Ex Parte Belanoff

Patent Trial and Appeal Board

Mar 11, 2013

10519008 (P.T.A.B. Mar. 11, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JOSEPH K. BELANOFF
__________

Appeal 2011-006791
Application 10/519,008
Technology Center 1600
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and
SHERIDAN K. SNEDDEN, Administrative Patent Judges.

SNEDDEN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of ameliorating the symptoms of psychosis associated with interferon α
(IFN-α) therapy. The Examiner has rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b). We reverse.

Appeal 2011-006791
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2
STATEMENT OF THE CASE
Claims 1-4 and 8-19 are on appeal. Claim 1, the only independent
claim on appeal, is representative and reads as follows (emphasis added):
1. A method of ameliorating the symptoms of psychosis
associated with interferon α therapy in a patient, comprising:
administering to the patient having received interferon α
therapy and suffering from psychosis associated with the
interferon α therapy, an amount of a glucocorticoid receptor
antagonist effective to ameliorate the symptoms of psychosis in
the patient, with the proviso that the patient is not otherwise in
need of treatment with a glucocorticoid receptor antagonist.

The claims stand rejected as follows:
I. Claims 1-4 and 8-17 under 35 U.S.C. § 103(a) as obvious over the
combination of Schatzberg
1
and Ademmer
2
as evidenced by
Shimizu.
3

II. Claims 18-19 under 35 U.S.C. § 103(a) as obvious over the
combination of Schatzberg, Ademmer and Dieterich.
4

Each rejection relies on the combination of Schatzberg and Ademmer
where the same issue is dispositive for each rejection. As such, we will
consider them together.

1
Schatzberg et al., US 6,150,349, issued Nov. 21, 2000.
2
Ademmer et al., Suicidal Ideation With IFN-α and Ribavirin in a Patient
With Hepatitis C, 42 PSYCHOSOMATICS 365-367 (2001).
3
Shimizu et al., Increase in serum interleukin-6, plasma ACTH and serum
cortisol levels after systemic interferon-alpha administration, 42 ENDOCR. J.
551-560 abstract only (1995).
4
Dieterich, Treatment of Hepatitis C and Anemia in Human
Immunodeficiency Virus-Infected Patients, 185 THE JOURNAL OF INFECTIOUS
DISEASES S128-37 (2002).
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Issue
The Examiner finds that Schatzberg “explicitly teaches the
amelioration of psychosis by the administration of a [glucocorticoid receptor
antagonist]” (Ans. 11). The Examiner finds that Ademmer “establishes that
it was well known [that] psychosis, such as suicidal ideation, is a well-
recognized symptom of IFN-alpha therapy” (id.). The Examiner finds that
“it is well known in the art that IFN-α therapy causes an increase in serum
cortisol levels” (Final Office Action 9, citing Shimizu). In reaching the
conclusion of obviousness, the Examiner finds that
for the ordinary skilled artisan to arrive at the claimed invention
requires no leap of faith or quantum leap in thinking to connect
the dots and conclude that treatment of psychosis associated
with IFN-alpha is obvious and would have had a reasonable
expectation of success, because psychosis is art-recognized as
resulting from glucocorticoid regulation dysfunction, IFN-alpha
is known to induce psychosis, and GRAs are indicated for the
treatment of psychosis

(Ans. 12).
Appellant argues that submitted evidence establishes that psychosis
due to IFN-α treatment is not linked to glucocorticoid dysregulation (see,
e.g., Reply Br. 4) and that “unless the Examiner can find a reference
disclosing the connection between psychosis due to treatment with IFN-α
and glucocorticoid dysregulation, the claims must be held non-obvious” (id.
at 2).
The issue presented is: Has Appellant submitted evidence sufficient to
rebut the Examiner’s prima facie case of obviousness?
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Findings of Fact
The following findings of fact (“FF”) are supported by a
preponderance of the evidence of record.
FF1. Schatzberg discloses “treating psychosis associated with
glucocorticoid related dysfunction by administration of an amount of a
glucocorticoid receptor antagonist” (Schatzberg, col. 3, ll. 47-49).
FF2. Schatzberg discloses as follows:
Patients with some forms of psychiatric illnesses have been
found to have increased levels of cortisol. For example, some
patients with depressed mood have had their mood improve
with treatments which lower the levels of cortisol. In some
individuals, reversing increased cortisol levels using inhibitors
of steroid biosynthesis can be effective in treating depression.
Alternatively, some depressed individuals can be responsive to
treatments which block the effect of cortisol, as by
administering [glucocorticoid receptor] antagonists.

(Schatzberg, col. 2, ll. 21-33.) (Citations omitted.)
FF3. Ademmer discloses that “[o]ne of the most serious side effects
of IFN-α treatment is the development of psychiatric symptoms, particularly
depression and suicidal ideation” (Ademmer 365, left col.).
FF4. Ademmer discloses the result of a case study in which IFN-α
was administered 3 times a week at 3 million units per dose, and suicidal
ideation arose at 4 months (id. at 365, right col.).
FF5. Shimizu discloses that “[s]ubcutaneous administration of IFN
significantly increased plasma ACTH and serum cortisol concentrations by 3
h after the injection” (Shimizu, Abstract).
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FF6. In a Declaration under 37 C.F.R. § 1.132, Dr. Joseph Belanoff,
Feb. 10, 2009, Declarant relies on the teachings of Gisslinger
5
for evidence
that elevation of cortisol after IFN-α treatment is transient (Belanoff
Declaration, 3). Declarant states “Gisslinger et al. ... looked at patients
treated with IFN-α for three weeks and concluded that the transient elevation
of cortisol was actually temporary and after 3 weeks, the cortisol elevation
disappeared” (id.).
FF7. Gisslinger discloses as follows:
The successful therapeutic use of interferon-α (IFN-α) in
myeloproliferative disorders offered the possibility to test its
acute and long-term effects on the hypothalamic-pituitary-
adrenal (HPA) axis in humans. ACTH and cortisol plasma
concentrations were measured in 8 patients hourly starting from
4 p.m. through 12 p.m. on three occasions. The first time all
patients were studied before initiation of therapy, when the
vehicle was injected alone. The patients were studied again on
day 1 of IFN-α therapy (5 million units) and once more after 3
weeks of therapy. On the control day, plasma concentrations of
ACTH and cortisol were in the range expected for this time of
day. In contrast, after the first administration of IFN-α a
significant stimulation of the HPA axis was observed. After 3
weeks of IFN-α therapy, no significant stimulation of the HPA
axis occurred after administration of IFN-α.
(Gisslinger, Abstract.)

5
Gisslinger et al., Interferon-α Stimulates the Hypothalamic-Pituitary-
Adrenal Axis in vivo and in vitro, 57 NEUROENDOCRINOLOGY 489-495
(1993).
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FF8. Declarant relies on, inter alia, Bozikas6 for evidence that IFN-
α-induced psychosis is not present within the 3 week window where IFN-α
elevates cortisol (Belanoff Declaration, 3).
FF9. Bozikas discloses the result of a case study in which the patient
“was receiving high doses of INF-α [sic], and psychotic symptoms appeared
after 11 months of continuous treatment” (Bozikas 137, left col.).
Principles of Law
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness.” In re
Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993). “After evidence or argument
is submitted by the applicant in response, patentability is determined on the
totality of the record, by a preponderance of evidence with due consideration
to persuasiveness of argument.” In re Oetiker, 977 F.2d 1443, 1445 (Fed.
Cir. 1992).
Analysis
In this case, we agree with Appellant that the preponderance of the
evidence of record fails to establish that IFN-α-induced psychosis was
sufficiently linked to glucocorticoid regulatory dysfunction (i.e., increased
levels of cortisol) such that a person of ordinary skill in the art would have
been motivated to treat IFN-α-induced psychosis with glucocorticoid
receptor antagonists according to the teachings of Schatzberg (see, e.g., App.
Br. 11-14; FF1 and FF2). While IFN-α was known to increase cortisol
(FF5), this effect is transient (FF6 and FF7) and does not correspond with

6
Bozikas et al., An interferon-α-induced psychotic disorder in a patient
with chronic hepatitis C, 16 EUR PSYCHIATRY 136-7 (2001).
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the time frame for the development of psychosis in a patient receiving IFN-α
therapy (FF4, FF8 and FF9) as set forth in claim 1.
The Examiner has not disputed the facts stated in the Declaration (FF6
and FF8) or provided contrary evidence establishing a link between IFN-α-
induced psychosis and glucocorticoid regulatory dysfunction. We therefore
conclude that this aspect of the rejection is not supported by a preponderance
of the evidence of record.
Conclusion of Law
We conclude that the preponderance of the evidence of record does
not support the Examiner’s conclusion the cited prior art renders claim 1
obvious. As claims 2-4 and 8-17 are dependent on claim 1, and thus
incorporate all of the limitations of claim 1, we reverse the rejection as to
those claims as well.
Claims 18-19 are also rejected under 35 U.S.C. § 103(a) as being
unpatentable over the combination of Schatzberg, Ademmer and Dietrich.
This rejection relies upon the combination of Schatzberg and Ademmer.
Having reversed the rejection of claim 1 over the combination of Schatzberg
and Ademmer, we necessarily reverse this obviousness rejection further
relying upon Dietrich because Dietrich, cited for disclosing neuropsychiatric
side effects of long-term use of IFN-α in patients with various diseases and
addictions (Ans. 9), does not cure the deficiencies of Schatzberg and
Ademmer discussed above.

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SUMMARY
We reverse all rejections on appeal.
REVERSED

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