Ex Parte Crooks et al

Board of Patent Appeals and Interferences

Feb 19, 2010

09881215 (B.P.A.I. Feb. 19, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte PETER A. CROOKS,
AIMEE K. BENCE, and DAVID R. WORTHEN
__________

Appeal 2009-013078
Application 09/881,215
Technology Center 1600
__________

Decided: February 19, 2010
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Before ERIC GRIMES, 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 claims to a method
of treating epilepsy with agmatine. We have jurisdiction under 35 U.S.C.
§ 6(b). We reverse.

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Statement of the Case
Background
“Epilepsy is a general term describing brain disorders that are
characterized by the occurrence of seizures” (Spec. 1, ll. 12-13). According
to the Specification “[a]nti-epileptic drugs are available for treating
epilepsies, but these agents have a number of shortcomings” (Spec. 2, ll. 21-
22).
The Specification teaches the use of agmatine “in the prevention
and/or treatment of all types of seizures and other electroconvulsive
disorders” (Spec. 4, l. 27 to 5, l. 3).
The Claims
Claims 5, 7, 9, 11, and 13-20 are on appeal. Claim 5 is representative
and reads as follows:
5. A method of treating, ameliorating, or preventing
seizures associated with epilepsy in a subject in need
thereof, the method comprising:
administering a pharmaceutical composition
comprising about 0.1 to about 500 mg of agmatine or an
agmatine analog, or a pharmaceutically acceptable salt
thereof per kilogram of the subject's weight to treat, reduce,
or prevent seizures associated with epilepsy in the subject,
wherein the agmatine analog has the following formula

wherein n is 0 to about 10;
Rl, R2, R3, R4, and R5, are each independently, or any
combination thereof: hydrogen, hydroxy, substituted or
unsubstituted C1-10 alkyl, substituted or unsubstituted C3-8
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cycloalkyl, substituted or unsubstituted arylalkyl
(comprising Ar-(CH2)m; where Ar is aromatic and m is 0 to
about 10) substituted or unsubstituted C1-10 alkoxyl,
substituted or unsubstituted C1-10 acyl, halogeno, amido,
phenyl, thio, or amino; and
X and Y are each independently: O, NH, CH2, CF2,
Se, C=O, C=N, or C=S, or X-Y together is HC=CH, C≡C,
N=N, N=CH, CH=N, or a saturated or unsaturated ring.

The prior art
The Examiner relies on the following prior art references to show
unpatentability:
Rajasekaran et al., Effect of acute and repeated administration of
nitric oxide (NO) precursor L-arginine, NO donor, sodium nitroprusside
and NO synthase inhibitor, N (omega)-L arginine methyl ester on
picrotoxin-induced seizure in rats, 6TH INTERNET WORLD CONGRESS FOR
BIOMEDICAL SCIENCE, poster 129 (2000).

Uzbay et al., Effect of agmatine on ethanol withdrawal syndrome in
rats, 107 BEHAVIOURAL BRAIN RESEARCH, 153-159 (2000).

The Appellants rely on the following prior art reference :

Li et. al., Agmatine is synthesized by a mitochondrial arginine
decarboxylase in rat brain, Annals New York Academy of Sciences, 763,
pp. 325-329 (1995).

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The issues
A. The Examiner rejected claims 5, 7, 9, 11, and 13-20 under 35 U.S.C.
§ 112, first paragraph “because the specification, while being enabling for
treatment of seizure using agmatine, does not reasonably provide
enablement for preventing seizure using agmatine” (Ans. 3-5).
B. The Examiner rejected claims 5, 7, 9, 11, and 13-20 under 35 U.S.C.
§ 103(a) as obvious over Uzbay and Rajasekaran (Ans. 5-7).
A. 35 U.S.C. § 112, first paragraph, enablement
The Examiner finds that “[s]ince compound structure and activity for .
. . pharmaceutical use must be determined from case to case by painstaking
experimental study, one of ordinary skill in the art would be burdened with
undue experimentation to determine the preventative effect of agmatine on
seizures” (Ans. 5).
Appellants argue that the “fact that different types of seizures are
treated with different agents does not in and of itself indicate[ ] that a person
having ordinary skill in the art would have to engage in experimentation that
would be burdensome to practice the claimed subject matter” (App. Br. 6).
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Have Appellants demonstrated that the Examiner erred in finding that
undue experimentation would have been required to prevent seizures
associated with epilepsy by administering agmatine or an agmatine analog?
Breadth of Claims
1. Claim 5 encompasses a method of “preventing seizures
associated with epilepsy” by “administering a pharmaceutical composition
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comprising . . . agmatine or an agmatine analog, or a pharmaceutically
acceptable salt thereof” (Claim 5).
Presence of Working Examples
2. The Specification teaches that the “Maximal Electroshock
Seizure (MES) . . . is an experimental model for generalized tonic-clonic
seizures that identifies compounds which prevent seizure spread. The MES
model is highly reproducible and has a consistent endpoint” (Spec. 14, ll. 24-
28).
3. The Specification teaches the “results of the MES test
demonstrate that agmatine is effective in preventing seizure spread in the
rat” (Spec. 15, ll. 18-19).
4. The Specification teaches that “[t]hese data indicate that the
oral administration of agmatine (30 mg/kg) may have both acute (0-1 hours)
and delayed (2-6 hours) inhibitory effects on MES-induced seizure spread”
(Spec. 15, ll. 26-29).
5. The Specification teaches that “[i]n rats and mice, agmatine was
demonstrated to be devoid of any neurological toxicity” (Spec. 17, ll. 3-4).
Amount of Direction or Guidance Presented
6. The Specification teaches that “agmatine, an agmatine analog,
or a pharmaceutically acceptable salt, complex or cogener thereof is
formulated into a pharmaceutical preparation comprising the active agent
and a pharmaceutically acceptable carrier” (Spec. 9, ll. 1-4).
7. The Specification teaches that “[i]t has been discovered that the
inventive compositions are useful in the prevention, palliation and/or
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treatment of seizures, conduction disturbances, and electroconvulsive
disorders of all types” (Spec. 9, ll. 4-6).
8. The Specification teaches that “[p]revention of the condition or
disorder is manifested by delaying the onset of the symptoms of the
conditions or disorder” (Spec. 14, ll. 7-8).
State of the Prior Art and Unpredictability of the Art
9. The Examiner finds that the “prior art does not recognize that
the prevention of seizures is done easily. According to Lance1 . . . different
types of seizures are treated with different agents. There are no teachings
directed to prevention of seizures” (Ans. 4).
10. The Specification teaches that “[a]nti-epileptic drugs are
available for treating epilepsies, but these agents have a number of
shortcomings” (Spec. 2, ll. 21-22).
11. The Specification teaches that “[e]ven while being treated with
one or a combination of the anti-epileptic drugs currently in clinical use,
30% of epileptic patients still experience seizures,” which indicates that
current drugs “prevent” 70% of patients from experiencing seizures (Spec. 2,
ll. 26-28).
12. The Examiner finds, without evidence cited, that the
“unpredictability of pharmaceutical and chemical art is high” (Ans. 4).

1 The Examiner has not included Lance in the “Evidence Relied
Upon” section of the Answer, nor has the Examiner provided a
copy of Lance in the record for review by Appellants or us.
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Quantity of Experimentation
13. The Examiner finds that “compound structure and activity for
such pharmaceutical use must be determined from case to case by
painstaking experimental study” (Ans. 5).
Skill in the Art
14. The Examiner finds that the “relative skill of those in the art is
high” (Ans. 4).
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.

In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).

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Analysis
The Examiner bears the burden of providing an explanation as to why
the claims are not adequately enabled by the Specification. In re Wright, 999
F.2d at 1561-1562. In this case, the Examiner's position appears to be that
the Specification is not enabled for preventing epileptic seizures by
administration of agmatine because “one of ordinary skill in the art would be
burdened with undue experimentation to determine the preventative effect of
agmatine on seizures” (Ans. 5).
In analyzing the Wands factors, based upon the evidence presented by
the Examiner, all of the factors are clearly either neutral or support the
enablement position of Appellants (FF 1-14). The claims are narrowly
drawn to treating and preventing seizures associated with epilepsy by
administering agmatine or an agmatine analog (FF 1; Claim 5). The
Specification has an in vivo working example which shows that “agmatine is
effective in preventing seizure spread in the rat” (Spec. 15, ll. 18-19; FF 3).
The working example also demonstrates that “oral administration of
agmatine (30 mg/kg) may have both acute (0-1 hours) and delayed (2-6
hours) inhibitory effects on MES-induced seizure spread” (Spec. 15, ll. 26-
29; FF 4).
The prior art clearly recognizes that drugs exist which are capable of
at least partially preventing seizures caused by some forms of epilepsy (FF
10-11). There is no evidence that a large quantity of experimentation would
be required (FF 13) nor is there specific evidence that the use of agmatine in
“preventing” seizures in epilepsy is unpredictable (FF 12).
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With regard to skill level in the art, the Examiner acknowledges that
the skill level is “high” (FF 14). While Appellants are correct that no
evidence is adduced to support this determination, the Examiner’s finding of
a “high” skill level supports enablement of the claims, since the skilled
artisan requires less disclosure in the Specification.
While we cannot directly address the Lance reference, since it was not
properly cited by the Examiner nor provided in the working file, a generic
reference teaching that different seizures are treated with different agents
would not persuasively overcome the Wands factors supporting enablement.
We are not persuaded by the Examiner’s argument, regarding the
Specification’s data, that “[s]uch data inhibit the occurrence of seizure in a
number of animals for a limited amount of time” (Ans. 7). This is evidence
supporting enablement which is not rebutted by the Examiner. The
Examiner has not provided the required evidence or scientific reasoning to
show that one of ordinary skill in the art would find that preventing seizures
associated with epilepsy by administration of agmatine or agmatine analogs
would have required “undue experimentation”. The Examiner's mere
assertions to that effect are not sufficient for establishing a prima facie case
of lack of enablement.
Conclusion of Law
Appellants have demonstrated that the Examiner erred in finding that
undue experimentation would have been required to prevent seizures
associated with epilepsy by administering agmatine or an agmatine analog.

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B. 35 U.S.C. § 103(a) over Uzbay and Rajasekaran
The Examiner finds that “Uzbay et al. teach the use of agmatine (40
mg) for the treatment of audiogenic seizure due to ethanol withdrawal”
(Ans. 6). The Examiner finds that “Rajasekaran et al. teach the
anticonvulsant activity of agmatine used in the treatment of seizure caused
by epilepsy” (Ans. 6). The Examiner concludes that “[i]t would have been
obvious to a person skilled in the art to modify Uzbay’s teachings in view of
Rajasekaran to treat seizure caused not only by ethanol withdrawal, but also
seizure due to epilepsy” (Ans. 6).
Appellants argue that the “teachings of Uzbay et al. are clearly limited
to and relevant only to ethanol withdrawal syndrome associated” (App. Br.
7). Appellants argue that the “data in Uzbay et al. establish a failed attempt
to treat seizures with agamatine, i.e., these studies agmatine was not
effective in treating seizures related to alcohol abuse” (App. Br. 8).
Appellants argue that “Rajasekaran et al. merely suggest that the
anticonvulsant activity of L-arg may be effected through agmatine, but they
offer no evidence to that effect” (App. Br. 9). Appellants argue that
“Rajasekaran et al. do not provide any data concerning agmatine to show
that it is effective for treating, ameliorating or preventing seizures associated
with epilepsy as required by claims 5 and 13” (App. Br. 10).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Have Appellants demonstrated that the Examiner erred in concluding
that the combination of Uzbay and Rajasekaran renders obvious the
treatment or prevention of epileptic seizures with agmatine?
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Findings of Fact
15. Uzbay teaches that “agmatine, an arginine metabolite, has some
inhibitory effects on the withdrawal syndrome in ethanol-dependent rats”
(Uzbay 156, col. 2).
16. Uzbay teaches that “[t]hese inhibitory effects of agmatine on
ethanol withdrawal syndrome may be explain[ed] by three mechanisms”
(Uzbay 156, col. 2).
17. The Examiner notes that Uzbay “differs from the claimed
invention in treating seizure caused by epilepsy” (Ans. 6), recognizing that
Uzbay is silent regarding epilepsy.
18. Rajasekaran teaches that “NO [nitric oxide] has been implicated
in the pathogenesis of neurodegenerative disorders including Alzheimer’s
disease, parkinsomism, Huntington’s disease and epilepsy” (Rajasekaran,
Introduction).
19. Rajasekaran teaches that “NO could be an important pathogenic
component in the mechanisms that regulate seizure induction, propogation
[sic] and progression. The role of NO in epilepsy remains debatable”
(Rajasekaran, Introduction).
20. Rajasekaran teaches that the “results of the present study
provide an evidence for the anticonvulsant activity of L-arginine as well as a
proconvulsant role for NO” (Rajasekaran, Discussion).
21. Rajasekaran teaches that the “anticonvulsant activity of L-arg
may be direct . . . or a product of its metabolism such as agmatine (Li et al.,
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1995) or to the possible accumulation of L-arg per se” (Rajasekaran,
Discussion).
22. Rajasekaran teaches that “we conclude that NO facilitates
seizures and that an inhibition of NO may prevent seizures. Further, the
results indicate that the anticonvulsant action of L-arginine may not be
essentially . . . mediated by the NOS [nitric oxide synthase] pathway”
(Rajasekaran, Conclusions).
23. Li teaches that “agmatine (decarboxylated arginine) is
contained in bovine brain” (Li 325, abstract).
24. Li discloses that “rat brain expresses an enzyme that can
synthesize agmatine and CO2 from L-arginine” (Li 328).

Principles of Law
“[R]ejections on obviousness grounds cannot be sustained by mere
conclusory statements; instead, there must be some articulated reasoning
with some rational underpinning to support the legal conclusion of
obviousness.” KSR Int'l v. Teleflex Inc., 550 U.S. 398, 418 (2007).
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992) (“[T]he examiner bears the initial burden, on review of the
prior art or on any other ground, of presenting a prima facie case of
unpatentability.”).
In O’Farrell, the court held that a conclusion of obviousness was
appropriate where the prior art “contained detailed enabling methodology for
practicing the claimed invention, a suggestion to modify the prior art to
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practice the claimed invention, and evidence suggesting that it would be
successful.” In re O'Farrell, 853 F.2d 894, 902 (Fed.Cir.1988).

Analysis
Uzbay teaches that agmatine has some efficacy in treating ethanol
withdrawal in rats, but provides no teaching or suggestion regarding the
application of agmatine to epilepsy as required by Claim 5 (FF 15-17).
Rajasekaran notes that nitric oxide has been linked to diseases including
epilepsy (FF 18), but notes that this linkage remains debatable (FF 19).
Rajasekaran teaches that L-arginine functions as an anticonvulsant (FF 20),
but does not determine the mechanism and merely suggests that one possible
modality is by the metabolic product agmatine (FF 21). Rajasekaran
demonstrates that the pathway of action of L-arginine is unpredictable and
may not be through NOS (FF 22). Further, Rajasekaran cites Li simply to
show that agmatine is a metabolic product of L-arginine, not to show a
relationship between agmatine or L-arginine and seizure or epilepsy (FF 23-
24).
The Examiner finds that the “mere fact that Rajasekaran et al. teach
the anticonvulsant activity of arginine may be due to its metabolite
agmatine, makes the use of agmatine as an anti-seizure drug obvious to a
person skilled in the art” (Ans. 8)
Appellants argue that “Rajasekaran et al. do not provide any data
concerning agmatine to show that it is effective for treating, ameliorating or
preventing seizures associated with epilepsy as required by claims 5 and 13”
(App. Br. 10).
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We find that Appellants have the better position. While Rajasekaran
indirectly connects agmatine and seizures (FF 18-22), on this particularized
set of facts, we do not agree with the Examiner that it was obvious that
agamatine would have predictably functioned to treat epilepsy.
We conclude that the application of agmatine to the treatment of
epilepsy was not predictable or simply the result of routine experimentation.
While O'Farrell states that “[o]bviousness does not require absolute
predictability of success”, O'Farrell identifies
two kinds of error. In some cases, what would have been
“obvious to try” would have been to vary all parameters or
try each of numerous possible choices until one possibly
arrived at a successful result, where the prior art gave either
no indication of which parameters were critical or no
direction as to which of many possible choices is likely to be
successful. . . . In others, what was “obvious to try” was to
explore a new technology or general approach that seemed
to be a promising field of experimentation, where the prior
art gave only general guidance as to the particular form of
the claimed invention or how to achieve it.

In re O'Farrell, 853 F.2d 894, 903 (Fed.Cir.1988). The instant situation fits
O'Farrell’s second kind of error, since the prior art of Rajasekaran at best
provides general guidance regarding metabolites of L-arginine that might
function as anticonvulsants. While inhibitors of NO might represent a
promising field of experimentation, the prior art cited by Rajasekaran
recognizes that the role of NO in epilepsy is debatable (FF 19). Rajasekaran
itself recognizes that the pathway by which L-arginine operates is unclear
(FF 22). With regard to even general guidance, neither Rajasekaran or
Uzbay identify or suggest agmatine as a treatment for epilepsy.
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Further, while KSR recognizes that “the fact that a combination was
obvious to try might show that it was obvious under § 103,” KSR teaches
that this applies “[w]hen there is a design need or market pressure to solve a
problem and there are a finite number of identified, predictable solutions”
and it is in that situation that “a person of ordinary skill has good reason to
pursue the known options within his or her technical grasp” KSR, 550 U.S.
at 421. The Examiner makes none of the requisite findings to demonstrate
that the use of agmatine as an anticonvulsant is predictable, that there are a
finite number of solutions, or that the use of agmatine for treatment of
epilepsy was even “obvious to try.”
Conclusion of Law
Appellants have demonstrated that the Examiner erred in concluding
that the combination of Uzbay and Rajasekaran renders obvious the
treatment or prevention of epileptic seizures with agmatine.

SUMMARY
In summary, we reverse the rejections of claims 5, 7, 9, 11, and 13-20
under 35 U.S.C. § 112, first paragraph.
We reverse the rejection of claims 5, 7, 9, 11, and 13-20 under 35
U.S.C. § 103(a) as obvious over Uzbay and Rajasekaran.

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REVERSED
alw

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