Ex Parte Antonia et al

Patent Trial and Appeal BoardAug 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). Appeal 2012-000644 Application 11/433,079 2 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. Appeal 2012-000644 Application 11/433,079 3 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). Appeal 2012-000644 Application 11/433,079 4 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 Appeal 2012-000644 Application 11/433,079 5 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 Appeal 2012-000644 Application 11/433,079 6 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. Appeal 2012-000644 Application 11/433,079 7 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 cdc