BioMarin Pharmaceutical Inc.v.Duke University

Patent Trial and Appeal Board

Feb 23, 2015

09902461 (P.T.A.B. Feb. 23, 2015)

Trials@uspto.gov Paper 86
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.
DUKE UNIVERSITY,
Patent Owner.
____________

Case IPR2013-00535
Patent 7,056,712 B2
__________

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

BONILLA, 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
Petitioner, BioMarin Pharmaceutical Inc. (“Petitioner”), filed a Petition
(Paper 5, “Pet.”) requesting inter partes review of claims 1–9, 11, 12, 15, and 18–
21 of U.S. Patent No. 7,056,712 B2 (Ex. 1001, “the  ’712 patent”). 35 U.S.C.
§ 311. Patent Owner Duke University (“Patent Owner”) filed a Preliminary
Response (Paper 13, “Prelim. Resp.”). We determined that the information
presented in the Petition demonstrated that there was a reasonable likelihood that
Petitioner would prevail in challenging claims 1–9, 11, 12, 15, and 18–21 of the
’712 patent as unpatentable. Paper 16 (“Dec. to Inst.”), 23.
We instituted this proceeding to review whether claims 1–9, 11, 12, 15, and
18–21 are unpatentable on the following grounds.
Reference(s) Basis Claims challenged
van Bree ’410 (Ex. 1005)
1
§ 102 1–9, 11, 12, 15, 20, and 21
Reuser ’771 (Ex. 1004)
2
in view of Van
Hove 1997 (Ex. 1007)
3

§ 103 1–9, 15, and 20

1
van Bree et al., U.S. Patent No. 7,351,410 B2, issued Apr. 1, 2008 (Ex. 1005).
2
Reuser et al., WO 97/05771, published Feb. 20, 1997 (Ex. 1004).
3
Van Hove et al., Purification of recombinant human precursor acid α-
glucosidase, 43(3) BIOCHEMISTRY & MOLECULAR BIOLOGY INT’L 613–623 (1997)
(Ex. 1007).
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Reference(s) Basis Claims challenged
Reuser ’771 in view of Van Hove 1997,
van der Ploeg (Ex. 1014),
4
and Bembi
(Ex. 1008)
5

§ 103 11, 12, and 21
Reuser ’771 in view of Van Hove 1997
and Brady (Ex. 1012)
6

§ 103 18 and 19
Dec. to Inst. 23.
After institution of trial, Patent Owner filed a Patent Owner Response.
Paper 59 (“PO Resp.”). Petitioner subsequently filed a Reply to the Response.
Paper 67 (“Reply”).
In addition, Petitioner filed a Motion to Exclude seeking to exclude certain
evidence. Paper 73. Patent Owner filed an Opposition to Petitioner’s Motion to
Exclude (Paper 76), and Petitioner filed a Reply (Paper 80). Likewise, Patent
Owner filed a Motion to Exclude seeking to exclude certain evidence. Paper 72.
Petitioner filed an Opposition to Patent Owner’s Motion to Exclude (Paper 77),
and Patent Owner filed a Reply (Paper 81).
An oral hearing was held on October 3, 2014. A transcript of the hearing
has been entered into the record. Paper 85 (“Tr.”).
We have statutory authority under 35 U.S.C. § 6(c). This Final Written
Decision is issued pursuant to 35 U.S.C. § 318(a). Petitioner has shown by a

4
van der Ploeg et al., Receptor-Mediated Uptake of Acid α-Glucosidase Corrects
Lysosomal Glycogen Storage in Cultured Skeletal Muscle, 24(1) PEDIATRIC RES.
90–94 (1988) (Ex. 1014).
5
Bembi et al., Enzyme Replacement Therapy in Type 1 and Type 3 Gaucher’s
Disease, 344 LANCET 1679-1682 (1994) (Ex. 1008).
6
Brady et al., Management of Neutralizing Antibody to Ceredase in a Patient With
Type 3 Gaucher Disease, 100(6) PEDIATRICS e11 (1997) (Ex. 1012).
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preponderance of the evidence that claims 1–9, 11, 12, 15, and 18–21 of the ’712
patent are unpatentable. Patent Owner’s Motion to Exclude is dismissed as moot,
and Petitioner’s Motion to Exclude is denied-in-part and dismissed-in-part.
A. Related Proceedings
The parties indicate that are no other related judicial or administrative
matters. Pet. 1, Paper 11, 3. 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. 7,351,410 (“van Bree ’410”) (IPR2013-00534) and U.S. Patent
No. 7,655,226 (“the ’226 patent”) (IPR2013-00537), respectively. Although the
’712 patent is not related to van Bree ’410 (Ex. 1005, in this proceeding) or the
’226 patent, all three patents relate to similar subject matter, i.e., methods of
treating Pompe disease.
B. The ’712 Patent
The ’712 patent relates to methods of treating glycogen storage disease type
II (“GSD-II”). Ex. 1001, Abstract. Glycogen storage disease type II, also known
as Pompe disease or acid maltase deficiency, is a genetic muscle disorder caused
by a deficiency of acid α-glucosidase (“GAA”), a glycogen degrading lysosomal
enzyme. Id. at 1:12–15. The disclosed methods involve enzyme replacement
therapy (“ERT”), including administering to an individual a therapeutically
effective amount of GAA. Id. at 1:62–66; 2:20–27. In a preferred embodiment,
the method uses recombinant human acid α-glucosidase (“rhGAA”), such as a
recombinant human GAA precursor form, produced in Chinese hamster ovary
(“CHO”) cell cultures. Id. at 3:57–4:4. In certain embodiments, the method
involves administering GAA in conjunction with other agents, such as
immunosuppressants. Id. at 5:29–33.
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Independent claims 1 and 20, reproduced below, are illustrative of the
claimed subject matter:
1. A method of treating glycogen storage disease type II in a human
individual having glycogen storage disease type II, comprising administering
to the individual a therapeutically effective amount of human acid α-
glucosidase periodically at an administration interval, wherein the human
acid α-glucosidase was produced in chinese hamster ovary cell cultures.
20. A method of treating cardiomyopathy associated with glycogen storage
disease type II in an human individual having glycogen storage disease type
II, comprising administering to the individual a therapeutically effective
amount of human acid α-glucosidase periodically at an administration
interval, wherein the human acid α-glucosidase was produced in chinese
hamster ovary cell culture.
Claims 2–9, 11, 12, 15, 18, 19, and 21 depend from claim 1.
II. ANALYSIS
A. Claim Construction
Consistent with the statute and legislative history of the America Invents
Act, the Board interprets claims using the “broadest reasonable construction in
light of the specification of the patent in which [they] appear[].” 37 C.F.R.
§ 42.100(b); see also Office Patent Trial Practice Guide,
77 Fed. Reg. 48756, 48766 (Aug. 14, 2012). There is a “heavy presumption” that a
claim term carries its ordinary and customary meaning. CCS Fitness, Inc. v.
Brunswick Corp., 288 F.3d 1359, 1366 (Fed. Cir. 2002) (citations omitted).
1. Claim Phrases Construed in the Decision to Institute
In our Decision to Institute, we construed the phrase “produced in chinese
hamster ovary cell cultures” recited in claims 1, 8, 9, and 20. Dec. to Inst. 6–7.
We did not construe the phrase as a product-by-process limitation, as urged by
Petitioner. Id. at 7. We agreed with Patent Owner that this claim language more
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closely identifies the protein source, rather than a product defined by a process that
allows one to claim “an otherwise patentable product that resists definition by
other than the process by which it is made.” SmithKline Beecham Corp. v. Apotex
Corp., 439 F.3d 1312, 1315 (Fed. Cir. 2006) (quoting In re Thorpe, 777 F.2d 695,
697 (Fed. Cir. 1985)). Dec. to Inst. 7. Thus, we concluded that “produced in
chinese hamster ovary cell cultures” in relation to the recited hGAA
7
corresponded
to a limitation of the challenged claims. Id. at 12.
In addition, in our Decision to Institute, we construed other phrases of the
challenged claims, as reproduced in the table below.
Claim(s) Claim Phrase Claim Construction
1 and 20 administering
“periodically at an
administration interval”
administering “at regular intervals” or
“from time to time,” which “need not
be a fixed interval, but can be varied
over time, depending on the needs of
the individual,” and includes
“monthly, bimonthly, weekly, twice
weekly, daily,” as distinguished from
a “one-time dose”
1, 5–7,
and 20
“therapeutically
effective amount” of
hGAA
“an amount of hGAA administered at
an interval that ameliorates, or lessens
the severity or frequency of,
symptoms of glycogen storage
disease type II,” including amounts
such as “15 mg, about 1–10 mg, or
about 5 mg hGAA per kilogram body
weight of the individual”

7
The acronym “hGAA” used herein refers to “human acid α-glucosidase” as
recited in the challenged claims.
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Claim(s) Claim Phrase Claim Construction
18 hGAA administered “in
conjunction with”
administered “at about the same time”
as hGAA, which includes “within a
short time frame (e.g., within 24
hours) of administration of the GAA”
Id. at 8–9.
Patent Owner does not propose alternative claim constructions for the
above-mentioned claim phrases in its Patent Owner Response, nor does Petitioner
challenge our constructions in its Reply. See, e.g., PO Resp. 15–16 (proposing
construction of other terms). We discern no reason to alter the above-mentioned
claim constructions in any respect for this Final Written Decision.
Claim 19, which depends from claims 1 and 18, recites that “the
immunosuppressant is administered prior to any administration” of hGAA to the
individual. In our Decision to Institute, we interpreted this phrase to refer to
administering an immunosuppressant before the first administration of any hGAA
within a particular administration interval. Dec. to Inst. 9. After considering the
entire record before us now, the Specification of the ’712 patent, and Patent
Owner’s contentions in its Response, we reevaluate that claim construction. See,
e.g., PO Resp. 54 (discussing Ex. 1012).
Most relevant to the language of claim 19, the Specification of the ’712
patent states that “[i]n a particularly preferred embodiment, the
immunosuppressive or immunotherapeutic regimen is begun prior to the first
administration of GAA, in order to minimize the possibility of production of anti-
GAA antibodies.” Ex. 1001, 5:55–59. In view of the claim language itself,
including the term “any,” as well as the above-mentioned description in the
Specification, we construe “administered prior to any administration” of hGAA in
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claim 19 to refer to administering an immunosuppressant prior to the first
administration of hGAA to the individual.
2. “Precursor” of rhGAA
In its Patent Owner Response, Patent Owner proposes that the term
“precursor” in claim 9 means “any precursor of recombinant hGAA (e.g. a 110-kD
form)” that is “exclusively . . . produced in CHO cell cultures.” PO Resp. 15, 22–
24. Petitioner does not propose an alternative claim construction in its Reply.
Reply 5.
We agree that Patent Owner’s proposed claim construction is the broadest
reasonable reading in view of the Specification and language in claim 9 itself. We
clarify, however, that claim 1, upon which claim 9 depends, recites a method
comprising administering hGAA. Neither claim 1 nor claim 9 precludes
administering a non-precursor form of hGAA or rhGAA, even if claim 9 requires
administering a precursor of recombinant hGAA that has been produced in CHO
cell cultures. Claims 1 and 9 encompass administering both precursor and non-
precursor forms at the same time, and are not limited to administering exclusively
a precursor form and no other form.
3. “Bimonthly” administration interval
Patent Owner proposes that the term “bimonthly” in claim 11 means “every
other week.” PO Resp. 15, 25–26. Petitioner does not propose an alternative
claim construction in its Reply. Reply 5–6. We agree that Patent Owner’s
proposed claim construction is the broadest reasonable reading of the term in view
of the Specification. See, e.g., Ex. 1001, 1:52–2:13 (describing administration
“monthly, bimonthly, weekly, twice weekly, daily”).
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B. Anticipation by van Bree ’410
Petitioner contends that van Bree ’410 anticipates claims 1–9, 11, 12, 15, 20,
and 21 of the ’712 patent. Pet. 33–37. BioMarin provides a claim chart to explain
how van Bree ’410 allegedly discloses the claimed subject matter, and relies upon
the Declaration of Dr. Gregory Pastores (“Pastores Declaration”) (Ex. 1020), and
the Declaration of Dr. Matthew Croughan (“Croughan Declaration”) (Ex. 1021), to
support its positions. Id. at Appendix 2; see also id. at 34, 36–37.
1. van Bree ’410 (Ex. 1005)
Van Bree ’410 describes “methods of treating Pompe’s disease using human
acid alpha glucosidase,” where a “preferred treatment regime comprises
administering greater than 10 mg/kg body weight per week to a patient.” Ex. 1005,
Abstract. Claim 1 in van Bree ’410 recites 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 . . . .”
Id. at 29:8–12. In examples, van Bree ’410 describes the use of rhGAA isolated
from the milk of transgenic mice, including for use in human clinical trials. Id. at
16:17–20:48; 24:10–25:20. For instance, Example 5 in the reference describes a
human clinical trial conducted in healthy male volunteers involving intravenous
infusion “administered two weeks apart.” Id. at 24:10–38.
When describing its “Therapeutic Methods” generally, van Bree ’410
discloses that “an alternative way to produce human acid α-glucosidase is to
transfect the acid α-glucosidase gene into a stable eukaryotic cell line (e.g., CHO)
as a cDNA or genomic construct operably linked to a suitable promoter,” but states
that such an approach is “more laborious to produce the large amounts . . . for
clinical therapy . . . .” Id. at 13:39, 58–64.
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In the same “Therapeutic Methods” section, van Bree ’410 discloses that
“ʻtherapeutically []’ . . . effective doses will depend on the severity of the condition
and on the general state of the patient’s health.” Id. at 14:12–15. Van Bree ’410
also discloses that hGAA “is usually administered at a dosage of 10 mg/kg patient
body weight or more per week to a patient,” and describes a preferred embodiment
where “10 mg/kg, 15 mg/kg . . . is administered once, twice or three times
weekly.” Id. at 14:16–27. In addition, “[t]reatment is typically continued for at
least 4 weeks, sometimes 24 weeks, and sometimes for the life of the patient.” Id.
at 14:27–29. One example of “a maintenance dose is at least about 5 to at least
about 10 mg/kg patient body weight per week . . . .” Id. at 14:40–42.
Van Bree ’410 also teaches that, “[t]ypically, the intravenous infusion occurs over
a period of several hours (e.g., 1–10 hours and preferably 2–8 hours, more
preferably 3–6 hours), and the rate of infusion is increased at intervals during the
period of administration.” Id. at 14:52–55. Van Bree ’410 further discloses the
“methods are effective on patients with both early onset (infantile) and late onset
(juvenile and adult) Pompe’s disease.” Id. at 15:10–14.
In another section titled “Conforma[t]ion of Lysosomal Proteins,”
van Bree ’410 states that “[r]ecombinant lysosomal proteins are preferably
processed to have the same or similar structure as naturally occurring lysosomal
proteins.” Id. at 5:36–38. The reference describes that “[l]ysosomal proteins are
glycoproteins that are synthesized on ribosomes bound to the endoplasmic
reticulum (RER).” Id. at 5:38–40. The reference explains that “N-linked
glycosylation process starts in the RER” with the transfer of “precursor
Glc3Man9GlcNAc2.” Id. at 5:42–45. Thereafter, in the RER and Golgi apparatus,
phosphorylation occurs through “a two-step procedure” involving a cleavage that
“exposes mannose 6-phosphate as a recognition marker and ligand for the mannose
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6-phosphate receptor mediating transport of most lysosomal proteins to the
lysosomes.” Id. at 5:45–58.
In that same section, van Bree ’410 describes that “[i]n addition to
carbohydrate chain modification, most lysosomal proteins undergo proteolytic
processing,” and describes details of the proteolytic processing. Id. at 5:59–6:11.
That process produces, as main species, “a 110/100 kD precursor, a 95 kD
intermediate and 76 kD and 70 kD mature forms.” Id. at 6:6–8.
Thereafter, in the same section, van Bree ’410 states that “post translational
processing of natural human acid α-glucosidase and of recombinant forms of
human acid α-glucosidase as expressed in cultured mammalian cells like COS
cells, BHK cells and CHO cells is similar.” Id. at 6:11–16. The reference also
describes that “[a]uthentic processing to generate lysosomal proteins
phosphorylated at the 6’ position of the mannose group can be tested.” Id. at 6:17–
21.
In Example 3, which describes analyzing acid α-glucosidase produced in the
milk of transgenic mice, van Bree ’410 states that “restoration of the endogenous
acid α-glucosidase activity by acid α-glucosidase isolated from mouse milk was as
efficient as restoration by acid α-glucosidase purified from bovine testis, human
urine and medium of transfected CHO cells.” Id. at 20:32–37. The example
describes also describes that “the N-terminal amino acid sequence of the
recombinant α-glucosidase produced in the milk of mice was shown to be the same
as that of α-glucosidase precursor from human urine.” Id. at 20:41–48.
2. Analysis—Claims 1–8, 12, 15 and 20
Petitioner contends that van Bree ’410 discloses every element of challenged
claims 1 and 20, as well as dependent claims 2–9, 11, 12, 15, and 21, citing a claim
chart and supporting evidence. Pet. 33–37, Appendix 2. For example, regarding
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“administering to the individual a therapeutically effective amount of human acid
α-glucosidase,” recited in claims 1 and 20, as well as specific amounts recited in
claims 5–7, Petitioner points to where van Bree ’410 describes “that a dose is
usually 10 mg/kg,” a dose used in the disclosed clinical trials, and that “preferred
regimes are 10, 15, 20, 30 or 40 mg/kg, 1–3 times per week.” Pet. 35. Petitioner
also contends that van Bree ’410 teaches a maintenance dose of 5mg/kg, as recited
in claim 7. Id; Ex. 1005, 14:40–42.
Petitioner contends also that van Bree ’410 describes using “recombinant”
hGAA produced in CHO cells in its methods, as recited in claims 1, 8, and 20. Pet.
33–35 (citing Ex. 1005, 5:36–38, 6:12–16, 10:57–11:42, 19:50–20:47), Appendix
2. Petitioner contends further that van Bree ’410 describes treating an infantile,
juvenile, and adult-onset form of GSD-II, as recited in claims 2–4. Id. at Appendix
A (citing Ex. 1005, 15:12–14). Petitioner contends that van Bree ’410 discloses
administering hGAA bimonthly, weekly, at an interval varied over time, and
intravenously, as recited in claims 11, 12, 15, and 21. Id. at 36, Appendix 2 (citing
Ex. 1005, 24:23; 14:26–43).
In its Response, Patent Owner contends that the section in van Bree ’410
titled “Therapeutic Methods” (discussed above), relied upon by Petitioner, “does
not disclose therapeutically effective amounts and administration intervals for use
specifically with hGAA produced in CHO cell cultures.” PO Resp. 19.
Specifically, according to Patent Owner, van Bree ’410 does not disclose the
combination of: “(i) administering a therapeutically effective amount of hGAA;
(ii) produced in CHO cell cultures; and (iii) periodically at an administration
interval arranged as recited in claims 1 and 20.” Id.
In addition, Patent Owner contends that an ordinary artisan would have
known that “the therapeutically effective amounts and administration intervals
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disclosed for the hGAA genus [in van Bree ’410] were not applicable to hGAA
produced in CHO cell cultures for several reasons,” citing Declarations by
Dr. Melissa Wasserstein (Ex. 2019) and Dr. Richard Cummings (Ex. 2020). PO
Resp. 20 (citing Ex. 2019 ¶ 64; Ex. 2020 ¶ 103). Patent Owner argues that an
ordinary artisan “knew that the characteristics of hGAA including glycosylation
and phosphorylation patterns vary significantly depending upon the source.” Id.
(citing Ex. 2019 ¶ 66; Ex. 2020 ¶¶ 105–107). After noting the importance of
hGAA having at least one mannose-6-phosphate group, Patent Owner contends
that U.S. Patent No. 6,537,785 (“Canfield”) (Ex. 2016) discloses “that less than 1%
of hGAA produced in CHO cell cultures bear the critical mannose-6-phosphate
group.” Id. (citing Ex. 2016, 20:29–31).
Thus, according to Patent Owner, “given the difference in properties of
hGAA produced in transgenic animals and hGAA produced in CHO cells,” an
ordinary artisan would have understood that the administration amounts and
intervals disclosed in van Bree ’410 (regarding administration of hGAA produced
in milk of transgenic mice) would not be applicable to hGAA produced in CHO
cells culture. PO Resp. 20–21 (citing Ex. 2019 ¶¶ 66–67; Ex. 2020 ¶ 107). Patent
Owner also contends that van Bree ’410 only discloses the possibility of using
CHO cells as a source, and discloses that such use “was expressly not preferred
because it was more laborious to produce large amounts” as needed for treatment
in humans. Id. at 21.
As pointed out by Patent Owner, Canfield (Ex. 2016) states that “production
and secretion of human acid α-glucosidase by CHO cells has been reported” in
Van Hove 1996 (Ex. 1016).
8
Ex. 2016, 20:21–27. Canfield states that the

8
Van Hove et al., High Level Production of Recombinant Human Lysosomal Acid
α-glucosidase in Chinese Hamster Ovary Cells Which Targets to Heart Muscle
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“carbohydrate structures of this preparation were not characterized” in Van Hove
1996, and contends that “this preparation was obtained and analyzed.” Id. at
20:27–29. Canfield states that its own results “showed that less than 1% of the
oligosaccharides contained any M6P,” and data “show that known preparations of
recombinant lysosomal enzymes contain no more than 5.2% phosphorylated
oligosaccharides.” Id. at 20:29–39. Patent Owner relies on this disclosure in
Canfield to support its contention that ordinary artisans would have known that the
administration amounts and intervals disclosed in van Bree ’410 in relation to
hGAA produced in transgenic animals would not have been applicable to hGAA
produced in CHO cell cultures.
Van Hove 1996 teaches methods for the “[h]igh-level production” of rhGAA
in CHO cells “which targets to heart muscle and corrects glycogen accumulation in
fibroblasts from patients with Pompe disease.” Ex. 1016, title. Van Hove 1996
indicates that addition of its hGAA produced in CHO cell cultures, including the
precursor 110 kDa form, caused fibroblasts from two patients to uptake the enzyme
“as seen in normal fibroblasts” in in vitro studies. Id. at 67, 2
nd
col., 68, ¶ spanning
1
st
and 2
nd
cols. In addition, hGAA produced in CHO cells demonstrated “acid α-
glucosidase activity [that] was strikingly higher in the liver and in the heart” in in
vivo animal studies, as compared to control animals. Id. at 68, 2
nd
col.
Similarly to Van Hove 1996, Canfield (Ex. 2016) describes methods for
producing “high mannose lysosomal hydrolases,” and methods for treating
“lysosomal storage diseases by administering a disease treating amount of the
highly phosphorylated lysosomal hydrolases of the present invention to a patient.”

and Corrects Glycogen Accumulation in Fibroblasts from Patients with Pompe
Disease, 93 PROC. NATL. ACAD. SCI. USA 65–70 (1996) (Ex. 1016).
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Ex. 2016, 21:38–22:62. In that context, Canfield describes that “[i]n a preferred
embodiment, recombinant human acid alpha glucosidase (‘rh-GAA’) is prepared
by culturing CHO cells secreting rh-GAA in Iscove’s Media modified by the
addition of an alpha 1,2-mannosidase inhibitor.” Id. at 22:23–27. In relation to its
own hGAA produced in CHO cell cultures, Canfield describes that “74% of the rh-
GAA oligosaccharides were phosphorylated,” and “[s]ince each molecule of rh-
GAA contains 7 N-linked oligosaccharides, 100% of the rh-GAA molecules are
likely to contain the mannose-phosphate modification.” Id. at 22:40–48.
Based on the above-mentioned disclosures, we are not persuaded that
Canfield indicates that an ordinary artisan would have known that the
administration amounts and intervals disclosed in van Bree ’410 would have been
inapplicable to hGAA produced in CHO cell cultures. For example, Van Hove
1996 indicates that its hGAA produced in CHO cells were taken up by heart cells
in in vivo animal studies, and Canfield teaches that its own hGAA produced in
CHO cell cultures were phosphorylated at a high level. Absent data or information
in Van Hove 1996 itself regarding glycosylation and phosphorylation of its own
hGAA produced in CHO cells, as used in those studies, we do not know the
glycosylation and phosphorylation status of Van Hove’s preparation. Furthermore,
we do not know from the record what exact “preparation was obtained” by Dr.
Canfield. Ex. 2016, 20:21–29.
In any event, as pointed out by Petitioner, van Bree ’410 itself indicates
hGAA produced in CHO cells would have similar characteristics as hGAA
produced in transgenic mice, including glycosylation and phosphorylation patterns.
Pet. 33–35. When describing its “Therapeutic Methods” generally, van Bree ’410
discloses that “an alternative way” to produce hGAA is to transfect the gene “into
a stable eukaryotic cell line (e.g., CHO).” Van Bree ’410 describes further that
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“[r]ecombinant lysosomal proteins are preferably processed to have the same or
similar structure as naturally occurring lysosomal proteins.” Id. at 5:36–38. The
reference describes that a glycosylation process that involves phosphorylation,
which leads to the addition of manose-6-phosphate on the protein. Id. at 5:42–58.
Moreover, van Bree ’410 describes that “[i]n addition to carbohydrate chain
modification, most lysosomal proteins undergo proteolytic processing.” Id. at
5:59–6:11. In that context, van Bree ’410 states that “post translational processing
of natural human acid α-glucosidase and of recombinant forms of human acid α-
glucosidase as expressed in cultured mammalian cells like COS cells, BHK cells
and CHO cells is similar.” Id. at 6:11–16. Furthermore, when describing its
analysis of hGAA produced in transgenic mice, van Bree ’410 states that
“[r]estoration of the endogenous acid α-glucosidase activity . . . was as efficient as
restoration by acid α-glucosidase purified from . . . medium of transfected CHO
cells.” Id. at 20:32–37.
Based on such disclosures in van Bree ’410 itself, we conclude that
Petitioner has established by a preponderance of the evidence that this reference
describes administering hGAA produced in CHO cell cultures to patients in the
same manner, i.e., using the same amounts and dosage intervals, as described for
hGAA produced in transgenic animals.
The Declarations of Dr. Wasserstein (Ex. 2019) and Dr. Cummings (Ex.
2020), cited by Patent Owner, do not persuade us otherwise. PO Resp. 19–21
(citing Ex. 2019 ¶¶ 64–67; Ex. 2020 ¶¶ 101–107). For example, Dr. Cumming
refers to where van Bree ’410 says “it is possible that other sources of [hGAA],
such as resulting from cellular expression systems, can also be used,” but “it is
more laborious to produce the large amounts” hGAA produced in stable eukaryotic
cell lines, such as CHO cells, as “needed for clinical therapy.” Ex. 1005, 13:53–64
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(emphasis added); Ex. 2020 ¶ 101 (citing Ex. 1005, 13:53–64); see also Ex. 2020
¶¶ 102–104, 106–111 (discussing van Bree ’410). Dr. Wasserstein similarly cites
van Bree ’410. Ex. 2019 ¶¶ 66–67. As discussed above, however, other portions
of van Bree ’410 indicate that hGAA produced in CHO cells would work upon
administration as it would work for hGAA produced in transgenic mice, even
assuming producing hGAA in CHO cells would be “more laborious.”
Dr. Cumming and Dr. Wasserstein also refer to Canfield (Ex. 2016). Ex.
2020 ¶ 102, Ex. 2019 ¶ 66. As discussed above, we are not persuaded that
Canfield indicates that an ordinary artisan would have known that the
administration amounts and intervals disclosed in van Bree ’410 would have been
inapplicable to hGAA produced in CHO cell cultures. Moreover, we find that
Canfield indicates that hGAA produced in CHO cells would work in methods for
treating lysosomal storage diseases, as does Van Hove 1996 in relation to Pompe
disease in particular.
In addition, we are not persuaded by Dr. Cummings’ and Dr. Wasserstein’s
citation to a conference poster indicating what was “later confirmed” in 2003, i.e.,
after the filing date of ’712 patent. Ex. 2020 ¶¶ 105, 112, 113 (citing “McVie-
Wylie Poster,” Ex. 2047); Ex. 2019 ¶ 66 (also relying on Dr. Cumming
Declaration). We note that the McVie-Wylie Poster itself discloses that both
hGAA produced in transgenic rabbits and rhGAA produced in CHO cells worked
to “clear glycogen” in mice, and that the “reduction in glycogen was more
significant in mice treated with the rhGAA produced in CHO cells.” Ex. 2047.
Such disclosures do not indicate that descriptions in van Bree ’410 regarding
administration amounts and intervals would apply only to hGAA produced in
transgenic mice, but not hGAA produced in CHO cell cultures, especially when
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van Bree ’410 itself discusses how hGAA produced from both sources are similar,
as discussed above.
Based on the record before us, we conclude that Petitioner has established by
a preponderance of the evidence that van Bree ’410 describes every element of
claims 1 and 20, as well as dependent claims 2–8, 12, and 15 of the ’712 patent.
3. Analysis—claim 9
As noted above, Petitioner contends that van Bree ’410 describes a
“precursor” form of recombinant hGAA produced in CHO cells cultures, as recited
in claim 9. Pet. 33–35 (citing Ex. 1005, 5:36–38, 6:12–16, 20:41–47, 19:50–
20:11); Appendix 2. For example, van Bree ’410, in a section titled
“Conforma[t]ion of Lysosomal Proteins,” states that the “main species recognized”
of post translational hGAA “are a 110/100 kD precursor, a 95 kD intermediate and
76 kD and 70 kD mature forms,” and that “post translational processing of natural”
hGAA and rhGAA “as expressed in cultured mammalian cells like . . . CHO cells
is similar.” Ex. 1005, 6:1–16.
In its Response, Patent Owner contends that administering a “precursor” in
claim 9 refers to “administering exclusively a precursor of recombinant hGAA that
has been produced in CHO cell cultures.” PO Resp. 22–23 (emphasis added).
Patent Owner further contends that the rhGAA precursor disclosed in van Bree is
only a precursor obtained from the milk of transgenic mammals. Id. at 23.
According to Patent Owner, van Bree ’410 “does not disclose administering
exclusively any precursor of recombinant hGAA, let alone a precursor of
recombinant hGAA produced in CHO cell cultures.” Id. at 23–25.
As noted above, we construe “precursor” in claim 9, and the rest of claims 1
and 9, as encompassing administering both precursor and non-precursor forms of
rhGAA at the same time, and not limited to administering exclusively a precursor
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form and no other form. Thus, we are not persuaded by Patent Owner’s position
that van Bree ’410 does not disclose administering exclusively any precursor of
rhGAA. In addition, for the reasons discussed above in relation to claims 1 and 20,
we also conclude that van Bree ’410 describes administering a precursor of
recombinant hGAA produced in CHO cell cultures, even assuming the reference
teaches administering a “mixture which ‘is preferably predominantly (i.e., >50%)
in the precursor form of about 100-110 kD.’” PO Resp. 23 (quoting Ex. 1005,
13:46–50).
Petitioner has established by a preponderance of the evidence that van Bree
’410 describes every element of claim 9 of the ’712 patent.
4. Analysis—claim 11
Petitioner contends that van Bree ’410 describes administering rhGAA
produced in CHO cell cultures, where the administration interval is bimonthly, as
recited in claim 11. Pet. 26, Appendix 2 (citing Ex. 1005, 24:23 (Example 5));
Reply 5–6.
Patent Owner responds that van Bree ’410 does not disclose administering
hGAA to a human individual that has GSD-II every other week, i.e., bimonthly.
PO Resp. 26–27. Patent Owner points out that Petitioner relies on Example 5 in
van Bree ’410, “which describes a phase I study involving administering hGAA to
healthy male volunteers,” i.e., a study that only assessed “the tolerability of
different doses of hGAA.” Id. at 27.
We agree with Patent Owner. While van Bree ’410 describes administering
hGAA produced in CHO cells to GSD-II patients “once, twice or three times
weekly” for the reasons discussed above, the reference does not describe
administering hGAA less frequently except in Example 5, which describes
administering hGAA to healthy volunteers. Ex. 1005, 14:12–55. Petitioner has
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not established by a preponderance of the evidence that van Bree ’410 expressly or
inherently describes treating GSD-II in a human by administering rhGAA
bimonthly, as required in claim 11.
5. Analysis—claim 21
Petitioner contends that van Bree ’410 describes administering rhGAA
produced in CHO cell cultures, where the administration interval is varied over
time, as recited in claim 21. Pet. 36 (citing Ex. 1005, 14:35–43). The passage in
van Bree ’410 cited by Petitioner describes that hGAA “is administered at an
initially ‘high’ dose (i.e., a ‘loading dose’),” such as “at least about 40 mg/kg
patient body weight 1 to 3 times per week,” followed by “administration of a lower
doses (i.e., a ‘maintenance dose’),” such as “at least about 5 to at least about 10
mg/kg patient body weight per week.” Ex. 1005, 14:35–43.
Patent Owner contends that this cited passage “does not disclose
administering an amount of hGAA that is varied over time depending on the needs
of the individual,” but rather is “regimented on a weekly or multiple times per
week basis without any variance from time to time.” PO Resp. 28–29 (citing Ex.
2019, ¶¶ 76, 80, 81). Patent Owner also contends that the “the initial loading dose
would not be understood” by an ordinary artisan “to be a therapeutically effective
amount of hGAA.” Id. at 29 (citing Ex. 2019, ¶ 80).
We disagree. Claim 21 requires, in relation to the method of claim 1, that
the administration interval is varied over time. In the context of a section on
“Therapeutic Methods,” van Bree ’410 describes administering rhGAA at a certain
dosages twice or three times a week “(e.g., for 1, 2, or 3 weeks)”, and thereafter at
different dosages less often, i.e., once per week. Ex. 1005, 14:35–43. The
reference also describes monitoring hGAA following treatment, and that “a further
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dosage is administered when detected levels fall substantially below (e.g., less than
20%) of values in normal persons.” Id. at 14:30–34.
Based on those descriptions, and for the reasons discussed above regarding
claim 1, Petitioner has established by a preponderance of the evidence that van
Bree ’410 discloses every element of claim 21. We are not persuaded otherwise by
Dr. Wasserstein’s testimony that an ordinary artisan would have appreciated that
the described loading dose in van Bree ’410 would not have corresponded to a
therapeutic dose. Ex. 2019, ¶ 80 (lacking evidence in support for this proposition).
C. Obviousness Over Reuser ’771 and Van Hove 1997
Petitioner contends that claims 1–9, 15, and 20 of the ’712 patent would
have been obvious over Reuser ’771 in view of Van Hove 1997. Pet. 26–33, 48–
51. Petitioner provides a claim chart to explain how the references allegedly
disclose or suggest claimed subject matter, and relies upon the Pastores
Declaration (Ex. 1020) and Croughan Declaration (Ex. 1021), to support its
positions. Id. at Appendix 2; see also id. at 26–33, 48–51.
1. Reuser ’771 (Ex. 1004)
Reuser ’771 relates generally to the production of lysosomal proteins, such
as GAA, in the milk of transgenic animals. Ex. 1004, 1:11–2:15. Reuser ’771
describes “[g]lycogen storage disease type II (GSD II; Pompe disease; acid maltase
deficiency) . . .” as having three clinical forms, infantile, juvenile and adult. Id. at
2:13–22. Reuser ’771 states that “attempts have been made to treat patients having
lysosomal storage diseases by (intravenous) administration of the missing enzyme,
i.e., enzyme therapy,” and describes prior animal testing involving “intravenously
administering purified acid α-glucosidase in phosphorylated and unphosphorylated
forms to mice.” Id. at 2:32–3:4.
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In this context, Reuser ’771 describes isolating lysosomal enzymes from
human and animal sources, and states that an “alternative way to produce human
acid α-glucosidase is to transfect the acid α-glucosidase gene into a stable
eukaryotic cell line (e.g., CHO) as a cDNA or genomic construct operably linked
to a suitable promoter.” Id. at 3:15–18. Because such production methods can be
expensive, however, Reuser ’771 describes another approach of using recombinant
proteins produced in the milk of a transgenic animal. Id. at 3:19–27.
Reuser ’771 teaches that “[t]he proteolytic processing of acid α-glucosidase
is complex,” and the “main species recognized are a 110/100 kDa precursor, a 95
kDa intermediate and 76 kDa and 70 kDa mature forms.” Id. at 9:19–26.
Reuser ’771 teaches further that “post translational processing of natural human
acid α-glucosidase and of recombinant forms of human acid α-glucosidase as
expressed in cultured mammalian cells like COS cells, BHK cells and CHO cells is
similar.” Id. at 9:29–34.
Regarding uses of such recombinant proteins in enzyme replacement therapy
in patients, Reuser ’771 describes a “typical composition for intravenous”
administration. Id. at 18:11–14; 19:34–37. According to Reuser ’771, a
“therapeutically-” or “prophylactically-effective dose” “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 20:24–28.
Examples in Reuser ’771 describe constructing transgenic mice that express
human GAA, as well as analyzing the activity of hGAA produced in the milk of
transgenic mouse lines. Id. at 21:14–28:24. In Example 3, recombinant “[a]cid α-
glucosidase purified from the milk was [] tested for phosphorylation by
administrating the enzyme to cultured fibroblasts from patients with GSD II
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(deficient in endogenous acid α-glucosidase).” Id. at 27:29–32. As also described
in this example, “restoration of the endogenous acid α-glucosidase activity by acid
α-glucosidase isolated from mouse milk was as efficient as restoration by acid α-
glucosidase purified from bovine testis, human urine and medium of transfected
CHO cells.” Id. at 28:10–14. In addition, “the N-terminal amino acid sequence of
the recombinant α-glucosidase produced in the milk of mice was shown to be the
same as that of α-glucosidase precursor from human urine.” Id. at 28:20–23.
2. Van Hove 1997 (Ex. 1007)
Van Hove 1997 describes a method for purifying recombinant hGAA
expressed in CHO cells. Ex. 1007, 613–614. This reference states that “[l]arge
quantities of recombinant acid α-glucosidase are needed for in vivo
experimentation of enzyme replacement therapy in Pompe disease,” and
“eventually for use in medicine.” Id. It also states that the disclosed method “is
amenable to scale up, and has increased speed, and improved reproducibility with
similar high yield and purification efficiency when compared to previous
methods.” Id. at 613. It describes producing “large quantities” of recombinant
hGAA in CHO cells, including recombinant “precursor” GAA. Id. at 613–614,
617.
When discussing Pompe disease, Van Hove 1997 further states that
“[p]atients with the most common infantile form present with a progressive
myopathy and hypertropic cardiomyopathy leading to death before age two years.”
Id. at 613.
3. Analysis
Petitioner contends that Reuser ’771, either alone or in view of Van Hove
1997, discloses or suggests every element of claims 1 and 20, as well as dependent
claims 2–9 and 15, citing a claim chart and supporting evidence. Pet. 26–33, 48–
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51; Appendix 2. For example, regarding “administering to the individual a
therapeutically effective amount of human acid α-glucosidase” recited in claims 1
and 20, as well as specific amounts recited in claims 5–7, Petitioner points to
teachings in Reuser ’771 that disclose administering to a GSD-II patient “from
about 0.1 to 10 mg of purified enzyme per kilogram of body weight.” Pet. 29–30;
Appendix 2; Ex. 1004, 20:9–28. We note that the ’712 patent itself similarly
describes a “preferred” therapeutically effective amount “in the range of about 1–
10 mg enzyme/kg body weight.” Ex. 1001, 6:11–17.
Petitioner indicates also where Reuser ’771 describes other recited elements,
such as “recombinant” hGAA, including “a precursor” form, as recited in claims 8
and 9. Pet. 30–31 (citing Ex. 1004, 9:30–34; 8:53–54; 9:24–25; 28:19–24; Ex.
1020 ¶ 57; Ex. 1021 ¶¶ 90–94). Petitioner identifies where Reuser ’771 teaches
that the main species of GAA include a 110/100 kDa precursor, and that post
translational processing of natural hGAA is similar to that of recombinant hGAA
expressed in CHO cells. Ex. 1004, 9:19–34. Regarding claims 2–4, Petitioner
further points to where Reuser ’771 teaches that glycogen storage disease type II
has three clinical forms, infantile, juvenile and adult. Id. at 29, Appendix 2; Ex.
1004, 2:15–22. Petitioner also identifies where Reuser ’771 teaches administering
hGAA intravenously, as recited in claim 15. Pet. 31, Appendix 2; Ex. 1004, 20:9–
10.
In addition, Petitioner contends that Reuser ’771 describes, or at least
suggests, the suitability of using CHO cells to produce recombinant hGAA for use
in treating GSD-II, even if the reference also teaches that such production might be
more expensive than production in the milk of transgenic animals. Pet. 27; Ex.
1021 ¶ 0094; Ex. 1004, 3:15–25; 11:29–34; 28:10–14. Petitioner further contends
that Van Hove 1997 “relates to the production of recombinant human acid α-
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glucosidase in CHO cells, particularly large scale production and purification for
producing a protein for enzyme replacement therapy.” Pet. 50.
Regarding independent claim 20, Petitioner contends that treating
cardiomyopathy is inherent in the teaching of Reuser ’771, which describes
treating GSD-II with GAA. Id. at 31 (citing Ex. 1020 ¶ 99). Petitioner relies on
the testimony of Dr. Pastores, who indicates, consistent with the claim language
itself, that cardiomyopathy is associated with, i.e., a symptom of, GSD-II (Pompe
disease). Ex. 1020 ¶ 99. Also consistently, as noted above, when discussing
Pompe disease, Van Hove 1997 states that “[p]atients with the most common
infantile form present with a progressive myopathy and hypertropic
cardiomyopathy leading to death before age two years.” Ex. 1007, 613.
Petitioner contends that the only element in challenged claims 1 and 20 that
is not mentioned expressly in Reuser ’771 is administering hGAA “periodically at
an administration interval.” Pet. 28. Petitioner also contends, however, relying on
testimony by Dr. Pastores, that a person of ordinary skill would have understood
“that ERT [enzyme replacement therapy] for GSD-II is not a one shot cure but
would require repeated and spaced administrations for the rest of the patient’s life.”
Id. (citing Ex. 1020 ¶¶ 60, 61, 84–87, 90, 98).
In its Preliminary Response, Patent Owner contends that BioMarin’s
“argument, at best, demonstrates that Reuser ’771 discloses the feature ‘at regular
intervals’ and maybe ‘from time to time.’” Prelim. Resp. 28. As discussed in our
Decision to Institute and above, however, we construe “periodically at an
administration interval” in claims 1 and 20 to encompass such administration.
In its Response after institution, Patent Owner contends that an ordinary
artisan would not have “combined Reuser and Van Hove, i.e., replaced the hGAA
produced in transgenic animals described in Reuser with the hGAA produced in
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CHO cells described in Van Hove,” relying on Declarations by Dr. Cummings (Ex.
2020) and Dr. Wasserstein (Ex. 2019). PO Resp. 30–31. We conclude that a
preponderance of the evidence establishes otherwise.
We find that Reuser ’771 suggests using, in its methods, rhGAA from
sources other than milk of transgenic mice, including as produced in CHO cell
culture. For example, Reuser teaches that “restoration of the endogenous acid α-
glucosidase activity by acid α-glucosidase isolated from mouse milk was as
efficient as restoration by acid α-glucosidase purified from bovine testis, human
urine and medium of transfected CHO cells.” Ex 1004, 28:10–18. In addition,
Van Hove 1997 describes methods for making large quantities of rhGAA in CHO
cells, and at least suggests using such rhGAA for the treatment of Pompe disease.
Ex. 1007, 613–614. In light of disclosures in the two references, both discussing
rhGAA produced in CHO cells and methods of treating Pompe disease, we find
that one would have had reason to combine teachings of those references.
Patent Owner acknowledges that the above-mentioned statement in Reuser
’771 (PO Resp. 31; Ex 1004, 28:10–18), but contends that an ordinary artisan
reading the reference would not have thought that hGAA from transgenic mice and
CHO cells shared similarities because Reuser ’771 “cites only previous in vitro
studies,” and no in vivo data, in support. PO Resp. 31–32. That contention
assumes, however, that one would have understood that statements in Reuser ’771,
indicating that hGAA from both sources (transgenic mice and CHO cells) would
work to restore endogenous GAA activity, were affirmatively incorrect in the
absence of in vivo data. A showing of obviousness here does not require in vivo
data as “proof” that an otherwise clear statement in Reuser ’771 is correct, when it
is reasonably based on in vitro studies and other information discussed in the
reference.
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As the Supreme Court has explained:
When there is a design need or market pressure to solve a problem and there
are a finite number of identified, predictable solutions, a person of ordinary
skill in the art has good reason to pursue the known options within his or her
technical grasp. If this leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and common sense.
KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 402–403 (2007). Here, Reuser ’771
identified rhGAA produced in CHO cells, in particular, and, especially in view of
Van Hove 1997, provided “good reason to pursue the known options within his or
her technical grasp” using such rhGAA for the treatment of Pompe disease, as
taught by Reuser ’771, including at the administration doses and intervals
disclosed in Reuser ’771.
In its Response, Patent Owner also acknowledges that Reuser ’771 teaches
that “post translational processing of natural human acid α-glucosidase and of
recombinant forms of human acid α-glucosidase as expressed in cultured
mammalian cells like COS cells, BHK cells and CHO cells is similar.” Id. at 32;
Ex 1004, 9:29–34. Patent Owner contends that this statement in Reuser ’771
relates to processing of the amino acid sequence of hGAA, but not glycosylation or
phosphorylation of hGAA. PO Resp. 32 (citing Ex. 2020 ¶ 136).
Patent Owner’s contention in this regard suffers the same shortcomings
discussed above in relation similar contentions by Patent Owner regarding van
Bree ’410. Similarly to van Bree ’410, Reuser ’771 includes a section titled
“Conformation of Lysosomal Proteins” discussing post translational processing of
GAA, which includes glycosylation, phosphorylation, and proteolysis. Ex. 1004,
8:25–10:3. It is in relation to “post translational processing,” not just proteolytic
processing, that Reuser ’771 states that the processing is similar for natural GAA
and rhGAA expressed in cultured mammalian cells, such as CHO cells.
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Patent Owner also contends that an ordinary artisan reading Van Hove 1997,
as well as Van Hove 1996 and Canfield (discussed above), would have understood
“the relative inferiority of CHO cells as a source for GAA.” PO Resp. 33–35. For
example, Patent Owner contends that Reuser ’771 describes that transgenic
animals were capable of secreting lysosomal proteins “at high levels of at least 10,
50, 100, 500, 1000, 2000, 5000 or 10,000 μg/ml,” while “Van Hove 1997
described the production of GAA using CHO cells in concentrations of up to only
90 μg/ml.” Id. at 33 (citing Ex. 2020 ¶ 130 (citing Ex. 1004, 17:16–17; Ex. 1007,
613)).
We disagree that Van Hove 1997 describes production in concentrations of
up to only 90 μg/ml. Rather, Patent Owner points to where Van Hove 1997 refers
to earlier work by others, including Van Hove 1996, producing GAA in such
quantities. PO Resp. 33; Ex. 1007, 613. In any event, Van Hove 1997 expressly
teaches how to produce rhGAA in CHO cells, and Van Hove 1997 and Reuser
’771 both provided the motivation to use such rhGAA in the methods described
Reuser ’771.
Relying on Van Hove 1996 and Canfield, Patent Owner also contends that
an ordinary artisan would have had no reason to use hGAA produced in CHO cell
cultures in the methods of Reuser ’771, and no reasonable expectation of success
that rhGAA produced in CHO cells, as taught by Van Hove 1997, would have
worked in the methods disclosed in Reuser ’771. PO Resp. 34–38. Patent Owner
again relies on alleged teaching in Van Hove 1996 that rhGAA produced in CHO
cells were “undesirably taken up by the liver,” as well as Canfield’s alleged
teaching that rhGAA in Van Hove 1996 were not sufficiently phosphorylated. Id.
at 34–35, 37. For the reasons discussed above, we do not agree with Patent
Owner’s characterization of those references. For example, as noted above, Van
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Hove 1996 teaches that its rhGAA produced in CHO cells exhibited “strikingly
increased enzyme levels in the heart following intravenous injection” in animal in
vivo studies. Ex. 1016, 69, 2
nd
col.; Reply 9.
Petitioner has established by a preponderance of the evidence that an
ordinary artisan reading Reuser ’771, in view of Van Hove 1997, with knowledge
of Van Hove 1996, Canfield and other references discussed herein, would have had
reason to use rhGAA produced in CHO cells, as taught by Van Hove 1997, in the
methods disclosed in Reuser ’771, and would have had a reasonable expectation of
success in doing so, in view of those references. Petitioner has established by a
preponderance of the evidence that claims 1–9, 15, and 20 of the ’712 patent would
have been obvious over Reuser ’771, in view of Van Hove 1997.
D. Obviousness Over Reuser ’771, Van Hove 1997, van der Ploeg, and
Bembi
Petitioner contends that claims 11, 12, and 21 of the ’712 patent would have
been obvious over Reuser ’771, in view of Van Hove 1997, van der Ploeg, and
Bembi, among other references. Pet. 51, 43–44. We discuss Reuser ’771 and
Van Hove 1997 above.
1. van der Ploeg (Ex. 1014)
Van der Ploeg describes cellular uptake of different species of hGAA by
muscle cells, including by a 110 kD precursor form of GAA purified from human
urine. Ex. 1014, 90, Abstract, 91, 1
st
col., 93, 2
nd
col. Van der Ploeg teaches that
the “half-life of endocytosed acid α-glucosidase varied between 6 and 9 days in
different experiments.” Id. at 91, 2
nd
col.
2. Bembi (Ex. 1008)
Bembi describes a protocol for enzyme replacement treatment in patients
with Gaucher’s disease. Ex. 1008, Summary. In this clinical study, “infusion
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frequency was weekly during the first 6-9 months and biweekly afterwards.” Id. at
1679, 2
nd
col, 1680, Table 1. Bembi discloses that such enzyme replacement
therapy can be effective with “a 2-week interval between infusions.” Id. at 1679,
1
st
col.
3. Analysis
Petitioner contends that Reuser ’771, in view of Van Hove 1997, van der
Ploeg, and Bembi, discloses or suggests every element of dependent claims 11, 12,
and 21, relying on arguments and evidence discussed above in relation to claim 1,
as well as testimony in the Pastores Declaration. Pet. 51, 43–44. Petitioner
contends that van der Ploeg “states that the tissue half-life of GAA is known to be
6-9 days.” Id. at 44. Petitioner relies on testimony by Dr. Pastores to support the
contention that, based on that known half-life, it would have been obvious to a
clinician to choose a dosing interval of once weekly or bimonthly, as recited in
claims 11 and 12. Id. Likewise, Petitioner contends that it would have been
obvious to vary the administration interval over time, as recited in claim 21. Id. In
that regard, Petitioner cites testimony by Dr. Pastores indicating that it would have
been obvious to vary an administration interval over time after observing patient
response to the enzyme. Id. (citing Ex. 1020 ¶ 86 (citing Ex. 1008, 1679, 2
nd
col.)).
Patent Owner contends that Petitioner has not established a reason to
combine the four references. PO Resp. 38–41. Patent Owner contends that
“van der Ploeg describes an in vitro experiment in which muscle cell cultures from
an infantile GSD-II patient were treated with hGAA purified from human urine.”
Id. at 39. Patent Owner argues that “[g]iven the known differences in
glycosylation and phosphorylation of hGAA from different sources,” an ordinary
artisan would have had no reason to combine teachings in van der Ploeg to those in
references disclosing hGAA produced in CHO cell cultures or transgenic animals.
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Id. at 39–40 (citing Ex. 2019 ¶¶ 97–100; Ex. 2020 ¶¶ 145–146). In addition,
according to Patent Owner, an ordinary artisan would not have considered the in
vitro half-life of hGAA from van der Ploeg to be relevant to an in vivo half-life
because of “the body’s sophisticated clearance mechanisms” and prior studies
showing that the “majority of hGAA, regardless of source, was taken up by the
liver.” Id. at 40 (citing Ex. 2019 ¶ 98).
Patent Owner contends also that an ordinary artisan would have had no
reasonable expectation of success “of obtaining the claimed inventions by
combining Reuser, Van Hove, van der Ploeg and Bembi,” relying on testimony by
Dr. Wasserstein (Ex. 2019) and Dr. Cummings (Ex. 2020). Id. at 41–44. For
instance, Patent Owner relies on testimony by Dr. Wasserstein stating that no data
demonstrated that “hGAA produced in CHO cell cultures could reach muscle cells
or be taken up by the lysosomes in vivo.” Id. at 42 (citing Ex. 2019 ¶ 99). In
addition, Patent Owner again points out that van der Ploeg discusses the half-life of
hGAA in vitro, and again refers to “known differences in glycosylation and
phosphorylation of hGAA from different sources.” Id. at 43–44. Patent Owner
also contends that because Bembi relates to treating Gaucher’s disease with a
different enzyme, rather than GSD-II with hGAA produced in CHO cells, relying
on Bembi to suggest administration intervals in relation to treating GSD-II is
“unsound.” Id. at 44 (citing Ex. 2019, ¶¶ 93–94).
As discussed above, Reuser ’771 suggests that “natural” hGAA (e.g.,
purified from urine) and hGAA produced in CHO cells or in transgenic animals
exhibit similar post translational processing, including glycosylation,
phosphorylation, and proteolysis, and similarly restore endogenous GAA activity
in cultured fibroblasts from patients with GSD-II. Ex. 1004, 8:25–10:3; 27:29–
28:14. While van der Ploeg describes studies conducted in culture cells in vitro,
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and the half-life of GAA in that context, Dr. Pastores’ testimony persuades us that
such teachings regarding the enzyme half-life would have suggested optimization
of therapy (as discussed ahead) to obtain a dosing interval of rhGAA of once
weekly or bimonthly, as recited in claims 11 and 12. Ex. 1020 ¶¶ 86–92. We are
also persuaded that Bembi suggests administration intervals of weekly and
bimonthly, and varying administration intervals over time, when treating patients
with enzyme therapy to treat a lysosomal protein deficiency. Ex. 1008, 1679.
In relation to in vivo treatment in humans, a preponderance of the evidence
establishes that an ordinary artisan would have engaged in routine optimization
when selecting doses and dosing intervals generally when practicing the enzyme
therapy disclosed in Reuser ’771 (Ex. 1005, 18:36–20:28), and such optimization
was achievable through the use of standard clinical trial procedures. Ex. 1020
¶¶ 74–92; Pet. 44, 51. The record before us establishes sufficiently that the
experimentation needed to achieve the dosing intervals in claims 11, 12, and 21
was “‘nothing more than routine’ application of a well-known problem-solving
strategy, . . . ‘the work of a skilled [artisan], 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 disclose in Reuser “flows from the
‘normal desire of scientists or artisans to improve upon what is already generally
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known.’” Pfizer, 480 F.3d at 1368 (quoting In re Peterson, 315 F.3d 1325, 1330
(Fed. Cir. 2003)).
A reasonable expectation of success does not require absolute predictability.
In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). 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 all that remained to be achieved over the prior art was the
determination that a suggested dose and dosing schedule would have been safe and
effective for the treatment of human patients. 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.” In re O’Farrell, 853 F.2d at 903;
Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1167 (Fed. Cir. 2006). Reuser
’771 discloses specific methods and doses for enzyme replacement therapy in
patients using rhGAA (Ex. 1004, 18:11–20:28), and suggests the use of rhGAA
produced in CHO cell culture in particular (id. at 3:15–25; 9:29–34, 28:8–14),
while Van Hove 1997 expressly discloses methods for producing rhGAA in CHO
cell culture with “high yield and purification efficiency” (Ex. 1007, 613,
summary).
This is also 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
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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. 1020 ¶¶ 77–82), would have been informed
by the clinical experience with Gaucher’s disease (id. at ¶ 86 (citing Ex. 1009,
1052,)), and that, because “it was well known that any 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 ’771” (Ex. 1020 ¶ 60).
Patent Owner’s contention that Bembi focuses on the use of β-
glucocerebrosidase to treat Gaucher’s disease, and not hGAA to treat Pompe
disease, does not persuade us otherwise. PO Resp. 40–41. Bembi provides
evidence of dosing intervals that an ordinary artisan would have considered when
routinely optimizing the therapy disclosed in Reuser ’771, which similarly related
to enzyme therapy to treat a lysosomal protein deficiency.
Petitioner has established by a preponderance of the evidence that claims 11,
12, and 21 of the ’712 patent would have been obvious over Reuser ’771, in view
of Van Hove 1997.
E. Obviousness Over Reuser ’771, Van Hove 1997, and Brady
Petitioner contends that claims 18 and 19 of the ’712 patent would have been
obvious over Reuser ’771, in view of Van Hove 1997 and Brady. Pet. 51, 45–46.
We discuss Reuser ’771 and Van Hove 1997 above.
1. Brady (Ex. 1012)
Brady discloses a clinical protocol to manage enzyme neutralizing
antibodies in patients during treatment of Gaucher’s disease with the enzyme
glucocerebrosidase. Ex. 1012, 1. Brady states that “the strategy we have used
(plasma exchange, cyclophosphamide, intravenous IgG, and large doses of
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enzyme) may provide benefit to such individuals.” Id. at Abstract. Brady further
discloses that “[i]t is also likely that this technique may be helpful when enzyme
replacement therapy is attempted in patients with other disorders in which the
genetic mutation abrogates the production of the protein (CRIM-negative
individuals).” Id. In the protocol, in an “effort to immunosuppress the patient,”
Brady teaches administering cyclophosphamide (an immunosuppressant) on the
same day as glucocerebrosidase enzyme, and in some cases before administering
the enzyme on a following day. Id. at 3, ¶ spanning 1
st
and 2
nd
cols., Table 1.
2. Analysis
Petitioner contends that Reuser ’771, in view of Van Hove 1997 and Brady,
discloses or suggests every element of dependent claims 18 and 19, relying on
arguments and evidence discussed above in relation to claim 1, as well as
testimony in the Pastores Declaration. Pet. 51, 45–46. Petitioner contends that
Brady discusses the use of the immunosuppressant cyclophosphamide in
conjunction with enzyme replacement therapy in Gaucher’s disease, and that such
a strategy is likely to be helpful in enzyme replacement therapy in other disorders
where a genetic mutation abrogates the production of the protein. Id. at 45–46.
Petitioner relies also on testimony by Dr. Pastores to support the contention that it
would have been obvious to administer an immunosuppressant in conjunction with
enzyme replacement therapy to treat GSD-II “to alleviate unwanted immune
responses.” Id. at 46 (citing Ex. 1020 ¶ 95).
Patent Owner contends that an ordinary artisan would have had no reason to
combine the cited references, arguing that an ordinary artisan “interested in
treating GSD-II with hGAA from CHO cells would have had no reason to also
administer an immunosuppressant.” PO Resp. 47–51. Patent Owner contends also
that an ordinary would not have considered Brady “relating to treating a single
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patient with Gaucher’s disease who had experienced a rare and severe
immunological response to administration of Ceredase isolated from human
placenta relevant to a treatment regimen for treating GSD-II with hGAA produced
in CHO cell cultures.” Id. at 49 (citing Ex. 2020, ¶ 154; Ex. 2019 ¶ 105). Patent
Owner also contends, citing testimony by Dr. Wasserstein, that “immunological
risks to GSD-II patients would be different than the immunological risks to
patients with Gaucher’s disease,” and that “Brady concerns administering an
immunosuppressant in response to an immunological reaction to exogenous
enzyme, not for the purpose of preventing production of anti-GAA antibodies.” Id.
at 50 (citing Ex. 2019 ¶¶ 107, 111–112). Patent Owner further contends that Brady
does not disclose administration of immunosuppressant prior to the first
administration of the enzyme within an administration interval, as required in
claim 19. Id. at 53–55.
We conclude that Dr. Pastores’ testimony in this regard is more persuasive.
Ex. 1020 ¶¶ 93–95. Brady discloses the use of an immunosuppressant,
cyclophosphamide, to manage neutralizing antibodies directed against a treatment
enzyme, Ceredase, in patients with Gaucher disease, a lysosomal protein
deficiency disease. Ex. 1012, 1. Brady expressly states that its “technique may be
helpful when enzyme replacement therapy is attempted in patients with other
disorders in which the genetic mutation abrogates the production of the protein.”
Id. Such teachings would have suggested to an ordinary artisan to use an
immunosuppressant similarly when administering enzyme replacement therapy,
such as rhGAA produced in CHO cells, to least some patients when treating a
different lysosomal protein deficiency, such as Pompe disease, even assuming one
understood that a severe neutralizing antibody response would have been rare. Ex.
1020, ¶¶ 93–95.
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Brady likewise would have suggested that after a neutralizing antibody
response occurred, an ordinary artisan would have had reason to administer
enzyme therapy, such as rhGAA produced in CHO cells, in conjunction with an
immunosuppressant (i.e., within a short time frame of each other, as required in
claim 18), and before the first administration of rhGAA in a next administration
interval. See, e.g., Ex. 1012, 3, ¶ spanning 1
st
and 2
nd
cols., Table 1 (describing
administering enzyme therapy (“GC”) and immunosuppressant cyclophosphamide
(“CTX”)).
Regarding claim 19, as discussed above, we construe the phrase
“immunosuppressant is administered prior to any administration” of hGAA to refer
to administering an immunosuppressant prior to the first administration of hGAA
to the individual. As noted by Patent Owner, Brady teaches administering both
enzyme and immunosuppressant on “Day 1,” i.e., the first day of treatment in the
individual. PO Resp. 54; Ex. 1012, 3, ¶ spanning 1
st
and 2
nd
cols., Table 1. Brady
further teaches administering the immunosuppressant (cyclophosphamide or
“CTX”) again prior to subsequent administrations of the enzyme. Id.
Brady teaches administering the immunosuppressant in this fashion in an
“effort to immunosuppress the patient” and reduce neutralizing antibodies in the
individual. Id. at 3. (including sections titled “Intervention” and “Reduction of
Neutralizing Antibody Titer”). Based on such teachings in Brady and the record
before us, we are persuaded that an ordinary artisan would have had reason to
administer an immunosuppressant, for example on Day 1 of treatment, prior to any
administration of enzyme therapy, such as rhGAA. See also Pet. 52 (citing Ex.
1020 ¶ 95 (testimony of Dr. Pastores stating that “[i]f there is a high incidence of
patients developing high antibody titers, an immunosuppressant could be
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administered prophylactically prior to any administration of the recombinant
enzyme begins to minimize the potential adverse effects of such.”)).
Petitioner has established by a preponderance of the evidence that claims 18
and 19 of the ’712 patent would have been obvious over Reuser ’771, in view of
Van Hove 1997 and Brady.
F. Secondary Considerations
We recognize that factual inquiries for an obviousness determination include
secondary considerations based on evaluation and crediting of objective evidence
of non-obviousness. 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, including objective evidence of non-obviousness, 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). Such a conclusion, however, 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 non-obviousness 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 contends that several lines of objective evidence (or
“secondary considerations”) demonstrate the non-obviousness of the challenged
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claims. PO Resp. 55–58. In particular, Patent Owner argues long-felt need and
failure by others (id. at 56), unexpected results (id. at 56–57), licensing (id. at 57),
commercial success (id. at 57–58), and praise and industry acceptance (id. at 58).
All of the challenged claims recite a method of treating GSD-II disease by
administering hGAA produced in a CHO cell culture. Patent Owner’s arguments
with regard to each of the secondary considerations, however, fail to establish a
nexus between those recited methods and the asserted objective evidence of non-
obviousness.
For example, Patent Owner does not explain adequately why the “successful
therapeutic treatment for Pompe disease with hGAA produced in CHO cell
cultures” as disclosed in the ’712 patent would have been unexpected upon reading
Reuser ’771, in view of Van Hove 1997 and other references, or how the subject
matter of ’712 patent overcame a “failure of others.” Id. at 56–57. For instance,
Patent Owner provides no evidence that the method taught in Reuser ’771 (Ex.
1004, 18:11–20:28), using rhGAA produced in CHO cells as suggested in Reuser
’771 and Van Hove 1997, would not, or did not, work in human patients.
Moreover, in relation to licensing, as noted by Petitioner, Patent Owner does
not discuss or address whether other patents or intellectual property might have
been involved in the “two significant rights transfers” mentioned by Patent Owner.
Id. at 57. Likewise, Patent Owner does not show adequately a nexus between what
is recited in the challenged claims of the ’712 patent in particular and the
commercial success of Myozyme/Lumizyme or the asserted praise and industry
acceptance. Id. at 57–58 (citing Ex. 2021 ¶ 57, 36), 58. For instance, although
Patent Owner points us to a Declaration by Mr. Phillip Green discussing
Myozyme/Lumizyme sales and royalty rates, Patent Owner does not explain
adequately, or point us to where Declaration addresses, the required nexus. Id.
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Accordingly, the objective evidence does not persuade us that the challenged
claims would have been non-obvious. When we balance Petitioner’s evidence of
obviousness against Patent Owner’s asserted objective evidence of non-
obviousness, we determine that a preponderance of the evidence supports
Petitioner’s position that challenged claims would have been obvious over the cited
references.
G. Conclusion
In view of the above, we conclude that Petitioner has demonstrated by a
preponderance of the evidence that van Bree ’410 anticipates claims 1–9, 12, 15,
and 18–21 of the ’712 patent, and that claims 1–9, 11, 12, 15, and 18–21 would
have been obvious over Reuser ’771 in view of Van Hove 1997, and van der Ploeg,
Bembi, and/or Brady.
III. MOTIONS TO EXCLUDE
A. Patent Owner’s Motion to Exclude Evidence
Patent Owner moves to exclude Petitioner’s Exhibit 1157 (a deposition
transcript of Dr. William Canfield), as well as Exhibits 1117, 1118, 1121, 1127,
1131, 1132, 1136, 1137, and 1161–1165, for different reasons. Paper 72. Because
we do not rely on any of these exhibits in reaching the Final Written Decision, we
dismiss Petitioner’s motion as moot.
B. Petitioner’s Motion to Exclude Evidence
Petitioner moves to exclude the Declaration of Mr. Philip Green (Ex. 2021),
portions of Dr. Cummings’ Declaration discussing Mr. Green’s testimony (Ex.
2020 ¶¶ 14, 155–160), as well as Exhibit 2070, which is a “Technology
Assignment Agreement,” and Exhibit C to a larger 2000 Agreement between
Synpac and Genzyme. Paper 73, 1.
Because we do not rely on paragraphs 14 and 155–160 of Dr. Cummings’
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Declaration (Ex. 2020), nor Exhibit 2070, in reaching the Final Written Decision,
we dismiss the portion of Petitioner’s Motion to Exclude relating to those exhibits
as moot.
As discussed above, however, we consider Mr. Green’s Declaration when
analyzing Patent Owner’s contentions regarding objective evidence of non-
obviousness. Petitioner argues that we should exclude this Declaration because:
(1) it “assumes that Myozyme and Lumizyme are the same product described and
claimed” in the ’712 patent; (2) Mr. Green has no “firsthand knowledge of the
chemical identity” of Myozyme and Lumizyme or whether the method clamed in
the ’712 patent is used to make Myozyme and Lumizyme; (3) “Mr. Green testified
that he did not know whether the cell line that was the subject of the 1996
Assignment Agreement . . . (Ex 2070) was the same cell line used by Genzyme to
create Myozyme and Lumizyme”; and (4) paragraphs 16–18 and 47–49 of Mr.
Phillip’s Declaration mention a 2000 “Agreement” that is not of record in this
proceeding. Paper 73, 4–8 (citing Federal Rules of Evidence 702 and 703).
We have reviewed the cited portions of the testimony provided by Mr. Green
and see no basis on which they would warrant the extreme remedy of exclusion.
Patent Owner’s above-mentioned contentions go to the weight and sufficiency of
Mr. Green’s 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 deny Petitioner’s Motion to Exclude in relation to the Declaration of Mr. Philip
Green (Ex. 2021).

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IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–9, 11, 12, 15, and 18–21 of the ’712 patent are
determined to be unpatentable;
FURTHER ORDERED that Patent Owner’s Motion to Exclude is dismissed
as moot;
FURTHER ORDERED that Petitioner’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:

John White
Herman Yue
COOPER & DUNHAM LLP
DukeIPR@cooperdunham.com
SynpacIPR@pbwt.com