Ex Parte Antonia et al

Patent Trial and Appeal Board

Aug 23, 2013

11433079 (P.T.A.B. Aug. 23, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte SCOTT ANTONIA, DMITRY I. GABRILOVICH,
SUNIL CHADA, and KERSTIN B. MENANDER1
__________

Appeal 2012-000644
Application 11/433,079
Technology Center 1600
__________

Before ERIC GRIMES, MELANIE L. McCOLLUM, and
ULRIKE W. JENKS, 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 tumor cells that are resistant to a chemotherapeutic agent. The
claims have been rejected for obviousness. We have jurisdiction under 35
U.S.C. § 6(b).
We reverse.

1 Appellants identify the Real Parties in Interest as Introgen Therapeutics,
Inc. and University of South Florida (Appeal Br. 2).
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STATEMENT OF THE CASE
Claims 1, 10-12, 26, 29-31, 42, 43, 45, 48-59, 61, 67, and 68 are on
appeal. Claims 1 and 59 are the only independent claims and read as
follows:
1. A method of conferring chemotherapeutic agent sensitivity to a
chemotherapeutic agent resistant tumor in a subject, comprising providing to
the subject a dendritic cell comprising a p53 expression construct, the
expression construct comprising a p53 gene under control of a promoter
operable in the dendritic cell, wherein chemotherapeutic agent sensitivity is
conferred to the tumor; and then providing a chemotherapy comprising the
chemotherapeutic agent to the chemotherapeutic agent sensitized tumor in
the subject.

59. A method of treating one or more cancer cells in a subject who has
been determined to have cancer cells that are resistant to a chemotherapeutic
agent, comprising providing to said subject a dendritic cell expressing a p53
gene product and then the chemotherapeutic agent.

The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 103(a) as obvious based on Gabrilovich,2 Sameshima,3 Lowe,4 Wen,5
Lynch,6 and Petak7 (Answer 7). The Examiner finds that Gabrilovich

2 Gabrilovich et al., WO 00/54839, published Sept. 21, 2000.
3 Sameshima et al., Alterations of the p53 gene are common and critical
events for the maintenance of malignant phenotypes in small-cell lung
carcinoma, 7 ONCOGENE 451-457 (1992).
4 Lowe et al., p53-Dependent Apoptosis Modulates the Cytotoxicity of
Anticancer Agents, 74 CELL 957-967 (1993).
5 Wen et al., Idiotypic Protein-pulsed Adherent Peripheral Blood
Mononuclear Cell-derived Dendritic Cells Prime Immune System in
Multiple Myeloma, 4 CLIN. CAN. RES. 957-962 (1998).
6 Lynch et al., US 7,150,992 B1, issued Dec. 19, 2006.
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teaches treatment of cancer via expression of a self-gene product, including
p53, in dendritic cells (id. at 7-8), optionally in combination with a
chemotherapeutic agent (id. at 9), but does not teach treating chemotherapy-
resistant cancer (id. at 10).
The Examiner finds that (1) Sameshima teaches chemotherapy
treatment of p53-expressing small cell lung cancer (id. at 10-11); (2) Lowe
teaches that “loss of p53 function leads to a dramatic increase in cellular
resistance to a variety of agents used in cancer therapy” and that, “in general,
patients with tumors that have acquired p53 mutations in their primary
tumors respond poorly to treatment with either radiation or chemotherapy”
(id. at 11); (3) Wen teaches treating chemotherapy-resistant myeloma with
dendritic cells pulsed with a tumor-specific protein followed by
chemotherapy (id.); and (4) that Lynch teaches using flt3-ligand/CD40 as an
adjuvant (id. at 12).8
The Examiner concludes that, based on these disclosures, it would
have been obvious to a person of ordinary skill in the art “to have used the
method of Gabrilovich et al. to treat chemoresistant cancers . . . because
Lowe et al. teach that in general, patients with tumors that have acquired p53
mutations in their primary tumors respond poorly to treatment with either
radiation or chemotherapy” (id.). The Examiner finds that Wen would have
provided a reasonable expectation of success because it “show[s] that

7 Istvan Petak and Janet A. Houghton, Shared Pathways: Death Receptors
and Cytotoxic Drugs in Cancer Therapy, 7 PATHOLOGY ONCOLOGY
RESEARCH 95-106 (2001).
8 The Examiner cites Petak as evidence that certain chemotherapeutic agents
are capable of upregulating expression of Fas (Answer 10).
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dendritic cell based cancer vaccine followed by high dose chemotherapy is
effective in treating refractory tumor” (id. at 13).
Appellants argue that Lowe teaches that p53 is required for apoptosis
following treatment with chemotherapeutic compounds, and that the absence
of p53 expression leads to an increase in resistance to such compounds
(Appeal Br. 11). Appellants argue that these teachings “would leave one of
skill in the art with serious doubts as to the success of the claimed invention
since the tumor cell is still effectively p53 deficient (i.e., functional p53 is
not being expressed in the p53 deficient cell) and would in fact teach one of
skill to not use a chemotherapeutic agent for which the tumor cell is already
identified to be resistant” (id. at 11-12). In particular, Appellants argue that
“[t]here is no evidence or reasoning provided that would explain why one of
skill would treat a tumor cell known to be resistant to a chemotherapy with
the same chemotherapy” (id. at 12).
We agree with Appellants that the Examiner has not persuasively
shown that the claimed methods would have been obvious to a person of
ordinary skill in the art based on the cited references. Claim 1 is directed to
a “method of conferring chemotherapeutic agent sensitivity to a chemo-
therapeutic agent resistant tumor” by administering dendritic cells
expressing p53 to the subject, “and then providing a chemotherapy
comprising the chemotherapeutic agent” (claim 1, emphasis added); i.e., the
same chemotherapeutic agent to which the tumor was resistant. Claim 59 is
similarly directed to a method of treating a subject having “cancer cells that
are resistant to a chemotherapeutic agent” by administering dendritic cells
expressing p53 “and then the chemotherapeutic agent” (claim 59, emphasis
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added); i.e., the same chemotherapeutic agent to which the cancer cells were
resistant.
The Examiner finds that Gabrilovich does not teach treating
chemotherapy-resistant cancer (Answer 10) and, as we understand it, relies
on Lowe and Wen to meet that claim limitation. Lowe teaches that “p53 is
required for the efficient activation of apoptosis following irradiation or
treatment with chemotherapeutic compounds. Thus, the absence of p53
expression leads to a dramatic increase in cellular resistance to these
agents.” (Lowe 958, left col.) Lowe discloses that its “study demonstrates
that loss of p53 function enhances cellular resistance to a variety of agents
used in cancer therapy” (id. at 964, left col.) and that “there may be a strong
correlation between a tumor’s p53 status and patient response to
chemotherapy” (id. at 964, right col.); i.e., tumor types in which a high
percentage of tumors acquire p53 mutations respond poorly to chemo-
therapy, while in other forms of cancer where tumors rarely exhibit p53
mutations, chemotherapy is “extremely effective” (id.)
As Appellants point out, however, Lowe’s teachings are limited to
expression of p53 in the tumor cells themselves. Lowe therefore provides a
reason to expect that restoring expression of p53 in a tumor cell will restore
sensitivity to a chemotherapeutic agent, but it provides no such expectation
for expressing p53 in dendritic cells administered to the patient.
Wen teaches treatment of a patient having myeloma, who had been
treated with three types of chemotherapy: VAD (vincristine, adriamycin,
and dexamethasone), HDC (high-dose cyclophosphamide), and miniBEAM
(which Wen does not define) (Wen 959, Table 1). The patient did not show
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a measurable response to the HDC or miniBEAM treatments (id.) and thus
can be understood to have tumor cells (or cancer cells) resistant to those
chemotherapeutic agents.
Wen discloses that the patient was treated with dendritic cells (DC)
pulsed with a protein (“Id”) produced by the malignant tumor cells (id. at
957, right col.; 958, right col.). The patient showed “minor but definite
transient” response to the first vaccination but “the disease rapidly escaped
and progressed, despite two additional rounds of DC vaccination” (id. at
959, right col.). “As a result, the patient received high-dose melphalan”
chemotherapy (id.). Notably, the subsequent chemotherapy was different
from any of the types of chemotherapy that the patient had previously
received.
Thus, neither Lowe nor Wen teach treating a patient having a tumor
(or cancer cells) that has developed resistance to a particular
chemotherapeutic agent with dendritic cells – or any other treatment – to
reverse the chemoresistance and provide an expectation that subsequent
treatment with the same chemotherapeutic agent would be effective. In
addition, neither reference teaches treating chemoresistant tumor cells with
dendritic cells expressing a particular protein, followed by treatment with the
same chemotherapeutic agent to which they had developed resistance.
In summary, the Examiner has not provided evidence or sound
technical reasoning to support the conclusion that the cited references would
have made it obvious to treat chemoresistant tumor cells with dendritic cells
expressing p53, followed by treatment with the same chemotherapeutic
agent to which they had been shown to be resistant.
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SUMMARY
We reverse the rejection of claims 1, 10-12, 26, 29-31, 42, 43, 45, 48-
59, 61, 67, and 68 under 35 U.S.C. § 103(a) based on Gabrilovich,
Sameshima, Lowe, Wen, Lynch, and Petak.

REVERSED

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