Genzyme Corporation

Patent Trials and Appeals Board

Apr 30, 2020

15049946 - (D) (P.T.A.B. Apr. 30, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/049,946 02/22/2016 Hanlan Liu 15979-20148.01 7001
89300 7590 04/30/2020
Sanofi/Genzyme c/o Morrison & Foerster LLP
755 Page Mill Road
Palo Alto, CA 94304
EXAMINER
HAVLIN, ROBERT H
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
04/30/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
EOfficePA@mofo.com
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte HANLAN LIU, CHRIS WILLIS, RENU BHARDWAJ,
DIANE P. COPELAND, ABIZER HARIANAWALA, JEFFREY SKELL,
JOHN MARSHALL, JIANMEI KOCHLING, GERARD PALACE,
JUDITH PETERSCHMITT, CRAIG SIEGEL, and SENG CHENG
____________

Appeal 2019-003550
Application 15/049,9461
Technology Center 1600
____________

Before FRANCISCO C. PRATS, TAWEN CHANG, and
DAVID D. COTTA, Administrative Patent Judges.

COTTA, Administrative Patent Judge.

DECISION ON APPEAL

This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating a human patient with Gaucher disease. The Examiner rejected
the claims on appeal as obvious under 35 U.S.C. § 103(a) and on the ground
of nonstatutory obviousness-type double patenting. A hearing was held on
March 2, 2020.2 We reverse.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. According to Appellant, the real party in interest is
Genzyme Corporation. App. Br. 3.
2 A transcript from the hearing has been entered into the record (“Tr.”).
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Application 15/049,946

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STATEMENT OF THE CASE
The Specification discloses that glycosphingolipids (“GSLs”) are a
class of naturally occurring compounds, the accumulation of which has been
linked to a number of disease, including Gaucher disease. Spec. 1. “GSLs
are derived from glucosylceramide (GlcCer).” Id. According to the
Specification, “[c]ompounds which inhibit GlcCer synthase can lower GSL
concentrations and have been reported to be useful for treating a subject with
[Gaucher] disease[].” Id. at 2.
The Specification discloses that “[t]he compound of Formula (I),
shown below, is a GlcCer synthase inhibitor currently in clinical trials for
the treatment of Gaucher disease:
.” Id. According to the Specification, “[i]t has now been found that the
compound of Formula (I) and pharmaceutically acceptable salts thereof
(including Formula (I) Hemitartrate) is metabolized by the liver, primarily
by cytochrome P450 enzymes.” Id. at 20. The Specification discloses that
“[t]he level of activity of P450 enzymes differs according to the individual,”
and that an “embodiment of the invention is to determine whether the
subject is a poor, intermediate and extensive/ultra rapid P450 metabolizer.”
Id. at 20–21. The Specification teaches that “[i]f the subject is an
intermediate or extensive/ultra rapid metabolizer, then the dose administered
to that subject should be raised to an ‘adjusted effective dose’, i.e., the
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Application 15/049,946

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amount which results in trough plasma levels of the compound of at least 5
ng/ml.” Id. at 21.
Claims 157–181 are on appeal. Claim 157 is representative and reads
as follows:
157. A method of treating a human patient with Gaucher
disease in need of treatment comprising:
(i) assessing said patient with Gaucher disease, prior to
initiation of treatment, through CYP2D6 genotyping, as being a
poor, intermediate, or extensive CYP2D6 P450 metabolizer;
and
(ii) administering a therapeutically effective amount of a
compound of formula (I).
or a pharmaceutically acceptable salt thereof to the patient
assessed as being a poor metabolizer, wherein the effective
amount of the compound is 84 mg per day of the compound of
formula (I), or an equivalent amount of a pharmaceutically
acceptable salt thereof.
App. Br. 20.

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The claims stand rejected as follows:
Claims 157–181 were rejected under 35 U.S.C. §103 as obvious over
the combination of Shayman,3 McEachern,4 Emoto,5 De Leon,6 FDA,7 and
Colby.8
Claims 157–181 were rejected on the ground of nonstatutory
obviousness-type double patenting over claims 1, 2, 6–9, 13, and 14 of U.S.
Patent No. 6,916,802 in view of McEachern, Emoto, De Leon, FDA, and
Colby.
OBVIOUSNESS
Shayman discloses “compounds which inhibit glucosyl ceramide
(GlyCer) formation by inhibiting the enzyme GlyCer synthase, thereby
lowering the level of glycosphingolipids.” Shayman Abstract. The
Examiner finds, and Appellant does not dispute, that the genus of
compounds disclosed in Shayman encompasses the claimed compound.
Ans. 4; App. Br. 6. Shayman further discloses that its Glycer synthase

3 Shayman et al., US Patent No. 6,916,802 B2, issued July 12, 2005
(“Shayman”).
4 K. McEachern et al., A Specific and Potent Inhibitor of Glucosylceramide
Synthase for Substrate Inhibition Therapy of Gaucher Disease, 91 Molecular
Genetics and Metabolism 259–267 (2007) (“McEachern”).
5 C. Emoto et al., Approach to Predict the Contribution of Cytochrome P450
Enzymes to Drug Metabolism in the Early Drug-Discovery Stage: The Effect
of the Expression of Cytochrome b5 with Recombinant P450 Enzymes, 37(9)
Xenobiotica 986–999 (2007) (“Emoto”).
6 J. De Leon et al, The AmpliChip™ CYP450 Genotyping Test, 10(3) Mol.
Diag. Ther. 135–151 (2006) (“De Leon”).
7 United States Food and Drug Administration, Guidance for Industry
Pharmacogenomic Data Submissions, March 2005 (“FDA”).
8 Colby et al., US Patent Publication No. 2009/0307179 A1, published Dec.
10, 2009 (“Colby”).
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inhibitors compounds are useful for treating Gaucher disease. Shayman,
34:46–49. McEachern discloses the claimed compound and teaches that
“therapy with [the claimed compound] represents a viable alternative
approach to enzyme therapy to treat the visceral pathology in Gaucher
disease.” McEachern Abstract. The Examiner acknowledges, however, that
neither Shayman nor McEachern teach “assessing the cytochrome P450
(CYP2D6) metabolizer status of a patient prior to administration of the
compound as in the instant claims.” Ans. 7.
With respect to the claim requirement for assessing cytochrome P450
(CYP2D6) metabolizer status, the Examiner found that “it was known in the
art at the time of invention that the cytochrome P450 metabolism of a drug
affects the safe and effective dosage which should be determined.” Ans. 7–8
(citing Emoto, De Leon, Colby, and FDA as support). The Examiner further
found Shayman taught that that cytochrome P450 inactivates compounds
related to the claimed compound and that McEachern disclosed that ADME
studies – which the Examiner asserts include probing cytochrome P450 (id.
at 6) – were conducted on the claimed compound. Id. at 7. The Examiner
thus concluded that the ordinary artisan “following the teachings of
Shayman and McEachern would have an expectation that a patient’s
metabolism of [the claimed compound] would affect the safe and effective
dosage which is determined by the cytochrome P450 activity.” Id. at 8.
Accordingly, the Examiner concluded that:
In determining the safe and effective dosage, one of ordinary
skill in the art would be motivated to determine a patient’s
metabolizer status of the “valid biomarker” CYP2D6 as
suggested by Emoto, Deleon, Colby, and FDA and readily
utilize the commercially available AmpliChip to make the
determination and arrive at the claimed invention, including the
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optimum safe and effective dosage for each metabolizer status -
i.e. 100 mg/day (84 mg/day eliglustat hemitartrate) for a PM
and twice that for the other metabolizers.
Id. The Examiner reasoned that “selecting the appropriate dosage is within
the ability of those of ordinary skill in the art . . . as specifically taught by
Shayman” and that “dosage adjustment based on CYP2D6 metabolizer
status has been successfully applied to other drugs (i.e. De Leon).” Id. at 10.
The Examiner thus concluded that “implementing the therapy identified by
Shayman and McEachern in a manner to account for the CYP2D6
metabolizer status as suggested by Emoto, De Leon, FDA and Colby would
be obvious.” Id.
Appellant argues that the cited art does not sufficiently connect the
claimed compound to dosing in a way that takes into account the CYP2D6
genotype of patients. See generally, App. Br.; Reply Br. As stated in In re
Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): “[T]he examiner bears the
initial burden . . . of presenting a prima facie case of unpatentability.”
Appellant has persuaded us that the Examiner has not carried the burden of
establishing that the claimed invention would have been obvious over the
cited art.
We recognize that it was known in the art to use the claimed
compound to treat Gaucher disease. See, e.g., McEachern, Abstract. We
further recognize that it was known to assess the contribution of cytochrome
P450 for certain drugs (Emoto, Abstract) and, more specifically, to assess
the contribution of CYP2D6 to metabolism of a particular drug. De Leon,
Abstract. However, it is also true that testing of CYP2D6 during the
relevant time period was poorly developed and focused on psychiatric drugs
rather than drugs for treatment of Gaucher disease. Id. at 148 (noting that it
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is “difficult to predict which drug will become the first to include
pharmacogenetic testing as standard practice” and that “almost no published
knowledge supports CYP2D6 genotyping use” and thus “studies are
needed”) (emphasis added); id. (noting that “pharmacogenetics may move
faster in psychiatry than in other areas of medicine” because “many
CYP2D6 dependent drugs are psychiatric drugs”).
We also recognize that Shayman discusses cytochrome P450
metabolism in the context of compounds disclosed to inhibit GlyCer
synthase. Specifically, Shayman discloses:
D-threo-PDMP was as found to be rather active in delaying
tumor cell growth or in producing complete cures in mice
(Inokuchi, J. et al., “Antitumor Activity in Mice of an Inhibitor
of Glycosphingolipid Biosynthesis,” Cancer Lett,. 38:23-30
(1987)) but high doses were needed. From the data in FIG. 1,
the inhibitors of the present invention are approximately 30
times as active, so the dosage levels are typical of clinically
useful drugs. The need to use high doses with PDMP was
attributed to rapid inactivation by cytochrome P450 (Shukla, A.
et al., “Metabolism of D-[3H]PDMP, an Inhibitor of
Glucosylceramide Synthesis, and the Synergistic Action of an
Inhibitor of Microsomal Monooxygenase,” J. Lipid Res.,
32:713-722 (1991)). Cytochrome P450 can be readily blocked
by various nontoxic drugs such as cimetidine, therefore high
levels of the compounds of the present invention can be
maintained.
Shayman, 22:11–27. The Examiner relies on this passage as teaching that “a
related compound was metabolized by cytochrome P450” and as suggesting
to block cytochrome P450 metabolism of the inventive compounds by
administering a P450 inhibitor such as cimetidine. Ans. 7; see also, id. at 5.
However, we are not persuaded that this passage supports administering the
claimed compound taking into account a patient’s CYP2D6 metabolism.
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First, the above passage focuses on cytochrome P450. The art teaches
that cytochrome P450 is a “superfamily of haem-containing
monooxygenases associated with the metabolism of many drugs.” Emoto,
987; see also, Spec. 20 (teaching that there are 11 CYPs expressed in a
typical human liver); Colby ¶ 165 (identifying 30 variants of CYP genes).
CYP2D6 is but one member of the cytochrome P450 superfamily. Spec. 20.
The Examiner does not identify, and we do not find, anything in Shayman
that directs the ordinary artisan to focus specifically on CYP2D6.
Second, other than asserting – without explanation – that the claimed
compound is “related” to PDMP, the Examiner does explain why the
ordinary artisan would have expected the claimed compound to be
metabolized in the same manner as PDMP. Ans. 5, 7, 10. As Appellant
points out, the claimed compound and PDMP have significant structural
differences. App. Br. 8. We acknowledge Shayman’s teaching that high
levels of the inventive compounds can be maintained by co-administering
them with cimetidine, a compound known to block PDMP. Shayman,
22:11–27. However, Shayman also teaches that the “inhibitors of the
present invention are approximately 30 times as active” as PDMP, and that
the need to use high doses of PDMP is attributable to “rapid inactivation by
cytochrome P450.” Id. This suggests that the Shayman’s inventive
compounds, in contrast to PDMP, may not be rapidly metabolized by
cytochrome P450.
Third, the above quoted passage in Shayman does not suggest taking a
patient’s cytochrome P450 genotype into account when determining dosing.
Id. At best, Shayman suggests the comparatively blunt instrument approach
of blocking cytochrome P450 metabolism by administering cimetidine.
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The Examiner points to McEachern’s teaching that the claimed
compound “was readily metabolized and cleared; both parent compound and
metabolites effectively cleared within 24 h as shown in single and repeat
oral dose ADME studies with 14C-radiolabelled compound in rats and
dogs.” McEachern, 264. According to the Examiner, “[a]n ‘ADME’ study
typically includes testing for metabolism pathways (i.e. Liu et al. (Curr.
Drug. Metab. 2007 Dec, 8(8), p. 815-829), probing cytochrome P450
including CYP2D6; NDA 205-494: pages 86-125, including testing for
CYP2D6 metabolism (p. 98-99)).” Ans. 6. However, that ADME studies
for a given compound may include testing for CYP2D6 metabolism, does
not necessarily support that the compound is metabolized by CYP2D6.
Thus, the Examiner has not persuasively explained why the general
statement in McEachern that the claimed compound was “readily
metabolized and cleared” would have suggested to the ordinary artisan that
the claimed compound was metabolized by CYP2D6, much less that dosing
for the claimed compound should be adjusted based on CYP2D6 genotype.
In sum, particularly given the relatively poorly developed state of the
art with respect to CYP2D6 pharmacogenetic drug dosing, we do not find in
the cited art a persuasive connection between, on the one hand,
pharmacogenetic assessment of CYP2D6 metabolism, and, on the other
hand, the claimed compound, compounds that inhibit GlyCer synthase,
and/or compounds that treat Gaucher disease. Absent such a persuasive
connection, we agree with Appellant that the Examiner has not carried the
burden to establish that the claimed method would have been obvious over
the cited art. Accordingly we reverse the Examiner’s rejection of claims
157–181 as obvious over the cited art.
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DOUBLE PATENTING
The Examiner rejected claims 157–181 on the ground of non-statutory
obviousness-type double patenting. The reference patent in this rejection –
U.S. Patent No. 6,912,802 – is the Shayman reference discussed above in
connection with the Examiner’s obviousness rejection. According to the
Examiner, “the basis for this rejection is the same as in the 35 USC 103
rejection.” Ans. 13. Accordingly, we reverse the Examiner’s rejection of
claims 157–181 on the basis of non-statutory obviousness type double
patenting for the reasons discussed above in connection with the Examiner’s
obviousness rejection.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
157–181 103 Shayman,
McEachern,
Colby, Emoto,
De Leon, FDA

157–181
157–181 Double
patenting
Shayman,
McEachern,
Colby, Emoto,
De Leon, FDA

157–181
Overall
Outcome
157–181

REVERSED