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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed April 8, 2026. The amendment, filed April 8, 2026, is entered, wherein claims 1, 4, and 8 are amended and claims 6 and 16 – 20 are withdrawn.
Claims 1 – 20 are pending in this application and claims 1 – 5 and 7 – 15 are currently examined.
Receipt is acknowledged of Declaration of Dr. Shao filed on April 8, 2026.
Priority
3. This application is a continuation in part of 17/315,061, filed May 7, 2021, which has a provisional application 63/021,333, filed May 7, 2020, and this application claims benefit of provisional application 63/262,313, filed October 8, 2021.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications, Application No. 62/021,333, 17/315,061, and 63/262,313, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed applications, 62/021,333, 17/315,061, and 63/262,313, do not provide support for the limitations of “administering a VCP inhibitor to the subject, wherein the subject has been determined to have increased levels of phosphorylation of Valosin-Containing Protein (VCP) at residue Ser784 relative to a reference value obtained from a control population” recited in claim 1; “ML 240”, “CB-5083”, and “CB-5339” recited in claim 2; “pancreatic ductal adenocarcinoma (PDAC)” recited in claim 3; “administering to the subject a genotoxic agent concurrently with or subsequent to the VCP inhibitor” recited in claim 4; “leucovorin”, “oxaliplatin”, “irinotecan”, and “paclitaxel” recited in claim 5; “administering a pharmaceutical composition comprising a VCP inhibitor” recited in claim 8; “ML 240” and “CB-5339” recited in claim 12; and “administering a genotoxic treatment to the subject concurrently with or subsequent to the administration of the VCP inhibitor” recited in claim 13. Thus, the priority date of claims 1 – 5, 8, and 12 – 13 and the dependent claims 7, 9 – 11, and 14 – 15 is October 11, 2022.
Withdrawn Objections
4. The objection of claim 8, in the previous Office Action, mailed January 9, 2026, is withdrawn in view of the amended claim 8.
Withdrawn Rejections
5. The rejection of claims 1, 3, and 5 in the previous Office Action, mailed January 9, 2026, under 35 U.S.C. 102(a)(1) as being anticipated by Principe et al. with evidence provided by Wang et al. is withdrawn in view of the amended claim 1.
The following are maintained / modified / new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed April 8, 2026, wherein claims 1, 4, and 8 are amended and claims 6 and 16 – 20 are withdrawn. Previously cited references have been used to establish the maintained / modified / new grounds of rejection.
Maintained Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code in para. [0042] and [00182]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Responses to Applicant’s Remarks:
Applicant states that the specification has been amended to remove the embedded hyperlink and/or other form of browser-executable code. However, Applicant has not removed other browser-executable code, such as www. Therefore, the objection to specification is maintained.
New Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 8 – 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception (e.g. a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim 8 recites “measuring in a cancer cell or tumor cell in a sample obtained from the subject, the level of Valosin-Containing Protein (VCP) phosphorylation at Ser784” and “administering a pharmaceutical composition comprising a genotoxic agent to the subject when the measured VCP phosphorylation level is reduced related to a reference value obtained from a control subject or control population who are non-responsive to genotoxic therapy or administering a pharmaceutical composition comprising a VCP inhibitor or inhibitor of one or more phosphatidylinositol 3-kinase-related kinases to the subject when the measured phosphorylation level is elevated relative to the reference value obtained from a control subject or control population who are responsive to genotoxic therapy”, which is a law of nature or natural phenomenon based on the natural correlation between the level of VCP phosphorylation at Ser784 in a cancer cell or tumor cell and the subject’s responsiveness or non-responsiveness to genotoxic therapy.
Step 1: Claims 8 – 15 are drawn to a method of selecting a treatment for a subject having a cancer or tumor, namely a process, thus, the claims fall into a statutory category of invention under 35 U.S.C. 101.
Step 2A1: Claim 8 recites a judicial exception in the form of a law of nature or natural phenomenon. In particular, claim 8 is based on the naturally occurring biological relationship between the level of VCP phosphorylation at Ser784 in a cancer cell or tumor cell and the subject’s responsiveness or non-responsiveness to genotoxic therapy. The claim requires measuring the level of VCP phosphorylation at Ser784 and then using whether that measured level is reduced or elevated relative to a reference value from responsive or non-responsive control subjects or control population to select and administer therapy. This relationship is a law of nature because it describes how cancer cells or tumor cells naturally behave in response to genotoxic therapy based on their naturally occurring VCP phosphorylation state. The correlation between reduced VCP phosphorylation and responsiveness to genotoxic therapy and between elevated VCP phosphorylation and resistance or non-responsiveness, exists as a biological fact apart from any human action. The claimed measuring step does not create the correlation; it merely detects the naturally existing phosphorylation level. Moreover, comparing the measured level to a reference value merely identifies the natural relationship between the biomarker and treatment response. Thus, the claim recites the natural biological correlation, which is pSer784-VCP level indicates whether a subject is likely responsive or non-responsive to genotoxic therapy. Such biomarker-response correlations are treated as law of natures or natural phenomena under MPEP § 2106.4(b) because they reflect naturally occurring relationships within the body or cells rather than a human-made rule or technological improvement.
Claims 9 – 15 depend directly or indirectly from claim 8. Therefore, they include the same judicial exception recited in claim 8, namely the natural correlation between VCP phosphorylation at Ser784 and responsiveness or non-responsiveness to genotoxic therapy. Claim 9 further limits the type of genotoxic agent in the pharmaceutical composition comprising the genotoxic agent and a pharmaceutical acceptable carrier. Claim 10 is drawn to the method, wherein the pharmaceutical composition comprising one or more PIKK inhibitor(s) further comprises other active pharmaceutical ingredients. Claim 11 is drawn to the therapeutic effect and intended results of the PIKK inhibitor. Claim 12 further limits the type of VCP inhibitor. Claim 13 is drawn to the administering step of the method and further limits the dosing regimen of the treatment. Claim 14 further limits the type of PIKK inhibitor in the pharmaceutical composition comprising the PIKK inhibitor. Finally, claim 15 further limits the type of genotoxic agent to be a specific species. These additional limitations of claims 9 – 15 merely further define the therapeutic agents, inhibitors, treatment combinations and regimen, or therapeutic effects after the natural correlation is applied, and do not alter the recited judicial exception.
Step 2A2: Claim 8 as a whole does not integrate the recited judicial exception into a practice application. Although claim 8 recites administering a pharmaceutical composition, the administering step is not a complete treatment protocol that meaningfully applies the biomarker result to effect treatment across the scope of the claimed method. Step (b) of claim 8 recites administering a genotoxic agent when the measured VCP phosphorylation is reduced relative to a non-responsive control, and administering a VCP inhibitor or PIKK inhibitor when the measured VCP phosphorylation level is elevated relative to a responsive control. However, step (b) does not specify what treatment is administered when the measured VCP phosphorylation level is elevated relative to a non-responsive control, equal to the reference value, reduced relative to a responsive control, or otherwise does not satisfy the two recited conditions. Thus, the administering step merely uses the measured VCP phosphorylation level as circumstances, rather than integrating the natural correlation into a complete practical treatment application.
Claims 9 – 15 also do not integrate the judicial exception into a practice application. As discussed above, claims 9 – 15 depend directly or indirectly from claim 8 and include the same natural correlation between VCP phosphorylation at Ser784 and responsiveness or non-responsiveness to genotoxic therapy. The additional limitations of claims 9 – 15 merely further define the therapeutic agents, inhibitors, treatment combinations and regimen, or therapeutic effects after the natural correlation is applied. Specifically, claim 9 merely further defines the genotoxic agent and pharmaceutical carrier. Claim 10 merely further defines the one or more PIKK inhibitor(s). Claim 11 is drawn to the therapeutic effect or intended result of the inhibitor. Claim 12 merely further defines the VCP inhibitor. Claim 13 merely adds the treatment combination and regimen to the method. Claim 14 merely further defines the PIKK inhibitor(s) and claim 15 merely further defines the genotoxic agent. These additional limitations do not make the claims patent eligible because they do not change how the judicial exception is used in the claims. The dependent claims still rely on the measured VCP phosphorylation level as the basis for applying the natural correlation and selecting or administering treatment. Merely narrowing the type of drugs, inhibitors, carriers, treatment combinations, regimens, or expected therapeutic effect does not meaningfully limit the natural correlation or transform it into a complete practical treatment application.
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited judicial exception, i.e., whether any additional element or combination of additional elements adds an inventive concept to the claim.
The additional elements of claim 8, considered individually and as a whole, do not amount to significantly more than the recited law of nature or natural phenomenon. The claim additionally recites measuring VCP phosphorylation at Ser784 in a cancer cell or tumor cell from a subject, comparing the measured level to a reference value from a control subject or control population, and administering a pharmaceutical composition comprising a genotoxic agent, VCP inhibitor, or inhibitor of PIKK based on the measured biomarker level. The measuring and comparison steps are data-gathering and analysis steps used to observe the natural correlation between pSer784-VCP level and responsiveness to genotoxic therapy. Such steps merely identify the natural biomarker level and apply the correlation, and therefore do not provide an inventive concept beyond the judicial exception. The administering step also does not provide significantly more because it broadly recites administering known classes of therapeutic agents based on the observed natural correlation. In this case, the claim does not recite an unconventional measuring technique, a particular improved treatment regimen, a specific dosage, or other additional technical feature that transforms the natural correlation into patent-eligible subject matter. For example Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, cited in the previous Office Action mailed January 6, 2026) teach that cancer is a highly heterogenous disease with complex underlying biology. It is clear that a cancer therapy that fits all the cases cannot be found, and as a result the design of the therapies tailored to the patient’s molecular characteristics is needed (Abstract). Regardless of treatment, while some patients respond to it, a great percentage of them exhibit or develop resistance. Resistance to cancer therapy is largely attributed to inter-patient heterogeneity as well as intra-tumor heterogeneity (page 53, Right Col., para. 2). The data for a pharmacogenomic study would be generate from patients to determine the effect of different treatments (page 54, Left Col., para. 3) Exvivo models involve taking a sample out of the organism or patient and studying it under more controlled conditions (page 55, Left Col., para. 2). This approach has been applied to the study of patient specific drug response (page 55, Right Col., para. 1). Thus, using patient molecular characteristics and sample-based testing to guide cancer treatment are known in the art. Accordingly, the additional elements of measuring a biomarker, comparing the result to a reference value, and administering a known class of therapeutic agents based on the comparison do not add an inventive concept beyond the natural correlation itself.
Claims 9 – 15 also do not add significantly more than the recited judicial exception under Step 2B. The additional limitations merely specify particular genotoxic agents, inhibitors, carriers, treatment combinations, regimens, or expected therapeutic effect. These limitations do not provide an inventive concept because they are conventional. For examples, Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 9, 2026) identifies that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC (Abstract). In the study conducted, Wang et al. treated four distinct PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient with SN38 (page 5, Figure 1; page 8, Figure 3). Wang et al. disclose that simultaneous treatment of SN38 with NMS-873 significantly increases the DNA damaging effects in PANC-1 cells (page 6, para. 1). Combination treatment of SN38 plus NMS-873 causes further decrease of cell viability specifically in pSer784-VCP-proficient PANC-1 cells. NMS-873 alone mildly decreases cell viability with a similar magnitude across all four PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient (page 6, para. 2). NMS-873 used in the study has demonstrated promising proof-of-concept anticancer effects in different preclinical models (page 12, para. 3). The data of the studies support the general notion that VCP inhibition is a promising strategy to overcome resistance of various cancer types to a broad range of genotoxic chemotherapies (page 13, para. 1). In another study conducted to determine the survival, PDAC patents receive standard post-surgery chemotherapy treatments consisting of genotoxic agents, such as gemcitabine, 5Fu, and cisplatin (page 9, para. 2). Wang et al. further disclose that CB-5339 is highly effective at inhibiting in vitro and in vivo growth of AML cell lines and mouse xenograft models as monotherapy. CB-5339 also synergizes with standard chemotherapies consisting of genotoxic anthracycline and cytarabine, supporting the general idea that VCP inhibition can be chemo-sensitizing (page 12, para. 3).
Zhang et al. (International Journal of Pharmaceutics, 2004, Vol. 270, Issue 1 – 2, page 93 – 107, cited in the previous Office Action mailed January 6, 2026) teach that SN38 is the active metabolite of irinotecan, a topoisomerase I inhibitor. SN38 is approximately 200 – 2000-fold more cytotoxic than irinotecan. However, SN38 has not been used as an anticancer drug due to its poor solubility in any pharmaceutically acceptable solvents. SN38 has low affinity to lipid membranes; it tends to precipitate in aqueous phase resulting in a very low drug-to-liposome entrapment. Therefore, a novel, liposome-based SN38 is formulated. This formulation contains liposomes of uniform size distribution and it is easy to use (Abstract).
Livingstone et al. (Cancer Research, 2005, Vol. 65, Issue 17, page 7533 – 7540, cited in the previous Office Action mailed January 6, 2026) teach that the response of eukaryotic cells to DNA damage includes the activation of PIKK, such as ATM, ATR, and DNA-dependent protein kinases (DNA-PK) (Abstract). Livingstone et al. map the site of VCP phosphorylation at Ser784 and show that VCP is phosphorylated by multiple PIKK family members (page 7533, Right Col., para. 4).
Drummond et al. (US10570119B2) teach that liposome formulations of ATR inhibitors, which have extended half-life in blood circulation and efficacy in treating tumors (Col. 2, lines 15 – 18).
Barnieh et al. (Current Research in Pharmacology and Drug Discovery, 2021, Vol. 2, cited in the previous Office Action mailed January 6, 2026) teach the three ATR inhibitors, VX970, AZD6738, and BAY-1895344, that have been studied in clinical trials. VX970 is a highly potent and selective ATR inhibitor, inhibiting ATR activity both in cell free assays and in cellular assays (page 9, Left Col., para. 5). VX970 is shown to be a strong sensitizer for chemotherapy both in vitro and in vivo, such that the efficacy of chemo-radiotherapy in pancreatic tumor xenografts is profoundly enhanced in combination with VX970 (page 9, Left Col., para .6; Right Col., para. 1). AZD6738 has been demonstrated to significantly inhibit cancer cell growth, with profound sensitivity in cells with ATM-pathway defects when used as a single agent across different panels of cancer cell lines in vitro. Moreover, AZD6738 has demonstrated strong synergy with various classes of chemotherapy (page 10, Right Col., para. 3 – 4). In one study, AZD6738 in combination with cyclophosphamide is also well-tolerated, exhibiting anti-tumor growth activity and regression (page 11, Left Col., para. 1). BAY-1895344 is an improved analogue of BAY-937 with enhanced aqueous solubility, bioavailability across species, and with an absence of significant hERG liabilities. In vitro, BAY-1895344 has proved to be a highly potent ATR inhibitor both in cell free and cellular assays.
Accordingly, claim 8 does not include additional elements that amount to significantly more than the recited judicial exception. Claims 9 – 15 depend from claim 8 and merely further recite particular genotoxic agents, inhibitors, carriers, treatment combinations, regimen, or expected therapeutic effect. These additional limitations do not alter the eligibility analysis because they continue to apply the same natural correlation using known therapeutic agents and routine treatment steps. Therefore, claims 8 – 15 are not patent eligible under 35 U.S.C. 101.
Maintained / Modified 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. 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.
Claims 1 – 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 9, 2026).
a. Wang et al. teach that PDAC patients have a dismal prognosis due in large part to chemotherapy resistance. Wang et al. identifies that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC (Abstract). In the study conducted, Wang et al. treated four distinct PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient with SN38 (page 5, Figure 1; page 8, Figure 3). Wang et al. disclose that simultaneous treatment of SN38 with NMS-873 significantly increases the DNA damaging effects in PANC-1 cells (page 6, para. 1). Combination treatment of SN38 plus NMS-873 causes further decrease of cell viability specifically in pSer784-VCP-proficient PANC-1 cells. NMS-873 alone mildly decreases cell viability with a similar magnitude across all four PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient (page 6, para. 2). NMS-873 used in the study has demonstrated promising proof-of-concept anticancer effects in different preclinical models (page 12, para. 3). The data of the studies support the general notion that VCP inhibition is a promising strategy to overcome resistance of various cancer types to a broad range of genotoxic chemotherapies (page 13, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the in vitro treatment strategy disclosed in Wang et al. to apply the method to a subject because Wang et al. clearly identify chemotherapy resistance in PDAC patients as the clinical problem motivating the disclosed study and demonstrate that VCP inhibition sensitizes PDAC cell lines to genotoxic agents. It is well-established in the art that in vitro models are predictive of in vivo responses, and are routinely used to develop therapeutic approaches that are later applied in patients. Moreover, Wang et al. disclose that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC. It would have been obvious for one of ordinary skill in the art to determine the levels of pSer784-VCP of a patient before administering genotoxic agents because Wang et al. clearly identify that pSer784-VCP will affect the efficacy of a genotoxic agent. It would have been obvious for one of ordinary skill in the art to administer genotoxic agent, such as SN-38 to subjects that do not have elevated pSer784-VCP because Wang et al. explicitly disclose that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify the in vitro treatment strategy disclosed in Wang et al. to apply the method to a subject because it is known in the art that clinical treatment are the extension of in vitro study.
Claims 8 and 12 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 6, 2026) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, cited in the previous Office Action mailed January 6, 2026).
b. Wang et al. teach that PDAC patients have a dismal prognosis due in large part to chemotherapy resistance. Wang et al. identifies that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC (Abstract). In the study conducted, Wang et al. treated four distinct PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient with SN38 (page 5, Figure 1; page 8, Figure 3). Wang et al. disclose that simultaneous treatment of SN38 with NMS-873 significantly increases the DNA damaging effects in PANC-1 cells (page 6, para. 1). Combination treatment of SN38 plus NMS-873 causes further decrease of cell viability specifically in pSer784-VCP-proficient PANC-1 cells. NMS-873 alone mildly decreases cell viability with a similar magnitude across all four PDAC cell lines that are pSer784-VCP-deficient and pSer784-VCP-proficient (page 6, para. 2). NMS-873 used in the study has demonstrated promising proof-of-concept anticancer effects in different preclinical models (page 12, para. 3). The data of the studies support the general notion that VCP inhibition is a promising strategy to overcome resistance of various cancer types to a broad range of genotoxic chemotherapies (page 13, para. 1). In another study conducted to determine the survival, PDAC patents receive standard post-surgery chemotherapy treatments consisting of genotoxic agents, such as gemcitabine, 5Fu, and cisplatin (page 9, para. 2). Wang et al. further disclose that CB-5339 is highly effective at inhibiting in vitro and in vivo growth of AML cell lines and mouse xenograft models as monotherapy. CB-5339 also synergizes with standard chemotherapies consisting of genotoxic anthracycline and cytarabine, supporting the general idea that VCP inhibition can be chemo-sensitizing (page 12, para. 3).
However, Wang et al. do not teach the step of measuring in a cancer cell or tumor cell in a sample obtained from the subject, the level of VCP phosphorylation at Ser784.
Kalamara et al. teach that cancer is a highly heterogenous disease with complex underlying biology. It is clear that a cancer therapy that fits all the cases cannot be found, and as a result the design of the therapies tailored to the patient’s molecular characteristics is needed (Abstract). Regardless of treatment, while some patients respond to it, a great percentage of them exhibit or develop resistance. Resistance to cancer therapy is largely attributed to inter-patient heterogeneity as well as intra-tumor heterogeneity (page 53, Right Col., para. 2). The data for a pharmacogenomic study would be generate from patients to determine the effect of different treatments (page 54, Left Col., para. 3) Exvivo models involve taking a sample out of the organism or patient and studying it under more controlled conditions (page 55, Left Col., para. 2). This approach has been applied to the study of patient specific drug response (page 55, Right Col., para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the treatment approach for PDAC subjects based on the patient’s level of pSer784 as taught by Wang et al. with the step of obtaining the cancer cell sample from the subject in view of Kalamara et al. because Wang et al. identify pSer784-VCP as a driver of chemotherapy resistance in PDAC and demonstrate in vitro that VCP inhibition restores sensitivity to genotoxic agents and Wang et al. further disclose that VCP inhibition is a promising strategy to improve chemotherapy response across various cancers. One would have been motivated to implement measuring the level of pSer784 when selecting the treatment because Wang et al. teach that the reduction of level of pSer784 will enhance the effectiveness of genotoxic agent, thereby, yielding an improved treatment plan for patients. Kalamara et al. explain that drug response can be predicted by generating ex vivo models from patient samples and testing treatment efficacy under controlled conditions, which is a well-established method for informing patient-specific drug selection. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the treatment approach for PDAC subjects based on the patient’s level of pSer784 as taught by Wang et al. with the step of obtaining the cancer cell sample from the subject in view of Kalamara et al. because Wang et al. disclose a routine application of biomarker-driven therapy and Kalamara et al. teach an established method for informing patient-specific drug selection based on drug responsiveness.
Regarding step (b) of claim 8, Wang et al. teach that pSer784-VCP is associated with resistance or non-responsiveness to genotoxic chemotherapy. In particular, Wang et al. identify pSer784-VCP as driving genotoxic chemotherapy resistance in PDAC and show that pSer784-VCP-proficient cells exhibit resistance to genotoxic agents, whereas reduction or inhibition of VCP sensitizes cells to genotoxic treatment. Thus, Wang et al. teach that elevated pSer784-VCP corresponds to non-responsive phenotype, and reduced pSer784-VCP corresponds to increased responsiveness/sensitivity to genotoxic therapy. Accordingly, Wang et al. teach the treatment-selection logic recited in step (b), which is administering a genotoxic agent when VCP phosphorylation is reduced relative to a non-responsive control population, and administering a VCP inhibitor when VCP phosphorylation is elevated relative to a responsive control population. Kalamara et al. is relied upon for the general teaching of obtaining patient samples and using patient-specific molecular or drug response information to guide therapy selection.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 6, 2026) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, cited in the previous Office Action mailed January 6, 2026) as applied to claims 8 and 12 – 13 above, and further in view of Zhang et al. (International Journal of Pharmaceutics, 2004, Vol. 270, Issue 1 – 2, page 93 – 107, cited in the previous Office Action mailed January 6, 2026).
c. Regarding claim 9, the references teach the limitations discussed above.
However, these references do not teach a composition comprising genotoxic agent and a pharmaceutically acceptable carrier.
Zhang et al. teach that SN38 is the active metabolite of irinotecan, a topoisomerase I inhibitor. SN38 is approximately 200 – 2000-fold more cytotoxic than irinotecan. However, SN38 has not been used as an anticancer drug due to its poor solubility in any pharmaceutically acceptable solvents. SN38 has low affinity to lipid membranes; it tends to precipitate in aqueous phase resulting in a very low drug-to-liposome entrapment. Therefore, a novel, liposome-based SN38 is formulated. This formulation contains liposomes of uniform size distribution and it is easy to use (Abstract).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine SN38 as taught by Wang et al. with liposomes of uniform size distribution in view of Zhang et al. to the treatment of cancer because Zhang et al. teach the formulation that will overcome the issues of using SN38. One would have been motivated to combine SN38 as taught by Wang et al. with liposomes of uniform size distribution in view of Zhang et al. to the treatment of cancer because the novel formulation disclosed by Zhang et al. will overcome the issue of using SN38. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine SN38 as taught by Wang et al. with liposomes of uniform size distribution in view of Zhang et al. to the treatment of cancer because it is known in the art that the novel formulation will improve the current downsides of SN38.
Claims 10 – 11 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 6, 2026) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, cited in the previous Office Action mailed January 6, 2026) as applied to claims 8 and 12 – 13 above, and further in view of Livingstone et al. (Cancer Research, 2005, Vol. 65, Issue 17, page 7533 – 7540, cited in the previous Office Action mailed January 6, 2026) and Drummond et al. (US10570119B2).
d. Regarding claims 10 – 11, the references teach the limitations discussed above.
However, these references do not teach administering pharmaceutical composition comprising inhibitor of one or more phosphatidylinositol 3-kinase-related kinases (PIKK) to the subject when the measured phosphorylation level is elevated relative to the reference value of a control subject, wherein the composition comprises one or more PIKK inhibitors and a pharmaceutically acceptable carrier, wherein the PIKK inhibitors are ATR inhibitors.
Livingstone et al. teach that the response of eukaryotic cells to DNA damage includes the activation of PIKK, such as ATM, ATR, and DNA-dependent protein kinases (DNA-PK) (Abstract). Livingstone et al. map the site of VCP phosphorylation at Ser784 and show that VCP is phosphorylated by multiple PIKK family members (page 7533, Right Col., para. 4).
Drummond et al. teach that liposome formulations of ATR inhibitors, which have extended half-life in blood circulation and efficacy in treating tumors (Col. 2, lines 15 – 18).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute VCP inhibitor as taught by Wang et al. with PIKK inhibitor in view of Livingstone et al. because Livingstone et al. teach that PIKK family members, including ATM, ATR, and DNA-PK, will phosphorylate VCP at Ser784. One would have been motivated to substitute VCP inhibitor as taught by Wang et al. with PIKK inhibitor in view of Livingstone et al. because Livingstone et al. teach the fact that PIKK family members, including ATM, ATR, and DNA-PK, will phosphorylate VCP at Ser784, which suggest that phosphorylation level of VCP at Ser784 will be reduced when PIKK is inhibited. One would have considered using PIKK inhibitor, such as ATR inhibitor, instead of VCP inhibitor, to reduce the phosphorylation level of VCP at Ser784. It would have been prima facie obvious for a person of ordinary skill in the art to combine PIKK inhibitor, such as ATR inhibitor, as taught by Livingstone et al. with liposome as a pharmaceutically acceptable carrier in a formulation in view of Drummond et al. because Drummond et al. teach that such liposome formulation will extend the half-life of ATR inhibitor in blood circulation and its efficacy in treating tumors. One would have been motivated to combine PIKK inhibitor, such as ATR inhibitor, as taught by Livingstone et al. with liposome as a pharmaceutically acceptable carrier in a formulation in view of Drummond et al. because of the improved properties disclosed by Drummond et al. As the disclosure of prior art meets all structural limitation of the claimed method, the intended result “sensitizing the subject to a genotoxic treatment” recited in claim 11 would be achieved. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to substitute VCP inhibitor as taught by Wang et al. with PIKK inhibitor in view of Livingstone et al. and to combine PIKK inhibitor, such as ATR inhibitor, as taught by Livingstone et al. with liposome as a pharmaceutically acceptable carrier in a formulation in view of Drummond et al. because Livingstone et al. disclose that PIKK will increase the phosphorylation level of VCP at Ser784 and lead one to consider replacing VCP inhibitor with PIKK inhibitor, such as ATR inhibitor, for reducing the phosphorylation level of VCP at Ser784 and Drummond et al. teach a liposome formulation of ATR inhibitor with enhanced properties.
Claims 14 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 10 October 2021, Vol. 13, Issue 20, cited in the previous Office Action mailed January 6, 2026) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, cited in the previous Office Action mailed January 6, 2026), Zhang et al. (International Journal of Pharmaceutics, 2004, Vol. 270, Issue 1 – 2, page 93 – 107, cited in the previous Office Action mailed January 6, 2026), Livingstone et al. (Cancer Research, 2005, Vol. 65, Issue 17, page 7533 – 7540, cited in the previous Office Action mailed January 6, 2026) and Drummond et al. (US10570119B2) as applied to claims 8 – 13 above, and further in view of Barnieh et al. (Current Research in Pharmacology and Drug Discovery, 2021, Vol. 2, cited in the previous Office Action mailed January 6, 2026).
e. Regarding claims 14 – 15, the references teach the limitation discussed above.
However, these references do not teach the PIKK inhibitors are AZD6738, VX970, and BAY-1895344 and the genotoxic agent is cyclophosphamide.
Barnieh et al. teach the three ATR inhibitors, VX970, AZD6738, and BAY-1895344, that have been studied in clinical trials. VX970 is a highly potent and selective ATR inhibitor, inhibiting ATR activity both in cell free assays and in cellular assays (page 9, Left Col., para. 5). VX970 is shown to be a strong sensitizer for chemotherapy both in vitro and in vivo, such that the efficacy of chemo-radiotherapy in pancreatic tumor xenografts is profoundly enhanced in combination with VX970 (page 9, Left Col., para .6; Right Col., para. 1). AZD6738 has been demonstrated to significantly inhibit cancer cell growth, with profound sensitivity in cells with ATM-pathway defects when used as a single agent across different panels of cancer cell lines in vitro. Moreover, AZD6738 has demonstrated strong synergy with various classes of chemotherapy (page 10, Right Col., para. 3 – 4). In one study, AZD6738 in combination with cyclophosphamide is also well-tolerated, exhibiting anti-tumor growth activity and regression (page 11, Left Col., para. 1). BAY-1895344 is an improved analogue of BAY-937 with enhanced aqueous solubility, bioavailability across species, and with an absence of significant hERG liabilities. In vitro, BAY-1895344 has proved to be a highly potent ATR inhibitor both in cell free and cellular assays.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to select specific PIKK inhibitors as taught by Barnieh et al. for the treatment of cancer or tumor because Livingstone et al. disclose that PIKK will increase the phosphorylation level of VCP at Ser784 and lead one to consider replacing VCP inhibitor with PIKK inhibitor, such as ATR inhibitor, for reducing the phosphorylation level of VCP at Ser784 and Barnieh et al. disclose that VX970, AZD6738, and BAY-1895344 have been studied in clinical trials to assess their anti-tumor properties and the results shown are promising. One would have been motivated to select VX970, AZD6738, and BAY-1895344 as the PIKK inhibitors used for treating cancer or tumor because Barnieh et al. teach promising results of anti-tumor effect. It would also have been obvious for one of ordinary skill in the art to substitute SN38 as taught by Zhang et al. with cyclophosphamide in view of Barnieh et al. because Barnieh et al. teach that the combination of AZD6738 and cyclophosphamide is known in the art for its anti-tumor growth activity. One would have been motivated to substitute SN38 as taught by Zhang et al. with cyclophosphamide in view of Barnieh et al. because the combination is known to exhibit anti-tumor growth activity, which is expected. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to select specific PIKK inhibitors as taught by Barnieh et al. for the treatment of cancer or tumor and to substitute SN38 as taught by Zhang et al. with cyclophosphamide in view of Barnieh et al. because Barnieh et al. teach the three PIKK inhibitors that are known to yield anti-tumor effect and the combination of AZD6738 and cyclophosphamide is also known to yield anti-tumor growth activity.
Responses to Applicant’s Remarks:
Applicant’s Remarks and the Declaration, filed April 8, 2026, have been fully considered and are found to be not persuasive.
Regarding the rejections, Applicant argues that Wang et al. do not qualify as a prior art because the Declaration of Dr. Shao declares that the portions of Wang et al. being applied against the claims in the Office Action can only be attributed to Dr. Shao and Marc Diamond and not to the other co-authors of Wang et al. However, the exception under 35 U.S.C. § 102(b)(1)(A) applies only to disclosures made one year or less before the effective filing date of the claimed invention. Here, the effective filing date of the claims is October 11, 2022. The MDPI webpage for Wang et al. identifies the article as published on October 10, 2021:
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Although the PDF version lists “Published: 11 October 2021”, the publisher’s article webpage identifies the publication date as “10 October 2021”. The earliest demonstrated date of public availability controls the prior-art purposes. Therefore, Wang et al. was publicly available more than one year before the effective filing date. Accordingly, even considering the relied upon subject matter originated from Dr. Shao and Marc Diamond, the disclosure falls outside the one-year grace period and is not disqualified from 35 U.S.C. § 102(b)(1)(A). The Declaration is therefore insufficient to overcome Wang et al. as prior art, and the rejection is maintained.
Regarding Kalamara et al., Applicant argues that Kalamara et al. merely disclose different experimental and computational approaches for use in treating cancer and Kalamara et al. does not disclose VCP Ser784 phosphorylation measurement, nor does it suggest treatment selection based on such measurement.
Regarding Zhang et al., Applicant argues that Zhang et al. disclose a liposome-based formulation of Irinotecan and does not address VCP phosphorylation for predicting stratified treatments.
Regarding Livingstone et al., Applicant argues that Livingstone et al. disclose that VCP phosphorylation at Ser784 accumulates at sites of DNA double-strand breaks, indicating a role of VCP in DNA repair and this mechanistic observation regarding DNA repair does not suggest a treatment selection encompassed by the pending claims.
Regarding Drummond and Barnieh et al., Applicant argues that Drummond and Barnieh et al. merely teach a class of drugs and do not disclose or suggest the method encompassed by the pending claims for determining when to use them.
Applicant further argues that the cited publications do not disclose or suggest Ser784 phosphorylation level as an indicator of treatment response in a subject and the cited publications merely disclose general therapeutic approaches and there is no reason a person of ordinary skill in the art would have modified the disclosure of the cited publications to arrive at treatment method of the pending claims, nor could the cited publications have led a person of ordinary skill in the art to predict the subjects could be stratified by pSer784 VCP levels for administering a genotoxic treatment.
However, these arguments are not persuasive because they are based on Wang et al. being unavailable as prior art. As discussed above, Wang et al. qualifies as prior art and remains available in the rejection. Wang et al. explicitly teach pSer784 VCP as relevant to genotoxic chemotherapy resistance and further teaches that VCP inhibition can sensitize cancer cells to genotoxic chemotherapy. Thus, Wang et al provide the missing teaching relied upon by Applicant. Applicant’s argument that Kalamara et al., Zhang et al., Livingstone et al., Drummond, and Barnieh et al. individually do not disclose the claimed treatment selection method is not persuasive because the rejection is based on the combined teachings of the references, not on any one secondary reference alone. In view of Wang et al. that teach pSer784 VCP is associated with resistance to genotoxic chemotherapy and the additional teachings of the cited references regarding cancer treatment, genotoxic agents, DNA repair, and ATR/VCP-related therapeutic approaches, one of ordinary skill in the art would have had reason to use pSer784 VCP level as an indicator for selecting or administering genotoxic treatment with a reasonable expectation of success.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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