Ex Parte Bryant et al

Board of Patent Appeals and Interferences

Sep 26, 2008

08309525 (B.P.A.I. Sep. 26, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte
HENRY U. BRYANT, GEORGE J. CULLINAN, JEFFREY A. DODGE,
KENNAN J. FAHEY, CHARLES D. JONES, CHARLES W. LUGAR,
and BRIAN S. MUEHL
__________

Appeal 2007-4510
Application 08/309,525
Technology Center 1600
__________

Decided: September 26, 2008
__________

Before TONI R. SCHEINER, ERIC GRIMES, 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 uterine fibroid disease. The Examiner has rejected the claims as
lacking enablement. We have jurisdiction under 35 U.S.C. § 6(b).

Appeal 2007-4510
Application 08/309,525

BACKGROUND
According to the Specification, “[u]terine fibrosis (uterine fibroid
disease) is an old and ever present clinical problem. . . . Essentially, [it] is a
condition where there is inappropriate deposition of fibroid tissue on the
wall of the uterus” causing “dysmenorrhea and infertility” (Spec. 4).
The claimed invention is directed to a method of treating uterine
fibroid disease in humans by administering an effective amount of a
naphthyl compound of formula I, or its pharmaceutically acceptable salt.
STATEMENT OF THE CASE
Claim 40 is representative of the claimed subject matter:
40. A method for treating uterine fibroid disease comprising administering
to a woman in need of such treatment an effective amount of a compound of
formula I:

wherein
R1 is -H, OH, -O(C1-C4 alkyl), -OCOC6-H5, -OCO(C1-C6 alkyl), or
-OSO2(C4-C6 alkyl);
R2 is -H, OH, -O(C1-C4 alkyl), -OCOC6-H5, -OCO(C1-C6 alkyl), or
-OSO2(C4-C6 alkyl);
n is 2 or 3; and
R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl -
1- pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, or 1-
hexamethyleneamino; or a pharmaceutically acceptable salt thereof.

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PROCEDURAL HISTORY
This is the second appeal of the rejection of claim 401 on the grounds
of lack of enablement. In the first appeal, the Examiner’s rejection of claim
40 for lack of enablement was vacated, and a new ground of rejection was
entered, also on the grounds of non-enablement, but based a different
analysis (Decision on Appeal in Appeal 2001-2044, dated August 21, 2003,
hereinafter “Decision”). Following an analysis under the well-known
Wands2 factors, the merits panel concluded that Appellants’ “disclosure
would not enable a person of skill in the art to practice the claimed invention
without undue experimentation” (Decision 6). The Decision reads, in
pertinent part:
While we would agree that activity in one or more of the
“Uterine Fibrosis Test Procedures” discussed in the specification
[at pages 71-73] would be reasonably predictive of the effects of
the compounds of Formula I on uterine fibrosis, no data are
reported for any of the assays. In our view, the bare assertion
that the compounds of Formula I are useful in treating uterine
fibrosis is entitled to very little weight, given the apparently
complex physiological and unpredictable effects of the
compounds of Formula I.

(Decision 6.)

1 Claim 40 was the sole claim involved in that first appeal, and has since
been amended to recite “treating,” rather than “inhibiting” uterine fibroid
disease, but is otherwise unchanged (Amendment filed October 16, 2003).
In addition, claims 41-53, directed to specific compounds within the scope
of the compound of formula I, were entered at that time.
2 See In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
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Following the Decision in Appeal 2001-2044, Appellants elected to have
the matter reconsidered by the Examiner under 37 C.F.R. § 1.197(c)(1),
submitting two declarations of Dr. Andrew G. Geiser (“1st Declaration” and
“2nd Declaration”, dated October 16, 2003 and December 9, 2004, respectively)
in support of the enablement of the claimed invention.
DISCUSSION
Claims 40-53 stand rejected under 35 U.S.C. § 112, first paragraph, as
lacking enablement. The Examiner’s rejection is essentially unchanged from
the new ground of rejection set forth in the Decision in Appeal 2001-2044.
According to the Specification, the exact cause of uterine fibrosis “is
poorly understood but evidence suggests that it is an inappropriate response
of fibroid tissue to estrogen” (Spec. 4: 32-34). “Such a condition has been
produced in rabbits by daily administrations of estrogen for 3 months. In
guinea pigs, the condition has been produced by daily administration of
estrogen for four months. Further, in rats, estrogen causes similar
hypertrophy” (id. at 4: 34-38).
The Specification outlines several protocols under the heading
“Uterine Fibrosis Test Procedures” (Spec. 71: 29 to 73: 9). Tests 1, 2, and 3
are designed to determine the effects of administering a compound of
formula I to women with uterine fibrosis for 3 months, 6 months, and 1 year,
respectively. Test 4 is designed to determine the effect of a compound of
formula I on estrogen-induced fibroid tumors in sexually mature guinea pigs
and implanted fibroid tissue in nude mice. Test 5 is designed to determine
the proliferative response of primary nontransformed cultures of cells from
uterine fibroid tumors in the presence of a compound of formula I.
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Immediately following the description of Tests 1-5, the Specification
indicates that “[a]ctivity in at least one of the above tests indicates [that] the
compounds of . . . [formula I] are of potential in the treatment of uterine
fibrosis” (Spec. 73: 10-12). However, no observations based on any of these
test procedures have been reported to date.
As a matter of clarification, we note that Appellants are correct that
neither Appellants’ disclosure, nor the Decision in Appeal 2001-2044,
should “be read to teach or mandate, respectively, that data showing activity
in one of the assays described on pages 71-73 of their specification was
‘required’ to confer enablement on the present claims” (App. Br. 6). The
Decision merely states that a showing of “activity in one or more of the
‘Uterine Fibrosis Test Procedures’ discussed in the specification would be
reasonably predictive of the effects of the compounds of formula I on uterine
fibrosis” (Decision 6), but no such showing was made. That is not to say
that no other test procedure could be used to establish enablement of the
claimed invention.
In response to the new ground of rejection in the Decision, and the
Examiner’s continuation of the rejection, Appellants submitted two
declarations by Dr. Geiser under the provisions of 37 C.F.R. § 1.132 in an
effort to establish that the claimed invention was enabled as of its filing date
(1st Declaration, 2nd Declaration). Both declarations provide data showing
that the compounds of formula I exhibit estrogen antagonist activity in an
assay termed the “3-Day Rat Uterus Antagonist Assay” (1st Declaration 3;
2nd Declaration ¶ 6). According to Dr. Geiser, “[t]his model for uterine
antagonism utilizes immature (3 week old) female rats that are highly
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sensitive to estrogenic stimulation of the uterus given that their circulating
estrogen levels are prepubertal. Administration of exogenous estrogen to
immature rats [for three days] produces a reliable elevation of uterine
weight, which can be used to study the uterine antagonistic effects of a test
compound” (1st Declaration 2).
In addition, the declarations discuss the relevance of the assay to
regulation of fibroid growth. Dr. Geiser states that “[c]linical data confirm
that estrogen is important in the regulation of fibroid growth” and “[t]hese
tumors increase rapidly in size during the hyperestrogenic state brought on
by pregnancy, and regress in hypoestrogenic states brought on by
menopause or ovariectomy” (2nd Declaration ¶ 5). According to Dr. Geiser,
“pharmacologic approaches that center on the blockade of estrogen
stimulation, such as GnRH agonists, have been very effective in controlling
uterine fibroid growth” (id.).
Dr. Geiser further states that “[u]terine weight measurements are
highly sensitive to estrogenic stimulation and have long been used as a
measure to determine the estrogenicity of substances . . . Likewise, the
immature rat uterus assay has been used to determine antiestrogenic activity
of compounds by way of opposing an estrogen stimulus” and “this pre-
clinical assay has done well at predicting uterine effects in the clinic” (2nd
Declaration ¶ 4).
The implication is that compounds that act as estrogen antagonists in
estrogen-stimulated normal uteri would have been expected to have an
antagonistic effect on uterine fibroids as well - thus, the compounds of
formula I, which act as estrogen antagonists in estrogen-stimulated normal
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rat uteri in the 3-Day Rat Uterine Antagonist Assay, would reasonably have
been expected to have an antagonistic effect on uterine fibroids as well.
The Examiner contends that the 1st Declaration “lacks enabling
support for the claims because . . . [data] was not correlated to leiomyoma or
fibroid tissue, [and] no evidence in the art was found to link the 3-day [rat]
uterus assay to treating uterine fibroid tumor” (Ans. 6). Similarly, the
Examiner contends that the 2nd Declaration is no more persuasive than the 1st
because “data of a 3-Day assay on estrogenicity of the normal ‘uterine’ i.e.
uterotrophic assay in rat, does not provide . . . enabling support for the
claims which are limited to the leiomyoma” (Ans. 8). The Examiner argues
that “[e]nablement must be completed at the time the application was filed
and cannot be continuously supplemented by new opinion by others using
non-disclosed procedures to supplement deficiency of the specification”
(Ans. 9).
Appellants concede that the 3-Day Rat Uterus Antagonist Assay was
not expressly described in the present Specification (App. Br. 4), but argue
that it was “in fact indirectly described by the present specification as one
relevant to uterine fibroid disease” (App. Br. 5). Appellants note that the
Specification teaches at page 4, lines 34-38, that uterine fibroids can be
induced in rabbits and guinea pigs by daily administration of estrogen for
three or four months, respectively, and “estrogen causes similar
hypertrophy” in rats (App. Br. 5). Appellants contend that this portion of the
Specification “should be read to teach that a compound that inhibits
estrogen-induced hypertrophy of a rat’s uterus has potential in the treatment
of uterine fibroids” (id.), when taken in combination with the statement
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immediately following the five “Uterine Fibrosis Test Procedures” on page
73, lines 10-12 of the Specification to the effect that “[a]ctivity in at least
one of the above tests indicates the compounds of the present invention are
of potential in the treatment of uterine fibroids.”
While we do not agree with Appellants’ that the 3-Day Rat Uterus
Antagonist Assay was described in the present Specification, “indirectly” or
otherwise, we do agree that one of skill in the art could reasonably infer
from the Specification that a compound that exhibits estrogen antagonist
activity in estrogen-stimulated normal uterine tissue would have been
expected to have an antagonistic effect on uterine fibroids as well. The
Declarations provide evidence that the compounds of formula I exhibit
estrogen antagonist activity in estrogen-stimulated normal rat uteri.
In our view, the declarations do not, as the Examiner put it,
“supplement[ ] by new opinion by others using non-disclosed procedures to
supplement deficiency of the specification” (Ans. 9). Rather, they provide
evidence that confirms the Specification’s statement (Spec. 9) that the
compounds of formula I can be used to treat fibroid disease. See In re
Brana, 51 F.3d 1560, 1567 n.19 (Fed. Cir. 1995)(Post-filing declaration may
not be used to “render an insufficient disclosure enabling” but may be used
to show the accuracy of a statement in the Specification.). Accordingly, we
conclude that the Specification is enabling for the claimed invention.
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CONCLUSION
The rejection of claims 40-53 as lacking enablement under 35 U.S.C. §
112, first paragraph, is reversed.

REVERSED

ELI LILLY & COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS IN 46206-6288

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