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
Applicant’s request for reconsideration of the finality of the rejection of the last Office Action is persuasive and, therefore, the finality of that action is withdrawn.
This Office Action is responsive to Applicant’s After Final, filed August 10, 2026. The amendment, filed August 10, 2026, is entered, wherein claim 8 is amended and claims 6 and 16 – 20 are withdrawn.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.
Priority
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
The objection of the disclosure in the previous Office Action, dated June 9, 2026, is withdrawn in view of the amended specification.
Withdrawn Rejections
The rejection of claims 8 – 15 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 101 has been considered and is withdrawn in view of the amended claim 8.
The rejection of claims 1 – 5 and 7 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 103 as being unpatentable over Wang et al. has been considered and is withdrawn in view of the corrected publication date of Wang et al.
The rejection of claims 8 and 12 – 13 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Kalamara et al. has been considered and is withdrawn in view of the corrected publication date of Wang et al.
The rejection of claim 9 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Kalamara et al. as applied to claims 8 and 12 – 13 above, and further in view of Zhang et al. has been considered and is withdrawn in view of the corrected publication date of Wang et al.
The rejection of claims 10 – 11 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Kalamara et al. as applied to claims 8 and 12 – 13 above, and further in view of Livingstone et al. and Drummond et al. has been considered and is withdrawn in view of the corrected publication date of Wang et al.
The rejection of claims 14 – 15 in the previous Office Action, dated June 9, 2026, under 35 U.S.C. 103 as being unpatentable over Wang et al. in view of Kalamara et al., Zhang et al., Livingstone et al., and Drummond et al. as applied to claims 8 – 13 above, and further in view of Barnieh et al. has been considered and is withdrawn in view of the corrected publication date of Wang et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 2, 4 – 5, 7 – 8, and 10 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (Cell Reports, 2020, Vol. 31, Issue 10, PTO-892).
Zhu et al. teach that VCP phosphorylation at Ser784 is associated with susceptibility and response to genotoxic chemotherapy. Specifically, Zhu et al. disclose that Ser784 phosphorylation is induced by DNA damage and is important for DNA damage response (DDR), DNA repair, and cell survival, and report that high phosphor- Ser784-VCP levels are significantly associated with poor outcome among chemotherapy-treated breast cancer patients, thereby identifying Ser784 phosphorylation as a potential predictive biomarker for chemotherapy treatments (Abstract). Zhu et al. teach that the clinical pSer784-VCP measurements are obtained from patient tumor specimens before treatment, stating that the pSer784-VCP level used for the analysis is in the surgical tumor samples taken before the adjuvant treatments and that it is the baseline pSer784-VCP level induced by endogenous DNA damage that predicts the survival for patients subsequently treated with adjuvant genotoxic chemotherapy (page 11, Right Col., para. 1). Zhu et al. further teach that Ser784 phosphorylation occurs in cell lines derived from various tissues and protect cells from a wide range of DNA-damaging agents, such that pSer784-VCP is likely a general predictor of genotoxic chemotherapy susceptibility for a broad range of cancer types (page 12, Left Col., para. 1). Importantly, Zhu et al. state that the data suggest tumors containing low levels of induced pSer784-VCP can be treated effectively by chemotherapy (page 12, Left Col., para. 2). Zhu et al. therefore provide clinical and experimental evidence that pSer784-VCP is a cancer prognostic biomarker that can potentially predict chemotherapy response because of its importance for DDR (page 13, Right Col., para. 2). Zhu et al. teach that nearly all of the chemotherapy drugs used to treat patients in the BCCancer series are genotoxins and identify cyclophosphamide, methotrexate, 5-fluorouracil (5FU), and anthracycline among those agents. Zhu et al. experimentally evaluate the functional significance of VCP Ser784 phosphorylation following treatment with a panel of genotoxic agents including 5FU, hydroxyurea (HU), cisplatin, and SN38, and report significantly reduced survival of cells expressing the non-phosphorylatable VCP(S784A) mutant relative to cells expressing VCP(WT) or the phosphomimetic VCP(S784D) following such genotoxic treatment (page 10, Right Col., para. 1). Thus, Zhu et al. teach the claimed cancer or tumor in a subject because Zhu et al. evaluate breast cancer patients and their tumor specimens; the claimed VCP phosphorylation at Ser784 because Zhu et al. measure pSer784-VCP in surgical tumor samples obtained from the patients before adjuvant treatment; and the claimed administration of a genotoxic agent because the patients are subsequently treated with genotoxic chemotherapy, including cyclophosphamide, methotrexate, 5-fluorouracil, and anthracyclines. Zhu et al. further teach the relationship underlying the claimed treatment of subjects having non-elevated pSer784-VCP because Zhu et al. teach that pSer784-VCP predicts susceptibility to genotoxic chemotherapy and state that tumors having low induced pSer784-VCP may be treated effectively by chemotherapy. Zhu et al. further identify 5FU as a genotoxic chemotherapy and experimentally demonstrate a functional relationship between VCP Ser784 phosphorylation and cellular survival following treatment with 5FU. Thus, the specific disclosure of 5FU of Zhu et al. corresponds to the limitation of claim 5.
However, Zhu et al. do not explicitly teach that the subject administered the genotoxic agent has been determined to have similar levels of phosphorylation of VCP at Ser784 relative to a reference value obtained from a control population as recited in claim 1. Zhu et al. do not teach determining that the subject has a VCP phosphorylation level at Ser784 that is reduced relative to a reference value obtained from a control subject or control population, nor do Zhu et al. teach administering the genotoxic agent to the subjected based on such a reference value determination.
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 utilize the pSer784-VCP level taught by Zhu et al. to identify subjects expected to be susceptible to genotoxic chemotherapy and to administer genotoxic chemotherapy to such subjects because Zhu et al. explicitly identify pSer784-VCP as a potential predictive biomarker for chemotherapy treatment, teach that baseline pSer784-VCP measured in tumor specimens before treatment predicts survival following subsequent genotoxic chemotherapy, and teach that tumors containing low levels of induced pSer784-VCP may be treated effectively by chemotherapy. Zhu et al. further teach that pSer784-VCP is likely a general predictor of genotoxic chemotherapy susceptibility for a broad range of cancer types. Thus, one of ordinary skill would have been motivated to use the measured pSer784-VCP level to identify subjects having a biomarker state associated with susceptibility to genotoxic treatment and administer a genotoxic agent to such subjects because doing so would apply the disclosed predictive biomarker of Zhu et al. to select subjects expected to benefit from genotoxic chemotherapy. A person of ordinary skill would have had a reasonable expectation of success because Zhu et al. provide both clinical evidence correlating pretreatment pSer784-VCP levels with subsequent chemotherapy outcome and experimental evidence showing that VCP Ser784 phosphorylation affects survival in response to genotoxic agents.
With respect to the limitation “(b)” of claim 1 requiring the subject to have been determined to have similar levels of phosphorylation of VCP at Ser784 relative to a reference value obtained form a control population, although Zhu et al. do not characterize the measured pSer784-VCP level as being “similar” to a reference value obtained from a control population, Zhu et al. teach that pretreatment pSer784-VCP level is predictive of susceptibility and response to genotoxic chemotherapy, that high pSer784-VCP is associated with poor outcome following chemotherapy, and that tumors containing low levels of induced pSer784-VCP may be treated effectively by chemotherapy. In view of these teachings, it would have been obvious to one of ordinary skill in the art to compare the measured pSer784-VCP level of a candidate subject with a reference value representative of a population exhibiting the pSer784-VCP state associated with susceptibility to genotoxic chemotherapy when the candidate subject exhibits a pSer784-VCP similar to that reference value. One of ordinary skill would have been motivated to make such a comparison because it would provide an objective and reproducible approach of applying the predictive biomarker of Zhu et al. to identify subjects expected to susceptible to genotoxic chemotherapy. One of ordinary skill would have had a reasonable expectation of success because the clinical data of Zhu et al. already demonstrate an association between pretreatment pSer784-VCP levels and subsequent outcome following genotoxic chemotherapy and Zhu et al. teach that low pSer784-VCP tumors may be effectively treated by chemotherapy. Similarly, with respect to claim 8, it would have been obvious to one of ordinary skill to implement the predictive biomarker of Zhu et al. by comparing the measured pSer784-VCP level of a candidate subject with a reference value representative of a control subject or population and administering genotoxic chemotherapy when the subject’s measured level is reduced relative to that reference. Such a comparison would provide an objective approach of identifying the lower pSer784-VCP state that Zhu et al. associate with susceptibility to genotoxic chemotherapy. One of ordinary skill would have been motivated to administer the genotoxic agent to a subject identified as having the lower pSer784-VCP state because Zhu et al. teach that tumors containing low levels of induced pSer784-VCP may be treated effectively by chemotherapy, and would have had a reasonable expectation of success based on the clinical and experimental evidence of Zhu et al. linking pSer784-VCP status to response to genotoxic chemotherapy.
Regarding claim 5, Zhu et al. identify 5-FU as a genotoxic agent and experimentally evaluate the relationship between pSer784-VCP phosphorylation and survival following 5-FU treatment. Because 5-FU is one of the alternatives recited in the closed group of claim 5, the 5-FU embodiment of Zhu et al. reads on the additional limitation of claim 5. The fact that Zhu et al. additionally disclose other genotoxic agents does not alter the disclosure of the specific 5-FU embodiment relied upon.
Regarding claims 2, 4, and 7, the additionally recited limitation further limit the treatment recited in alternative (a) of claim 1, which requires administration of a VCP inhibitor to a subject determined to have increased levels of VCP phosphorylation at Ser784 relative to a reference value obtained from a control population. However, alternative (a) is a contingent alternative and is not required to be performed when the condition associated with that alternative is not satisfied. The rejection of claim 1 relies upon alternative (b), wherein a genotoxic agent is administered to a subject determined to have similar levels of VCP phosphorylation at Ser784 relative to the reference value obtained from the control population. Thus, when the condition corresponding to alternative (a) is not satisfied, administration of the VCP inhibitor recited therein need not be carried out in order for the claimed method of claim 1 to be performed. Accordingly, the further limitations of claims 2, 4, and 7 directed to the VCP inhibitor treatment of alternative (a) are contingent limitations and need not be performed in the relied-upon embodiment.
With respect to claims 10 – 14, the additionally recited limitation further limit the VCP inhibitor or phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitor treatment recited in the alternative of claim 8 requiring administration of such an inhibitor to a subject determined to have an elevated VCP phosphorylation level at Ser784 relative to the reference value. However, this inhibitor treatment alternative is contingent and is not required to be performed when the condition associated with that alternative is not satisfied. The rejection of claim 8 relies upon the alternative wherein a genotoxic agent is administered to a subject determined to have a reduced VCP phosphorylation level at Ser784 relative to the reference value. Thus, when the condition corresponding to the elevated pSer784-VCP/inhibitor alternative is not satisfied, administration of the VCP or PIKK inhibitor need not be carried out in order for the claimed method of claim 8 to be performed. Accordingly, the further limitations of claims 10 – 14 directed to the inhibitor treatment alternative are contingent limitations and need not be performed in the relied-upon embodiment.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (Cell Reports, 2020, Vol. 31, Issue 10, PTO-892) as applied to claims 1 – 2, 4 – 5, 7 – 8, and 10 – 15 above, and further in view of Mahajan et al. (Gastroenterology, 2021, Vol. 161, Issue 3, page 996 – 1010, PTO-892).
Zhu et al. teach the limitations discussed above.
However, Zhu et al. do not teach that the cancer is pancreatic ductal adenocarcinoma (PDAC).
Mahajan et al. teach that the fluoropyrimidine 5-FU has been used as a backbone for neoadjuvant, adjuvant, or palliative chemotherapy as the standard care of PDAC (page 997, Left Col., para. 3). Thus, Mahajan et al. teach the limitation of claim 3, wherein the cancer is PDAC.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to apply the pSer784-VCP-based genotoxic chemotherapy teachings of Zhu et al. to a subject having PDAC in view of Mahajan et al. because Zhu et al. teach that pSer784-VCP is likely a general predictor of genotoxic chemotherapy susceptibility for a broad range of cancer types and specifically identify 5-FU as a genotoxic agent evaluated in connection with VCP Ser784 phosphorylation and Mahajan et al. teach that 5-FU has been used as a backbone of chemotherapy for PDAC. Thus, one of ordinary skill in the art would have been motivated to apply pSer784-VCP biomarker teachings of Zhu et al. to PDAC patients receiving 5-FU-containing genotoxic chemotherapy in order to identify subjects expected to be susceptible to such chemotherapy. One of ordinary skill in the art would have had a reasonable expectation of success because Zhu et al. teach that the pSer784-VCP relationship is applicable to a broad range of cancer types, while Mahajan et al. establish the clinical use of 5-FU-containing chemotherapy for PDAC.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (Cell Reports, 2020, Vol. 31, Issue 10, PTO-892) as applied to claims 1 – 2, 4 – 5, 7 – 8, and 10 – 15 above, and further in view of Kumar et al. (International Journal of Nanomedicine, 2011, PTO-892).
Zhu et al. teach the limitations discussed above.
However, Zhu et al. do not teach a composition comprising genotoxic agent and a pharmaceutically acceptable carrier.
Kumar et al. teach a nanoparticle pharmaceutical formulation of 5-FU for cancer chemotherapy (Title). Kumar et al. disclose the preparation and evaluation of 5-FU-entrapped poly (D, L0lactic-co-glycolic acid) (PLGA) nanoparticles and teach that the 5-FU-loaded PLGA nanoparticles provide prolonged and sustained release of 5-FU and exhibit antitumor activity (Abstract). Kumar et al. further state that 5-FU nanoparticles having PLGA as a carrier are successfully prepared and describe development of a PLGA-based nanoparticle delivery system for 5-FU (page 1688, Left Col., para. 5). Thus, Kumar et al. teach a composition comprising 5-FU and PLGA as a carrier, which corresponds to the limitation of claim 9 requiring a pharmaceutical composition comprising a genotoxic agent and a pharmaceutically acceptable carrier, with 5-FU corresponding to the recited genotoxic agent alternative.
It would have been prima facie obvious for one of ordinary skill in the art to formulate the genotoxic agent taught by Zhu et al., particularly 5-FU, with the PLGA carrier in view of Kumar et al. because Kumar et al. explicitly teach PLGA as a carrier to 5-FU and demonstrate prolonged/sustained drug release and improved antitumor efficacy relative to free 5-FU. One of ordinary skill in the art would therefore have been motivated to employ the PLGA formulation to provide controlled delivery of the genotoxic agent, with a reasonable expectation of success because Kumar et al. successfully prepared and biologically evaluated 5-FU-loaded PLGA nanoparticles for cancer chemotherapy.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed August 10, 2026, have been fully considered.
Applicant argues that Wang et al. do not qualify as prior art because Wang et al. was published on October 11, 2021, and constitutes a disclosure made by the inventors not more than one year before the effective priority date of the claims. The examiner acknowledges the argument and has withdrawn the previous 103 rejections.
Applicant argues that, even assuming arguendo that Wang et al. qualify as prior art, Wang et al. fails to disclose a central feature of the claimed methods, which is determining VCP Ser784 phosphorylation in a patient-derived sample for purposes of selecting a therapeutic regimen. Accordingly to Applicant, Wang et al. is directed to mechanistic studies and the effects of VCP inhibition under experimental conditions and does not teach or suggest a clinically implemented workflow in which patient samples are analyzed and individual patients are prospectively stratified for treatment according to measured VCP Ser784 phosphorylation levels. However, the argument are moot because the previous rejections relying upon Wang et al. have been withdrawn and Wang et al. is not relied upon in the present rejection.
Applicant argues that the remaining cited references do not cure the alleged deficiencies of Wang et al. Specifically, Applicant asserts that Kalamara et al. do not teach VCP Ser784 phosphorylation, measurement thereof in patient-derived tumor samples, use thereof as a predictive biomarker, or treatment selection according to measured Ser784 phosphorylation levels. Applicant further asserts that Zhang et al. do not address VCP phosphorylation for predicting stratified treatment; Livingston et al. merely teach that VCP phosphorylation at Ser784 accumulates at sites of DNA double-strand breaks; and Drummond et al. and Barnieh et al. disclose inhibitors for cancer treatment but do not teach or suggest determining when such inhibitors should be administered based on VCP Ser784 phosphorylation. However, the arguments are moot because these arguments are directed to the previous combinations of references, including Wang et al., wherein those previous rejections have been withdrawn.
Finally, Applicant argues that the cited references, whether considered individually or in combination, provide no reason for a person of ordinary skill in the art to modify the references to arrive at the claimed treatment methods and would not have provided a reasonable expectation of success. In particular, Applicant contends that the references do not disclose or suggest using VCP Ser784 phosphorylation levels as an indicator of treatment response or provide sufficient guidance to predict that subjects could successfully be stratified according to pSer784-VCP levels for administration of genotoxic treatment. However, the arguments are moot as applied to the previous rejections based on Wang et al. because those rejections have been withdrawn.
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
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