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 .
Priority
The present application claims priority to the application, EP 21305196.4, with effective
filing date of 17 February 2021.
Claim Status
This Office Action is in response to Applicant’s Amendment filed, 23 April 2026, wherein the Applicant amended claims 1-9 and added new claim 10.
Claims 1-10 are pending.
Rejections Withdrawn
Claim Rejections – 35 USC § 112
1. Claim 4 was rejected for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention, in particular, reciting a broad range or limitation together with a narrow range or limitation. Claim 4 was amended to recite the cancer is solid or non-solid and remove the limitations of the type of cancer. Applicant’s amendment, see pages 2-3, with respect to claim 4 has been fully considered. The rejection of claim 4 has been withdrawn.
2. Claim 4 was rejected for failing to comply with the enablement requirement: for failing to reasonably provide enablement for a) preventing any and all cancer and b) treating all cancer, specifically colon cancer, a bone cancer, a thyroid cancer, an ovarian cancer, a lung cancer, a glioma, a cervical cancer, an endometrial cancer, a head and neck cancer, a liver cancer, a renal cancer, a skin cancer, a stomach cancer, a testis cancer, an urothelial cancer, and an adrenocortical carcinoma. Claim 4 was amended to recite the cancer is solid or non-solid and remove the limitations of the type of cancer. Applicant’s amendment, see pages 2-3, with respect to claim 4 has been fully considered. The rejection of claim 4 has been withdrawn.
3. Claims 2-4 and 7-9 were rejected for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention, in particular, reciting a broad range or limitation together with a narrow range or limitation. Claims 2-4 were amended to only specify one range that limits the SERCA2 inhibitor. Similarly, claim 7-9 were amended to specify only one range that limits the STING agonist. Applicant’s amendment, see pages 2-4, with respect to claims 2-4 and 7-9 has been fully considered. The rejection of claims 2-4 and 7-9 has been withdrawn.
Claim Rejections – 35 USC § 102
4. Claims 1-9 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wang (US 2021/008190, published 14 Jan 2021, of record, see IDS filed 7 Nov 2024) as evidenced by Merriam-Webster (“Inhibitor,” Merriam-Webster.com Dictionary, Merriam-Webster, https://www.merriam-webster.com/dictionary/inhibitor, accessed 13 Nov 2025).
Applicant amended claims 1 and 5-6 (the independent claims) to specify a specific list of SERCA2 inhibitors and STING agonists, which no longer recite the SERCA2 inhibitor, curcumin. Applicant’s argument, see page 7, with respect to claims 1-9 has been fully considered. The 102(a)(1) and 102(a)(2) rejection of claims 1-9 has been withdrawn.
Rejections: New/Modified or Maintained
Claim Rejections – 35 USC § 112
5. (Maintained) Claims 1 and 5-6 were rejected as being unpatentable under 35 U.S.C. § 112(a) for failing to comply with the written description requirement: for failing to reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention.
Applicant’s amendment and arguments, see page 5-6 of Remarks and the Rule 132 Declaration, with respect to the rejection of claims 1 and 5-6 have been fully considered but they are not persuasive.
Applicant amended claim 1 and 5-6 to remove “and/or preventing.” Applicant asserts that it is clear that Applicant was in possession of the invention as presently claimed at the time of filing as reflected in the original specification and claims. Applicant further asserts in the Rule 132 Declaration, which cites Inoue (Cell Reports, 2019, 27(4), 1221-1230) and states that SERCA2 is expressed in all cells including cancerous and immunity cells and STING is expressed in cells, including tumorous cells at low level. Accordingly, Applicant asserts that a person of ordinary skill in the art would have recognized that the present claims apply to all cancers.
However, while Applicant states that SERCA 2 is expressed in all cells as taught by Inoue (including cancerous and immunity cells) and that all cancer cells express SERCA2 and STING and thus the claimed invention will apply to all cancer, Genovese (Cell Calcium, 2020, 92(102308), 1-18, of record, see PTO-892 filed 2 Dec 2025) teaches that there is a contradiction in reduction in ER-mitochondria Ca2+ signal (page 3, column 1, paragraph 3). Genovese teaches that mitochondria modulate Ca2+ load in response to pathophysiological conditions, leading to either cell proliferation or cell growth arrest and death (page 2, column 1, paragraph 5). Genovese teaches several mitochondria-associated ER membranes that regulate Ca2+: IP3R3, SERCA, VDAC1, and the MCU complex (page 3, column 1, paragraph 1). Genovese teaches that there are several more contradictions regarding mitochondria-associated ER membranes, wherein limited Ca2+ transfer from the ER to mitochondria has been related to a reduced stress-induced cell death rate but also states that in three recent studies, reduced ER-mitochondria Ca2+ signal is present in anti-apoptotic and pro-tumoral models and drives oncogenesis and malignant cell transformation (page 3, column 1, paragraphs 2-3). Additionally, Genovese teaches that the ER-mitochondria Ca2+ transfer is double-faceted: pro-apoptotic or anti-apoptotic (page 3, column 1, paragraph 5). Further, Genovese teaches that overexpression of MICU1 is related to chemoresistance and poor prognosis in ovarian cancer but overexpression of MICU1 in MDA-MB-231 breast cancer is related to a better prognosis (page 3, column 2, paragraph 3-4). Thus, Genovese highlights the contradictions and unpredictability in mitochondria-associated ER membranes across various cancer types. Additionally, Applicant failed to provide the reference, Inoue, as evidence of SERCA2 expression in cancer cells. However, the Examiner was able to furnish the reference (see PTO-892), and Inoue teaches that SERCA2b is a ubiquitously expressed membrane protein but is silent to SERCA2 in cancer cells and its expression therein. Accordingly, Inoue does not remedy the teachings of Genovese and is not persuasive.
Thus, the rejection of claims 1 and 5-6 as being unpatentable under 35 U.S.C. § 112(a) is maintained.
6. (Maintained) Claims 1 and 5-6 were rejected as being unpatentable under 35 U.S.C. § 112(a) for failing to comply with the enablement requirement: for failing to reasonably provide enablement for a) preventing any and all cancer and b) treating all cancer, specifically colon cancer, a bone cancer, a thyroid cancer, an ovarian cancer, a lung cancer, a glioma, a cervical cancer, an endometrial cancer, a head and neck cancer, a liver cancer, a renal cancer, a skin cancer, a stomach cancer, a testis cancer, an urothelial cancer, and an adrenocortical carcinoma.
Applicant’s amendment and arguments, see page 6-7 of Remarks and the Rule 132 Declaration, with respect to the rejection of claims 1 and 5-6 have been fully considered but they are not persuasive.
Applicant amended claim 1 and 5-6 to remove “and/or preventing.” Applicant amended claims 1 and 5-6 to specify a specific list of SERCA2 inhibitors and STING agonists. Applicant further asserts in the Rule 132 Declaration, which cites Inoue (Cell Reports, 2019, 27(4), 1221-1230, of record, see Rule 132 Declaration) and states that SERCA2 is expressed in all cells including cancerous and immunity cells and STING is expressed in cells, including tumorous cells at low level. Accordingly, Applicant asserts that a person of ordinary skill in the art would have recognized that the present claims apply to all cancers.
However, while Applicant amended claims 1 and 5-6 to only specify specific SERCA2 inhibitors and STING agonists, claims 1 and 5-6 still specify all cancers. Accordingly, the breadth is still great. Additionally, while Applicant states that SERCA 2 is expressed in all cells as taught by Inoue (including cancerous and immunity cells) and that all cancer cells express SERCA2 and STING and thus the claimed invention will apply to all cancer, Genovese (Cell Calcium, 2020, 92(102308), 1-18, of record, see PTO-892 filed 2 Dec 2025) teaches that there is a contradiction in reduction in ER-mitochondria Ca2+ signal (page 3, column 1, paragraph 3). Genovese teaches that mitochondria modulate Ca+ load in response to pathophysiological conditions, leading to either cell proliferation or cell growth arrest and death (page 2, column 1, paragraph 5). Genovese teaches several mitochondria-associated ER membranes that regulate CA2+: IP3R3, SERCA, VDAC1, and the MCU complex (page 3, column 1, paragraph 1). Genovese teaches that there are several contradictions regarding mitochondria-associated ER membranes, wherein limited Ca2+ transfer from the ER to mitochondria has been related to a reduced stress-induced cell death rate but also states that in three recent studies, reduced ER-mitochondria Ca2+ signal is present in anti-apoptotic and pro-tumoral models and drives oncogenesis and malignant cell transformation (page 3, column 1, paragraphs 2-3). Additionally, Genovese teaches that the ER-mitochondria Ca2+ transfer is double-faceted: prop-apoptotic or anti-apoptotic (page 3, column 1, paragraph 5). Further, Genovese teaches that overexpression of MICU1 is related to chemoresistance and poor prognosis in ovarian cancer but overexpression of MICU1 in MDA-MB-231 breast cancer is related to a better prognosis (page 3, column 2, paragraph 3-4). Thus, Genovese highlights the contradictions and unpredictability in mitochondria-associated ER membranes across various cancer types. Additionally, Inoue teaches that SERCA2b is a ubiquitously expressed membrane protein but is silent to SERCA2 in cancer cells and its expression therein. Accordingly, Inoue does not remedy the teachings of Genovese and is not persuasive.
Thus, the rejection of claims 1 and 5-6 as being unpatentable under 35 U.S.C. § 112(a) is maintained.
7. (Maintained) Claims 1-9 were rejected under 35 U.S.C. § 103 as being unpatentable over Wang (US 2021/008190, published 14 Jan 2021, of record, see IDS filed 7 Nov 2024) as evidenced by Merriam-Webster (“Inhibitor,” Merriam-Webster.com Dictionary, Merriam-Webster, https://www.merriam-webster.com/dictionary/inhibitor, accessed 13 Nov 2025; of record; see PTO-892 filed 2 Dec 2025) in view of Genovese (Cell Calcium, 2020, 92(102308), 1-18, of record, see PTO-892 filed 2 Dec 2025) as evidenced by Davidson (J. Biol. Chem., 1995 270(20), 11731-11734; of record; see PTO-892 filed 2 Dec 2025).
Applicant’s amendment and arguments, see page 7-12 of Remarks and the Rule 132 Declaration, with respect to the rejection of claims 1-9 have been fully considered but they are not persuasive.
Applicant asserts that the cited references do not disclose or suggest each and every element of the current claims taken either singly or in combination. Applicant states that Wang most relates to cell surface anchoring conjugates, STING agonists, methods to enhancing immunity in a subject, and treating tumor cells and cancer. Applicant further states that Wang does not disclose or suggest treating cancer with one of the compositions of Applicant’s claims. Applicant further asserts that the curcumin used in Wang is to trap free radicals and the Rule 132 Declaration states that curcumin has multiple cellular effects (page 16, item 15). Applicant’s claims obtain surprising and unexpected beneficial results not possible using prior art methods and compositions. Applicant further states that the results obtained clearly demonstrate that the present claims advantageously and surprisingly achieve an unexpected synergistic effect.
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s argument that Wang does not teach nor suggest treating cancer with a composition of Applicant’s claims, Wang teaches formulations and methods of treating cancer via utilizing a STING agonist and an inhibitor of SERCA2 (curcumin; abstract; [0124]). While Applicant’s claims no longer recite curcumin as a limitation, Applicant defines curcumin as a SERCA2 inhibitor (page 4, lines 29-32). Further, Products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. See MPEP § 2112.01. Accordingly, curcumin of Wang inhibits SERCA2.
In response to Applicant’s surprising and unexpected beneficial results (i.e. synergy), rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997). See MPEP § 2145. Applicant, indeed, shows synergistic effect between a SERCA2 inhibitor and STING activator (Rule 132 Declaration), but there is no dosing information available in Figure 1 of Appendix A of the Rule 132 Declaration.
To ascertain if the proffered evidence is commensurate in scope with the claimed invention, the Examiner evaluated the results demonstrated in the specification. [[I]]n order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020). "A presumption of nexus requires both that the product embodies the invention and is coextensive with it." Volvo Penta of the Americas, LLC v. Brunswick Corp., 81 F.4th 1202,1211-12, 2023 USPQ2d 1000 (Fed. Cir. 2023) … In determining the relative weight to accord to rebuttal evidence, considerations such as whether a nexus exists between the claimed invention and the proffered evidence, and whether the evidence is commensurate in scope with the claimed invention, are appropriate. The mere presence of some credible rebuttal evidence does not dictate that an obviousness rejection must always be withdrawn. See MPEP § 2145. There appears to be a dose-dependent response in the combination of a SERCA2 inhibitor (thapsigargin) and a STING activator (ADUS100), wherein the combination of thapsigargin and ADUS100 showed high expression of IFNβ (an inflammatory response marker) at 12.5 nM thapsigargin but then showed a steep decline in IFNβ expression at 6.25 nM thapsigargin (Figure 6A of the specification). Thus, there is a dose-dependent response from the administration of a SERCA2 inhibitor and a STING activator. Accordingly, the synergistic effect of a SERCA2 inhibitor and a STING activator demonstrated by Applicant is not commensurate with the claims.
Accordingly, the rejection of claims 1 and 5-6 as being unpatentable under Wang in view of Genovese as evidenced by Merriam-Webster and Davidson is maintained.
7. (New) Claims 10 is rejected under 35 U.S.C. § 103 as being unpatentable over Wang (US 2021/008190, published 14 Jan 2021, of record, see IDS filed 7 Nov 2024) as evidenced by Merriam-Webster (“Inhibitor,” Merriam-Webster.com Dictionary, Merriam-Webster, https://www.merriam-webster.com/dictionary/inhibitor, accessed 13 Nov 2025; of record; see PTO-892 filed 2 Dec 2025) in view of Genovese (Cell Calcium, 2020, 92(102308), 1-18; of record; see PTO-892 filed 2 Dec 2025) as evidenced by Davidson (J. Biol. Chem., 1995 270(20), 11731-11734; of record; see PTO-892 filed 2 Dec 2025).
Wang teaches formulations and methods of treating cancer via utilizing a STING agonist and a SERCA2 inhibitor (abstract; page 12, [0105]). Wang specifically teaches injecting both curcumin and ADU-S100 into a Her2 positive tumor (a solid tumor) (page 12, [0105]). Wang further teaches a formulation comprising: a) at least one inhibitor of SERCA2 (curcumin; defined as a SERCA2 inhibitor by claim 3) and b) at least one activator of STING (ADU-S100), which is injected into a solid tumor (page 12, [0105]). Because the products (curcumin and ADU-S100) exist as a formulation that is injected, they are administered simultaneously (page 12, [0105]).
Regarding claim 10, Wang fails to teach a SERCA2 inhibitor that is thapsigargin, cyclopiazonic acid, artemisinin, CAD204520, casearin J, CXL017, DBHQ, or sHA 14-1.
Genovese teaches methods of treating specific types of cancer via SERCA2 inhibitor or
STING agonist. Genovese specifically teaches a selective inhibitor (thapsigargin) that is non-competitive and specific to SERCA2 (page 11, column 2, paragraph 3). While Genovese does not explicitly teach that thapsigargin is a non-competitive inhibitor of SERCA2, this is an inherent property of thapsigargin, as evidenced by Davidson. Davidson specifies that thapsigargin binds in the stalk region in a non-competitive manner and not at the catalytic site (page 11732, column 2, paragraph 1). This non-competitive binding is present in Genovese as described by Davidson, because Davidson teaches the mechanism of action for thapsigargin acting upon SERCA2 (abstract; page 11732, column 2, paragraph 1), and Genovese teaches that thapsigargin is a selective inhibitor of SERCA2 (page 11, column 2, paragraph 3). See MPEP 2163.07(a). Thus, Genovese teaches a non-competitive inhibitor that is specific to SERCA2 (thapsigargin; page 11, column 2, paragraph 3; page 10, Table 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select the SERCA2 inhibitor (thapsigargin) of Genovese to develop a method of treating breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, melanoma, leukemia, or lymphoma via the combination of a STING activator and a SERCA2 inhibitor, to arrive at instant claim 10. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Wang teaches formulations and methods of treating cancer via utilizing a STING agonist in combination with a SERCA2 inhibitor,
-Wang teaches that STING plays an important role in innate immunity and discloses methods to treat a tumor cell and cancer in addition to boosting immunity against a tumor cell,
-Genovese teaches cancer is the second leading cause of death worldwide and that a hallmark of cancer is reprogramming of metabolic needs and energy metabolism, in which mitochondria play a crucial role,
-Genovese teaches that mitochondria represent central hubs for the regulation of Ca2+ flux in cells and influence the decision between cell life and death, particularly for cancer cell fate,
-Genovese teaches that Ca2+ is fundamental for mitochondrial health, function, and metabolism, and that sufficient impairments in Ca2+ homeostasis have detrimental effects on ATP production and cell viability, and
-Genovese teaches therapies centered on mitochondrial-dependent signaling pathways are under increasing investigation since they provide intriguing and successful strategies for cancer and other disease treatment as well as the latest findings in mitochondria-oriented cancer
therapy.
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection, to predictably arrive at a method of treating breast cancer, bladder cancer, prostate cancer, pancreatic cancer, colorectal cancer, melanoma, leukemia, or lymphoma with a
STING activator and a SERCA2 inhibitor.
Conclusion
No claim is allowed.
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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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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