Ex Parte Bolondi et al

Patent Trial and Appeal Board

Oct 7, 2016

12452825 (P.T.A.B. Oct. 7, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/452,825 03/17/2010
23117 7590 10/12/2016
NIXON & V ANDERHYE, PC
901 NORTH GLEBE ROAD, 11 TH FLOOR
ARLINGTON, VA 22203
FIRST NAMED INVENTOR
Luigi Bolondi
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
GRT/4161-55 7353
EXAMINER
SCHULTZ, JAMES
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
10/12/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
PTOMAIL@nixonvan.com
pair_nixon@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LUIGI BOLONDI, CATIA GIOV ANNIN!,
PASQUALE CHIECO, and KENNETH MARCU 1
Appeal2014-006957
Application 12/452,825
Technology Center 1600
Before ERIC B. GRIMES, DONALD E. ADAMS, and RYAN H. FLAX,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating hepatocellular carcinoma, which have been rejected as obvious.
We have jurisdiction under 35 U.S.C. § 6(b ).
We reverse.
STATEMENT OF THE CASE
"The four known Notch receptors (Notchl--4) are single-pass
transmembrane receptors that mediate signaling from the cell surface to the
1 Appellants identify the Real Party in Interest as Universita di Bologna.
(Br. 3.)
Appeal2014-006957
Application 12/452,825
nucleus." (Spec. 1:30-31.) "Because of increasing evidence that the Notch
signalling pathway is abnormally deregulated in human cancer, Notch
receptors are potential targets for selective killing [of] malignant cells." (Id.
at 1 :27-29.)
Claims 16-18, 20, 21, 23, 25, 26, 28, and 30 are on appeal. Claim 16
is illustrative and reads as follows:
16. A method of treating Hepatocellular Carcinoma (HCC),
the method comprising: administering a pharmaceutical
composition comprised of a Notch3 inhibitor, one or more anti-
tumoral chemotherapeutic agents causing cellular apoptosis or
acting on cellular proliferation, and a pharmaceutically acceptable
carrier to a patient in need thereof, in one or more therapeutically
effective doses.
In response to an election-of-species requirement, Appellants elected
small interfering RNA (siRNA) as the Notch3 inhibitor and sorafenib as the
chemotherapeutic agent (Office Action mailed Nov. 30, 2011, page 2).
DISCUSSION
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as obvious based on Giovannini, 2 Freier, 3 Li, 4 and Abou-Alfa. 5
(Ans. 2.) The Examiner finds that Freier teaches Notch3-specific siRNA, in
2 Catia Giovannini et al., Notch3 Intracellular Domain Accumulates in
HepG2 Cell Line, 26 ANTICANCER RES. 2123-2128 (2006).
3 Freier et al., US 2004/0102390 Al, published May 27, 2004.
4 Honghai Li et al., Use of Adenovirus-Delivered siRNA to Target
Oncoprotein p28GANK in Hepatocellular Carcinoma, 128
GASTROENTEROLOGY 2029-2041 (2005).
5 Ghassan K. Abou-Alfa et al., Phase II Study of Sorafenib in Patients With
Advanced Hepatocellular Carcinoma, 24 J. CLINICAL ONCOLOGY 4293-
4300 (2006).
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Appeal2014-006957
Application 12/452,825
combination with chemotherapeutics, for treating hyperproliforative
diseases, although not specifically hepatocellular carcinoma (HCC). (Id. at
3.) The Examiner finds that Giovannini "suggests that deregulation of
Notch receptor activity may be involved both in the differentiation and
spread of HCC." (Id.) The Examiner finds that Abou-Alfa teaches that
sorafenib is effective in HCC treatment and Li teaches treatment of HCC
using adenovirus-delivered siRNA. (Id.)
The Examiner concludes that it would have been obvious to treat
HCC with a combination of sorafenib and a Notch3-specific siRNA because
it was known from "Giovannini that Notch3 signaling may be involved in
both the differentiation and spread of HCC," "from Freier that Notch3-
specific siRNA in combination with a chemotherapeutic is effective in
treating cancer generally," and from "Abou-Alfa that sorafenib is effective
in specifically treating HCC." (Id. at 3--4.)
Appellants argue, among other things, that they discovered an
"unexpected interaction between Notch3 inhibition and doxorubicin, in
which there is an increased anti-tumor effect on hepatocellular carcinoma
cells." (Br. 12.) Appellants argue that "Notch3 inhibition sensitizes HCC
cells to the action of an anti-tumoral chemotherapeutic agent causing cellular
apoptosis or acting on cell proliferation, which proves to be surprisingly
effective." (Id. at 13-14.) Appellants cite the Specification's Figure 3 as
showing that "Notch3 inhibition alone has no effect on cell viability ... [but
that a] combination ofNotch3 inhibition and drug-induced apoptosis
exhibited a statistically significant increase in effectiveness of doxorubicin
against HCC cells." (Id. at 14.)
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Appeal2014-006957
Application 12/452,825
We agree with the Examiner that the cited references support a prima
facie case of obviousness, but we also agree with Appellants that the
evidence shows that treatment of hepatocellular carcinoma cells with a
combination of a Notch3-specific siRNA and a chemotherapeutic agent is
unexpectedly effective.
Freier discloses that oligonucleotides that inhibit Notch3 (Freier i-f 31 ),
including those that induce RNA interference6 (id. at i-fi-132-33) "may prove
to be a useful point for therapeutic intervention in ... hyperproliferative or
autoimmune disorders." (Id. at i-f 9.) Freier also discloses "pharmaceutical
compositions containing one or more oligomeric compounds and one or
more other chemotherapeutic agents." (Id. at i-f 114.)
Giovannini discloses that "high expression of endogenous NICD
[Notch intracellular domain], indicative of persistent Notch signaling, could
be necessary for malignant liver cell proliferation." (Giovannini 2126, right
col.) "In order to detect Notch signaling activity, HES 1 gene expression was
investigated by real-time PCR. HESl was found to be expressed in [an
HCC cell line]." (Id.) Abou-Alfa discloses that "[a]lthough single-agent
sorafenib has modest efficacy in HCC, the manageable toxicity and
mechanisms of action support a role for combination regimens with other
anticancer agents." (Abou-Alfa 4293, Conclusion.)
Thus, based on the cited references, it would have been obvious to
treat HCC with a combination of a Notch3-specific siRNA that induces
RNA interference and sorafenib, because both agents were taught to be
6 "RNA interference (RNAi) is a powerful tool to silence gene expression.
The adenoviral vector expressing small interfering RNA (siRNA) is highly
effective in mammalian cells." (Li 2029, left col.)
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Appeal2014-006957
Application 12/452,825
effective in treating HCC. A skilled worker would therefore have expected
that the combination would be more effective in treating HCC than either
agent alone.
The evidence provided in Appellants' Specification, however, shows
that the combination of a chemotherapeutic agent (doxorubicin) and a
Notch3-specific siRNA is much more effective than the simple additive
effect of each agent by itself. Figure 3 of the Specification is shown below:
100
90
#' so
~ 70
(i!
"' 60 ll (h J
GCS B N3S
FIG. 3
Figure 3 shows the effect of doxorubicin in HCC cells that express
either a Notch3-specific siRNA ("N3S") or a control siRNA ("CS"). (Spec.
17:4--8.)
The Specification states that expression of a Notch3-specific siRNA
by itself did not affect the growth rate of the cells, assessed one week post-
infection (id. at 17:2-3), and did not affect cell viability (id. at 3:12-14).
Those statements are supported by Figure 3, which shows that all of the cells
excluded trypan blue dye at time zero, when the doxorubicin treatment was
started. Figure 3 also shows that, in the cells that expressed the negative
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Appeal2014-006957
Application 12/452,825
control siRNA, doxorubicin treatment caused about 25% mortality after 24
hours, but in cells expressing a Notch3-specific siRNA, treatment with
doxorubicin resulted in about 75% mortality after 24 hours. (See Spec.
3: 17-20: "[T]he mortality of HepG2 cells stably expressing Notch3
shRNAs[7J (in comparison to a luciferase shRNA negative control) doubled
and tripled in response to doxorubicin ... treatments of 6 and 24 hours
respectively, as revealed by trypan blue dye exclusion (Fig. 3).")
In other words, even though the Notch3-specific siRNA had no cell-
killing effect by itself (after a week of potential action on the cells) and
doxorubicin killed 25% of the cells by itself, the combination of the two
killed 75% of the cells (in just a single day). We cannot agree with the
Examiner's conclusion (Ans. 9-10) that combining a Notch3-specific siRNA
and a chemotherapeutic agent provides no more than additive results.
The Examiner also points out that the claims are not limited to the
specific combination of agents that are exemplified in the results shown in
the Specification's Figure 3. (Ans. 11.) However, the Specification states
that "Notch3 expression ... functions at least in part as a specific positive
effector of multi-drug resistance by preventing the activation ofp53-
dependent apoptosis and, as a consequence, engenders HCC with resistance
to chemotherapeutics." (Spec. 3:23-25.) The Specification also provides
evidence that p53 is required in order for an enhanced apoptotic reaction in
cells treated with a Notch3-specific siRNA and doxorubicin. (Id. at 18:6-
23.) Thus, the Specification provides a reasonable basis for concluding that
a Notch3-specific siRNA would also demonstrate enhanced cell killing in
7 The acronym "shRNAs" refers to "short hairpin RN As" (see Spec. 2: 17).
6
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Application 12/452,825
combination with other chemotherapeutic agents. The Examiner has
provided no persuasive evidence or technical reasoning to the contrary.
SUMMARY
We reverse the rejection of claims 16-18, 20, 21, 23, 25, 26, 28, and
30 under 35 U.S.C. § 103(a) based on Giovannini, Freier, Li, and Abou-
Alfa.
REVERSED
7