DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the species of lung cancer in the reply filed on 09/08/2025 is acknowledged.
Claims 27-46 are currently pending.
Claim 29-34 and 39-44 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/08/2025.
Claims 27-28, 35-38 and 45-46 will be examined on the merits.
Rejoinder
The species of cervical cancer has been rejoined for examination in order to facilitate compact prosecution.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 27-28, and 37-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ohshio (Ohshio, et al., Canc. Sci. 2015 106(2):134) in view of Hanley (Hanley, et al., JNCL JNatl Cancer Inst (2018; first available online 2017) 110(1):dx121)
Ohshio teaches on the subject of immunosuppressive effects of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) (Ohshio, Abstract). Ohshio teaches that the complexity of the TME is currently an obstacle for cancer immunotherapy (Ohshio, p 134, ¶ 2). Ohshio teaches that CAFs support tumor growth through secretion of soluble factors that contribute to proliferation, invasion and metastasis of cancer cells (Ohshio, p 134, ¶ 3). Ohshio also teaches that CAFs modulate the immune system in the TME via secretion of multiple immune suppressive cytokines (Ohshio, p 134, ¶ 3). Ohshio teaches that the work of Ohshio was centered around testing if in vivo CAF inhibition would affect antitumor immune responses in tumor-bearing mice (Ohshio, p 135, ¶ 1-2). Oshio teaches that the CAF-inhibiting agent used in the work of Oshio was the drug tranilast (Oshio, p 135, ¶ 2). Ohshio teaches that CAF inhibition resulted in reduction of immune suppressor cells in the TME (Ohshio, p 135, ¶ 4-5). Ohshio teaches that inhibition of CAF activity led to a reduction of immunosuppressive Tregs and MDSCs in tumor draining lymph nodes as well as increased TAA-specific T cells in such nodes (Ohshio, p 137, ¶ 2-3). Ohshio also teaches that inhibition of CAF activity enhanced the efficacy of DC-based vaccines (which comprised tumor-associated antigen (TAA)-loaded DCs (see Oshio, p 135, ¶ 2)), with the anti-CAF therapy displaying a synergistic suppressive effect in a LLC1 lung cancer model (Ohshio, p 139, ¶ 2). Ohshio teaches that this enhancement of vaccine efficacy occurs due to the anti-CAF therapy attenuating the immunosuppressive effects of CAFs in the TME (Ohshio, p 139, ¶ 3-4).
Ohshio does not teach a method of treating resistance/restoring sensitivity of a cancer cell to a cancer vaccine immunotherapeutic, said method comprising administration of the cancer vaccine in combination with 2-(2-cholorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (same as GKT137831).
Hanley teaches that despite their diversity, CAFs are most commonly defined by acquisition of an “activated” myofibroblastic phenotype (Hanley, p 110, ¶ 1-2). Hanley teaches that NOX4 was identified as being associated with myofibroblast transdifferentiation (Hanley, p 111, ¶ 4-5). Hanley teaches that NOX4 was found to be expressed primarily in myofibroblastic CAFs in HNSCC, EAC and COAD cancers (Hanley, p 114, ¶ 1-2). Hanley teaches that NOX4 was examined for therapeutic potential by treating CAFs from human tumors were treated with shRNA and the NOX4 inhibitor GKT137831 (Hanley, p 114, ¶ 4). Hanley teaches that in a 5PT+HFFF2 xenograft (HSNCC) model, tumors were allowed to establish for four days and then administered GKT137831, which was shown to significantly reduce myofibroblastic CAF accumulation (Hanley, p 114, ¶ 6). Hanley also teaches in a TC1 (lung) cancer model, myofibroblastic stroma were generated and then GKT137831 was administered, which significantly reduced myofibroblast accumulation (Hanley, p 114, ¶ 7).
It would be prima facie obvious to use the GKT137831of Hanley as the anti-CAF agent in the method anti-CAF + DC-based cancer vaccination method of Oshio, wherein the cancer is lung cancer, in view of the teachings of Hanley. The net result of this combination would be a method of increasing sensitivity/overcoming resistance in a lung tumor to the DC-based vaccine of Oshio, said method comprising administering the DC-based vaccine of Oshio and the GKT137831of Hanley. One of ordinary skill in the art would be motivated to do this in order to better treat lung cancer. One of ordinary skill in the art would have a reasonable expectation of success forming a method of increasing sensitivity/overcoming resistance in a lung tumor to the DC-based vaccine of Oshio, said method comprising administering the DC-based vaccine of Oshio and the GKT137831 of Hanley because: 1) Ohshio teaches that pharmacological of CAF activity with transilat attenuated immunosuppressive effects associated with CAFs in the TME, leading to increased efficacy of the DC-based vaccine of Oshio, 2) Hanley teaches that administration of GKT137831 leads to reduced levels of active myofibroblastic CAFs in numerous tumor models, 3) one of ordinary skill in the art would reasonably deduce that the GKT137831 of Hanley could be used in place of the transilat of Oshiro because the drugs share the property of reducing the level of CAF activity and 4) both Oshio and Hanley included lung cancer models.
Claim(s) 27-28, 35, 37-38 and 45 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Ohshio (Ohshio, et al., Canc. Sci. 2015 106(2):134) in view of Hanley (Hanley, et al., JNCL JNatl Cancer Inst (2018; first available online 2017) 110(1): dx121) as applied to claims 27-28 and 37-38 above and in further view of de Graaf (Gujar, et al., Front. In Oncol. 2014 Vol. 4; Article 77).
The combined teachings of Ohshio and Hanley are discussed above.
The combined teachings of Ohshio and Hanley do not teach a method of treating resistance/restoring sensitivity of a lung tumor to an immunotherapeutic that is an oncolytic virus, said method comprising administering GKT137831 in combination with the oncolytic virus to a patient in need thereof.
Gujar teaches on the subject of oncolytic virus-mediated reversal of impaired tumor antigen presentation (Gujar, Abstract). Gujar teaches that Gujar teaches that oncolytic viruses are viruses that preferentially infect and lyse cancer cells via a process called oncolysis (Gujar, p 1, ¶ 2). Gujar teaches that a wide range of oncolytic virus classes, such as adenoviruses, reoviruses, herpes simplex viruses (HSVs), vaccina and vesicular stomatitis viruses (VSVs) have been shown to target cancers of nearly every possible tissue origin (e.g., breast, ovarian, prostate, etc….) both in vitro and in vivo (Gujar, p 1, ¶ 2). Gujar teaches that oncolytic viruses in cancer therapies target cancers through two distinct mechanisms direct oncolysis and induction of anti-tumor immune responses (Gujar, p 1, ¶ 2-3). Gujar teaches that there are three signals necessary for the stimulation of antigen-specific T cells: antigen presentation, co-stimulation by molecules such as CD86/CD80 and inflammatory cytokine signals (Gujar, p 2, ¶ 2-4; Fig. 1). Gujar also teaches that numerous methods of tumor immune evasion have been observed in a wide range of cancers, wherein defects in antigen presentation alone or in combination with defects in co-stimulation lead to dysfunctional anti-tumor immune responses (Gujar, p 3, ¶ 2-3). Gujar teaches that oncolytic viruses are able enhance anti-tumor immune responses and reverse tumor-associated impaired antigen presentation (Gujar, p 3, ¶ 4). Gujar teaches that oncolytic viruses kill tumor cells exposing previously inaccessible antigens, have been shown to induce multiple immunostimulatory cytokines and to even directly enhance the antigen presentation capacity of DCs (Gujar, p 4, ¶ 1-3).
It would be prima facie obvious to one of ordinary skill in the art to combine the method of applying the method of restoring sensitivity/treating resistance of a lung tumor to an immunotherapeutic that is a cancer vaccine comprising administration of GKT137831 and the cancer vaccine collectively taught by Ohshio and Hanley and discussed above to enhance sensitivity to an oncolytic herpes virus vaccine in view of the teachings of Gujar. One of ordinary skill in the art would be motivated to do this in order to better treat lung cancer. One of ordinary skill in the art would have a reasonable expectation of success applying the method of restoring sensitivity/treating resistance of a lung tumor to a cancer vaccine that a cancer vaccine, said method comprising administering GKT137831 in combination with the cancer vaccine to an oncolytic herpes virus vaccine because: 1) Ohshio teaches that the CAF-targeting method of Ohshio enhances the efficacy of anti-cancer vaccines via attenuation of the multiple immunosuppressive effects of CAFs in the tumor microenvironment, 2) Gujar teaches that in addition to directly lysing tumor cells oncolytic viruses used in cancer treatment also comprise an important immunological component, both release new TAAs and enhancing the capacity of DCs to present TAAs and 3) one of ordinary skill in the art would reasonably deduce that the attenuation of the immunosuppressive effects of CAFs in the TME would be likely to enhance the immunological component of the anti-cancer effect of the vaccine.
Claim(s) 27-28, 36, 37-38 and 46 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Ohshio (Ohshio, et al., Canc. Sci. 2015 106(2):134) in view of Hanley (Hanley, et al., JNCL JNatl Cancer Inst (2018; first available online 2017) 110(1): dx121) as applied to claims 27-28 and 37-38 above and in further view of Friedman (Friedman, et al., US 9,284,355 B2; Date 3/15/2016)
The combined teachings of Ohshio and Hanley are discussed above.
The combined teachings of Ohshio and Hanley do not teach a method of treating resistance/restoring sensitivity of a cervical tumor to an immunotherapeutic that is a herpes simplex targeting vaccine, said method comprising administering GKT137831 in combination with the herpes simplex targeting vaccine to a patient in need thereof.
Friedman teaches on the subject of herpes simplex virus (HSV) vaccines comprising two or more recombinant HSV proteins selected from a gD protein, a GC protein and gE protein (Friedman, Abstract). Friedman teaches that the HSV-targeting vaccine of Friedman is administered to subjects prone to the development of cancers caused by viruses including Kaposi’s sarcoma, cervical cancer or lymphoma (Friedman, Col. 58, lines 60-67). Friedman teaches that the HSV-targeting vaccine of Friedman is administered in methods of treating, inhibiting or preventing such cancers (Friedman, col. 68, lines 44-59).
It would be prima facie obvious to one of ordinary skill in the art to combine the combined teachings of Ohshio and Hanley with the HSV-targeting vaccine of Friedman administered in methods of treating cervical cancer to form a method of treating cervical cancer, said method comprising administration of the HSV-targeting vaccine of Friedman in combination with GKT137831, wherein the GKT137831 acts to sensitize/decrease resistance of the subject to the vaccine. One of ordinary skill in the art would be motivated to do this in order to better fight cervical cancer. One of ordinary skill in the art would have a reasonable expectation of success forming a method of treating cervical cancer, said method comprising administration of the HSV-targeting vaccine of Friedman in combination with GKT137831 because: 1) Friedman teaches that cervical cancer is associated with HSV infection, 2) Friedman also teaches that the HSV-targeting vaccine of Friedman is administered in methods of treating cancers and 3) one of ordinary skill in the art would reasonably expect the GKT137831 to enhance the immunological effect of the HSV-targeting vaccine of Friedman because the combined teachings of Ohshio and Hanley demonstrate that the immunostimulatory effects of GKT137831 in tumor microenvironments are very general immunostimulatory effects likely to enhance a wide range of immunotherapies.
Conclusion
Claims 27-28, 35-38 and 45-46 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643