DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 08 June 2026 in which claims 15, 59, 67 and 78 were amended to change the scope and breadth of the claims.
Claims 1, 2, 6, 7, 9, 15, 26, 28, 36, 50, 59, 60, 65, 67 and 69-78 are pending in the current application and are examined on the merits herein.
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 .
Drawings
A copy of the drawings in color is respectfully requested.
Withdrawn Rejections
Applicant’s amendment, filed 08 June 2026, with respect to the rejection of claims 59, 60, 65 and 67 under 35 U.S.C. § 101, has been fully considered and is persuasive.
Claim 59 has been amended to require treating a subject identified as having an M2 enrichment score higher than 0.27, and administering to the subject an effective amount of a STING agonist conjointly with an effective amount of a PARP inhibitor, an effective amount of a TK inhibitor, and/or an effective amount of a DNA synthesis inhibitor.
Claim 67 has been amended to require performing an active step of administering an effective amount of a STING agonist and PARP inhibitor.
The rejection is hereby withdrawn.
Applicant’s amendment, filed 08 June 2026, with respect to the rejection of claims 15, 67 and 78 under 35 U.S.C. § 112(b), second paragraph, for indefiniteness, has been fully considered and is persuasive, because claim 67 has been amended to require performing an active step; and claims 15 and 78 now recite and/or between the last optional two steps.
The rejection is hereby withdrawn.
Applicant’s arguments, filed 08 June 2026, with respect to the rejection of claims 1, 2, 6, 7, 9, 15, 26, 28, 36, 50 and 69-72 under 35 U.S.C. § 102(a)(1) as being anticipated by Pantelidou 2021, has been fully considered and is persuasive. Applicant argues Pantelidou 2021 does not expressly disclose administering a STING agonist systemically, as required by claim 1. The argument is found persuasive, the rejection is hereby withdrawn.
Allowable Subject Matter
Claims 59, 60, 65 and 67 are allowed.
There is no prior art reference which teaches treating a patient population having an M2 enrichment score for a tumor higher than 0.27.
Maintained Rejections
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.
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) 1, 2, 6, 7, 9, 15, 26, 28, 36, 50 and 69-78 are rejected under 35 U.S.C. 103 as being unpatentable over Pantelidou 2021 (bioRxiv, preprint posted 27 January 2021, cited in previous Office Action) in view of Pantelidou 2019 (Cancer discovery, 2019, vol. 9, no. 6, pp. 722-737, cited in previous Office Action; hereinafter referred to as Pantelidou 2019).
Pantelidou 2021 teach the use of a PARP inhibitor in combination with STING agonism in BRCA-associated breast cancer (abstract). Combined PARP inhibition and STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human and mouse triple-negative breast cancer cell lines (abstract). The combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival (abstract).
Pantelidou 2021. teach testing ADU-S100 as a STING agonist in a K14-Cre;Brca1f/f TNBC (triple negative breast cancer) mouse model (p.6, first para). Olaparib (species of PARP inhibitor) was administered by intraperitoneal injection at a dose of 50 mg/kg daily. ADU-S100 (STING agonist) was administered in a single 40 µl injection of 50 µg (1.25 µg/µL) intratumorally weekly (p.6, first para). Combination therapy significantly increased total T-cell counts compared to monotherapies, with both CD8+ and CD4+ T cell subsets significantly augmented (p.9-10, bridging para).
ADU-S100 is a modified nucleotide STING agonist. The STING agonist and PARP inhibitor are administered concurrently.
Pantelidou 2021 does not expressly disclose DMXAA (STING agonist). Pantelidou 2021 does not expressly disclose administering the STING agonist by systemic delivery (present claims 1 and 73).
Pantelidou 2019 demonstrates cross-talk between PARP inhibition and STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8+ T-cell recruitment and antitumor efficacy (abstract). Pantelidou 2019 specifically demonstrated this relationship in triple-negative breast cancer (TNBC), specifically K14-Cre-Brca1f/f;Trp53f/f immunocompetent genetically engineered mouse model (GEMM) of TNBC (p.723-724, bridging para). Pantelidou 2019 teaches olaparib-treated K14 cells demonstrated a dose-dependent increase in the expression of phospho-TBK1Ser172, phosphor-IRF3Ser396, and phosphor-H2AXSer139 expression, comparable to that of the STING agonist DMXAA (p.726, left column, last para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer DMXAA conjointly with an effective amount of olaparib to a subject having breast cancer carrying a BRCA mutation.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, olaparib was observed to have a positive antitumor immune response on BRCA deficient triple negative breast cancer cells by activating the STING pathway in these tumor cells, and DMXAA, a STING agonist, was also observed to have a positive antitumor immune response on BRCA deficient triple negative breast cancer cells. Thus, the skilled artisan would have been motivated to combine the two drugs for the treatment of breast cancer carrying a BRCA mutation.
Additionally, the ordinary artisan would have been motivated to substitute the ADU-S100 of Pantelidou 2021, with DMXAA because they are both recognized as STING agonists, and both were studied in TNBCs carrying the same BRCA mutation. The ordinary artisan would have had a reasonable expectation of success in treating TNBCs carrying a BRCA mutation with conjoint administration of DMXAA and olaparib, because Pantelidou et al. 2021 found combined PARP inhibition and STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human and mouse triple-negative breast cancer cell lines. The combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival.
It would have been obvious to administer the STING agonist systemically, because olaparib was administered systemically and found to activate the STING pathway. Thus, it would have been obvious to also administer the STING agonist systemically with a reasonable expectation of success.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 1, 2, 6, 7, 9, 15, 26, 28, 36, 50 and 69-78 are rejected under 35 U.S.C. 103 as being unpatentable over Pantelidou 2019 (Cancer discovery, 2019, vol. 9, no. 6, pp. 722-737, cited in previous Office Action; hereinafter referred to as Pantelidou 2019).
Pantelidou 2019 teach as discussed above.
Pantelidou 2019 does not expressly disclose conjointly administering DMXAA and olaparib.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer DMXAA conjointly with an effective amount of olaparib to a subject having breast cancer carrying a BRCA mutation.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, olaparib was observed to have a positive antitumor immune response on BRCA deficient triple negative breast cancer cells by activating the STING pathway in these tumor cells, and DMXAA is a STING agonist which also observed to have a positive antitumor immune response on BRCA deficient triple negative breast cancer cells. Thus, the skilled artisan would have been motivated to combine the two drugs for the treatment of breast cancer carrying a BRCA mutation, with a reasonable expectation of success.
It would have been obvious to administer the STING agonist systemically, because olaparib was administered systemically and found to activate the STING pathway. Thus, it would have been obvious to also administer the STING agonist systemically with a reasonable expectation of success.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Response to Arguments
Applicant's arguments filed 08 June 2026 have been fully considered but they are not persuasive.
Applicant contends neither Pantelidou 2021 nor Pantelidou 2019 teach administering a STING agonist systemically.
The above argument is not found persuasive. As noted in the Office Action at page 9, the ordinary artisan would have been motivated to administer the STING agonist systemically with a reasonable expectation of success, because olaparib, which activates the STING pathway (i.e. same mechanism of action), was administered systemically.
It is also noted that administering a STING agonist systemically would have been obvious because it would have been easier than intra-tumoral administration, and simplified treatment.
Applicant contends “early-generation STING agonists were unsuitable for systemic delivery”, “due to e.g. rapid degradation in the bloodstream, poor cellular permeability, and severe off-target toxicity”. Thus, Applicant contends “In view of the state of the art, there would have been no reasonable expectation that a systemic delivery of a STING agonist would provide any therapeutic benefits” (see Applicant’s arguments on p. 14 of the Remarks submitted 08 June 2026).
The above argument is not found persuasive. There is ample evidence in the art before the effective filing date of systemic administration of STING agonists, particularly second-generation STING agonists. Pan et al., for example, expressly teach orally administering MSA-2, and recognize it as a STING agonist (title and abstract; Science, 2020, cited in IDS submitted 12 December 2023).
Furthermore, if Applicant contends not all STING agonists can be delivered systemically, then the scope of the present claims may not be fully enabled or meet the written description requirement. The current claims are not drawn towards improving the formulation of a STING agonist for systemic delivery. Thus, it is not clear what makes the current scope, drawn towards any STING agonist, capable of systemic delivery, while the “early-generation STING agonists were unsuitable for systemic delivery”.
Applicant argues their claimed invention of systemic delivery of a STING agonist demonstrates unexpected and superior efficacy compared to intratumoral delivery. Applicant has pointed to figures 12B and 11G-H, which shows breast tumors failed to respond to the combination of olaparib and a STING agonist administered intratumorally, while they responded effectively to systemic delivery of STING agonist in combination with PARP inhibitor.
The alleged unexpected results referred to, are not commensurate in scope with the present claims which include any STING agonist. Furthermore, present claim 1, does not require administering a PARP inhibitor.
See MPEP 716.02(d) “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.".
Thus, the rejection is hereby maintained.
Conclusion
Claims 59, 60, 65 and 67 are allowed.
Claims 1, 2, 6, 7, 9, 15, 26, 28, 36, 50 and 69-78 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
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