Ex Parte Goldsmith et al

Patent Trial and Appeal Board

Jul 18, 2016

11696554 (P.T.A.B. Jul. 18, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
111696,554 0410412007 Mark A. Goldsmith
26111 7590 07119/2016
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
1100 NEW YORK A VENUE, N.W.
WASHINGTON, DC 20005
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
2662.0040002/JAG/KRM 4665
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
MAILDATE DELIVERY MODE
07/19/2016 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARK A. GOLDSMITH and ELIZABETH VADAS 1
Appeal2013-009985
Application 11/696,554
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and
JACQUELINE T. HARLOW, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
pharmaceutical dosage form, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b ).
We reverse.
STATEMENT OF THE CASE
"Antiplatelet drugs, which decrease platelet aggregation and inhibit
thrombus formation, have been shown to be beneficial in the treatment and
prevention of thrombotic disorders." (Spec. i-f 3.) However, "antiplatelet
1 Appellants identify the Real Party in Interest as KG Acquisition, LLC.
(Br. 3.)
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Application 11/696,554
agents, such as aspirin and clopidogrel, have been associated with
gastrointestinal disorders such as ulcers and gastrointestinal bleeding." (Id.
at i-f 4.) The Specification discloses oral dosage forms that contain both an
antiplatelet drug, such as clopidogrel, and a proton pump inhibitor (PPI)
such as omeprazole. (Id. at i-f 6.)
Claims 195, 200, 202, and 203 are on appeal. Claims 195 and 200 are
illustrative and read as follows:
195. A single unit oral dosage form comprising: a) an adenosine
diphosphate (ADP) or P2Y12 antagonist or a pharmaceutically acceptable salt
or enantiomer thereof, in a therapeutically effective amount to provide
anti platelet activity; and b) a proton pump inhibitor (PPI) or a
pharmaceutically acceptable salt or enantiomer thereof, in a therapeutically
effective amount to prevent or reduce a gastrointestinal disorder associated
with use of said ADP or P2 Y12 antagonist or said ADP or P2 Y12 antagonist
and aspirin, wherein said PPI is enterically coated.
200. The single unit oral dosage form of claim 195, wherein said
i\~DP or P2 Y i2 antagonist or pharmaceutically acceptable salt or enantiomer
thereof is clopidogrel and said PPI or pharmaceutically acceptable salt or
enantiomer thereof is omeprazole.
DISCUSSION
The Examiner has rejected claims 195 and 200 under 35 U.S.C.
§ 103(a) as obvious based on Ng2 and Chen3 (Ans. 3), and has rejected
2 Ng et al., High incidence of clopidogrel-associated gastrointestinal
bleeding in patients with previous peptic ulcer disease, 18 Aliment
Pharmacol. Ther. 443--449 (2003).
3 Chen et al., US 2004/0175427 Al, published Sept. 9, 2004.
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Application 11/696,554
claims 202 and 203 under 35 U.S.C. § 103(a) as obvious based on Ng, Chen,
and Herbert4 (Ans. 6). The same issue is dispositive for both rejections.
The Examiner finds that Ng discloses treating patients with a
combination of clopidogrel and a PPI (lansoprazole or omeprazole ). (Ans.
3.) The Examiner finds that Ng teaches that none of the patients
administered clopidogrel and a PPI exhibited re-bleeding, but nine of the
other patients (who were administered either clopidogrel alone or
clopidogrel and an H2-receptor antagonist) did. (Id.) The Examiner finds
that Chen discloses enteric coating of omeprazole. (Id. at 5.)
The Examiner concludes that it would have been obvious to combine
clopidogrel and omeprazole in a single oral dosage form to reduce the
number of pills a patient must take and increase patient compliance (id. at 4),
and to enterically coat the dosage form because Chen teaches that
omeprazole is inactivated by acidic conditions (id. at 5).
Appellants argue that the references would not have made it prima
facie obvious to combine clopidogrel and omeprazole in a single oral dosage
form. (Appeal Br. 7-13.) Appellants also argue that they have provided
secondary evidence of nonobviousness; specifically, evidence of skepticism
in the art (id. at 13-20) and unexpected results (id. at 21-25).
We agree with Appellants that the rejections are not supported by a
preponderance of the evidence of record. However, as the Examiner
concluded, Ng supports a prima facie case of obviousness, although not a
particularly strong one. Ng states that anti-platelet therapy using aspirin is
4 Herbert et al., US 5,576,328, issued Nov. 19, 1996.
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Application 11/696,554
frequently associated with gastrointestinal adverse events, including
bleeding. (Ng 443, left col.) Ng states that clopidogrel is an anti-platelet
agent that is associated with significantly less GI hemorrhage than aspirin.
(Id. at 444, left col.) Ng describes a "retrospective study ... to evaluate the
incidence of upper gastrointestinal complications in high-risk patients
receiving clopidogrel." (Id.)
Ng found that "[o]fthe 70 high-risk patients recruited, clopidogrel-
associated significant gastrointestinal bleeding occurred in nine (14%)." (Id.
at 447, right col.) "Re-bleeding occurred in four of 24 patients (16%)
receiving H2-receptor antagonist, but in none of the patients receiving proton
pump inhibitor." (Id. at 448, left col.) Ng states that "[c]lopidogrel
treatment alone may not be safe in high-risk patients and concomitant proton
pump inhibitor prophylaxis should be considered." (Id.)
Thus, Ng expressly suggests that treatment of patients with both
clopidogrel and a PPI (including omeprazole, see id. at 444, left col.) should
be considered, at least for high-risk patients. On the other hand, Ng notes
the limits of its study. Ng states that " [ f]urther studies are needed to clarify
the effectiveness of concomitant proton pump inhibitor in reducing the
recurrence of peptic ulcer in high-risk patients taking clopidogrel." (Id. at
448, left col.) Ng also states that its study has limitations: it was
retrospective; the sample size was too small to allow firm conclusions; there
was no control group of patients not taking clopidogrel; and use of acid
suppression was not standardized. (Id. at 448.)
In summary, Ng provides a reason to treat patients with a combination
of clopidogrel and omeprazole, and states that its data show that the
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Application 11/696,554
combination reduces the incidence of re-bleeding but notes that its
conclusions are based on data having significant limitations.
Appellants have submitted evidence of secondary considerations.
Specifically, Appellants rely on the Declaration under 37 C.F.R. § 1.132 of
Thomas J. Simon, dated Sept. 24, 2010. Appellants argue that the Simon
Declaration and references cited therein provide evidence that a person of
ordinary skill in the art would been skeptical about practicing the claimed
dosage form with a reasonable expectation of success. (Br. 13.) More
specifically, Appellants argue that Dr. Simon opined that those skilled in the
art would have been skeptical of success because of, among other things,
concerns that the interactions of clopidogrel and omeprazole with
cytochrome P450 would reduce the efficacy of the clopidogrel. (Id. at 14.)
Dr. Simon testified that "clopidogrel is a prodrug, which depends on
the function of several cytochrome P450 (CYP) enzymes, including CYP
3A4 and CYP 2C19, for metabolic activation." (Simon Deel. i-f 21.) Dr.
Simon cites several prior art references as support for this statement. 5 Savi6
states that clopidogrel is inactive in vitro and requires metabolic activation in
5 Some of the references cited in the Simon Declaration were published after
the filing date of the instant application. Appellants argue that these
references should be considered nonetheless as evidence of skepticism at the
time of the invention. (See Br. 17-19.) With respect to the COGENT trial
presentation, discussed further below, we agree. We find it unnecessary to
rely on any of the other post-filing references in order to decide the issue on
appeal.
6 Savi et al., The Antiaggregating Activity of Clopidogrel Is due to a
Metabolic Activation by the Hepatic Cytochrome P450-JA, 72 Thrombosis
and Haemostasis 313-317 (1994).
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the liver to be effective in vivo. (Savi 313, left col.) Savi reports that "SKF-
525-A, a global cytochrome P450 inhibitor, dramatically decreased the
antiaggregating effect of clopidogrel, therefore indicating that cytochrome
P450 enzymes are involved in the hepatic activation." (Id., abstract.)
Clarke7 states that, "[t]o identify the human P450s responsible for
clopidogrel oxidation, genetically engineered microsomes containing a
single human P450 isozyme were tested for their ability to oxidize
clopidogrel." (Clarke, abstract.) Clarke reports that "CYP3A4 and 3A5
metabolized clopidogrel at a significantly higher rate than eight other P450
isozymes, suggesting that CYP3A4 and 3A5 are primarily responsible for in
vivo clopidogrel metabolism." (Id.)
Lau8 likewise reports that CYP3A4 is involved in clopidogrel's
metabolic activation. (Lau 166, abstract.) Lau states that "[e]rythromycin
and troleandomycin, CYP3A4 inhibitors, decreased clopidogrel efficacy, as
did atorvastatin lactone, a competitive CYP3A4 substrate." (Id. at 168, right
col.)
The cited evidence amply supports Dr. Simon's testimony that
CYP3A4, at least, was known as of the filing date of the present application
to be involved in metabolic activation of clopidogrel.
7 Clarke and Waskell, The Metabolism of Clopidogrel is Catalyzed by
Human Cytochrome P450 3A and is Inhibited by Atorvastatin, 31 Drug
Metabolism and Disposition 53-59 (2003).
8 Lau et al., Contribution of Hepatic Cytochrome P450 3A4 Metabolic
Activity to the Phenomenon of Clopidogrel Resistance, 109 Circulation 166-
171 (2004).
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Dr. Simon also testified that omeprazole inhibits CYP3A4. (Simon
Deel. ,-r 24.) Dr. Simon cites Marechal9 and Li, 10 among other references, in
support. Marechal presents "in silico predictions based on the crystal
structures of CYP3A4" and concludes that "of 33 common[ly] comedicated
drugs, 10 were predicted to be inhibitors of CYP3A4." (Marechal 534,
abstract.) Marechal states that "omeprazole ... w[as] identified by our in
silico and in vitro screens as [a] relatively potent inhibitor[] of CYP3A4."
(Id.)
Li "compare[s] the potency and specificity of [five] PPis ... as
inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and
3A4)." (Li 821, abstract.) Lee reports that omeprazole inhibits the activity
of CYP3A4 activity with a Ki of 42 µM. (Id. at 824, right col.) Thus, the
cited evidence supports Dr. Simon's position that, as of this application's
filing date, omeprazole was known to inhibit the activity of CYP3A4.
In sum, the Simon Declaration provides evidence that a person of
ordinary skill in the art, as of this application's effective filing date, would
have been skeptical that clopidogrel and omeprazole could be combined in a
single dosage form without decreasing the efficacy of clopidogrel' s efficacy
as an anti-platelet drug.
9 Marechal et al., In Silica and In Vitro Screening for Inhibition of
Cytochrome P450 CYP3A4 by Comedications Commonly Used by Patients
with Cancer, 34 Drug Metabolism and Disposition 534--538 (2006)).
10 Li et al., Comparison of Inhibitory Effects of the Proton Pump-Inhibiting
Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and
Rabeprazole on Human Cytochrome P450 Activities, 32 Drug Metabolism
and Disposition 821-827 (2004).
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The COGENT trial presentation that is of record confirms this
skepticism. 11 The presentation states that one of the aims of the trial was
"[t]o determine if there was any cardiovascular interaction between
clopidogrel and PPL" (COGENT presentation, "Aims" slide.) The
presentation describes the COGENT trial as a multi-center, international
phase 3 efficacy and safety study of administration of aspirin in combination
with a single-dosage form comprising clopidogrel and omeprazole, as
compared to administration of aspirin and clopidogrel. (Id., first "Methods"
slide.) The presentation states that the initial planned sample size was 3200
patients (id., second "Methods" slide), although a total of 3627 patients were
actually enrolled (id., "Results" slide).
Thus, the COGENT trial presentation is evidence that, even as late as
2008 to 2009, 12 those skilled in the relevant art considered a large-scale
clinical trial to be necessary to determine whether there was a cardiovascular
interaction between clopidogrel and omeprazole. In other words, despite the
publication of Ng in 2003, its tentative recommendation to co-administer
clopidogrel and omeprazole had not been accepted in the art. In our view,
the COGENT trial presentation provides evidence that, even as of the instant
application's filing date, a person of ordinary skill in the art would have
been skeptical about combining clopidogrel and omeprazole in a single oral
dosage form.
11 Dr. Simon cites the COGENT trial results as evidence of unexpected
results but in our view it is also evidence of skepticism in the art. For the
reasons discussed above, we do not reach the issue of unexpected results.
12 The COGENT trial presentation was presented at a meeting in September
2009, but the presentation does not state when the COGENT trial began.
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In summary, Ng provides a reason for combining clopidogrel and
omeprazole in a single dosage form, but Appellants have provided evidence
that a person of ordinary skill in the art would have had reason to doubt
whether the combination would successfully provide the anti-platelet effect
for which clopidogrel is administered. On balance, therefore, we cannot say
that the rejection is supported by a preponderance of the evidence of record.
"After evidence or argument is submitted by the applicant in response [to the
prima face case], patentability is determined on the totality of the record, by
a preponderance of evidence with due consideration to persuasiveness of
argument." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). Because
the rejection based on Ng and Chen is not supported by a preponderance of
the evidence, we reverse it.
The Examiner has rejected claims 202 and 203 as obvious based on
Ng, Chen, and Herbert (Ans. 6). However, Herbert is relied on only for its
disclosure of clopidogrel in powder form. (Id.) Thus, we reverse this
rejection for the same reasons discussed above.
SUMMARY
We reverse both of the rejections on appeal.
REVERSED
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