Ex Parte Thor

Board of Patent Appeals and Interferences

Feb 4, 2009

10049427 (B.P.A.I. Feb. 4, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte KARL BRUCE THOR
__________

Appeal 2008-29791
Application 10/049,427
Technology Center 1600
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Decided: February 4, 2009
__________

Before TONI R. SCHEINER, ERIC GRIMES, and
MELANIE L. MCCOLLUM, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the Examiner’s final
rejection of claims 37-42 and 51-54, all the claims pending. We have
jurisdiction under 35 U.S.C. § 6(b).

1 Heard January 13, 2009. The real party in interest is APBI Holdings, LLC,
which is a subsidiary of Pharmaceutical Product Development, Inc.
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STATEMENT OF THE CASE
“Several psychiatric drugs have been reported to have side effects of
inhibiting ejaculation. Thus oral pharmacotherapy for premature ejaculation
using . . . certain selective serotonin re-uptake inhibitor drugs has been
studied as an alternative to behavioral therapy” (Spec. 2: 27-30). However,
“[t]he daily or chronic use of conventional SSRIs . . . for such therapy may
result in adverse effects . . . In addition, chronic or daily administration of
conventional SSRIs is . . . burdensome[,]” as is “not experiencing benefit
from a drug with a single, or the first, administration” (id. at 5: 26-33).
“The invention relates to methods for the prevention, treatment, or
management of . . . premature ejaculation in men, by administering a
therapeutically effective amount of [dapoxetine] a rapid-onset selective
serotonin reuptake inhibitor, or a pharmaceutically acceptable salt thereof,
on an as-needed basis shortly before sexual activity” (id. at 1: 6-10), “while
avoiding priming doses” (id. at 19: 24-25).
Claim 37 is representative of the subject matter on appeal, and reads
as follows:
37. A method of treating or managing sexual dysfunction in a mammal in
need of treatment which comprises administering on an as-needed basis to
the mammal a therapeutically effective amount of dapoxetine or a
pharmaceutically acceptable salt thereof, wherein the sexual dysfunction is
premature ejaculation, wherein the mammal is a human male, and wherein
said administration of dapoxetine is effective for treating or managing
premature ejaculation in the absence of priming doses.

The Examiner relies on the following evidence:
Robertson et al. (Robertson) US 5,135,947 Aug. 4, 1992
Eli Lilly ZA 930694 Feb. 1, 1993
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R. M. Lane, A critical review of selective serotonin reuptake inhibitor-
related sexual dysfunction; incidence, possible aetiology and implications
for management, 11(1) Journal of Psychopharmacology 72-82 (1997).

Chris G. McMahon & Kamal Touma (McMahon), Treatment of premature
ejaculation with paroxetine hydrochloride as needed: 2 single-blind placebo
controlled crossover studies, 161(6) J. Urol. 1826-1830 (1999).

In addition, Appellant relies on the following evidence:
Declaration of David A. Rivas, MD, originally submitted July 27, 2006,
under the provisions of 37 C.F.R. § 1.132 (hereinafter “Declaration”).

The Examiner rejected claims 37-42 and 51-54 under 35 U.S.C.
§ 103(a) as unpatentable over McMahon and Lane in view of Eli Lilly and
Robertson.
We reverse.
ISSUE ON APPEAL
The issue raised by this appeal is whether the Examiner has
established that it would have been obvious for one skilled in the art to use
the selective serotonin reuptake inhibitor, dapoxetine, on an as-needed basis,
to treat premature ejaculation.
FINDINGS OF FACT
FF1 Appellant claims a method of treating or managing premature
ejaculation in human males by administering a therapeutically effective
amount of the selective serotonin reuptake inhibitor, dapoxetine, on an as-
needed basis, wherein the administration is effective in the absence of
priming doses.
FF2 According to the Specification, “[t]he terms ‘as-needed,’ ‘as-
needed basis,’ ‘prn,’ and ‘prn dosing,’ as used herein, mean administering a
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therapeutically effective amount of [dapoxetine] . . . at a time interval
sufficient to provide an improved therapeutic profile . . . in the prevention,
treatment, or management of sexual dysfunction while avoiding priming
doses, chronic administration, and/or overdosing” (Spec. 19: 20-25).
FF3 According to Dr. David A. Rivas, “[t]he concept of a priming
dose refers to a prior dose of a drug that has not been cleared from the body
at the time of administration of a subsequent dose of the drug” (Declaration
¶ 5).
FF4 The Examiner rejected claims 37-42 and 51-54 under 35 U.S.C.
§ 103(a) as unpatentable over McMahon and Lane in view of Eli Lilly and
Robertson.
FF5 Lane teaches that the use of SSRI antidepressants is associated
with various forms of sexual dysfunction, including orgasm dysfunction,
erectile dysfunction, decreased sexual desire, and delayed ejaculation (Lane
72), and suggests that because of these side effects, “SSRIs may be of use in
the management of premature ejaculation in males” (id. at 79, col. 1).
FF6 Lane also teaches that different SSRIs (e.g., paroxetine,
sertraline, fluoxetine, and fluvoxamine) have different effects on the
incidence of sexual dysfunction. Lane suggests that this is due to their
differing effects on the reuptake of dopamine (Lane 76, col. 1-2). According
to Lane, “[t]he high selectivity of paroxetine for serotonin reuptake relative
to dopamine reuptake may mean that paroxetine causes a relatively higher
incidence of sexual dysfunction than other SSRIs” (id. at 79, col. 2).
FF7 Lane suggests that “[t]he use of low doses on an as needed
basis prior to intercourse [to treat premature ejaculation] is a possibility for
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SSRIs such as fluvoxamine, paroxetine and sertraline which have half-lives
of approximately 1 day or less” (Lane 79, col. 2).
FF8 McMahon teaches that “[i]n the rat model the central
neurotransmitter serotonin has an inhibitory effect on sexual function, while
dopamine is generally stimulatory” and “[s]exual effects can occur through
any shift in this serotonin-dopamine balance by an increase or decrease in
either or both neurotransmitters” (McMahon 1826, col. 1).
FF9 McMahon evaluated the effects of administering paroxetine, a
selective serotonin reuptake inhibitor, on premature ejaculation in normally
potent men. In Study 1, the men received either 20 mg paroxetine or
placebo as needed 3 to 4 hours before planned intercourse, and their cases
were reviewed every 2 weeks. In Study 2, the men received either 10 mg
paroxetine daily for 2 weeks followed by 20 mg paroxetine as needed 3 to 4
hours before planned intercourse for a further 4 weeks, or placebo daily for 3
weeks followed by placebo as needed for 4 weeks, and their cases were
reviewed every 2 weeks (McMahon 1827, col. 1).
FF10 According to McMahon,
Study 1 demonstrated that within 1 to 2 weeks . . . paroxetine
administered as needed prolonged the ejaculatory interval. This
effect was significantly superior to that after 2 weeks of placebo
as needed. Study 2 demonstrated that the improved ejaculatory
control achieved with paroxetine daily was maintained with
continued administration of the drug as needed. Furthermore,
studies 1 and 2 demonstrated that ejaculatory control achieved
with paroxetine as needed was significantly better if patients
were initially treated with the drug daily.

(McMahon 1828, col. 1).

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FF11 Further according to McMahon,
Paroxetine as needed appeared to be more efficacious after
initial chronic dosing. . . . As a result of first pass metabolism,
which is almost exclusively mediated by the P450 2D6 enzyme,
the amount of paroxetine available to the systemic circulation is
less than that absorbed from the gastrointestinal tract. However,
paroxetine is also a potent inhibitor of this enzyme, thereby
effectively inhibiting its own metabolism and demonstrating
nonlinear pharmacokinetics. Therefore, as paroxetine
concentration increases with multiple dosing, the P450 2D6
activity decreases and, thus, prolongs drug clearance and results
in a disproportionately greater increase in concentration with
every dose.

(McMahon 1829, col. 1-2 (internal citations omitted).)
FF12 Eli Lilly discloses “a use of fluoxetine/lovan, dapoxetine,
duloxetine, amersergide, 228729, and zatosetron, to treat tobacco withdrawal
symptoms” (Eli Lilly 1), as well as hundreds of additional cravings,
disorders, diseases, symptoms, phobias, and conditions (id. at 1-8), including
premature ejaculation (id. at 8).
FF13 Eli Lilly does not disclose a method of administering any of the
compounds, nor does the reference disclose their effects on dopamine
reuptake, or their pharmacokinetic properties.
FF14 Robertson discloses dozens of specific 1-phenyl-3-
naphthalenyloxypropanamine compounds, “which are selective inhibitors of
serotonin uptake” (Robertson, col. 1, ll. 36-38), including dapoxetine (N,N-
Dimethyl-1-(3-methoxyphenyl)-3-(1-naphthalenyloxy)propanamine) (id. at
col. 3, ll. 35-36).
FF15 Robertson teaches that the compounds “have a prolonged
duration of action, and therefore are capable of inhibiting the uptake of
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serotonin for an extended period of time” (id. at col. 19, ll. 25-28), and might
be useful in treating “physiologic functions . . . subject to influence by brain
serotoninergic neural systems . . . such as obesity, depression, alcoholism,
pain, loss of memory, anxiety and smoking” (id. at col. 19, ll. 35-41).
PRINCIPLES OF LAW
“In determining whether obviousness is established by combining the
teachings of the prior art, the test is what the combined teachings of the
references would have suggested to those of ordinary skill in the art.” In re
GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal quotations
omitted). “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’l Co. v. Teleflex Inc., 550 U.S. 398, ___, 127 S.Ct. 1727,
1739 (2007).
When there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable
solutions, a person of ordinary skill has good reason to pursue
the known options within his or her technical grasp. If this
leads to the anticipated success, it is likely the product not of
innovation but of ordinary skill and common sense. In that
instance the fact that a combination was obvious to try might
show that is was obvious under § 103.

Id. at ___, 127 S.Ct. at 1742.
ANALYSIS
The Examiner concluded that “substituting the SSRIs as disclosed by
McMahon and Lane with another SSRI, specifically dapoxetine” (Ans. 11),
would have been “obvious to try” (id.), because McMahon teaches the use of
paroxetine on an as-needed basis to treat premature ejaculation, “Lane
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teaches the use of SSRIs broadly” (id.), and “Eli Lilly and Robertson
disclose finite embodiments of SSRIs as known in the art” (id.), and
“[t]herefore, a predictable potential solution to a recognized problem or need
in the art had been identified” (id.).
Appellant acknowledges that “SSRIs were known to affect sexual
function,” but contends that “multiple compounds were being considered in
the prior art for treatment of PE. . . . [and] the skilled person would not have
had a reasonable expectation of success for the use of dapoxetine to
effectively treat PE on an as-needed basis in the absence of priming doses
without the benefit of hindsight using the Applicant’s disclosure” (App. Br.
3). Appellant contends that the Examiner’s reliance on an “obvious to try”
rationale is misplaced (Reply Br. 6) because “it cannot be concluded that the
use of dapoxetine would predictably solve the problem” (id.) of treating
premature ejaculation on an as-needed basis in the absence of priming doses,
thus, “the presently claimed invention does not meet those defined
conditions of ‘a finite number of identified, predictable solutions’” set out in
KSR (id. at 3).
Appellant has the better argument. The evidence of record establishes
that SSRIs have variable effects on sexual dysfunction (FF6), and that these
variable effects are due in part to their different selectivities for serotonin
and/or dopamine reuptake (FF6), as well as their different pharmacokinetics
(FF11). For example, McMahon teaches that paroxetine exhibits non-linear
pharmacokinetics, even when administered on an as-needed basis because of
its ability to inhibit the enzyme that metabolizes it (FF11). That is, the
effects of paroxetine intensify with multiple as-needed doses because its
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clearance is prolonged, and its concentration disproportionately increased, as
each successive dose of paroxetine cumulatively inhibits its own metabolism
(FF10, 12). Eli Lilly, on the other hand, teaches “a use of” dapoxetine, and
several other compounds, in treating hundreds of addictions, cravings,
disorders, diseases, symptoms, phobias, and conditions, including premature
ejaculation (FF12), but says nothing about any of the compounds’ selectivity
for serotonin and/or dopamine reuptake, how they should be administered,
or their pharmacokinetics (FF13). Robertson mentions dapoxetine among
dozens of other SSRIs (FF14), but does not mention premature ejaculation at
all, and teaches that the compounds “have a prolonged duration of action”
(FF15).
Thus, while the prior art may have identified a finite number of
SSRIs, and taught that various SSRIs are associated with various sexual side
effects, we agree with Appellant that the Examiner has not established that
dapoxetine was known to have any of the properties that would have made it
a predictable, obvious-to-try solution to the problem of treating premature
ejaculation on an as-needed basis.
CONCLUSION OF LAW
The Examiner has not established that it would have been obvious for
one skilled in the art to use the selective serotonin reuptake inhibitor,
dapoxetine, on an as-needed basis, to treat premature ejaculation.
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SUMMARY
We reverse the Examiner’s rejection of 37-42 and 51-54 under 35 U.S.C.
§ 103(a) as unpatentable over McMahon and Lane in view of Eli Lilly and
Robertson.
REVERSED

LP

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