Ex Parte Bzik et alDownload PDFPatent Trial and Appeal BoardMar 3, 201713276577 (P.T.A.B. Mar. 3, 2017) Copy Citation United States Patent and Trademark Office 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/276,577 10/19/2011 David J. Bzik DC0369US.P3 3320 26259 7590 03/07/2017 LICATA & TYRRELL P.C. 66 E. MAIN STREET MARLTON, NJ 08053 EXAMINER LEONARD, ARTHUR S ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 03/07/2017 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): PTOactions@licataandtyrrell.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DAVID J. BZIK, BARBARA A. FOX, STEVEN N. FIERING, JOSE R. CONEJO-GARCIA, and JASON BAIRD Appeal 2016-005291 Application 13/276,577 Technology Center 1600 Before DONALD E. ADAMS, DEMETRA J. MILLS, and FRANCISCO C. PRATS, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL1 This appeal under 35 U.S.C. § 134(a) involves claims 9 and 10 (App. Br. 3). Examiner entered rejections under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellants identify the real party in interest as “the Trustees of Dartmouth College” (App. Br. 1). Appeal 2016-005291 Application 13/276,577 STATEMENT OF THE CASE The claims are directed to “a method for preventing or treating cancer by administering to a subject in need of treatment an effective amount of an attenuated mutant of Toxoplasma gondii” (Spec. ^ 6). Claims 9 and 10 are representative and reproduced below: 9. A method for preventing or treating ovarian cancer comprising administering to a subject in need of treatment an effective amount of an attenuated mutant of Toxoplasma gondii that stimulates maturation of immature immunosuppressive dendritic cells and anti-tumor immunity to prevent or treat the subject’s ovarian cancer. 10. A method for preventing or treating melanoma comprising administering to a subject in need of treatment an effective amount of an attenuated mutant of Toxoplasma gondii that comprises in its genome recombinant nucleic acid molecules encoding one or more melanoma antigens thereby preventing or treating the subject’s melanoma. (App. Br. 15.) The claims stand rejected as follows: Claim 9 stands rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Kim,2 Subauste,3 and Hobohm.4 2 Ju-Ock Kim et al., Inhibition of Lewis Lung Carcinoma Growth by Toxoplasma gondii through Induction ofTHl Immune Responses and Inhibition of Angiogenesis, 22 J. Korean Med. Sci. Suppl. S38-46 (2007). 3 Carlos S. Subauste and Matthew Wessendarp, Human Dendritic Cells Discriminate Between Viable and Killed Toxoplasma gondii Tachyzoites: Dendritic Cell Activation After Infection with Viable Parasites Results in CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and - Independent T Cell Production ofIFN-y, 165 J. of Immunology 1498-05 (2000). 4Uwe Hobohm, Fever and cancer in perspective, 50 Cancer Immunol. Immunother 391-96 (2001). 2 Appeal 2016-005291 Application 13/276,577 Claim 10 stands rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Hunter,5 Donald,6 Ren,7 Pardoll,8 and Dubensky.9 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? The rejection over the combination of Kim, Subauste, and Hobohm: FACTUAL FINDINGS (FF) FF 1. Appellants disclose that: Ovarian cancer is most frequently found as a disease compartmentalized in the peritoneal cavity, which facilitates the adoptive transfer of immune cells or the application of adjuvants directly in the tumor microenvironment. Unfortunately, multiple immunosuppressive mechanisms converge at ovarian cancer locations to eventually abrogate both ongoing anti-tumor immunity and the effect of adoptively transferred tumor-reactive lymphocytes. . . . While these immature [dendritic cells (DC)] are immune-suppressed by the ovarian tumor, they possess the ability to phagocytose antigen in their tumor environment, and acquire the capacity to effectively present processed antigens in the right milieu. . . . However, rather than boosting adaptive immune responses, ovarian cancer-associated DCs are not activated to mature, are strongly immunosuppressive, and 5 Christopher A. Hunter et al., Cutting Edge: Systemic Inhibition of Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis, J. of Immunology 5878-81 (2001). 6 Robert G. K. Donald, Toxoplasma gondii Cyclic GMP-Dependent Kinase: Chemotherapeutic Targeting of an Essential Parasite Protein Kinase, 1 Eukaryotic Cell 317-28 (2002). 7 Ren et al., US 6,214,888 Bl, issued Apr. 10, 2001. 8 Drew M. Pardoll, Spinning Molecular Immunology Into Successful Immunotherapy, 2 Nature Reviews Immunology 227-38 (2002). 9 Dubensky et al., WO 2005/009463 A2, published Feb. 3, 2005. 3 Appeal 2016-005291 Application 13/276,577 support blood vessel formation, which promotes tumor development. . . . Adjuvant therapy that could mediate the maturation of these immature dendritic cells would reverse the immunosuppression and foster immunostimulation for therapeutic purposes. Such an approach could be used as a primary immunotherapy, as a conditioning therapy for adoptive T cell therapy, or as a therapy to boost T-cell antitumor responses. (Spec. H 4.) FF 2. Appellants disclose that “[i]n the context of [their] invention, a mutation includes a substitution, deletion, or insertion at the desired locus which decreases or abolishes the activity of the protein encoded by said locus” {id. U 15). FF 3. Appellants disclose that “[wjhile the instant mutant T. gondii may be used as is in the prevention or treatment of cancer, the [T. gondii] mutant can also be further modified to deliver one or more tumor antigens,” wherein “[t]he T. gondii-Qxpressed tumor antigen subsequently enters the mammalian antigen presenting cell’s (APC) antigen processing and presenting pathway as a substrate for generation of class I and class II peptides which generate CD8 and CD4 T cell responses” {id. ^ 20). According to the Specification, the mutant T. gondii is a “T. gondii attenuated mutant strain of T. gondii (i.e., CPS) that cannot replicate in vivo, but can elicit a strong Thl immune response characterized by high local levels of IL-12 and IFN-y and high systemic levels of IL-12p70” (Spec. 5 and 7). FF 4. Kim discloses that T. gondii “is an obligate intracellular protozoan parasite that induces anti-tumor activity against certain types of cancers” (Kim, Abstract). FF 5. Kim discloses that “in order to determine the antitumor and anti- angiogenic activities of T. gondii infection in [Lewis lung carcinoma,] LLC- 4 Appeal 2016-005291 Application 13/276,577 bearing mice, C57BL/6 mice were injected with LLC cells alone or in combination with T. gondii” (Kim, S38-S39; see also id. at S39: col. 1, first full paragraph (“mice were orally infected with the ME49 strain to evaluate antitumor activity”); Ans. 4). FF 6. Examiner finds that the ME49 strain of T. gondii is an avirulent strain of T. gondii (Ans. 4). FF 7. Kim discloses that: Lung cancer immunotherapy may represent one new approach that has low toxicity and high specificity, but implementation has been a challenge due to poor antigenic characterization and the ability of lung cancers to escape immune responses []. Several different immunotherapeutic treatment strategies and mouse models have been developed. In this study, we utilized LLC cells, which remain highly tumorigenic in C57BL/6 mice and produce primary tumors and lung metastases histologically indistinguishable from the original tumor line. . . . After T. gondii infection, tumor volumes were significantly decreased in the TG/FFC- and TG/FFC/QA-injected mice as compared with the EEC- and FFC/QA[10]-injected mice. (Kim S44: col. 2, first full paragraph (emphasis added; endnotes removed); see generally Ans. 12.) FF 8. Subauste discloses that “dendritic cells (DC). . . infected with viable [T. gondii] parasites up-regulated the expression of CD40, CD80, CD86, and HFA-DR and down-regulated expression of CD115. These changes are indicative of DC activation induced by T. gondii” (Subauste, Abstract; Ans. 4). FF 9. Examiner finds that “Kim and Subauste are silent with respect to [a] method using attenuated T. gondii to treat ovarian cancer” (Ans. 4). 10 Kim defines “QA” as the Quil-A adjuvant (see Kim, Abstract and S39: col. 1, third full paragraph). 5 Appeal 2016-005291 Application 13/276,577 FF 10. Examiner relies on Hobohm to disclose that “it was known that DCs generated an antitumor immune response in vivo to a variety of cancer types including melanoma, ovarian cancer, and lung cancer in response to bacterial infections/toxins” {id. at 5 (citing Hobohm 393-394: Tables 1 and 2); see also Hobohm 394: col. 2, last full paragraph). ANALYSIS Based on the combination of Kim, Subauste, and Hobohm, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious to activate DCs with T. gondii and use the T. gondii activated DCs to treat, inter alia, melanoma and ovarian cancer in vivo (Ans. 5). In this regard, Examiner finds that a person of ordinary skill in this art would have considered the use of T. gondii activated DCs to treat cancer types that share a biological nexus with respect to in vivo immunotherapy predictable and nothing more than the expected properties of the immune response to microorganisms, such that “the successful treatment of one cancer type (i.e., lung cancer) provides a reasonable expectation of success in treating the others (to wit, ovarian cancer)” {id.). We are not persuaded. We recognize Examiner’s characterization of “the avirulent ME49 strain” of T. gondii as “an attenuated mutant of Toxoplasma gondii” (Ans. 4). Examiner, however, failed to establish an evidentiary basis on this record to support a conclusion that the avirulent ME49 strain of T. gondii is a mutant, rather than a wild-type strain of T. gondii {see App. Br. 7; see id. at 10; FF 6; cf. Ans. 4). In addition, there is no dispute on this record that Subauste discloses “the effect of unattenuated wild-type Toxoplasma gondii {i.e., the virulent RH strain) on maturation of dendritic cells” (App. Br. 7; 6 Appeal 2016-005291 Application 13/276,577 see id. at 10; see generally FF 8). In this regard, we recognize Examiner’s assertion that “the only limitation that Subauste teaches in regard to [wild- type] T. gondii" s ability to mature DCs is that it must be viable, and not killed” (Ans. 9). As Appellants explain, however, Examiner failed to establish an evidentiary basis on this record to support a conclusion that the combination of Kim and Subauste suggests “an attenuated mutant Toxoplasma gondii,” as is required by Appellants’ claim 9 (App. Br. 7-8 and 10; Reply Br. 2-3; see FF 2). In addition, Appellants explain that “Hobohm highlights the use of infectious bacteria that cause illness. In contrast, the present invention is directed to the use of an attenuated mutant of Toxoplasma sondii, i.e., a protozoan” (App. Br. 8; see FF 10; cf. FF 4). Thus, as Appellants explain “the teachings of Hobohm are of little relevance to [Appellants’] invention” (id.). Further, we note that Kim discloses that T. gondii “is an obligate intracellular protozoan parasite that induces anti-tumor activity against certain types of cancers” (FF 4 (emphasis added)). In this regard, Examiner recognizes that “Kim and Subauste are silent with respect to [a] method using attenuated T. gondii to treat ovarian cancer” (FF 9). Thus, while Hobohm may suggest that “it was known that DCs generated an antitumor immune response in vivo to a variety of cancer types including melanoma, ovarian cancer, and lung cancer in response to bacterial infections/toxins,” Examiner failed to establish that the combination of Kim, Subauste, and Hobohm make obvious a method of preventing or treating ovarian cancer, which comprises the administration of an effective amount of an attenuated mutant of the Toxoplasma gondii protozoan (FF 10 (emphasis added); cf. App. Br. 15 (Appellants’ claim 1); see generally App. Br. 8 and 10). In re 7 Appeal 2016-005291 Application 13/276,577 Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (“rejections on obviousness grounds cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness”). The rejection over the combination of Hunter, Donald, Ren, Pardoll, and Dubensky: FACTUAL FINDINGS (FF) FF 11. Hunter “found that infection with toxoplasma gondii effectively blocked neoplastic growth of a nonimmunogenic B16.F10 melanoma” and that “this effect was independent of cytotoxic T or NK cells, production of NO by macrophages, or the function of the cytokines IL-12 and TNF-a,” suggesting “that antitumor cytotoxicity was not the primary mechanism of resistance,” but instead was the result of “severe hypoxia and avascular necrosis that are incompatible with progressive neoplastic growth.” Thus, Hunter’s “results identify the suppression of tumor neovascularization as a novel mechanism critical for infection-induced resistance to tumors” (Hunter, Abstract; see Ans. 6).11 FF 12. Examiner finds that “Hunter is silent with respect to [a] method using attenuated T. gondii that is a genetically modified strain comprising melanoma antigens” (Ans. 6). FF 13. Examiner finds that Donald discloses “that T. gondii can be genetically modified to stably (i.e., genomic incorporation of exogenouse 11 We recognize Examiner’s characterization of Hunter’s “avirulent ME49 strain” of T. gondii as “an attenuated mutant of Toxoplasma gondii” (Ans. 6). Examiner, however, failed to identify a disclosure in Hunter, or any other document of record, that supports Examiner’s characterization of Hunter’s ME49 strain of T. gondii. 8 Appeal 2016-005291 Application 13/276,577 DNA) express the heterologous protein PKG” (id. (citing Donald, Abstract and 318: col. 1, first full paragraph)). FF 14. Donald discloses that “[a] genetic disruption of T. gondii PKG can only be achieved if a complementing copy of PKG is provided in trans, arguing that PKG is an essential protein” and that “[sjtrains of T. gondii, disrupted at the genomic PKG locus and dependent upon the T. gondii T761 [Q or M]-substituted PKGs, are as virulent as wild type in mice,” but “unlike mice infected with wild-type T. gondii that are cured by [trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-( 1 -methylpiperidine-4-yl)- lH-pyrrol-3-yl]pyridine (compound 1)], mice infected with the laboratory generated strains of T. gondii do not respond to treatment,” leading Donald to “conclude that PKG represents the primary molecular target responsible for the antiparasitic efficacy of compound 1” (Donald, Abstract; see generally Ans. 6). FF 15. Ren discloses “that monoterpene diols result in induction of melanogenesis in S91 mouse melanoma cells by stimulating the nitric oxide/cyclic GMP/protein kinase G signal transduction pathway” (Ren 13: 6-10; see Ans. 6 (Examiner finds that Ren discloses “that increased PKG signaling has been correlated with melanoma . . . and therefore would be considered a melanoma antigen to one of ordinary skill in the art”). FF 16. Pardoll discloses that: Antigen-based immunotherapy of cancer is crucially dependent on the identification of tumour-rejection antigens. The largest number of immunologically defined tumour antigens has been discovered by the serological screening of phage-display libraries from tumours using the serum of cancer patients[]. Although this approach identifies hundreds of antigens recognized by antibodies circulating in cancer patients, it does 9 Appeal 2016-005291 Application 13/276,577 not provide insights into which of these antigens could generate effective antitumour immunity. (Pardoll 228: Box 1 (endnotes omitted); see generally Ans. 6-7.) FF 17. Pardoll discloses that “[t]he most commonly identified melanoma antigens are not tumour-specific but rather, melanocyte specific. Examples include tyrosinase, tyrosinase-related protein 1 (TRP1), TRP2, gplOO and MARTl/melan-A[]” (Pardoll 228: Box 1 (endnotes omitted); see Ans. 6-7). FF 18. Pardoll discloses that there is a “growing armamentarium of vaccine vectors,” wherein “[o]f the three main classes of microbes—virus, bacterium and fungus—viruses and bacteria have been investigated most intensively” (Pardoll 234: col. 1, first full paragraph; see Ans. 6-7). FF 19. Dubensky discloses that “[a] variety of strategies are presently being developed to isolate and generate autologous dendritic cells (DC), and subsequently load them with antigen or peptides ex vivo prior to patient vaccination,” however, “[djespite the development of a variety of methods to load and to stimulate the activation and maturation of dendritic cells that has led to encouraging clinical data, there still are not standard efficient and cost effective methods for combining antigen loading with dendritic cell activation and maturation” (Dubensky 5; see generally Ans. 7). FF 20. Dubensky discloses that: Cultured dendritic cells infected ex vivo with antigen delivery vectors can, in response to infection, undergo activation, maturation, and MHC-restricted presentation of epitopes. Dendritic cells, however, are sometimes poorly infected by the selected antigen delivery vector. Also, the selected antigen delivery vector can sometimes interfere with dendritic cell function or development. (Dubensky 6; see generally Ans. 7.) 10 Appeal 2016-005291 Application 13/276,577 FF 21. Dubensky “provides novel uses of modified microbes such as bacteria, and attenuated Listeria, in particular, to load and to induce the activation and maturation of antigen-presenting cells, such as dendritic cells, in vitro or ex vivo. The resulting antigen-presenting cells are useful in vaccines and immunotherapy” (Dubensky 7; see Ans. 7). FF 22. Dubensky discloses the “[tjherapeutic vaccination of mice using Listeria strains with and without S-59 treatment,” wherein “a C57B1/6 mouse melanoma tumor model was used” (Dubensky 281-282; see also id. 8 (“4’-(4-amino-2-oxa)butyl-4,5’,8-trimethylpsoralen, also referred to [by Dubensky] as ‘S-59’”); see Ans. 7). FF 23. Dubensky discloses that “microbes of [Dubensky’s] invention may be altered to contain a heterologous nucleic acid sequence encoding a specific tumor antigen” (Dubensky 174; see Ans. 7 (citing Dubensky ^ 174 (Examiner finds that Dubensky “contemplates the use of melanoma specific antigens gplOO, TRP and MART”)). ANALYSIS Based on the combination of Hunter, Donald, Ren, Pardoll, and Dubensky, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious to “combine the presence of a tumor antigen as taught by Donald and Ren” with Hunter’s method of using T. gondii to suppress tumor neovascularization (see Ans. 6; see generally FF 11-15). In this regard, Examiner finds that Pardoll and Dubensky provide a reasonable expectation of success to the combination of Hunter, Donald, and Ren by disclosing the use of “attenuated microbes as platforms for delivering tumor antigens to dendritic cells as a means of cancer immunotherapy” (Ans. 7). We are not persuaded. 11 Appeal 2016-005291 Application 13/276,577 As Appellants explain, although “Hunter teaches that infection with attenuated wild-type Toxoplasma gondii. . . blocks neoplastic growth of nonimmunogenic B16.F10 melanoma,” Hunter “does not teach or suggest the use of an attenuated mutant Toxoplasma gondii that comprises in its genome recombinant nucleic acid molecules encoding one or more melanoma antigens” (App. Br. 11). Therefore, Appellants contend, “given that the effect of the Toxoplasma gondii was attributed to the suppression of angiogenesis, this reference would not have suggested the use of Toxoplasma gondii to express a tumor antigen” (App. Br. 11-12; see FF 11- 12). We agree with Appellants’ contention that Examiner failed to establish a nexus between the use of Tgondii to suppress angiogenesis and the use of T. gondii encoding one or more melanoma antigens to elicit an immune response in a subject (see App. Br. 11-13; Reply Br. 5-6). In this regard, we note that the evidence relied upon by Examiner supports a conclusion that “[ajntigen-based immunotherapy of cancer is crucially dependent on the identification of tumour-rejection antigens” and, as Appellants explain, Examiner failed to establish that PKG is such an antigen (see FF 16; see also App. Br. 12 (“there is no suggestion anywhere in the teachings of Donald that the parasitic PKG proteins therein are tumor antigens” and “nowhere does Ren suggest that PKG protein is a tumor antigen”); cf. FF 17 and 23). Further, while Pardoll and Dubensky do suggest melanoma antigens, they neither disclose the use of PKG protein as a melanoma antigen nor disclose the use of T. gondii as a vehicle for the delivery of such an antigen in vivo (see FF 16-23; see also App. Br. 13 (“neither of [Pardoll and Dubensky] teaches or suggests an attenuated mutant of Toxoplasma gondii that comprises in its genome recombinant 12 Appeal 2016-005291 Application 13/276,577 nucleic acid molecules encoding one or more melanoma antigens”); cf. Ans. 14-15). In sum, Examiner failed to establish that the combination of Hunter, Donald, Ren, Pardoll, and Dubensky make obvious the subject matter of Appellants’ claim 10. Kahn, 441 F.3d at 988. CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. The rejection of claim 9 under 35 U.S.C. § 103(a) as unpatentable over the combination of Kim, Subauste, and Hobohm is reversed. The rejection of claim 10 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hunter, Donald, Ren, Pardoll, and Dubensky is reversed. REVERSED 13 Copy with citationCopy as parenthetical citation