Ex Parte CLOZEL

Patent Trial and Appeal Board

Sep 29, 2016

13604148 (P.T.A.B. Sep. 29, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/604,148 09/05/2012
50446 7590 10/03/2016
HOXIE & ASSOCIATES LLC
75 MAIN STREET, SUITE 203
MILLBURN, NJ 07041
FIRST NAMED INVENTOR
Martine CLOZEL
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.
AC-66-USC 5499
EXAMINER
CARTER, KENDRA D
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
10/03/2016 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):
HoxiePatentMail@hoxpat.com
HoxiePatentMail@gmail.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MAR TINE CLOZEL
Appeal2014-009320
Application 13/604,148 1
Technology Center 1600
Before LORA M. GREEN, FRANCISCO C. PRATS, and
KRISTI L. R. SA WERT, Administrative Patent Judges.
SA WERT, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the rejection of claims
1-14 ofU.S. Patent Application No. 13/604,148 ("the '148 application").
We have jurisdiction under 35 U.S.C. § 6(b).
1 Appellants identify Actelion Pharmaceuticals Ltd. as the real party in
interest. Appeal Br. 2.
Appeal2014-009320
Application 13/604,148
STATEMENT OF THE CASE
Claims 1-14 are on appeal and stand rejected as unpatentable under
35 U.S.C. § 103(a) over Bolli2 in view ofKeyser3. Final Off. Act. 11.
Claims 1-14 also stand rejected on the ground of non-statutory obviousness-
type double patenting over claims 8 and 9 of Bolli '781 4 in view of Bolli and
Keyser. Id. at 3-5. The Examiner has also provisionally rejected claims 1-
14 on the ground of non-statutory obviousness-type double patenting over
claims 1, 9, 10, and 18 of Adesuyi '1425 in view ofBolli and Keyser, id. at
6-8, and over claims 1-11 of Clozel '8476 in view ofBolli and Keyser, id. at
8-10.
Claim 1 is illustrative of the claims on appeal. Claim 1 provides:
1. A method for the treatment of hypertension,
pulmonary hypertension or pulmonary arterial hypertension,
comprising administering simultaneously, separately or over a
period of time, to a patient in need thereof~ an effective amount
of a compound of formula (I):
2 Martin Bolli et al., WO 02/053557 Al (published July 11, 2002) ("Bolli").
3 Donald Keyser and Richard Dixon, WO 2006/026395 Al (published
March 9, 2006) ("Keyser").
4 Martin Bolli et al., U.S. Patent No. 7,094,781 B2 (issued August 22, 2006)
("Bolli '781 ").
5 Charles Tokunbo Adesuyi, U.S. Application No. 12/388,142 (filed Feb. 18,
2009) (issued as U.S. Patent No. 8,367,685 B2 on February 5, 2013)
("Adesuyi '142").
6 Martine Clozel, U.S. Patent No. 8,268,847 B2 (issued September 18, 2012)
("Clozel '84 7").
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Appeal2014-009320
Application 13/604,148
0)
in free or pharmaceutically acceptable salt form, and at least
one compound having PDE5-inhibitory properties, in free or
pharmaceutically acceptable salt form.
Appeal Br. 12.
DISCUSSION
We have reviewed Appellant's arguments in the Briefs, the
Examiner's Final Office Action, and the Examiner's Answer to the
Appellant's arguments. Although we find that the Examiner made an
adequate prima facie case of obviousness, we also find that the Examiner did
not adequately respond to Appellant's argument that the claimed invention
produces unexpectedly superior results. Thus, we reverse the rejection of
claims 1-14 for obviousness over Bolli in view of Keyser, for non-statutory
obviousness-type double patenting over claims 8 and 9 ofBolli '781 in view
of Bolli and Keyser, and for non-statutory obviousness-type double
patenting over claims 1, 9, 10, and 18 of Adesuyi '142 in view ofBolli and
Keyser. However, because the unexpectedly superior results do not apply to
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Application 13/604,148
the Examiner's rejection of claims 1-11 of Clozel '847 in view of Bolli and
Keyser, we affirm this rejection.
Background
The subject matter disclosed in the' 148 application relates to a
pharmaceutical product comprising the compound of formula (I):
(I)
in combination with at least one comnound havirn.r PDE5 7-inhibitorv
~ ~ J
properties. Spec. 1. The Specification teaches that the compound of
formula (I) is a known endothelin-receptor antagonist useful for the
treatment of various diseases involving vasoconstriction (e.g., heart failure,
angina pectoris, pulmonary and systemic hypertension, and erectile
dysfunction). Id. In addition, the Specification teaches that
pyrazolopyrimidinone derivatives (e.g., sildenafil, vardenafil, tadalafil, and
udenafil) are known PDE5 inhibitors also useful for the treatment of the
same vasoconstriction-related diseases. Id.
7 PDE5 stands for cyclic guanosine 3 ', 5 '-monophosphate ( cGMP)
phosphodiesterase type 5. Spec. 2.
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Application 13/604,148
The Specification states that the claimed invention is based on the
"surprising[]" finding "that the combination of the compound of formula (I)
with a compound having PDE5-inhibitory properties results in an
unexpected synergistic effect in the treatment of diseases wherein
vasoconstriction is involved." Id. at 2. In test Example 1, for example, the
administration of a compound of formula (I) decreased blood pressure with
an ABC ("area above the curve") of 25 6, and the administration of tadalafil
decreased blood pressure with an ABC of 310. But, the administration of a
combination of a compound of formula (I) and tadalafil decreased blood
pressure with an ABC of 923, which the Specification describes as a
"synergistic effect." Id. at 9; see also id. at 9-10 (Examples 2 and 3).
The Examiner rejected claims 1-14 for obviousness over Bolli in view
of Keyser. Final Off. Act. 11. Bolli discloses pyrimidine-sulfamides of the
general formula I. Bolli 12-14. Of those compounds, Bolli specifically
discloses the compound of formula (I) presently claimed in the '148
application. See id. at 28 (top right-hand comer). Bolli teaches that the
compounds act as endothelin-receptor antagonists, id. at 1, useful "for
treatment of diseases, which are associated with an increase in
vasoconstriction, proliferation or inflammation due to endothelin," such as
hypertension and pulmonary hypertension, id. at 11. Moreover, Bolli
teaches that the compounds of general formula I "may also be used in
combination with one or more other therapeutically useful substances," such
as a- and B-blockers, vasodilators, calcium-antagonists, ACE-inhibitors,
potassium activators, angiotensin II receptor antagonists, diuretics,
sympatholitics, "and other therapeutics which serve to treat high blood
pressure or any cardiac disorders." Id. at 17.
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Appeal2014-009320
Application 13/604,148
Bolli does not specifically teach that the "other therapeutics" may be
PDE5 inhibitors. Final Off. Act. 12. The Examiner relied on Keyser to
make up for this deficiency. Keyser discloses "combination therapies"
comprising an endothelin A receptor (ET A)8 antagonist and a PDE5 inhibitor
for the treatment and prevention of cardiac disorders such as pulmonary
arterial hypertension. Keyser (Abstract). Keyser specifically identifies
sildenafil, tadalafil, vardenafil, and dasantafil as PDE5 inhibitors. Id. ii 29.
Keyser also lists several known peptide and nonpeptidic ETA antagonists,
including: "cyclic peptides, acyltripeptides, hexapeptide analogs, certain
anthraquinone derivatives, indanecarboxylic acids, certain N-
pyrimidinylbenzenesulfonamides, certain benzenesulfonamides, and certain
naphthalenesulfonamides." Id. ii 48. Finally, Keyser teaches that the ETA
antagonist and PDE5 inhibitor may be administered together in a "dual drug
tablet[]," or in "separate dosage formulations so that each may be
administered substantially concurrently or [] sequentially to provide required
therapeutic amounts." Id. ii 32.
Keyser does not identify the compound of formula (I) presently
claimed in the '148 application. However, the Examiner argued that it
would have been obvious to
combine the compound of Formula I and a PDE5 inhibitor such
as tadalafil and sildenafil to treat pulmonary arterial
hypertension, because the compound of Formula I is a ET
antagonist, and Keyser et al. teach that an ET antagonist and
PDE5 inhibitors such as sildenafil and tadalafil can be
8 There are two types of endothelin receptors: endothelin A (ETA) and
endothelin B (ETB). ETA is predominant in cardiovascular tissues. Keyser
ii 12.
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Application 13/604,148
combined to treat pulmonary hypertension, hypertension and
pulmonary arterial hypertension.
Final Off. Act. 13.
Analysis
A.
We agree with the Examiner that it would have been prima facie
obvious to administer the compound of formula (I) as disclosed in Bolli and
a PDE5 antagonist as taught by Keyser to treat hypertension.9 Accordingly,
we adopt the Examiner's fact findings and rationales provided in pages 11-
13 of the Final Office Action. Where we disagree, however, is with the
Examiner's treatment of Appellant's alleged unexpectedly superior results.
It is well established that "the prima facie case is merely a procedural
device that enables an appropriate shift of the burden of production" from
the examiner to the applicant. Hyatt v. Dudas, 492 F.3d 1365, 1369 (Fed.
Cir. 2007). Here, the Appellant responds to the prima facie case with
evidence of unexpectedly superior results. "After evidence or argument is
9 For the sake of completeness, we note that Appellant's extensive "lead
compound" arguments are inapposite to this case because the compound of
formula (I) is not novel. See Takeda Chem. Indus., Ltd. v. Alphapharm Pty.,
Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007) ("We have held that structural
similarity between claimed and prior art subject matter, proved by
combining references or otherwise, where the prior art gives reason or
motivation to make the claimed compositions, creates a prima facie case of
obviousness. In addition to structural similarity between the compounds, a
prima facie case of obviousness also requires a showing of adequate support
in the prior art for the change in structure." (citations and quotations
omitted)).
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Application 13/604,148
submitted by the applicant in response, 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). Indeed, "[i]n reviewing the examiner's decision on appeal, the
Board must necessarily weigh all of the evidence and argument." Id.
Upon reviewing the evidence of record, we find that Appellant
submitted persuasive evidence of unexpectedly superior results that the
Examiner did not adequately rebut. Specifically, Appellant found that the
administration of the compound of formula (I) and a PDE5 antagonist
decreased blood pressure in an amount much greater than either compound
alone, thus producing a synergistic effect. Spec. 9-10 (Examples 1-3). In
the case of synergistic effects, the "key question" as to obviousness is
whether the combination of the compound of formula (I) and a PDE5
antagonist "proved more effective than what would have been expected in
view of the prior art." Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd., 719
F.3d 1346, 1351-52 (Fed. Cir. 2013) (emphasis added). Here, the
Examiner's response to Appellant's assertion of unexpected results consists
of the following:
With regard to the unexpected and synergistic results, the
Examiner has considered the results and still does not find it
persuasive to overcome the rejections of record because of the
reasons above. Particularly, a combination of an ET antagonist
and a PDE5 inhibitor is taught. There is no evidence that the
claimed compound is unexpected to be better than the N-ethyl
analog (closest tested compound of art) taught by Bolli et al. for
instance. Therefore the Applicant's arguments are non-
persuasive to overcome the 35 U.S.C. 103(a) and obviousness
type double patenting rejections of record.
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Application 13/604,148
Ans. 14.
The Examiner refers to the N-ethyl analog of the compound of
formula (I) disclosed in Bolli, and appears to imply that Appellant had a
burden to test the effectiveness of that compound in combination with a
PDE5 inhibitor. We disagree; the combination of the N-ethyl analog and a
PDE5 inhibitor does not exist in the prior art. "It is not required that the
claimed invention be compared with subject matter that does not exist in the
prior art. The applicant is not required to create prior art, nor to prove that
his invention would have been obvious if the prior art were different than it
actually was." In re Geiger, 815 F.2d 686, 690 (Fed. Cir. 1987) (Newman,
J. concurring). Thus, we find that the Examiner has not persuasively showed
by a preponderance of the evidence that Appellant's synergistic effects
would have been expected from the prior art.
Moreover, we find that Appellant has presented persuasive evidence
that an ordinarily skilled artisan would not have expected the synergistic
effects produced by the administration of the compound of formula (I) and a
PDE5 inhibitor. The compound of formula (I) is a dual ETA-ETB (i.e.,
nonselective) inhibitor. Appeal Br. 8-9. Keyser teaches that "[ u ]se of a
nonselective ET receptor [inhibitor] interferes with multiple pathways
whereas use of a specific ETA antagonist will act in a complementary
fashion for the multiple pathways (PDE and/or prostacyclin and/or ETA) to
provide superior efficacy and/or dosage regimes and/or reduction in side
effects." Keyser ,-i 67.
Specifically, Keyser explains that ETA causes vasoconstriction. Id. at
,-i 68. Thus, administration of an ETA antagonist results in less
vasoconstriction, which in tum ameliorates the symptoms of hypertension.
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Application 13/604,148
ETB, on the other hand, causes vasodilation. Id. ETB-mediated vasodilation
occurs through a series of steps leading to an increase in cGMP 10 levels. Id.
cGMP relaxes blood vessels, but PDE5 breaks down cGMP. Id.
Administration of a PDE5 antagonist prevents the breakdown of cGMP, thus
leading to "increased vasodilation and better efficacy of both" the ET A
antagonist and the PDE5 antagonist. Id. Conversely, Keyser explains,
"[ n ]onselective antagonists would not function as effectively because they
block the ETB stimulated cGMP production." Id.
Based on this description, we find that an ordinarily skilled artisan
would not have expected the administration of a nonselective ET antagonist,
such as the compound of formula (I), and a PDE5 antagonist to have
produced the synergistic results provided in Appellant's Specification. If
anything, the skilled artisan most likely would have expected inferior results
based on the discussion in Keyser. See Keyser ,-i,-i 68-69. For these reasons,
we determine that the Examiner's rejection of claims 1-14 for obviousness
over Bolli in view of Keyser is unsupported by a preponderance of the
evidence and therefore we reverse this rejection.
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Application 13/604,148
B.
For the same reasons, we also determine that the Examiner's
rejections of claims 1-14 for non-statutory obviousness-type double
patenting over claims 8 and 9 ofBolli '781 in view ofBolli and Keyser, and
for non-statutory obviousness-type double patenting over claims 1, 9, 10,
and 18 of Adesuyi '142 in view of Bolli and Keyser, lack support by a
preponderance of the evidence. Like Bolli, both Bolli '781 and Adesuyi
'142 teach the compound of formula (I). But neither reference teaches or
suggests that the synergistic results obtained from the presently claimed
invention would have been expected to an ordinarily skilled artisan. Thus,
we reverse these non-statutory obviousness-type double patenting rejections.
c.
Finally, we affirm the obviousness-type double patenting rejection of
claims 1-14 over claims 1-11 of Clozel '84 7 in view of Bolli and Keyser.
Clozel '84 7 teaches a method for treating hypertension or pulmonary
hypertension by administering an effective amount of the compound of
formula (I) in combination with a PDE5 inhibitory compound. See, e.g.,
Clozel '847 (col. 8, 11. 29-35); see also Final Off. Act. 8-10. But, as
Appellant notes, the '148 application is a continuation of the application
leading to the '847 patent, Appeal Br. 11, and therefore is not prior art to the
present application. We agree with the Examiner that a non-statutory
obviousness-type double patenting rejection is appropriate in this case
because representative claim 1 is not patentably distinct from the claims of
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Application 13/604,148
Clozel '847. Specifically, representative claim 1 would be anticipated11 by
the claims of Clozel '84 7, but for the fact that Clozel '84 7 is not prior art. In
re Goodman, 11 F.3d 1046, 1052-53 (Fed. Cir. 1993). Appellant makes no
argument against the merits of this rejection. Therefore, we affirm.
SUMMARY
We affirm the obviousness-type double patenting rejection of claims
1-14 over claims 1-11 of Clozel '847 in view ofBolli and Keyser. We
reverse all other standing rejections.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.136(a).
AFFIRMED
11 Specifically, Clozel '84 7 discloses all elements of representative claim 1,
except for the treatment of "pulmonary arterial hypertension." Final Off.
Act. 8-9. But because representative claim 1 recites pulmonary arterial
hypertension in the alternative (i.e., "the treatment of hypertension,
pulmonary hypertension or pulmonary arterial hypertension"), Clozel '84 7
anticipates. See Titanium Metals Corp. of Am. v. Banner, 778 F.2d 775, 782
(Fed. Cir. 1985) ("It is also an elementary principle of patent law that when,
as by a recitation of ranges or otherwise, a claim covers several
compositions, the claim is 'anticipated' if one of them is in the prior art.").
12