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. Claims 1 – 20 are pending in this application.
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 to the subject a VCP inhibitor if the subject has increased levels of phosphorylation of Valosin-Containing Protein (VCP) at Ser784 relative to a reference value of 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 6 – 7, 9 – 11, and 14 – 20 is October 11, 2022.
Election/Restrictions
4. Applicant’s election without traverse of group I, claims 1 – 15, drawn to a method of treating a cancer or tumor in a subject in need, filed October 10, 2025, is acknowledged. The following species were elected by Applicant with traverse in the reply, filed October 10, 2025, with claims 1 – 5 and 7 – 15 reading on the elected species:
(i) A specific genotoxic agent recited in claims 5 – 7: SN38
(ii) A specific combination of the pharmaceutical composition recited in claim 8: CB-5339, AZD6738, VX970, BAY-1895344, and cyclophosphamide.
As Applicant’s Remarks indicate traversal to the election of species requirement, a reconsideration of such requirement is provided below.
The traversal is on the ground that the search and examination of other PIKK inhibitors will not present a serious burden on the examiner because the elected PIKK inhibitors are specific ATR inhibitors, which have a common mode of action. Any search of the prior art involving one ATR inhibitor will be co-extended. The similar reasoning applies to genotoxic agent as several genotoxic agents trigger similar downstream signaling events and are used as combination therapy. Thus, a search and examination of these species may be made without serious burden on the Office. The examiner acknowledges that the elected PIKK inhibitors are all ATR inhibitors. However, the traversal of the election of species requirement is not persuasive because the claimed PIKK inhibitors include other inhibitors, such as CHEK1 inhibitor, which has a different mechanism of action and the claimed genotoxic agents include compounds, such as cisplatin, a platinum agents, and SN38, a topoisomerase inhibitors, that also have different mechanism of action. Therefore, the requirement is deemed proper and made final.
Accordingly, claims 6 and 16 – 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected invention, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/02/2024 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
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.
Claim Objections
Claim 8 is objected to because of the following informalities:
Claim 8, line 2, “;” immediately after “comprising” should read “:”.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Principe et al. (Frontiers in Oncology, 2021, Vol. 11, Reference included with PTO-892) with evidence provided by Wang et al. (Cancers, 2021, Vol. 13, Issue 20, Reference included with PTO-892).
a. Independent claim 1 is directed to a method of treating cancer or tumor in a subject in need thereof, wherein the method comprises administering to the subject a genotoxic agent if the subject has similar levels of phosphorylation of Valosin-Containing Protein (VCP) at Ser784 relative to the reference value of the control population. Dependent claim 3 is directed to the method, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). Dependent claim 5 is directed to the method, wherein the genotoxic agent is irinotecan.
Principe et al. discuss the current state of pancreatic cancer therapy, whereas this review highlights an unmet clinical need to improve the understanding of poor therapeutic responses seen in patients with PDAC (Abstract). Irinotecan is an analog of Camptothecin and irinotecan entered clinical trial and was approved by the FDA as a second-line monotherapy for metastatic colorectal cancer in 1996. In a subsequent trail, the addition of irinotecan to 5-FU/leucovorin results in twice the response rate compared to 5-FU/leucovorin monotherapy, resulting in the approval of irinotecan as first-line therapy in 1998. Irinotecan is approved for metastatic PDAC in 2013, where it is currently used as part of the multidrug regimen FOLFIRINOX (page 15, Left Col., para .1).
For the subject being treated, Wang et al. teach that pSer784-VCP drives genotoxic chemotherapy resistance of PDAC (Abstract). Therefore, it is inherent that the subjects effectively treated with irinotecan in Principe et al. had non-elevated levels of pSer784-VCP, as those with elevated levels would not respond to treatment.
For these reasons above, Principe et al. with evidence provided by Wang et al. anticipate the claimed invention.
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, 2021, Vol. 13, Issue 20, Reference included with PTO-892).
b. Regarding claims 1 – 5 and 7, 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. 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, 2021, Vol. 13, Issue 20, Reference included with PTO-892) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, Reference included with PTO-892).
c. Regarding claims 8, 12 – 13, 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 step by step method of selecting a treatment for a subject.
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 determining subject’s responsiveness to chemotherapeutics 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 determining subject’s responsiveness to chemotherapeutics 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.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Cancers, 2021, Vol. 13, Issue 20, Reference included with PTO-892) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, Reference included with PTO-892) 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, Reference included with PTO-892).
d. 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, 2021, Vol. 13, Issue 20, Reference included with PTO-892) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, Reference included with PTO-892) as applied to claims 8 and 12 – 13 above, and further in view of Livingstone et al. (Cancer Research, 20054, Vol. 65, Issue 17, page 7533 – 7540, Reference included with PTO-892) and Drummond et al. (US10570119B2).
e. 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 imply 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, 2021, Vol. 13, Issue 20, Reference included with PTO-892) in view of Kalamara et al. (Current Opinion in Systems Biology, 2018, Vol. 10, page 53 – 62, Reference included with PTO-892), Zhang et al. (International Journal of Pharmaceutics, 2004, Vol. 270, Issue 1 – 2, page 93 – 107, Reference included with PTO-892), Livingstone et al. (Cancer Research, 20054, Vol. 65, Issue 17, page 7533 – 7540, Reference included with PTO-892) 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, Reference included with PTO-892).
f. 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.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693