner fails to identify specifically the
portions of Ex. 1002 that it believes to be prejudicial and confusing, or why
we would be unable to weigh this evidence without prejudice or confusion.
Rather, Patent Owner’s objections go more to the weight that Ex. 1002
should be afforded, rather than to its admissibility. A motion to exclude is

20
Exhibit 1144 has the LexisNexis® trade inscription.
21
The Duke Press Release is dated September 2, 1997.
22
Fed. R. Evid. 902. Evidence that Is Self-Authenticating
The following items of evidence are self-authenticating; they require no
extrinsic evidence of authenticity in order to be admitted:
. . . .
(6) Newspapers and Periodicals. Printed material purporting to be a
newspaper or periodical.
(7) Trade Inscriptions and the Like. An inscription, sign, tag, or label
purporting to have been affixed in the course of business and indicating
origin, ownership, or control.
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25
not the proper vehicle to challenge the sufficiency of evidence. It is within
our discretion to assign the appropriate weight to be accorded evidence.
Moreover, we note that there is a strong public policy for making all
information filed in an administrative proceeding available to the public,
especially in a inter partes review, which determines the patentability of
claims in an issued patent. It is better to have a complete record of the
evidence submitted by the parties than to exclude particular pieces of
evidence.
With regard to Patent Owner’s hearsay argument, we agree with
Petitioner that Ex. 1002 is offered as evidence of what it describes to an
ordinary artisan, not for proving the truth of the matters addressed in the
document. Paper 65, 8. Accordingly, Ex. 1002 is not hearsay requiring the
remedy of exclusion.
Patent Owner further argues that the existence of minor typographical
errors in Ex. 1002 prove that Ex. 1002 was not created by Duke University.
Paper 65. We are not persuaded. Ex. 1002 appears to be an Internet copy of
the original press release, obtainable from a Duke University library. Ex.
1182. Ex. 1002 and the original press release (Ex. 1182, Ex. C) are
substantively the same. The presence of minor typographical errors in Ex.
1002 does not persuade us that the content of Ex. 1002 was not created and
released by Duke University on September 2, 1997.
2. Exs. 1030 and 1033
Patent Owner seeks to exclude portions of the declarations of
Petitioner’s experts Dr. Pastores (Ex. 1030) and Dr. Croughan (Ex. 1033),
based on their alleged admissions that they lack expertise on in the areas of
pre-clinical studies or scaling, and because their testimony allegedly is based
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26
on insufficient facts or data. Paper 55, 10–14 (citing FRE 702).
Specifically, Patent Owner seeks to exclude paragraphs 25, 26, 31, 38, 39,
44–47, 5157, 59, 63, 66–71, 74–79, 8489, 91, 93, and 94 of Ex. 1030 and
paragraphs 77–85, 87, 92, 93, 96–100, 102, 108–111, and 114–116 of Ex.
1033.
We have reviewed the cited portions of the testimony provided by Dr.
Pastores and Dr. Croughan, and see no basis which would warrant the
extreme remedy of exclusion. Patent Owner’s objections go to the weight
and sufficiency of the testimony, rather than its admissibility. We are
capable of discerning from the testimony, and the evidence presented,
whether the witness’ testimony should be entitled to any weight, either as a
whole or with regard to specific issues. We weigh such testimony on an
issue-by-issue basis, as appropriate. Furthermore, Patent Owner had the
opportunity to address any alleged deficiencies in the testimony of Dr.
Pastores and Dr. Croughan in its Patent Owner’s Response and we are
capable of taking note of those inadequacies and weighing that testimony
accordingly.
Thus, we deny Patent Owner’s motion seeking to exclude the
testimony of Dr. Pastores and Dr. Croughan in this proceeding.
3. Exs. 1021, 1063, 1064, 1071, 1072, 1116, 1174, and 1175
Patent Owner seeks to exclude Exhibits 1021, 1063, 1064, 1071,
1072, 1116, 1174, and 1175 as inadmissible hearsay. Paper 55, 9 and 14–15.
Because we do not rely on any of these exhibits to reach the final decision,
we dismiss Patent Owner’s motion to exclude Exhibit 1021, 1063, 1064,
1071, 1072, 1116, 1174, and 1175 as moot.
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IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1 and 36 of the ’226 patent is determined to
be unpatentable;
FURTHER ORDERED that Petitioner’s Motion to Exclude is
dismissed as moot;
FURTHER ORDERED that Patent Owner’s Motion to Exclude is
denied-in-part and dismissed-in-part; and
FURTHER ORDERED that because this is a Final Written Decision,
parties to the proceeding seeking judicial review of the decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

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PETITIONER:

Gerald M. Murphy, Jr.
MaryAnne Armstrong, Ph.D
Eugene T. Perez
BIRCH, STEWART, KOLASCH & BIRCH, LLP
mailroom@bskb.com
gmm@bskb.com
maa@bskb.com
etp@bskb.com

PATENT OWNER:

Raymond Mandra
Filko Prugo
Christina Schwarz
FITZPATRICK, CELLA, HARPER & SCINTO
rmandra@fchs.com
fprugo@omm.com
cschwarz@fchs.com