Ex Parte Gilbert et al

Board of Patent Appeals and Interferences

Jan 21, 2009

10663533 (B.P.A.I. Jan. 21, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ADAM M. GILBERT and GARY P. STACK
__________

Appeal 2008-5876
Application 10/663,533
Technology Center 1600
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Decided: January 21, 2009
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving a claim to methods
of treatment. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

Appeal 2008-5876
Application 10/663,533

Statement of the Case
Background
“Recent studies with the selective 5-HT1A antagonist WAY-100635
have confirmed a role for 5-HT1A receptors in learning and memory” (Spec.
1:10-11). The Specification teaches that “post-training administration of
WAY-100635 reversed the learning deficit induced by scopolamine, a
cholinergic antagonist, in an autoshaping learning task” (Spec. 1:20-22).
The Claims
Claims 26 and 33-52 are on appeal. We will focus on claim 26, which
is representative and reads as follows:
26. A method of treating a subject suffering from a
condition selected from the group consisting of Alzheimer's
disease, appetite control, disorders of thermoregulation, and
sleep dysfunction, comprising the step of:
providing to the subject suffering from said condition,
a therapeutically effective amount of a compound of formula
I

wherein
R1 is a straight-chained alkyl of 1 to 6 carbon atoms,
or a branched chain alkyl of 3 to 8 carbon atoms; and
R2 is phenyl, naphthyl, anthracyl, phenanthryl,
pyridyl, pyrimidyl, triazinyl, furyl, pyrrolyl, pyrazolyl,
indolyl, imidazolyl, benzofuryl, benzothienyl, oxazolyl, or
thiazolyl each optionally substituted with 0 to 3 substituents
selected from straight-chain alkyl of 1 to 6 carbon atoms,
branched-chain alkyl of 3 to 8 carbon atoms, alkoxy of 1 to
2
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Application 10/663,533

6 carbon atoms, mono- or dialkylamino of 1 to 6 carbon
atoms, nitro, halo, amino, cyano, trifluoromethyl,
trifluoromethoxy and hydroxy;
or a pharmaceutically acceptable salt thereof.

The prior art
The Examiner relies on the following evidence to show
unpatentability:
Barnes et al., A review of central 5-HT receptors and their function,
38 NEUROPHARMACOLOGY 1083-1152 (1999).

Brubacher et al., Serotonin syndrome from venlafaxine-
tranylcypromine interaction, 38 VETERINARY HUM. TOXICOLOGY 358-61
(1996)(abstract only).

Bjorvatn et al., Changes in sleep and wakefulness following 5-HT1A
ligands given systemically and locally in different brain regions, 9 REV.
NEUROSCIENCE 265-73 (1998)(abstract only).

Ebenezer et al., Effects of the 5-HT1A Receptor Agonist 8-OH-DPAT
on Operant Food Intake in Food-Deprived Pigs, 67 PHYSIOLOGY BEHAVIOR
213-217 (1999)(abstract only).

Fletcher et al., A pharmacological analysis of the eating response
induced by 8-OH-DPAT injected into the dorsal raphe nucleus reveals the
involvement of a dopaminergic mechanism, 100 PSYCHOPHARMACOLOGY
188-94 (1990)(abstract only).

Gillin et al., Inhibition of REM sleep by ipsapirone, a 5HT1A agonist,
in normal volunteers, 116 PSYCHOPHARMACOLOGY 433-6 (1994)(abstract
only).

Kwon et al., List of Drugs in Development for Neurodegenerative
Diseases, 1 NEURODEGENERATIVE DISEASE 113-152 (2004).

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Application 10/663,533

Lanfumey et al., 5-HT1 Receptors, 3 CURRENT DRUG TARGETS – CNS
& NEUR. DISEASE 1-10 (2004).

Matuszewich et al., Partial antagonism of 8-OH-DPAT’s effects on
male rat sexual behavior with a D2, but not a 5-HT1A, antagonist, 820
BRAIN RESEARCH 55-62 (1999) (Abstract only).

Moreau et al., Behavioral profile of the 5HT1A receptor antagonist
(S)-UH-301 in rodents and monkeys, 29 BRAIN RESEARCH BULLETIN 901-4
(1992) (Abstract only).

Oerther et al., Temperature set-point changes induced by DA D2/3
and 5-HT1A receptor agonists in the rat, 11 NEUROREPORT 3949-51 (2000)
(Abstract only).

Ootsuka et al., 5-Hydroxytryptamine 1A receptors inhibit cold-
induced sympathetically mediated cutaneous vasoconstriction in rabbits,
552 J. PHYSIOLOGY 303-14 (2003).

Schechter et al., The potential utility of 5-HT1A receptor antagonists
in the treatment of cognitive dysfunction associated with Alzheimer’s
disease, 8 CURRENT PHARMACEUTICAL DESIGN 139-45 (2002)(Abstract
only).

Sorensen et al., The selective 5-HT(1A) receptor antagonist p-MPPI
antagonizes sleep-waking and behavioural effects of 8-OH-DPAT in rats,
121 BEHAVIOURAL BRAIN RESEARCH 181-7 (2001)(Abstract only).

Wijngaarden et al., Serotonin agonists and antagonists, 112 RECL.
TRAV. CHIM. PAYS-BAS 126-130 (1993).

The issue
The Examiner rejected claims 26 and 33-52 under 35 U.S.C. § 112,
first paragraph as being nonenabled (Ans. 4-8).
The Examiner finds that “the nexus between Alzheimer’s disease . . .
and 5HT1A receptor antagonism is not established” (Ans. 7). The Examiner
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finds that the “prior art shows that there is no umbrella drug known to be
effective in treating all the diseases/conditions claimed” (Ans. 7). The
Examiner finds that it would require “undue experimentation in order to
make and use the invention” (Ans. 8).
Appellants contend that “there is an established nexus between the
antagonism at the 5-HT1A receptor and treatment of the claimed conditions”
(App. Br. 4). Appellants cite “references to establish the nexus between
each of the listed conditions and the antagonism at the 5-HT1A receptor”
(App. Br. 5). Appellants further contend that “the skilled artisan would
accept the disclosed model as reasonably correlating to the claimed effects
and, as such, the Office must consider accept the object truth of the
information unless there is evidence in the record to the contrary” (App. Br.
8).
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Did the Examiner err in finding that it would require undue
experimentation to treat Alzheimer’s disease and other disorders using the
compounds of Formula I?
Findings of Fact (FF)
Breadth of Claims
1. The Examiner finds that the “claims are broad due to the high
number of compounds and diseases they embody. Formula I encompasses
many different compounds due to the breadth of its variables” (Ans. 5).
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Presence of Working Examples
2. The Specification teaches that “the compounds of this invention
have potent affinity for and antagonist activity at brain 5-HT1A serotonin
receptors” (Spec. 11:9-10).
3. The Examiner finds that “[n]o working example exists showing
that a claimed compound is effective at treating all the claimed diseases”
(Ans. 8).
Amount of Direction or Guidance Presented
4. The Examiner finds that the “evidence fails to show that the
claimed compounds are capable of treating the claimed diseases” (Ans. 8).
5. The Specification only mentions “Alzheimer’s disease” once,
stating that the “compounds of the invention are exceedingly interesting and
useful for treating the cognitive deficits due to . . . Alzheimer’s disease”
(Spec. 11:10-12).
State of the Prior Art and Unpredictability of the Art
6. The only suggestion connecting 5-HT1A serotonin receptor
antagonist with Alzheimer’s is found in Schechter, who states that “a very
compelling rationale has been developed for the therapeutic potential of 5-
HT1A receptor antagonists in Alzheimer’s disease” (Schechter abstract).
(The Lanfumey reference simply cites Schechter’s work (see Lanfumey 5,
col. 1). Schechter provides no evidence to support this position (see
Schechter abstract).
7. Barnes teaches the unpredictability of clinical treatments with
5-HT1A antagonists, noting that “[r]ecent clinical studies have reported
evidence that the therapeutic effect of antidepressant drugs can be improved
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by the adjunctive treatment with pindolol . . . although this has not been
confirmed in other studies” (Barnes 1091, col. 1).
8. Kwon teaches that “[n]eurodegenerative diseases are an
increasingly important issue in our society. There are, however, still many
obstacles on the way to finding methods for cure” (Kwon 113).
9. Kwon teaches 551 different drugs (see Kwon 113-151). Kwon
teaches that research and development of DPP-225, a putative Alzheimer’s
drug that was a 5-HT antagonist, was discontinued (see Kwon 124, #159).
10. Kwon teaches that SB-271046, a putative Alzheimer’s drug that
was a 5-HT antagonist, was discontinued (Kwon 145, #464).
11. The Examiner finds that the “high degree of unpredictability is
well recognized in the 5HT1A receptor ligand art” (Ans. 6).
Quantity of Experimentation
12. The Examiner finds that the “quantity of experimentation
necessary to make or use the disclosed invention is high” (Ans. 8).
13. Kwon teaches that even after identification of the drug
compound and prior to clinical testing, a very large quantity of
experimentation is required (see Kwon 152). Specifically, Kwon notes that
the “Discovery” phase involves
[l]ate research state, preparation for human testing:
adaptation of research chemical synthesis (mg) to
larger scale (kg), selection of salt form, selection of
galenical form, design of clinical proof of concept
studies, definition of endpoints, selection of
biomarkers for clinical testing, additional safety
testing, IND (investigational new drug) filing, clinical
ethical review boards.

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(Kwon 152, col. 1.)
Skill in the Art
14. The Examiner finds that the “art requires a high level of skill to
perform. 5HT1A receptors have subclasses differing in their structures,
regional distribution, pharmacology, modes of actions, and functions” (Ans.
7).
Principles of Law
When rejecting a claim under the enablement
requirement of section 112, the PTO bears an initial
burden of setting forth a reasonable explanation as to
why it believes that the scope of protection provided
by that claim is not adequately enabled by the
description of the invention provided in the
specification of the application.

In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993). “[T]he question of
undue experimentation is a matter of degree. The fact that some
experimentation is necessary does not preclude enablement; what is required
is that the amount of experimentation ‘must not be unduly extensive.”’ PPG
Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558, 1564 (Fed. Cir. 1996).
Factors to be considered in determining
whether a disclosure would require undue
experimentation … include (1) the quantity of
experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or
absence of working examples, (4) the nature of the
invention, (5) the state of the prior art, (6) the relative
skill of those in the art, (7) the predictability or
unpredictability of the art, and (8) the breadth of the
claims.
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In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Analysis
The Examiner concludes that a “person of ordinary skill in the art
would be subjected to undue experimentation in order to make and use the
invention” (Ans. 8). Based upon balancing the factors in the Wands
analysis, we agree.
The claim is very broad, encompassing treatment of a number of
different disease conditions with a large number of different chemical
compounds (FF 1). See Impax Laboratories, Inc. v. Aventis
Pharmaceuticals, Inc., 545 F.3d 1312, 1315 (Fed. Cir. 2008)(“[T]he trial
court opined that formula I of the alleged prior art discloses hundreds or
thousands of compounds and several diseases”).
While the Examiner finds a “high” skill level (FF 14), the
Specification provides no working examples of any treatment of any disease
with the claimed compounds (FF 2-3) and provides no guidance or teaching
in the application of the compounds to diseases as diverse as Alzheimer’s
disease (FF 4-5).
There is evidence showing the large quantity of experimentation
necessary (FF 12-13). There is also evidence demonstrating the
unpredictability of 5-HT1A agonists and other compounds in treating
neurological diseases such as Alzheimer’s disease (FF 7-11).
While Schechter (directly and as cited by Lanfumey) speculates that
5-HT1A antagonists have therapeutic potential for Alzheimer’s disease, the
reference does not provide any evidence, whether in vivo, in vitro, or other
experimental evidence in an Alzheimer’s disease model to support this
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speculation (FF 6). See Impax, 545 F.3d at 1315. (“[T]he language in the
′940 patent discussing conditions implicating glutamate is speculative, at
best”).
We are not persuaded by Appellants’ argument that “there is an
established nexus between the antagonism at the 5-HT1A receptor and
treatment of the claimed conditions” (App. Br. 4). Focusing on Alzheimer’s
disease, other than the speculation by Schechter discussed above, there is no
cited evidence linking antagonism at the 5-HT1A receptor and treatment of
Alzheimer’s disease. There is evidence, however, from the Kwon reference,
that attempts to treat Alzheimer’s disease using antagonists at the 5-HT
receptor were discontinued (FF 9-10).
We are not persuaded by Appellants’ argument that “the skilled
artisan would accept the disclosed model as reasonably correlating to the
claimed effects” (App. Br. 8). While Appellants cite Brana, the facts of
Brana are inapposite. In Brana, the evidence presented to demonstrate in
vivo effectiveness was that the “specification illustrates the cytotoxicity of
the claimed compounds against human tumor cells, in vitro.” In re Brana,
51 F.3d 1560, 1563 (Fed. Cir. 1995). Thus, Brana relied upon evidence of
efficacy in a disease model to demonstrate enablement. Id. In the instant
fact pattern, Appellants have not identified any model for Alzheimer’s
disease nor does the Specification contain any evidence of efficacy in any
disease model whatsoever (FF 2-5).

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Conclusions of Law
The Examiner did not err in finding that it would require undue
experimentation to treat Alzheimer’s disease and other disorders using the
compounds of Formula I.
SUMMARY
In summary, we affirm the rejection of claim 26 under 35 U.S.C. §
112, first paragraph as being nonenabled. Pursuant to 37 C.F.R. §
41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 33-52 as these
claims were not argued separately.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).

AFFIRMED

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