Ex Parte Kucharik

Board of Patent Appeals and Interferences

Jul 31, 2012

10846822 (B.P.A.I. Jul. 31, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/846,822 05/13/2004 Robert F. Kucharik 18184-0013US1 2645
7590 08/01/2012
Daniel A. Monaco, Esq.
Drinker Biddle & Reath LLP
One Logan Square
18th and Cherry Streets
Philadelphia, PA 19103-6996
EXAMINER
SPIVACK, PHYLLIS G
ART UNIT PAPER NUMBER
1629
MAIL DATE DELIVERY MODE
08/01/2012 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ROBERT F. KUCHARIK
__________

Appeal 2011-002615
Application 10/846,822
Technology Center 1600
__________

Before TONI R. SCHEINER, DEMETRA J. MILLS, and
LORA M. GREEN, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating irritable bowel syndrome. The Examiner has rejected the claims
as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses that tofisopam, “a racemic mixture of (R)-
and (S)-enantiomers,” (Spec. 1:15), “is a non-sedative anxiolytic that … has
been used in the treatment of gastrointestinal disorders, including irritable
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bowel syndrome” (id. at 1:17-20). In contrast, the present invention is
directed to “a method of treating or preventing altered bowel motility in an
individual … comprising administering to the individual an effective amount
of enantiomerically-pure (R)-tofisopam” (id. at 4:21-26).
Claims 11-16 and 21-26 are on appeal. Claim 11, the only
independent claim, reads as follows:
11. A method of treating irritable bowel syndrome in an individual in
need of such treatment, comprising administering to the individual an
effective amount of enantiomerically-pure-(R)-tofisopam; or a
pharmaceutically-acceptable salt thereof.
The Examiner has rejected claims 11-16 and 21-26 under 35 U.S.C. §
103(a) as being obvious in view of Hanajima
1
and Landry.
2

ISSUES
Does the evidence of record support the Examiner‟s conclusion that
treating irritable bowel syndrome by administering the (R)-enantiomer of
tofisopam would have been obvious given the teachings of the prior art?
If so, has Appellant presented evidence of unexpected results that
outweighs the evidence supporting the prima facie case of obviousness?
FINDINGS OF FACT
The Prior Art
FF1. Hanajima discloses that “[m]any diseases are known in which
psychological and social factors appear to be intimately related to the

1
Hiroshi Hanajima, Effects of Tofisopam (Grandaxin) or Irritable Colon
and Cardiac Neurosis, 15(5) Department of Internal Medicine, Kosei
Hospital 307-317 (1987).
2
Landry et al., US 6,080,736, issued Jun. 27, 2000.
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development of physical abnormalities and lesions” (Hanajima 1). One such
disease is irritable bowel syndrome (IBS) (id.).
FF2. Hanajima discloses that many patients with IBS also complain
of psychological and mental symptoms, including depression with associated
anxiety and irritability (Hanajima 3), and “[t]ranquilizers, antidepressants,
autonomic nerve stabilizers, etc., are used as drug therapies together with
psychotherapy” to treat IBS (id. at 1).
FF3. Hanajima discloses that the “effects of tofisopam (Grandaxin
tablets®) were studied in 15 patients with irritable bowel syndrome” (id. at
17), and the “global effect was excellent in one patient (6.7%), good in six
(40%), fair in four (26.7%), poor in four (26.7%), and exacerbation [was
observed] in 0. The efficacy rate consisting of an at least fair result was
73.3%” (id.).
FF4. Hanajima discloses that “tofisopam appears to be effective for
improving irritable bowel syndrome and … is a highly safe drug” (id. at 18).
FF5. Landry teaches that Grandaxin™, a racemic mixture of
tofisopam, is a tranquilizer, i.e., an anxiolytic drug, that “possesses
antianxiety activity and provides therapy and reduction of symptoms.
However, this racemic mixture causes adverse effects including but not
limited to excess stimulation, agitation and inability to sleep” (Landry, col.
6, ll. 16-33; 15, ll. 27-32).
FF6. Landry discloses that treating or preventing anxiety and anxiety
disorders in humans by administering a therapeutically effective amount of
“the R enantiomer of tofisopam substantially free of its S enantiomer . . .
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result[s] in diminished adverse effects and accordingly an improved
therapeutic index” with respect to anxiety (id. at col. 15, ll. 18-27, 34-36).
The “term „substantially free of its S enantiomer‟ . . . means that the
composition contain[s] at least 90% by weight of R-tofisopam and 10% by
weight or less of S-tofisopam” (id. at col. 15, ll. 40-43).
FF7. Landry discloses that “R-tofisopam may be administered before,
along with, or after other psychoactive compounds, particularly those with
antidepressant activity” (id. at col. 16, ll. 31-33).
FF8. Landry discloses that individuals with Generalized Anxiety
Disorder “often have associated somatic symptoms such as headaches or
irritable bowel syndrome” (Landry, col. 12, ll. 4-8).
Secondary Considerations
FF9. Appellant has provided a declaration under 37 C.F.R. § 1.132
(Declaration of Henry I. Jacoby, filed Nov. 6, 2008, Appeal Br. B1-B14).
FF10. Dr. Jacoby declares that a “glass bead test was performed to
compare the effects of racemic tofisopam, (R)-tofisopam and (S)-tofisopam
on stimulated colonic propulsion. The protocol of Example 2 of the
patent application was followed, except that the drug doses were 4, 8, 16 and
32 mg/kg IP.” (Jacoby Declaration ¶ 7).
FF11. Dr. Jacoby declares that the results of glass bead test are shown
in Table 1 (id.), which is presented below:
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FF12. Dr. Jacoby declares that the “results demonstrate that the
effective dose of R-tofisopam to produce 50% inhibition (ED50) of
stimulated colonic propulsion was estimated to be 9.9 mg/kg, while the dose
of racemic tofisopam producing the same effect was estimated to be 24.5
mg/kg” (id. at ¶ 8).
FF13. Dr. Jacoby declares that “the findings of this study demonstrate
that (R)-tofisopam is more than twice as potent as racemic tofisopam in
inhibiting stimulated colonic propulsion. These results, therefore, are
surprising and unexpected” (id. at ¶ 10).
FF14. Dr. Jacoby declares that even if all of the activity in the
racemic mixture was with the R-tofisopam, one of skill in the art “would
expect that the fully-active isomer would have, at most, twice the potency of
the racemate” (id. at ¶ 9).
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FF15. The Specification, Example 2, discloses a colonic propulsion
study using glass beads in mice (Spec. 17:25-18:16).
FF16. The Specification discloses that “(RS)-, (R)- and (S)-tofisopam
were evaluated for their ability to increase or decrease the time for expulsion
of the glass bead” (id. at 18:4-7).
FF17. The Specification discloses that the results of the study are
shown in Table 1 (id. at 18:4-13), which is presented below:

FF18. The Specification discloses that “(R)- and (S)-tofisopam
significantly prolonged (i.e., slowed) colonic expulsion, with (R)- and (S)-
tofisopam producing near maximal inhibition at most doses tested” (id. at
18:14-16).
ANALYSIS
Claim 11 is directed to a method of treating irritable bowel syndrome
in an individual in need of such treatment, comprising administering to the
individual an effective amount of enantiomerically-pure (R)-tofisopam, or a
pharmaceutically-acceptable salt thereof.
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We agree with the Examiner that it would have been obvious to
modify the IBS treatment protocol disclosed in Hanajima by administering
enantiomerically-pure (R)-tofisopam, rather than racemic tofisopam, in order
to achieve an improved side-effect profile as disclosed in Landry, given the
fact that Hanajima discloses that tofisopam is a highly safe drug which is
effective for improving irritable bowel syndrome (FF4), and the fact that
Landry discloses that the use of (R)-tofisopam substantially free of (S)-
tofisopam results in diminished adverse effects compared to the racemate
(FF6), and for the reasons discussed below in connection with Appellant‟s
arguments.
Appellant argues that Hanajima does not discuss the R-enantiomer of
tofisopam, and does not even “demonstrate that racemic tofisopam was
particularly effective in treating IBS” (Appeal Br. 4-5), while Landry merely
discloses the treatment of anxiety with the R-enantiomer and “[t]here is
nothing in . . . Landry suggesting that (R)-tofisopam would be useful for
treating IBS” (id. at 5). Appellant contends that “IBS and anxiety are
separate disorders” (id. at 6), and the fact that they are “occasionally
comorbid . . . does not mean that one is subsumed in the other, or that one
causes the other, or that treatment of one will result in alleviation of the
other” (id.). Appellant contends that “Landry‟s statement that [Generalized
Anxiety Disorder] sufferers may have „associated somatic symptoms such as
. . . irritable bowel syndrome‟” is “not a teaching to administer (R)-
tofisopam to treat IBS” (id.). Appellant contends that “[j]ust because (R)-
tofisopam is effective as an anxiolytic does not necessarily mean that it will
be effective in a totally different indication, IBS” (id.at 10), and one skilled
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in the art could not have reasonably predicted the activity of (R)-tofisopam
in treating IBS, based on its activity in treating anxiety (id. at 7).
Appellant‟s arguments are not persuasive. First, as set forth above,
Hanajima does teach that administration of racemic tofisopam is effective in
treating IBS. In fact, Hanajima teaches that racemic tofisopam produces a
fair or better result 73.3% of the time, and explicitly states that “tofisopam
appears to be effective for improving irritable bowel syndrome and … is a
highly safe drug” (FFs 3, 4).
Second, while we agree with Appellant that IBS and anxiety are
separate disorders, and we agree with the general principle that comorbidity
does not mean that treatment of one disorder will result in alleviation of a
co-occurring disorder, the fact is that Hanajima establishes that this
particular disorder, IBS, is often treated with psychoactive drugs, like
tranquilizers and antidepressants (FF2). Inasmuch as Landry discloses that
the R-enantiomer of tofisopam, like racemic tofisopam, retains its anxiolytic
(i.e., tranquilizer) activity (FF6), and produces fewer undesirable side
effects, we agree with the Examiner‟s conclusion that treating IBS with the
R-enantiomer of tofisopam would have been prima facie obvious, and one of
ordinary skill in the art would have reasonably expected the R-enantiomer to
have a beneficial effect on IBS, similar to the racemate (Ans. 8).
Nevertheless, Appellant argues that any prima facie case of
obviousness has been overcome by evidence of unexpected results (App. Br.
11-16). Appellant contends that the Jacoby Declaration and Example 2 of
the Specification “demonstrate[] (R)-tofisopam‟s unexpectedly superior
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results when compared to racemic tofisopam in animal models relevant to
treating IBS” (id. at 11).
It is well settled that “[a]fter a prima facie case of obviousness has
been established, the burden of going forward shifts to the applicant. . . . If
rebuttal evidence of adequate weight is produced, the holding of prima facie
obviousness, being but a legal inference from previously uncontradicted
evidence, is dissipated.” In re Piasecki, 745 F.2d 1468, 1472, (Fed. Cir.
1984) (citations omitted).
We have considered Appellant‟s invention in light of the proffered
evidence, but agree with the Examiner that the evidence presented in the
Jacoby Declaration and the Specification is insufficient to rebut the
conclusion that the claimed invention would have been obvious over the
prior art.
The assertion in the Jacoby Declaration is that, based on extrapolation
from the dose-response data shown in Table 1, the amount of tofisopam
required to produce 50% inhibition of colonic propulsion is 24 mg/kg for the
racemate and 9.9 mg/kg for the R-enantiomer, i.e. more than twice as much
of the racemate, is required. Thus, Dr. Jacoby asserts that this data indicates
that the R-enantiomer is more than twice as effective as the racemate, which
would be unexpected.
However, Appellant has not explained how the estimate of 9.9 mg/kg
to obtain 50% inhibition is a reliable estimate since the data actually show
that a dose of 16 mg/kg of the R-enantiomer only resulted in the 35%
inhibition of colonic propulsion. Further, the data show that at a dose of 8
mg/kg, the racemic tofisopam produced a better result, i.e. 42% inhibition,
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than the R-enantiomer, i.e. 32% inhibition. In view of these discrepancies in
the data, we conclude that the evidence presented in the Jacoby Declaration
are not of adequate weight to rebut to the prima facie case of obviousness.
As for Example 2 of the Specification, Appellant argues that the
results of that study on colonic propulsive motility also demonstrate
unexpected results (Appeal Br. 11-12). Appellant argues that the results of
the study show that “(R)-tofisopam at 16 mg/kg produced 100% inhibition of
colonic propulsive motility. At double (32 mg/kg) and even quadruple (64
mg/kg) this dose, the racemate was still not able to induce 100% inhibition”
(id. at 11). Appellant argues that even if the “(R) isomer is solely
responsible for the therapeutic activity of tofisopam against IBS …, the
expectation would have been that 32mg/kg racemate would provide 100%
inhibition of colonic propulsive motility” (id. at 12).
We agree with the Examiner that the evidence presented in Example 2
of the Specification is insufficient to overcome the prima facie case of
obviousness. We note that the data presented in Example 2 and the data
presented in the Jacoby Declaration are inconsistent. For example, the
Jacoby Declaration discloses that, in general, a greater degree of colonic
mobility inhibition was achieved with the racemate versus (S)-tofisopam,
and that R-tofisopam was the most effective of the three in inhibiting colonic
motility. However, Example 2 of the Specification discloses that the both
(R)-tofisopam and (S)-tofisopam show a comparable ability to inhibit
colonic motility, which was significantly better than the ability of the
racemate to inhibit colonic motility. Since there are major inconsistencies in
the data presented, we conclude that the evidence presented in Example 2 of
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the Specification, when viewed in conjunction with the Jacoby Declaration,
is not of adequate weight to rebut to the prima facie case of obviousness.
Therefore, we affirm the rejection of claim 11 as obvious in view
Hanajima and Landry. Claims 13, 15, 25, and 26 have not been argued
separately and therefore fall with claim 11. 37 C.F.R. § 41.37(c)(1)(vii).
Appellant also argues the rejection of claim 12. Claim 12 depends
from claim 11 and further requires that the “(R)-tofisopam is administered
with a second drug.” Appellant argues that “the only reference that pertains
to the treatment of IBS, Hanajima, does not suggest a second drug. It is not
„clearly‟ indicated that the skilled artisan would combine modify Hanajima
to substitute (R) tofisopam for its racemate, and then make the further
modification of administering a second drug” (Appeal Br. 17-18).
Appellant‟s argument that Hanajima does not suggest a second drug is
not persuasive. Hanajima discloses that various classes of drugs may be
used to treat IBS, including tranquilizers, antidepressants, and autonomic
nerve stabilizers (FF2). Thus, it would have been obvious to treat IBS with
both tofisopam and a second drug such as an antidepressant in order to
optimize the therapeutic response. In addition, we note that Landry
expressly discloses that tofisopam and antidepressants may be used together
for the treatment of anxiety disorders (FF7).
Therefore, we affirm the rejection of claim 12 as obvious in view
Hanajima and Landry. Claims 14 and 16 have not been argued separately
and therefore fall with claim 12. 37 C.F.R. § 41.37(c)(1)(vii).
Appellant also argues the rejection of claim 21. Claim 21 depends
from claim 11 and further requires that “said (R)-tofisopam comprises 85%
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by weight or greater of the (R) enantiomer of tofisopam and 15% by weight
or less of the (S) enantiomer of tofisopam.” Appellant argues that Landry
“teaches (R)-tofisopam enantiomer purities of 90%, 95% and 99%. But these
enantiomer purities are for treating anxiety, a disorder that is distinct from
… IBS” (Appeal Br. 18). Appellant argues that “there is nothing in the prior
art of record that recognizes that the enantiomeric purity of tofisopam is a
result-effective variable” in the treatment of IBS (id. at 18).
This argument is not persuasive. As discussed above, the combination
of Hanajima and Landry would have made obvious the treatment of IBS
with the R-tofisopam in order to minimize side effects associated with the
racemate, and Landry discloses a composition that is greater than 85% R-
tofisopam by weight.
Therefore, we affirm the rejection of claim 21 as obvious in view
Hanajima and Landry. Claims 22-24 have not been argued separately and
therefore fall with claim 21. 37 C.F.R. § 41.37(c)(1)(vii).
CONCLUSION OF LAW
The evidence of record supports the Examiner‟s conclusion that the
cited references would have made obvious the claim 11 method of treating
irritable bowel syndrome. Appellant has not provided evidence of
unexpected results that outweighs the evidence supporting the prima facie
case of obviousness.
SUMMARY
We affirm the rejection 11-16 and 21-26 under 35 U.S.C. § 103(a).
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TIME PERIOD FOR RESPONSE
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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