Ex Parte Koppiker et al

Board of Patent Appeals and Interferences

May 19, 2008

10731905 (B.P.A.I. May. 19, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte NANDAN P. KOPPIKER and ELIOT R. FORSTER
__________

Appeal 2008-0407
Application 10/731,905
Technology Center 1600
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Decided: May 19, 2008
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Before DONALD E. ADAMS, ERIC GRIMES, and RICHARD M.
LEBOVITZ, 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 composition, which the Examiner has rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
BACKGROUND
“Neuropathy is a general term which describes a disease process
which leads to the dysfunction of the nervous system. There are many
causes of neuropathy affecting both the autonomic and peripheral nervous
systems, such as metabolic disorders e.g. diabetes” (Spec. 1). Treatment of
diabetic neuropathy focuses on providing pain relief (id. at 12: 33 to 14: 3).
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The Specification discloses “the use of cyclic guanosine 3’, 5’-
monophosphate phosphodiesterase type five (cGMP PDE5) inhibitors,
including in particular the compound sildenafil, for the treatment of
neuropathy, including in particular the treatment of diabetic neuropathy”
(id.).
DISCUSSION
1. CLAIMS
Claims 17-34 are pending and on appeal. Claims 17 and 27 are
representative and read as follows:
Claim 17: A combination comprising
a therapeutically effective amount of a cGMP PDE5 inhibitor and
a therapeutically effective amount of pregabalin or gabapentin.

Claim 27: A method of treating neuropathy in a patient suffering
therefrom which comprises administering a patient in need of therapy
thereof a therapeutically effective amount of a combination of a cGMP
PDE5 inhibitor and pregabalin or gabapentin.

2. OBVIOUSNESS
Claims 17-34 stand rejected under 35 U.S.C. § 103(a) as obvious in
view of Yamasaki, 1 Ellis, 2 Singh, 3 Bueno, 4 and Stedman’s Medical
Dictionary.5 The claims have been argued in four groups: claims 17-20 and
22-26 (Group 1), claim 21 (Group 2), claims 27-31, 33, and 34 (Group 3),

1 Yamasaki, US 6,166,219, Dec. 26, 2000.
2 Ellis et al., WO 94/28902, Dec. 22, 1994.
3 Singh, WO 98/03167, Jan. 29, 1998.
4 Bueno et al., US 6,127,418, Oct. 3, 2000.
5 Stedman’s Medical Dictionary, 22nd ed., published 1972 by The Williams
& Wilkins Company, (Baltimore), pg. 1000, “polyneuropathy”.

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and claim 32 (Group 4). The claims in each group stand or fall together. 37
C.F.R. § 41.37(c)(1)(vii).
The Examiner relies on Yamasaki as disclosing “a pharmaceutical
composition comprising a cGMP PDE5 inhibiting benzimidazole
compound” having a specific formula, and “a method of treating a disorder
that is responsive to treatment with a cGMP PDE5 inhibiting compound by
administering an effective amount” of the compound (Ans. 3). The
Examiner further finds that Yamasaki also discloses “various medical
conditions which are responsive to treatment with the cGMP PDE5
inhibiting compounds, including diabetic neuropathy” (id. at 4).
The Examiner finds that Yamasaki does not teach the cGMP PDE5
inhibitor in combination with gabapentin or pregabalin, as in claims 17 and
27, but relies on Singh as disclosing “the use of gabapentin or . . . pregabalin
… for the treatment of diabetic neuropathy” (id. at 5).
The Examiner concludes that it would “have been obvious to a person
of ordinary skill in the art to employ either gabapentin or pregabalin in
combination with a cGMP PDE5 inhibiting composition as disclosed by
Yamasaki … because each compound was known in the art to be successful
for achieving the same therapeutic effect” (id.). The Examiner finds that
“[m]otivation to administer both compounds flows logically from the
efficacy of each compound in treating diabetic neuropathy as demonstrated
in the prior art and further, because each compound has been previously
administered for this same therapeutic objective, at least additive results
would have been … expected” (id.).
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The Examiner relies on Ellis for disclosing dependent claim
limitations, as discussed below. The Examiner also relies on Stedman’s
Medical Dictionary for disclosing limitations of dependent claims that have
not been argued separately.
We conclude that the Examiner has set forth a prima facie case that
claims 17 and 27 would have been obvious to the ordinary artisan.
Yamasaki discloses benzimidazole compounds having a specific formula (I)
(Yamasaki, abstract). Yamasaki also discloses that the “benzimidazole
derivatives … are effective for preventing and treating various disorders …
based on their blood sugar level-depressing activity,” as well as for treating
“diabetic complications (e.g., . . . diabetic neuropathy, diabetic cataract,
diabetic retinopathy, etc.) … based on their cGMP-PDE (especially PDE-V)-
inhibiting activity” and other activities (id. at col. 35, ll. 22-63).
Singh discloses that gabapentin and pregabalin are effective
analgesics (Singh,6 p. 2, ll. 17-18; p. 9, ll. 12-13) and suggests that
compounds of the invention, preferably pregabalin, can be used to treat
chronic pain disorders such as diabetic neuropathy (id. at p. 1, l. 17 to p. 2,
l. 18).
We agree with the Examiner that it would have been prima facie
obvious to one of skill in the art at the time the invention was made to
combine the teachings of the cited references and thereby arrive at the
invention of claims 17 and 27. Given the explicit teaching in the cited art

6 Singh refers to pregabalin as 3-aminomethyl-5-methyl-hexanoic acid and
(S)-3-(aminomethyl)-5-methylhexanoic acid (Singh, p. 2, ll. 17-18). Bueno
discloses that these compounds are “known generically as pregabalin”
(Bueno at col. 2, ll. 51-53).
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that pregabalin, gabapentin, and a cGMP PDE5 inhibitor can all be used to
treat the same condition (i.e., diabetic neuropathy), persons of ordinary skill
in the art would have reason to have combined the claimed compounds to
treat diabetic neuropathy for their expected additive effects. As shown by
the Specification’s working example (Spec. 12-14), it was known that
treatment of diabetic neuropathy focuses on pain relief, and it is well-known
to combine pain relievers to achieve more effective pain relief.
Appellants argue that there was no motivation in the art to combine
the recited compounds because, in Yamasaki, “it is clear that the treatment
of diabetic neuropathy by the benzimidazole compounds could be mediated
by some other listed mechanism of action(s) (e.g., smooth muscle cell
suppressing activity or yet another cGMP PDE isoform)” (App. Br. 7).
Appellants further argue that Yamasaki “never directly links the two i.e.,
cGMP PDE5 inhibition and diabetic neuropathy,” and that “[w]hile
Yamasaki … discloses cGMP PDE5 and separately diabetic neuropathy, any
connection between the two is confounded by other confusing and/or
conflicting … statements” (id.).
We are not persuaded by this argument. As set forth above, Yamasaki
expressly discloses that the disclosed benzimidazole compounds can be used
to treat diabetic neuropathy, among other things, “based on their cGMP-PDE
(especially PDE-V)-inhibiting activity, smooth muscle relaxing activity,
bronchodilating activity, vasodilating activity, smooth muscle cell
suppressing activity, and antiallergic activity” (Yamasaki, col. 35, ll. 52-55).
Appellants’ argument, as we understand it, is that, based on this disclosure,
one of ordinary skill in the art could not reasonably conclude that the use in
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treating diabetic neuropathy was attributable to the “cGMP-PDE (especially
PDE-V)-inhibiting activity,” as opposed to one of the other listed activities.
In our view, however, the evidence of record supports the Examiner’s
position (Ans. 9) that the physiological effects listed by Yamasaki (“smooth
muscle relaxing activity, bronchodilating activity,” etc.) are the result of the
biochemical effect of inhibiting cGMP PDE5 activity. For example,
Yamasaki states that “[b]ecause of their blood sugar-depressing effect or
PDE5 inhibitory effect,” the disclosed compounds are useful for treating
diabetic complications, among other disorders (Yamasaki, abstract). The
same statement is repeated in addressing “Industrial Applicability” (id. at
col. 164-165). Yamasaki does not mention smooth muscle relaxing activity,
bronchodilating activity, etc. at either place, supporting the Examiner’s
position that the physiological effects listed in column 35 are merely the
result of inhibiting cGMP PDE5.
Further evidence supporting the Examiner’s position is provided by
Ellis, which states that inhibition of cyclic guanosine 3’,5’-monophosphate
phosphodiesterases (cGMP PDEs)
leads to elevated cGMP levels which, in turn, provides the basis
for . . . treatment of stable, unstable and variant (Prinzmetal)
angina, hypertension, pulmonary hypertension, congestive heart
failure, atherosclerosis, conditions of reduced blood vessel
patency e.g. post-percutaneous transluminal coronary
angioplasty (post-PTCA), peripheral vascular disease, stroke,
bronchitis, allergic asthma, chronic asthma, allergic rhinitis,
glaucoma, and diseases characterised by disorders of gut
motility, e.g. irritable bowel syndrome (IBS).
(Ellis 2.) Ellis also discloses that cGMP PDE inhibitors “are useful in the
treatment of erectile dysfunction” (id.).
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Many of the disorders listed by Ellis as being treatable based on
cGMP PDE inhibition are also listed by Yamasaki as being treatable “based
on their cGMP-PDE (especially PDE-V)-inhibiting activity, smooth muscle
relaxing activity, bronchodilating activity, vasodilating activity, smooth
muscle cell suppressing activity, and antiallergic activity.” The overlapping
disorders include
• hypertension (Yamasaki, col. 35, l. 36),
• pulmonary hypertension (id. at col. 35, l. 37),
• congestive heart failure (id.),
• atherosclerosis (id. at col. 35, l. 40),
• restenosis after PTCA (compare to Ellis’ “conditions of reduced
blood vessel patency e.g. . . . post-PTCA”)(Yamasaki, col. 35, l. 51),
• cerebral apoplexy (compare to Ellis’ “stroke”)(id. at col. 35, l. 42),
• bronchitis (id. at col. 35, l. 43),
• allergic asthma (id.),
• chronic asthma (id.),
• allergic rhinitis (id. at col. 35, l. 44),
• glaucoma (id.),
• diseases characterized by enteromotility disorders (compare to Ellis’
“diseases characterised by disorders of gut motility”)(Yamasaki, col.
35, l. 44-45), and
• impotence (compare to Ellis’ “erectile dysfunction”)(Yamasaki, col.
35, l. 46).
The overlapping disorders include some that would appear to be
treated by agents having bronchodilating activity (chronic asthma),
vasodilating activity (hypertension), smooth muscle cell suppressing activity
(restenosis after PTCA), and antiallergic activity (allergic asthma, allergic
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rhinitis). Our conclusion that all of the physiological effects listed by
Yamasaki result from the biochemical effect of inhibiting cGMP PDE
inhibition is supported by the substantial overlap between the disorders
listed by Ellis as being treatable based on cGMP PDE inhibition and those
listed by Yamasaki as being treatable based on “cGMP-PDE (especially
PDE-V)-inhibiting activity, smooth muscle relaxing activity,” etc. Our
conclusion is also supported by the fact that treatment of the disorders listed
by Ellis reasonably appear to require one of the physiological effects listed
by Yamasaki such as bronchodilation, vasodilation, etc. We therefore agree
with the Examiner that one of ordinary skill in the art would have
understood Yamasaki to disclose treating diabetic neuropathy with
compounds having “cGMP-PDE (especially PDE-V)-inhibiting activity.”
Appellants also argue that the Examiner has not established a prima
facie case of obviousness (App. Br. 6). In particular, Appellants argue that
the Yamasaki “passages relied on by the Examiner are simply a classic
invitation to experiment to determine which disease/condition should be
linked with a particular mechanism of action” (id. at 7). Appellants further
argue that “drug combinations may have drug-drug interactions, and it is the
unpredictability of such drug-drug interactions that is an important aspect of
the lack of a reasonable expectation of success” (id. at 8).
We are not persuaded by this argument. “Obviousness does not
require absolute predictability of success. . . . For obviousness under § 103,
all that is required is a reasonable expectation of success.” In re O’Farrell,
853 F.2d 894, 903-04 (Fed. Cir. 1988). In the instant case, Singh suggests
pregabalin or gabapentin for treating diabetic neuropathy and demonstrates
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that the compounds have pain relieving effect in an animal model.
Yamasaki expressly suggests treating diabetic neuropathy with a compound
that is a cGMP PDE5 inhibitor. Although specific examples demonstrating
the treatment of diabetic neuropathy or other pain are not provided by
Yamasaki, such specific demonstrations are not required. “In patent
prosecution, the examiner is entitled to reject application claims [in view of]
a prior art patent without conducting an inquiry into whether or not that
patent is enabled. . . . The applicant, however, can then overcome that
rejection by proving that the relevant disclosures of the prior art patent are
not enabled.” Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313,
1355 (Fed. Cir. 2003). Thus, “a presumption arises that both the claimed
and unclaimed disclosures in a prior art patent are enabled” (id.).
In view of the pain relief demonstrated in Singh and the presumption
of enablement that applies to the disclosure of Yamasaki, and the absence of
any evidence rebutting that presumption, we find that one of skill in the art
would have had a reasonable expectation of success in treating neuropathy
using a combination of a cGMP PDE5 inhibitor and pregabalin or
gabapentin. While we acknowledge that drug-drug interactions may occur,
an absolute predictability of success is not required, but only a reasonable
expectation of success. Thus, even in view of the possibility of drug-drug
interactions, the prior art supports a reasonable expectation of success for the
claimed invention.
Claims 21 and 32, which Appellants argue separately, are directed to a
composition and method, respectively, that are similar to those of claims 17
and 27, respectively, but require that the cGMP PDE5 inhibitor is sildenafil.
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With regard to claims 21 and 32, the Examiner finds that Yamasaki does not
“expressly teach the use of the cGMP PDE5 inhibitor sildenafil …. as a
compound for treating diabetic neuropathy” (Ans. 6). The Examiner relies
on Ellis as disclosing that sildenafil is “a potent and selective inhibitor of
cGMP-specific PDE5” (id.).7
The Examiner concludes that “it would have been an obvious
conclusion to one of ordinary skill in the art that the treatment of a condition
known to be responsive to a cGMP PDE5 inhibiting agent would not be
solely limited to those compounds disclosed by Yamasaki …, but that
effective treatment of such a condition would have been reasonably expected
to occur with any one or more other compounds known to exert the same
effect (i.e., the inhibition of cGMP PDE5)” (id.). The Examiner further
concludes that it would have been obvious to use sildenafil to treat diabetic
neuropathy because sildenafil “was well known in the art to exert inhibitory
effects on cGMP-PDE5 and … would have been reasonably expected to
demonstrate the same, or substantially similar, efficacy in treating diabetic
neuropathy, as that shown by the benzimidazole cGMP-PDE inhibiting
compounds” of Yamasaki (id.).
We conclude that the Examiner has set forth a prima facie case that
claims 21 and 32 would have been obvious to the ordinary artisan. Ellis
discloses pyrazolopyrimidinones for the treatment of impotence (Ellis,

7 The Examiner relies on the instant Specification as establishing that the
compound referred to by Ellis as 5-[2-ethoxy-5-(4-methyl-1-
piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one is also known as sildenafil (id.; citing the
Spec. at pg. 1, ll. 12-13).
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abstract). Ellis also discloses that one of the preferred compounds is
sildenafil (id. at pg. 7, ll. 1-3). Ellis also discloses that sildenafil is an
inhibitor of cGMP PDE5 (id. at pg. 9, last para.). We agree with the
Examiner that Ellis’s teaching that sildenafil is a potent inhibitor of cGMP
PDE5 would have reasonably suggested to one of skill in the art substituting
sildenafil for the benzimidazole compounds of Yamasaki in the method
suggested by the references of treating neuropathy using a combination of a
cGMP PDE5 inhibitor and pregabalin or gabapentin.
Appellants argue that there is nothing to motivate the particular
selection of sildenafil (or its pharmaceutically acceptable salts) from among
cGMP inhibitors (Appeal Br. 6).
We are not persuaded by this argument. In view of the Examiner’s
well-stated arguments set forth above, we agree that the references as a
whole suggest the substitution of the cGMP PDE5 inhibitor sildenafil of
Ellis for the cGMP PDE-inhibiting benzimidazoles of Yamasaki, and thus
suggest the claimed invention.
SUMMARY
The Examiner’s rejection is supported by the preponderance of the
evidence of record. We therefore affirm the rejection of claims 17-34 under
35 U.S.C. § 103.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED

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