Ex Parte Horiuchi et al

Patent Trial and Appeal Board

Mar 16, 2018

11484132 (P.T.A.B. Mar. 16, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111484, 132 07/11/2006
65989 7590 03/20/2018
KING & SPALDING
1185 A VENUE OF THE AMERICAS
NEW YORK, NY 10036-4003
FIRST NAMED INVENTOR
Masatsugu Horiuchi
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.
17620-105001US1 7300
EXAMINER
SZNAIDMAN, MARCOS L
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
03/20/2018 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):
usptomailnyc@kslaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MASATSUGU HORIUCHI, MASARU IWAI,
TOSHIO SADA, and MAKOTO MIZUNO
Appeal 2016-003023
Application 11/484, 132 1
Technology Center 1600
Before JEFFREY N. FREDMAN, TIMOTHY G. MAJORS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
NEWMAN, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to a
pharmaceutical composition. The Examiner entered final rejections for
obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
1 Appellants identify Daiichi Sankyo Company, Limited as the real party in
interest. App. Br. 2.
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Application 11/484, 132
STATEMENT OF THE CASE
Background
Currently, calcium channel blockers and inhibitors of the
renin-angiotensin system are widely used clinically for the
prophylaxis and treatment of hypertension. Various types of
calcium channel blockers are used, and among them 1,4-
dihydropyridine derivatives .... Furthermore, as inhibitors of
the renin-angiotensin system, clinical use of angiotensin II
receptor antagonists is growing larger and larger since, first,
angiotensin II receptor antagonists lack side effects such as
cough, which has been a cause of troubles elicited by
angiotensin converting enzyme (ACE) inhibitors, and second,
they exert protective effects on the cardiovascular and renal
systems. However, the blood pressure of patients with
hypertension cannot be fully controlled by only one kind of
these drugs in many cases.
Spec. 1-2.
The Specification discloses "medicaments to prevent or to inhibit the
proliferation of vascular smooth muscles and neointima formation in blood
vessels [and] that effectively inhibit remodeling of vessels and prevent
progression of arteriosclerosis as well as restenosis of vessels following
[percutaneous coronary intervention (PCI)]." Id. at 5.
Claims 1 and 8-11 are on appeal. 2 App. Br. 3. Claim 1, the only
independent claim, is illustrative and reads as follows:
1. A pharmaceutical composition consisting of
pharmaceutically effective amounts of the following active
ingredients:
2 Claims 2-7 and 12 are cancelled. App. Br. 3.
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Application 11/484, 132
(A) an angiotensin II receptor antagonist which is
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-
l-methylethyl)-2-propyl-l-[[2 '-(IH-tetrazol-5-
yl)biphenyl-4-yl]methyl]imidazol-5-carboxylate and
(B) a calcium channel blocker which is amlodipine
or amlodipine besylate, and optionally a
pharmacologically acceptable carrier.
Appellants seek our review of the rejection of claims 1 and 8-11
under 35 U.S.C. § 103(a) as being unpatentable over Norwood, 3 Faulkner,4
Sato, 5 MacGregor, 6 Webb, 7 and Gaviraghi. 8 Ans. 2. We select claim 1 as
representative of the claims on appeal. 37 C.F.R. § 41.37(c)(l)(iv).
3 Daryl Norwood, et al.,Olmesartan Medoxomilfor Hypertension: A
Clinical Review, 27: Drug Forecast, P&T, 611-618 (2002) (hereinafter
"Norwood").
4 Michele A. Faulkner et al., Amlodipine/benazepril: fixed dose
combination therapy for hypertension, 2, 1: EXPERT OPINION ON
PHARMACOLOGY, 165-178 (2001) (hereinafter "Faulkner").
5 Keiichiro Sato, et al., 18(5): CLIN. AND EXPER. HYPERTENSION 607---624
(1996) (hereinafter "Sato").
6 Graham A. MacGregor, et al., Efficacy of Candesartan Cilexetil Alone or
in Combination With Amlodipine and Hydrochlorothiazide in Moderate-to-
Serve-Hypertension, 36: HYPERTENSION JOURNAL OF THE AMERICAN HEART
ASSOCIATION, 454--460 (2000) (hereinafter "MacGregor").
7 Webb et al., US 6,204,281 Bl, issued March 20, 2001 (hereinafter
"Webb").
8 Gaviraghi, et al., WO 00/27396 Al, published May 18, 2000 (hereinafter
"Ga viraghi ").
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DISCUSSION
The Examiner finds that Norwood, teaches "a method of treating
hypertension comprising administering a pharmaceutical composition
comprising the ARB [angiotensin (AT) receptor antagonist] Olmesartan
Medoxomil." Ans. 3 (emphasis omitted). The Examiner finds that Faulkner
teaches "a method of treating hypertension comprising administering a
pharmaceutical composition comprising the CCB [calcium channel blocker]
Amlodipine or Amlodipine besylate." Id. (emphasis omitted). The
Examiner finds that Sato and MacGregor each teach that "combinations of
ARBs and CCBs are effective in treating hypertension," and that Gaviraghi
teaches that "a combination of the ARB telmisartan and the DHP-CCB
lacidipine is effective in treating cardiovascular disorders such as
hypertension, atherosclerosis and ischemic heart disease." Id. at 3, 5
(emphasis omitted). The Examiner finds that Gaviraghi discloses that "f!
synergistic antihypertensive effect is achieved" by combining lacidipine and
telmisartan, and suggest that the combined use would provide "synergistic
antihypertensive effects, antihypertensive effect over a longer period and/or
allow a better management of any potential drug-related side effects." Id. at
5.
The Examiner finds that Webb teaches a method of treating
hypertension comprising "the administration of an ARB (or AT 1 receptor
antagonist) like Valsartan and a CCB, wherein the preferred CCB is
Amlodipine or Amlodipine besylate." Id. at 4, 5. The Examiner finds that
Webb discloses motivation for combining "different and complementary
mechanics" to control hypertension and the "surprising ... experimental
finding that the combined administration of the ARB valsartan and a CCB
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results not only in a synergistic therapeutic effect but also in additional
benefits resulting from combined treatment such as a surprising prolongation
of efficacy and a broader variety of therapeutic treatment." Id. at 4--5. The
Examiner finds that Webb discloses that "combination therapy with
valsartan and a CCB results in a more effective antihypertensive therapy
through improved efficacy as well as greater respon[se] rate." Id. at 5.
The Examiner finds that Norwood teaches:
Although the ARBs have some structural and pharmacokinetic
differences, few pharmacological differences separate these
agents from one another[.] In fact, the order of binding affinity
to the ATl receptor, compared with the AT2 receptor for ARBs
appears to be as follows: valsartan > olmesartan > candesartan
> irbesartan > telmisartan > losartan > eprosartan.
Id. at 6 (citation and emphasis omitted). The Examiner further finds that
Norwood teaches that "all the ARBs including valsartan, candesartan,
telmisartan and olmesartan have very similar pharmacological properties,
with olmesartan being more effective than valsartan in reducing blood
pressure." Id.
The Examiner concludes that the skilled artisan would have found it
obvious "to treat hypertension [by] combining two compositions
(Olmesartan Medoxomil and Amlodipine) each of which is taught by the
prior art to be useful for the same purpose (treating hypertension), in order to
form a third composition to be used for the very same purpose." Id. (citing
In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980)).
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Application 11/484, 132
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness may be rebutted with evidence of secondary
considerations, and, when such evidence is submitted, all of the evidence is
considered anew. In re Piasecki, 745 F.2d 1468, 1472-73 (Fed. Cir. 1984).
Secondary considerations include, inter alia, long-felt but unsolved needs,
failure of others, and unexpected results. In re Rouffet, 149 F.3d 1350, 1355
(Fed. Cir. 1998).
Analysis
We agree with the Examiner that, based on the cited references, it
would have been prima facie obvious to treat hypertension by administering
an ARB and a CCB in combination. The references cited by the Examiner
disclose the use of ARBs and CCBs for treatment of hypertension, disclose
that multiple types of ARBs and CCBs are known in the art, and specifically
disclose use of a combination of both an ARB and a CCB to achieve an
added benefit of combination therapy resulting in a more effective
antihypertensive therapy. See Norwood 611-12; Faulkner 165, 167-8; Sato
615; MacGregor 454, 459; Webb 1:8-57, 21-5, 34--61; 3:12-16; 7:25-32;
and Gaviraghi 1 :26-2:9. Thus, we agree with the Examiner that the skilled
artisan would have found it prima facie obvious to treat hypertension using
the claimed combination of an ARB and a CCB, olmesartan medoxomil and
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Application 11/484, 132
amlodipine, or amlodipine besylate, in a composition as taught by these
references, to achieve the benefit of combination therapy.
To respond to the prima facie case of obviousness, Appellants
advance the Declaration of Nigel John Michael Birdsall, 9 which Appellants
argue shows "that Appellants' claimed method of treating hypertension
comprising administering olmesartan medoxomil and amlodipine or
amlodipine besylate provides a synergistic response, and furthermore that
this superior efficacy was in fact unexpected by one skilled in the art as of
the priority date of January 31, 2003." App. Br. 8. Appellants argue that
"[b ]y providing evidence of unexpected results based on the observations of
synergy confirmed in the Birdsall Declaration, Appellants have rebutted the
prima facie basis of obviousness that was lacking in Kerkhoven, therefore
making the Examiner's continued reliance on Kerkhoven improper." Id.
With regard to the application of Kerkoven, the Examiner responds
that "reliance on in re Kerkhoven is appropriate, since in re Kerkhoven
provides the motivation to combine two compositions, each of which was
taught by the prior art to be useful for the same purpose" and that
demonstration of unexpected properties is a separate issue unrelated to the
application of Kerkoven. Ans. 12-13.
We agree with the Examiner that the application of Kerkoven is a
separate issue from whether evidence of unexpected results, when
considered with the prima facie case, results in a conclusion of
nonobviousness, and further agree that the Examiner properly applied
9 Declaration of Dr. Nigel John Michael Birdsall under 37 C.F.R. § 1.132,
executed October 17, 2013 (hereinafter "Birdsall Deel.").
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Kerkoven in reasoning that the skilled artisan would have been motivated to
substitute a known ARB or CCB for another such known compound, based
on the knowledge in the art that the known compounds are useful for the
same purpose. Kerkoven, 626 F .2d at 850. We agree with the Examiner that
Kerkoven supports a conclusion that the claimed invention, which claims an
ARB and a CCB known in the art at the time of the invention, is prima facie
obvious.
However, as we discuss in greater detail below, Appellants provided
persuasive and countervailing objective evidence of nonobviousness,
particularly the analysis provided by Dr. Birdsall that the composition
provided synergistic effects to recipients that were significantly greater than
would have been expected from adding the known effects of the respective
individual compounds, and the Examiner has not provided an adequate basis
to show that the increased effect would have been expected. When this
evidence is considered along with the teachings of the applied prior art, the
decision tilts in Appellants' favor.
In the Birdsall Declaration submitted by Appellants, Dr. Birdsall
opines, among other points, that "the combination of olmesartan medoxomil
and amlodipine provide[s] unexpected synergy" and that as of the time of
the invention,
because of different targets of both ARBs and especially CCBs,
one skilled in the art could not have predicted whether the
olmesartan medoxomil and amlodipine would be synergistic
because one skilled in the art could not predict whether the
combination of any ARB and any CCB not previously
combined would provide a synergistic beneficial effect.
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Application 11/484, 132
Birdsall Deel. i-f 9(C), (G). Dr. Birdsall opines that the prior art contained
evidence that the combination of certain ARBs and CCBs "did not give
synergy." Id.i-f 9(A).
With regard to identifying synergy, Dr. Birdsall opines that the
preferred analysis is the "Chou-Talalay method [of statistical analysis,
which] provides a mathematical means of quantitating the synergism (and
distinguishing it from additive or inhibitory effects) of drug combinations
when there are dose response-curves for the individual actions of the drugs."
Id. at i-f 11.4.
With regard to the Examiner's findings that Webb discloses a
synergistic effect of a valsartan (ARB) and CCB combination, Dr. Birdsall
reports that he attempted to obtain the data in Webb to analyze the results,
but reported he was unable to do so, and that the experimental data that was
reported in Webb "relates to survival rates for the combination of valsartan
and verapamil in an experimental model of diabetes" and does not relate to
hypertension. Id. at i-f 12.5. Dr. Birdsall opines that "one skilled in the art
can give no credibility to the claim of synergy made in Webb in the absence
of data to support the claim" and provides "[e]xperimental evidence that
contradicts the Webb's claims of synergy." Id. ,-r 12.11 .
Dr. Birdsall opines that he applied the Chou-Talalay method to data
published in Davis, 10 which "describe[d] the disparate effects of angiotensin
II antagonists and channel blockers on hypertension and albuminuria in an
10 Davis et al., Disparate Effects of Angiotensin II Antagonists and Calcium
Channel Blockers on Albuminuria in Experimental Diabetes and
Hypertension: Potential Role of Nephrin, 21: J. HYPERTENS. 209--216 (2003)
(hereinafter "Davis").
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Application 11/484, 132
experimental model of diabetes in spontaneously hypertensive (SHR) rats."
Id. i-f A. I. Dr. Birdsall opined that his analysis of Davis' "experimental
results for the combination valsartan with either of two CCBs that have
different mechanisms of action are in direct opposition to the statements in
Webb that are not supported by experimental data" and that the "analysis
... shows a strong, less than additive effect" when a combined therapy of
valsartan with either amlodipine or verapramil was administered. Id. i-fi-1 A.6,
A.11. From this analysis, Dr. Birdsall opines that "one skilled in the art
would not have been able to infer the activity of the combination of
olmesartan medoxomil and amlodpine from the activity of a different sartan,
valsartan, with a different CCB, verapamil, having a different mechanism of
action than amlodipine," and that "[t]he experimental data of Davis
contradict the statements in Webb that valsartan combined with amlodipine
or verapamil exhibit synergy in their antihypertensive actions or their effects
on renal disease." Id. i-fi-1 A.13, A.15. Dr. Birdsall further opines that
because of these results and others, the skilled artisan "would not have
expected a combination of olmesartan medoxomil and amlodipine would
impart more than a 'less than additive' effect (e.g., a synergistic or an
additive benefit) in reducing blood pressure." Id. i-f A.16.
The Examiner responds that "the synergistic properties of the instant
combination ... for reducing hypertension cannot be considered unexpected
since the prior art already teaches several cases of synergistic combinations
of ARBs and CCBs that were already mentioned in the above 103 rejection."
Ans. 15-16 (emphasis omitted) (citing Webb (disclosing the use of "ARB
Valsartan and the DHP-CCB Amlodipine besylate.")) (citing Gaviraghi
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(disclosing use of "the ARB tehnisartan and the DHP-CCB lacidipine.")) 11
The Examiner further responds that Appellants have failed to compare the
claimed composition to the closest prior art, Webb and MacGregor. Id. at 17
(citing MacGregor's use of "ARB candesartan and CCB amlodipine")), but
concedes later in the Answer that "MacGregor ... is silent regarding
whether the combination of the ARB candesartan and the CCB amlodipine is
synergistic or not." Id. at 29.
With regard to Dr. Birdsall's claim that no testing data were available
from Webb regarding co-administered Valsartan and Amlodipine, the
Examiner cites Webb's description of the testing (Webb 4:36-66) and finds
these statements "clearly indicate[] that experimental data was provided for
the combination of valsartan and amlodipine for the treatment of
hypertension in hypertensive rats, and that the combination shows
unexpected synergistic effects." Ans. 31.
The Examiner further responds that the Davis reference is
completely irrelevant to the current discussion, since the Davis
reference studied the effect of mixtures of the ARB valsartan
with either the CCB amlodipine or the CCB phenylalkylamine
on the progression of renal disease and the expression of the
podocyte slit pore protein, nephrin in an accelerated model of
diabetic nephropathy, which is a different study than the one
11 The Examiner further cites post-filing references "wherein studies show
that the valsartan-amlodipine combination, not only is effective for the
treatment of hypertension, it is also safe and synergistic." Ans. 17. The
prohibition against post-filing date art applies to "the impermissible
application of later knowledge about later art-related facts ... which did not
exist on the filing date." In re Hogan, 559 F.2d 595, 605 (CCPA 1977).
Because we confine our review to the record before us as viewed by the
skilled artisan at the time of the invention, we do not address this issue.
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disclosed by Webb, which measured blood pressure in
spontaneously hypertensive rats.
Ans. 31-32 (emphasis omitted). The Examiner concludes that the data of
Davis "cannot be correlated with the effect on blood pressure that will result
by administering the same mixture in the SHR (spontaneously Hypertensive
Rats) rats as disclosed by Webb" and reiterates that Webb's statements are
"not a denial that synergy occurred" and "leaves the door open that synergy
might exist." Id. at 32-33.
In reply, Appellants note that "Webb doesn't provide any
experimental data for the valsartan and amlodipine combination," and that
the Examiner's interpretation of the Webb data as "meaning that there could
be more than an additive effect," is error. Reply Br. 2-3. Appellants
additionally argue that the Examiner does not accurately differentiate
between the types of improvements disclosed in the various references. Id.
at, e.g., 4--5. Appellants argue that the prima facie burden has been
overcome because "Birdsall provides substantial objective factual evidence
of non-equivalence of the various ARBs and various CCBs," which
overcomes the Examiner's presumption that the claimed combination of
olmesartan medoxomil and amlodipine, as an ARB and CCB, would be
expected to provide a synergistic effect. Id. at 7; see also Ans. 40-41
(regarding the Examiner's presumption that "the expectation is that some or
all mixtures of ARBs and CCBs could also be synergistic, or in other words,
it should be expected that any future mixtures of ARBs and CCBs could be
synergistic.").
We find this to be a close case. As discussed above, the Examiner has
established a prima facie case that combining an ARB and a CCB for the
purpose of achieving a combined beneficial effect is obvious. However, we
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are persuaded by Dr. Birdsall's opinion that the synergistic effect of the
combination of olmesartan medoxomil and amlodipine in reducing
symptoms of hypertension was an unexpected result at the time of the
invention. See, e.g., Birdsall Deel. i-f 9A (referencing Annex 3). In
particular, we are persuaded by Dr. Birdsall's analysis of the best available
data, from Davis, which combined the claimed compound amlodopine and
valsartan, another sartan compound with a similar structure to the claimed
ARB, olmesartan medoxomil, and found no synergistic effect. Id.AI (see
Opinion A). We therefore agree with Appellants that there is factual
evidence of non-equivalence of the ARBs and CCBs, undermining the
Examiner's Kerkoven rationale.
We acknowledge but are unpersuaded by the Examiner's opinion that
any combination of an ARB and CCB would have been expected to provide
a synergistic effect at the time of the invention. Ans. 40-41. Although we
agree that a skilled worker would have reasonably expected the combination
of an ARB and CCB to be more effective than either compound alone, we
conclude that the Examiner has not provided a reasonable basis for
concluding that the observed synergy as calculated by the Chou-Talalay
method would have been expected for every such claimed combination,
including the claimed composition. Birdsall Deel. i-f E. l-E.13 (Section D,
Annex 3). In particular, we agree with Appellants that although Webb
describes testing of the valsartan and amlodipine combination, no data are
provided in Webb to permit analysis, and Dr. Birdsall' s sworn statement
indicates the data were not obtainable. Birdsall Deel. i-f 12.6. We are further
unpersuaded that the data analyzed in Davis are irrelevant as the data
measured are "the disparate effects of angiotensin II antagonists and channel
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blockers on hypertension and albmninuria in an experimental model of
diabetes in spontaneously hypertensive (SHR) rats." Id. i-f A. I. As such, the
data are comparable to those in Webb for purposes of analysis of the subject
composition.
When the Examiner's prima-facie case is considered anew, in light of
all the evidence of record, we are unpersuaded that claim 1 would have been
obvious over Norwood, Faulkner, Sato, MacGregor, Webb, and Gaviraghi.
Appellants have provided persuasive argument and objective evidence of
nonobviousness that outweighs the evidence of obviousness. Mintz v. Dietz
& Watson, Inc., 679 F.3d 1372, 1379 (Fed. Cir. 2012) ("Obviousness
requires ... walk[ing] a tightrope blindfolded (to avoid hindsight}-an
enterprise best pursued with the safety net of objective evidence.") This is
not a case where the prima facie case is so strong that it controls the
obviousness determination. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1372 (Fed. Cir. 2007). We thus reverse the rejection of claim 1 and its
dependent claims. In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992)
("[D]ependent claims are nonobvious if the independent claims from which
they depend are nonobvious.") Because the arguments pertaining to the
proposed combination of olmesartan medoxomil and amlodipine or its salt
apply equally to claims 8-11, we likewise reverse the rejection of under 35
U.S.C. § 103 over claim 1 and its dependent claims 8-11.
Conclusion of Law
The preponderance of the evidence of record does not support the
Examiner's conclusion that claims 1 and 8-11 would have been obvious.
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SUMMARY
We reverse the rejection of all claims.
REVERSED
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