Ex Parte Guglielmotti et al

Board of Patent Appeals and Interferences

May 14, 2010

10560836 (B.P.A.I. May. 14, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ANGELO GUGLIELMOTTI, LORENZO POLENZANI,
ALESSANDRA ALISI and NICOLA CAZZOLLA
__________

Appeal1 2009-007941
Application 10/560,836
Technology Center 1600
__________

Decided: May 14, 2010
__________

Before ERIC GRIMES, JEFFREY N. FREDMAN, and STEPHEN
WALSH, Administrative Patent Judges.

WALSH, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for treating neuropathic pain. The Patent Examiner rejected the
claims on the ground of obviousness. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm-in-part.

1 Oral hearing held April 22, 2010.
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STATEMENT OF THE CASE
The Specification cites European patent application EP-A-0 630 376
for its disclosure of “a large number of compounds of formula I,” said to be
“active in the treatment or the prophylaxis of gastrointestinal, cardiac and
central nervous system disorders.” (Spec. 1:6-14.) The Specification
discloses that compounds of formula I in which substituent “R” is H, a linear
or branched alkyl chain having from 1 to 12 carbon atoms or an arylalkyl
radical, are “particularly active in neuropathic pain.” 2 (Id. at 1:10-18.) The
Specification designates that subgenus of formula I as “Compound (I).”
(Id.) “Typical examples of pathological conditions characterized by
neuropathic pain are diabetes, cancer, immunodeficiency, traumas,
ischaemia, multiple sclerosis, sciatic neuralgia, trigeminal neuralgias and
post-herpetic syndromes.” (Id. at 2:29-3:2.) The Specification states that
“[t]he analgesic activity of Compound (I) has been proved by means of two
experimental models in the rat: allodynia3 induced by ligature of the sciatic
nerve and mechanical hyperalgesia in diabetic neuropathy induced by
streptozotocin.” (Id. at 4:14-17.)
Claims 6-12 and 14-23, which are all the pending claims, are on
appeal. Claims 6, 18 and 20 are representative and read as follows:
6. A method for the treatment of neuropathic pain comprising:
administering to a subject in need thereof a compound of formula I:

2 According to an article Appellants provide from MedicineNet.com,
“[n]europathic pain is a complex, chronic pain state that usually is
accompanied by tissue injury.” (App. Br., Evid. Appx.)
3 According to an article Appellants provide from Wikipedia, “[a]llodynia,
meaning ‘other pain’, is an exaggerated response to otherwise non-noxious
stimuli and can be either static or mechanical.” (App. Br., Evid. Appx.)
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wherein
R is H, a linear or branched alkyl chain having from 1 to 12 carbon
atoms, or an arylalkyl group;
or a pharmaceutically acceptable acid-addition salt thereof.

18. The method of claim 6, wherein said subject has neuropathic pain
associated with diabetes.

20. The method of claim 6, wherein said subject has neuropathic pain
associated with immunodeficiency, trauma, ischaemia, multiple
sclerosis, sciatic neuralgia, trigeminal neuralgia or a post-herpetic
syndrome.

The Examiner rejected the claims as follows:
• claims 6-12 and 14-17 under 35 U.S.C. § 103(a) as unpatentable
over Gaster,4 Smith5 and Jørum;6
• claims 6-12 and 14-17 under 35 U.S.C. § 103(a) as unpatentable
over Gaster, Burstein7 and Jørum;

4 EP 0630376 B1, issued to Laramie Mary Gaster et al., June 2, 1999.
5 M.I. Smith et al., 5-HT4 receptor antagonism potentiates inhibition of
intestinal allodynia by 5-HT3 receptor antagonism in conscious rats,
271 NEUROSCIENCE LETTERS 61-64 (1999).
6 E. Jørum et al., Cold allodynia and hyperalgesia in neuropathic pain: the
effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine—a
double blind, cross-over comparison with alfentanil and placebo, 101 PAIN
229-235 (2003).
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• claims 18-20 under 35 U.S.C. § 103(a) as unpatentable over Gaster,
Smith, Jørum and Wickenden;8 and
• claims 20-23 under 35 U.S.C. § 103(a) as unpatentable over Gaster,
Smith, Jørum and Omoigui.9
Claims 7-12 and 14-17 have not been argued separately and therefore
stand or fall with claim 6. Claims 19 and 20 have not been argued
separately with respect to the third rejection and therefore stand or fall with
claim 18 for that rejection. Claims 21-23 have not been argued separately
with respect to the fourth rejection and therefore stand or fall with claim 20
for that rejection. 37 C.F.R. § 41.37(c)(1)(vii).

OBVIOUSNESS
The Issue
The Examiner’s position is that Gaster taught the compounds of
formula 1 as 5-HT4 receptor antagonists and taught administering the
compounds to treat conditions including migraine, but did not teach treating
neuropathic pain. (Fin. Rej. 3-4.) The Examiner found that Smith taught
that 5-HT4 receptor antagonists inhibit intestinal allodynia, and that Jørum
taught that allodynia and hyperalgesia were frequent clinical findings in
patients with neuropathic pain. (Id. at 4.) The Examiner reasoned that
inhibiting allodynia as Smith taught would provide a method of treating

7 Rami Burstein et al., The development of cutaneous allodynia during a
migraine attack, 123 BRAIN 1703-1709 (2000).
8 Alan David Wickenden et al., Methods For Treating Or Preventing Pain,
US 6,326,385 B1 (Dec. 4, 2001).
9 Osemwota Omoigui, Method Of Treatment Of Persistent Pain,
US 2004/0038874 A1 (Feb. 26, 2004).
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neuropathic pain because Jørum taught that allodynia was a frequent finding
in patients with neuropathic pain. (Id.) The Examiner concluded it would
have been obvious to use one of Gaster’s 5-HT4 receptor antagonists in
place of Smith’s 5-HT4 antagonist in the treatment of neuropathic pain.
(Id.)
The Examiner found that Burstein taught “that most migraine patients
exhibit cutaneous allodynia during a fully developed migraine attack,” but
Burstein did not identify allodynia as neuropathic pain. (Id. at 5.) The
Examiner concluded it would have been obvious to use the compounds of
formula I in the treatment of neuropathic pain because (i) Gaster taught their
administration in relieving migraine attack, (ii) Burstein taught that
allodynia was exhibited during a migraine attack, (iii) Jørum taught that
allodynia and hyperalgesia are frequent clinical findings in patients with
neuropathic pain, and (iv) “by treating migraine attacks in patients allodynia
is treated and in turn the neuropathic pain.” (Id.)
Addresing claims 18-20, the Examiner found that while Gaster, Smith
and Jørum did not disclose that neuropathic pain was associated with
diabetes, cancer, or trigeminal neuralgia, Wickenden taught that neuropathic
pain was associated with injury to the central or peripheral nervous system
due to cancer, diabetes, diabetic neuropathy, or trigeminal neuralgia. (Id. at
5-6.) Reasoning again that Gaster, Smith and Jørum suggested treating
neuropathic pain with Gaster’s compounds, the Examiner concluded that it
would have been obvious to use the same compounds to treat neuropathic
pain associated with the neuropathic conditions discussed by Wickenden.
Addressing claims 20-23, the Examiner found that Omoigui taught a
method of treating persistent pain disorders including neuropathic pain by
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administering a serotonin receptor antagonist. (Id. at 7.) According to the
Examiner, Omoigui disclosed that (i) inflammation was the underlying basis
for pain, including neuropathic pain, (ii) antagonizing the inflammatory
response will relieve pain of every type, (iii) chronic allodynia and
hyperalgesia are hallmarks of neuropathic pain, and (iv) persistent pain
disorder is neuropathic pain, including neuralgia and post herpetic neuralgia.
(Id.) In view of Omoigui’s teaching to administer serotonin receptor
antagonists, the Examiner concluded it would have been obvious to
administer Gaster’s serotonin receptor antagonist compounds to treat
neuropathic pain such as trigeminal neuralgia or post herpetic syndrome.
(Id.)
Appellants dispute that the prior art provided a reasonable
expectation of success that a compound of formula I could have been used to
treat neuropathic pain. (App. Br. 12.) Appellants contend that
“[n]europathic pain is a specific type of pain associated with nerve damage
that is distinct from nociceptive pain (pain sensed by undamaged nervous
tissue).” (Id. at 13.) Appellants argue that Gaster “does not disclose or
suggest use of [its] compounds for treating neuropathic pain associated with
damaged nerves.” (Id. at 14.) “The Examiner is alleging that 5-HT receptor
antagonists generally ameliorate neuropathic pain, but there is no support in
the prior art for this allegation.” (Id.) “Moreover, the thermal allodynia
(Jørum) and mechanical allodynia (Smith) are distinct from one another and
involve different types of nociception.” (Id.) Further, Appellants read
Smith to teach only that “5-HT4 receptor antagonism potentiates inhibition
of intestinal allodynia by 5-HT3 receptor antagonism” and as “not
disclos[ing] that a 5-HT4 receptor antagonist would have any effect on
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intestinal allodynia in the absence of a 5-HT3 receptor antagonist.” (Id. at
15.)
Concerning the Omoigui publication, Appellants argue that the
content of papers on which the publication is based “is highly speculative
and theoretical, . . . and provides no reasonable expectation of success for
treating neuropathic pain using a compound of formula I.” (Id. at 21.)
Appellants further contend that the Examiner used a hindsight
approach. (Reply Br. at 2.) “The missing link in the Examiner’s argument
[is] any nexus in the prior art that the pain disorders described by Gaster and
Smith are mediated by the same mechanism as those responsible for causing
neuropathic pain, and that the mechanism causing neuropathic pain is
targeted by the compound of formula (I).” (Id.) According to Appellants,
“[b]oth allodynia and hyperalgesia are generic clinical findings of different
pathologic states having different origins . . . . The prior art does not provide
a reasonable expectation that pain, including allodynia or hyperalgesia,
associated with radically different disorders having different etiologies and
pathological manifestations, could be treated with the same compound.” (Id.
at 3.)

Findings of Fact
1. Gaster taught that compounds of formula (I) have 5-HT4 receptor
antagonist activity. (Gaster, 2:[0006] and [0007].)
2. The Examiner found that Gaster taught a method of treating irritable
bowel syndrome, migraine, and other conditions, by administering a
compound of formula (I). (Ans. 3, citing Gaster 6:42-43.)
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3. The Examiner found that Gaster did not teach a method of treating
neuropathic pain. (Id.)
4. The Examiner found that Smith taught that a 5-HT4 receptor
antagonist such as SB 207266 potentiated inhibition of intestinal
allodynia. (Id. at 4, citing Smith at Abstract and at 63:11-12.)
5. Smith disclosed that their data “suggests that 5-HT4 receptor
activation enhances the ability of 5-HT3 receptor activation to induce
intestinal allodynia.” (Smith, Abstract.)
6. The Examiner found Jørum taught that “allodynia and hyperalgesia
are frequent clinical findings in patients with neuropathic pain.” (Ans.
4, citing Jørum 229:1-5.)
7. The Examiner found that “inhibiting allodynia in patients provides a
method of treatment of neuropathic pain.” (Ans. 4.)
8. The Examiner found that one of ordinary skill in the art would have
been motivated to use one of Gaster’s compounds in place of Smith’s
compound to treat allodynia. (Ans. 4.)
9. Burstein disclosed that “most migraine patients exhibit cutaneous
allodynia inside and outside their pain-referred areas when examined
during a fully developed migraine attack.” (Burstein, Abstract.)
10. Wickenden disclosed that neuropathic pain can be caused by injury to
the central or peripheral nervous system due to cancer, diabetes,
diabetic neuropathy, or trigeminal neuralgia. (Wickenden, col. 27,
claim 8.)
11. Omoigui’s disclosure related to a method for treating persistent pain
by inhibiting mediators of inflammation including serotonin.
(Omoigui, Abstract.)
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12. Omoigui taught: “antagonism of inflammation and the inflammatory
response will relieve pain of every origin, type and character.” (Id. at
1:[0004].)
13. Omoigui taught: “[t]he hallmarks of neuropathic pain are chronic
allodynia and hyperalgesia.” (Id. at 8:[0072].)
14. Embodiments of Omoigui’s method included treating “neuropathic
pain syndrome including neuralgia or nerve pain, . . . post herpetic
neuralgia” (id. at 11, claim 12), and administering a serotonin receptor
antagonist (id. at 13, claim 80).
15. According to an article entitled “Migraine” in the Evidence Appendix
provided with the Appeal Brief:
[m]igraine was once thought to be initiated by problems with
blood vessels . . . Current thinking is that a phenomenon known
as cortical spreading depression is responsible for the disorder.
In cortical spreading disorder, neurological activity is depressed
over an area of the cortex of the brain. This situation results in
the release of inflammatory mediators leading to irritation of
cranial nerve roots, most particularly the trigeminal nerve,
which conveys the sensory information for the face and much
of the head.

(Migraine, pagina 3 di 8.)
15. The Specification states: “[t]he analgesic activity of Compound (I)
has been proved by means of two experimental models in the rat:
allodynia induced by ligature of the sciatic nerve and mechanical
hyperalgesia in diabetic neuropathy induced by streptozotocin.”
(Spec. 4:14-17.)
16. According to the Specification, the model based on ligature of the
sciatic nerve “is well known … [as] an effective instrument for the
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study of drugs for use in the treatment of neuropathic pain in man and,
in particular, in the control of conditions such as allodynia and
hyperalgesia.” (Id. at 4:21-5:2.)

Principles of Law
“Obviousness does not require absolute predictability of success. . . .
[A]ll that is required is a reasonable expectation of success.” In re
O'Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).

Analysis
A. The rejections of claims 6-12 and 14-17 over Gaster, Smith, Jørum
and claims 18-20 over Gaster, Smith, Jørum and Wickenden.
According to the rejections, a key finding links the teachings of these
references: that Smith taught that the 5-HT4 receptor antagonist SB 207266
showed an anti-allodynic activity. (Ans. 4.) Appellants dispute that the
evidence supports that finding. (App. Br. 15.) Appellants argue that Smith
“does not disclose that a 5-HT4 receptor antagonist would have any effect
on intestinal allodynia in the absence of a 5-HT3 receptor antagonist.” (Id.,
emphasis deleted.) Instead, according to Appellants, Smith “only indicates
that 5-HT4 receptor antagonists potentiate inhibition of intestinal allodynia
by a 5-HT3 receptor antagonist.” (Id., emphasis deleted.)
We agree that Smith did not disclose administering a 5-HT4 receptor
antagonist without a 5-HT3 receptor antagonist, and that Smith described the
role of the 5-HT4 receptor antagonist as potentiating the 5-HT3 receptor
antagonist. That evidence does not support finding that Smith described an
anti-allodynic effect attributable to a 5-HT4 receptor antagonist alone, and
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we find the other references do not make up for that deficiency. Without
more, the evidence is insufficient to support finding an expectation of
success in these references.

B. The rejection of claims 6-12 and 14-17 over Gaster, Burstein and
Jørum.
Burstein disclosed that most migraine patients exhibit cutaneous
allodynia. (FF 9.) Gaster taught treating migraine with a serotonin receptor
antagonist (FF 2), but did not teach treating neuropathic pain (FF 3). The
rejection reasons that one of skill in the art would have used Gaster’s
compounds to treat migraine, and in so doing would have treated allodynia.
The rejection concludes from this that “[h]ence by treating migraine attacks
in patients allodynia is treated and in turn the neuropathic pain.” (Ans. 5.)
The missing link is evidence that allodynia means neuropathic pain is
present. On this record, there is no evidence that allodynia means that
neuropathic pain is necessarily present or that migraine is neuropathic.
Jørum taught that allodynia and hyperalgesia are frequent clinical findings in
patients with neuropathic pain (FF 6), but Jørum does not supply the missing
evidence.

C. The rejection of claims 18-20 over Gaster, Smith, Jørum and
Omoigui.
We earlier found that Smith did not support finding an expectation of
success for treating neuropathic pain. In contrast to the earlier rejection,
Smith is here combined with Gaster, Jørum and Omoigui. Omoigui
explicitly taught treating neuropathic pain with a serotonin receptor
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antagonist. (FF14.) Given Omoigui’s direct teaching, we agree with the
Examiner that it would have been obvious to use one of Gaster’s serotonin
receptor antagonists to treat neuropathic pain.
Appellants argue that little weight should be given to Omoigui’s
association of neuropathic pain with inflammation because “these teachings
are merely hypothetical and theoretical.” (App. Br. 20.) Osemwota
Omoigui’s patent application publication references “Sota Omoigui’s Law”
concerning pain. (See Omoigui, 1:[0001].) In the “Evidence Appendix” to
their brief, Appellants provide copies of two articles published by Sota
Omoigui in the journal Medical Hypotheses, and the “Guide for Authors”
from the journal. According to Appellants, “the content of these literature
references . . . provides no reasonable expectation of success for treating
neuropathic pain using a compound of formula I.” (App. Br. 21.)
“Moreover, a plain reading of Omoigui [0051] and [0068-0069] does not
reveal a common mechanism linked to Substance P between the
naturopathic pain and pain associated with migraine.” (Id.)
We find Appellants’ evidence and argument insufficient to discount
Omoigui’s published patent application. First, the rejection relied on the
published patent application as evidence concerning the state of the prior art;
it did not rely on the articles Appellants provide. We find that the arguments
about the Medical Hypotheses journal are beside the point. Further, while
the journal’s “Guide for Authors” indicates that the journal “will consider”
speculative ideas, that does not mean that a person of ordinary skill in the art
would have rejected published hypotheses as per se unreliable. We also find
Appellants’ discussion of Substance P misdirected. The Examiner relied on
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Omoigui’s instruction to use a serotonin receptor antagonist, and not the
portion of Omoigui that discussed Substance P.

CONCLUSIONS
A. Gaster, Smith and Jørum, taken as a group with or without
Wickenden, did not provide sufficient evidence to support finding an
expectation of success for administering a Gaster compound to treat
neuropathic pain.
B. Gaster, Burstein and Jørum, taken as a group, did not provide
sufficient evidence to support finding an expectation of success for
administering a Gaster compound to treat neuropathic pain.
C. Gaster, Smith, Jørum and Omoigui, taken as a group, provided
sufficient evidence to support finding an expectation of success for
administering a Gaster compound to treat neuropathic pain.

SUMMARY
We reverse the rejection of claims 6-12 and 14-17 under 35 U.S.C.
§ 103(a) as unpatentable over Gaster, Smith and Jørum; and we reverse the
rejection of claims 18-20 under 35 U.S.C. § 103(a) as unpatentable over
Gaster, Smith, Jørum and Wickenden.
We reverse the rejection of claims 6-12 and 14-17 under 35 U.S.C.
§ 103(a) as unpatentable over Gaster, Burstein and Jørum.
We affirm the rejection of claims 20-23 under 35 U.S.C. § 103(a) as
unpatentable over Gaster, Smith, Jørum and Omoigui.
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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-IN-PART

lp

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