Ex Parte Sasakawa et al

Patent Trial and Appeal Board

Jan 29, 2013

10486833 (P.T.A.B. Jan. 29, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte YUKA SASAKAWA and
YOSHINORI NAOE
____________

Appeal 2011-003520
Application 10/486,833
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, STEPHEN WALSH, and
ULRIKE W. JENKS, Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to directed
to a method of treating prostate cancer. The Examiner has rejected the
claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We
reverse.

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Appeal 2011-003520
Application 10/486,833

3
ISSUE
The Examiner takes the position that:
Based on the encouraging in vivo data presented by Ueda in
two kinds of solid tumors A549 and MCF-7 in xenograft
models in mouse, one of ordinary skill in the art would be
motivated to develop a method for treating prostate cancer
using FK228 because Sandor has shown that the drug has a
unique toxicity profile in arresting the cell cycle growth of PC-
3 prostate carcinoma cells lines at the Gl and G2 cycles.
(Ans. 5.)
Appellants contend that “in vitro data alone are not enough to
establish a reasonable correlation, nor is the reliance upon Ueda et al, which
do not disclose or suggest prostate carcinoma cell lines in any context.”
(App. Br. 11.)
The issue is: Has the Examiner set forth a prima facie case of
obviousness based on the combination of Sandor, Ueda, and Thompson?

FINDINGS OF FACT
FF1. Sandor disclosed “[d]epsipeptide, FR901228, a novel cyclic
peptide inhibitor of histone deacetylase with a unique cytotoxicity profile is

D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR
901228, 83 BRITISH J. OF CANCER 817-825 (2000)
2 Hitotsugu Ueda et al., FR901228, A novel antitumor bicyclic depsipeptide
produced by Chromobacterium violaceum No. 968, 47 J. OF ANTIBIOT. 301-
310 (1994)
3 Thompson, U.S. Patent No. US 6,252,058 B1 (filed Nov. 5, 1998) (issued
Jun. 26, 2001).
Appeal 2011-003520
Application 10/486,833

4
currently in phase I clinical trials. Here we demonstrate that, in addition to
G2/M arrest, FR901228 causes G1 arrest with Rb hypophosphorylation. In
vitro kinase assays demonstrated no direct inhibition of CDK activity,
however, an inhibition was observed in CDKs extracted from cells exposed
to FR901228.” (Sandor Abstract; Ans.3)
FF2. Sandor disclosed that “[i]n addition to a G1 cell cycle arrest, a
G2 cell cycle arrest can be seen. The ability of FR901228 to cause a G1 cell
cycle arrest in the p53-null PC3 cell line suggests a p53-independent effect.”
(Sandor 818-819; Ans. 3.)
FF3. Ueda disclosed:
The antitumor activity of FR901228 was examined
against two kinds of human tumors, A549 [(lung
adenocarcinoma)] and MCF-7 [(mammary adenocarcinoma)],
implanted under the kidney capsule of immunosuppressed BDF
1 mice (SRC assay). . . . FR901228 significantly inhibited the
growth of human tumors A549 and MCF-7 in a dose dependent
manner at doses from 0.56 to 3.2 mg/kg and from 1.0 to 3.2
mg/kg, respectively.

(Ueda 308; Ans. 4.)
FF4. Thompson disclosed:
Surgery or radiotherapy is the treatment of choice for
early prostatic neoplasia. . . . Endocrine therapy is the treatment
of choice for more advanced forms. The aim of this therapy is
to deprive the prostate cells, and presumably the transformed
prostate cells as well, of testosterone. . . . Although often
initially sensitive to removal of androgens, prostate cancer cells
Appeal 2011-003520
Application 10/486,833

5
eventually lose this response and continue to grow and spread
even in the absence of androgenic steroids. . . . Current
therapeutic regimens for metastatic disease typically involve
both chemical and surgical androgen ablation, which although
has been demonstrated to extend life when compared to
untreated patients, almost invariably results in the development
of hormone-refractory disease and the demise of the patient.
(Thompson col. 2, l. 66 to col. 3, l. 29.)
FF5. Thompson disclosed:
[I]n vitro model system for both human and mouse cell
lines. . . . A panel of three human prostate cancer cell lines that
have been stably transfected with vector control as well as
antisense or sense caveolin are established, depending on
caveolin expression. These cell lines are identified as ND-l and
PC-3 (high caveolin expression) and LNCaP (low to
undetectable caveolin).
(Thompson col. 24, ll. 49-60.)
FF6. Johnson disclosed:
For 39 clinical agents, relationships between xenograft
response levels, averaged by histology, and the phase II
response rates were investigated. The Spearman rank
correlation coefficients (r) for all histologies are plotted in
Figure I. Only non-small cell lung (NSCL) xenografts were
predictive of clinical activity in the same histology (r = 0.814, P
= 0.004). Breast xenograft models were the most useful for
predicting clinical response against any disease, correlating
with clinical activity against NSCL (r = 0.565, P = 0.008),
melanoma (r = 0.540, P = 0.007) and ovarian (r = 0.611, P =
0.003) cancer, but interestingly, not with clinical breast cancer.
Activity in colon xenografts predicted for clinical melanoma
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Appeal 2011-003520
Application 10/486,833

7
(Spec. Fig.1 ) The Figure shows solid tumor growth relative to time,
intravenous administration of FR901228 was in four doses starting at day
zero and every four days thereafter. (Spec. 20, l. 1 to 21, l. 28.)

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. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993).
ANALYSIS
This was a very close case. The Examiner relies on Sandor to show
that FR901228 (a.k.a. FK223, depsipeptide) is a cell cycle inhibitor and is
effective on PC-3 prostate cancer cells in vitro (Ans. 3). According to the
Examiner, Ueda shows in vivo xenograft mouse models using FK228
(FR901228) on human lung adenocarcinoma and human mammary
adenocarcinoma cells (Ans. 4). While Ueda establishes that FK228 can be
administered to a patient, specifically, to a mouse, in sufficient quantity to be
effective against lung and mammary tumors, the reference does not address
whether FK228 would be effective against a prostate tumor in vivo.
The Examiner asserts that “the PC-3 cell line is a model for studying
the human prostate carcinoma according to Thompson.” (Ans. 5) However,
what is missing from the Thompson reference is a correlation between the in
Appeal 2011-003520
Application 10/486,833

8
vitro cell model and in vivo predictability that a particular compound that is
found to be effective in the test tube will also be effective in an in vivo
model system, and eventually in a patient. The Examiner relies on Johnson4
to supply evidence of such a correlation, and further asserts that
“‘obviousness does not require absolute predictability, however, at least
some degree of predictability is required. Evidence showing there was no
reasonable expectation of success may support a conclusion of
nonobviousness’ (emphasis added by the office).” (Ans. 11.) Here, the
Examiner attempts to establish that in vitro models for testing compounds
somehow provide a predictive measure to establish that success of these
compounds in vitro would be reasonably expected to show in vivo success
as well.
“Appellants submit that there is nothing of record establishing a link
between cytotoxicity in the alleged in vitro ‘model’ system, such as PC-3,
and efficacy in vivo, much less viability as an anti-neoplastic agent.” (Reply
Br. 4.) We agree with the Appellants’ position. We find that the Examiner’s
reliance on Johnson appears to be misplaced. Johnson disclosed that “only
non-small cell lung (NSCL) xenografts were predictive of clinical activity”
(FFs 6, 7). Breast cancer xenografts appear to be useful for predicting
clinical response for other tumors, “but interestingly, not with clinical breast

4 JI Johnson et al., Relationships between drug activity in NCI preclinical in
vitro and in vivo models and early clinical trials, 84 BRITISH J. OF CANCER,
1424-1431 (2001)
Appeal 2011-003520
Application 10/486,833

9
cancer” (FF6). Thus, “with the exception of lung [cancer cells], histological
matches were not found between in vivo models and clinical response,
activity in multiple xenograft models does appear to predict for some degree
of clinical activity.” (FF7) A finding that the art recognizes that a particular
in vitro model correlates to treating a specific condition in vivo, requires
evidence that the model is accepted. In re Brana, 51 F.3d 1560, 1566 (Fed.
Cir. 1995). Here, Johnson establishes that the in vitro models, although
useful as screening tools, do not correlate with the compound’s effect
against the particular disease in vivo.
With respect to the declarations provided during prosecution, the
Examiner takes the position that Dr. Ross’s opinion declaration “addresses a
species of prostate cancer (HRPC) patients and not prostate cancer in general
as stated in our previous response to appellant's arguments. As mentioned
before, treatment of HRPC in patients is not supported by the instant
specification.” (Ans. 18.) We note that the McClulloch5,6 declarations and
the Ross7 declaration rely on the results of a phase II clinical trial disclosed
in Molife.8 Molife’s results are directed to patients having hormone resistant

5 William McCulloch, Declaration under 37 C.F.R. § 1.132, dated Nov. 31,
2006.
6 William McCulloch, Declaration under 37 C.F.R. § 1.132, dated May 15,
2007.
7 Robert W. Ross MD, Declaration under 37 C.R.R. § 1.132, dated Feb. 21,
2007.
8 R. Molife et al., A Phase II Study Evaluating the Activity and Tolerability
of Depsipeptide (FK228) in Patients with Hormone-Refractory Prostate
Appeal 2011-003520
Application 10/486,833

10
prostate cancer. Prostate cancers during the course of the disease eventually
lose their ability to respond to hormone and, thus, eventually develop
hormone resistance (FF4). Hormone resistant prostate cancer, as
acknowledged by Appellants (App. Br. 12), is a species of prostate cancer
that is further along in the disease process and is more difficult to treat
because it is refractive to conventional therapy. The Examiner has provided
no articulated reason for doubting that results shown for HRPC would not be
generally applicable to earlier stages of prostate cancer, especially in light of
the disease progression that leads to hormone resistance in prostate cancer.
We find that the evidence of this record fails to support the
Examiner’s conclusion that claims 45 and 60 are obvious over Sandor in
view of Ueda in light of Thompson. We therefore reverse the rejection of
claims 45 and 60 under 35 U.S.C. § 103(a) as being obvious.

SUMMARY
We reverse the rejection of claims 45 and 60 under 35 U.S.C. § 103(a)
as unpatentable over Sandor in view of Ueda in light of Thompson.

REVERSED

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Cancer, (2006) and (2009).