DETAILED ACTION
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 .
Application Status
The amended claims filed with the Response to the non-final Office Action filed on June 18, 2026 are acknowledged. Claims 1-9 have been canceled. Claims 10-14 are amended.
Claims 10-16 are pending and under examination herein.
Priority
The present application, filed February 10, 2023, is a continuation-in-part (CIP) of U.S. Patent Application No. 17/480,831, filed September 21, 2021, which is a continuation (CON) of U.S. Patent Application No. 16/303,846 (now U.S. Patent No. 11,124,571), filed November 21, 2018, which is a 371 of PCT/US2017/034285, filed May 24, 2017, which claims priority from U.S. Provisional Patent Application Nos. 62/432,131, filed December 9, 2016, and 62/341,459, filed May 25, 2016.
The priority date of the instant claims is February 10, 2023 as set forth in the non-final Office Action mailed December 22, 2025.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objection to the disclosure is withdrawn in view of Applicant's amendments to the specification filed June 18, 2026.
All prior objections and rejections to claims 1-9 are rendered moot by the cancelation of the claims.
The objection to claim 12 is withdrawn in view of Applicant's amendments to the claim.
The rejection of claims 10-16 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's amendments to claims 10 and 13.
The rejection of claims 10-16 under 35 U.S.C. § 101 is withdrawn in view of Applicant's amendments to claim 10.
The rejection of claims 10-16 under 35 U.S.C. § 102(a)(1) as being anticipated by Dorand (Cancer Immunology Research (2016) 4 (11_Supplement): Abstract A050) is withdrawn in view of Applicant's claim amendments.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Rejections - 35 USC § 103
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.
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.
(1)
Claims 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Graeber (US 2022/0244263 A1) in view of Dorand (Science (2016) 353(6297): 399-403; cited in PTO-892; hereinafter “Dorand (July 2016)”). This is a new rejection necessitated by claim amendment.
Graeber describes methods for identifying and treating small cell neuroendocrine (SCN) tumors and small-round-blue cell tumor (SRBCT) (e.g., Abstract). Pertinent to claims 10-11 and 15, Graeber teaches a method of identifying and/or treating SCN tumors which comprises measuring the level of expression of one or more biomarkers from Tables 1-3 (e.g., IRF2BP2 among others) in a biological sample from a cancer patient, and administering a cancer treatment to the patient that is selected from Tables 4A (e.g., AT-7519 or roscovitine among others) and/or Table 4B (e.g., dinaciclib, roscovitine, or AT-7519 among others), wherein the cancer to be treated is rhabdomyosarcoma or medulloblastoma (e.g., ¶ 0008-0016; Table 1 at page 85, right column; Table 4A at pages 160, 162; Table 4B at pages 165, 171, 199; claims 1, 11-19, 23, 26-29). Graeber provides for further methods of prognosing or diagnosing a SCN or SRBCT cancer that comprise the steps of measuring the expression level of at least one biomarker to a control level of expression and diagnosing the patient as having a SCN or SRBCT cancer based on the comparison between the measured and control expression levels (e.g., ¶ 0012). Pertinent to claims 12-14, Graeber teaches that immune checkpoint inhibitors such as MK-3475 (pembrolizumab), AMP-224, or MEDI4736 (durvalumab) may be administered in combination with the cancer therapies recited in Tables 4A and 4B (e.g., ¶ 0061-0072).
However, Graeber does not expressly recite an embodiment in which a subject is administered an effective amount of the selected Cdk5 inhibitor in a subject having cancer cells with reduced expression or phosphorylation of IRF2BP2.
Dorand (July 2016) teaches that IFN-γ, a major CD4+ T cell effector cytokine, is known to induce PD-L1, a factor expressed on many cancers that allows cancer cells to evade immune surveillance (e.g., Abstract; page 401). Dorand (July 2016) further teaches that IFN-γ-induced expression of PD-L1 in medulloblastoma and rhabdomyosarcoma tumors is dependent on Cdk5, as disruption of Cdk5 expression in these tumors resulted in decreased PD-L1 upregulation in vitro (e.g., pages 400-401; Figure 2; Figure S4). Dorand (July 2016) further investigated members of the IFN-γ receptor signaling pathway in murine medulloblastoma (MM1) cells after IFN-γ exposure, including IRF2, which is a negative regulator of PD-L1 transcription (e.g., page 401). Dorand (July 2016) observed that expression of IRF2 and its corepressor IRF2BP2 is elevated in Cdk5-deficient MM1 cells after IFN-γ exposure and that IRF2BP2 is among the most highly phosphorylated proteins in Cdk5-deficient cells (e.g., page 401; Figure 3). Dorand (July 2016) further teaches that Cdk5 itself allows medulloblastoma tumors to evade immune surveillance, as disruption of Cdk5 expression in MM1 tumors decreased tumor growth and increased tumor-free survival (e.g., page 399-400; Figures S2-S3; Figure 1). Based on these findings, Dorand (July 2016) concludes, “Loss of Cdk5 results in persistent expression of the PD-L1 transcriptional repressors, the interferon regulatory factors IRF2 and IRF2BP2, which likely leads to reduced PD-L1 expression on tumors”, highlighting a central role for Cdk5 in immune checkpoint regulation by tumor cells (Abstract).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the method taught by Graeber to comprise the steps of detecting the expression levels of IRF2BP2 in cancer cells (e.g., medulloblastoma cells), identifying that said cancer cells are more likely to evade immune surveillance based on said expression levels, and subsequently treating the subject by administering a Cdk5 inhibitor, alone or in combination with a PD-1 and/or PD-L1 antagonist, based on the further teachings of Dorand (July 2016). The skilled artisan would have been motivated to do so because Dorand (July 2016) teaches that IRF2 and IRF2BP2 negatively regulate PD-L1 expression on tumors, meaning that lower expression in the tumor would be expected to result in higher tumoral PD-L1 expression and, by extension, greater evasion of immune surveillance by the tumor. The skilled artisan would also have been motivated to do so because Dorand (July 2016) additionally sets forth that inhibiting Cdk5 in these tumors not only increases expression and phosphorylation of IRF2 and IRF2BP2 (which would decrease PD-L1 expression on the tumor, thereby reducing immune tolerance) but also decreases tumor growth and promotes increased tumor-free survival so there would be a clear advantage to inhibiting Cdk5 in a cancer with reduced phosphorylation of IRF2BP2. There would have been a reasonable expectation of success because it was recognized in the art at the time of filing that IRF2 and IRF2BP2 regulate expression of PD-L1, a factor known to be involved in immune tolerance of tumors, as shown by Dorand (July 2016); that PD-L1 and Cdk5 are each implicated in the evasion of immune surveillance in at least medulloblastoma and rhabdomyosarcoma, as shown by Dorand (July 2016); and that administration of Cdk5 inhibitors and PD-1/PD-L1 antagonists were each known to be suitable for the treatment of cancer, as taught by Graeber and Dorand (July 2016).
(2)
Claims 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Graeber (US 2022/0244263 A1; supra) in view of Dorand (July 2016) (Science (2016) 353(6297): 399-403; supra) as applied to claims 10-15 above, further in view of Dorand (Cancer Immunology Research (2016) 4 (11_Supplement): Abstract A050; cited in PTO-892; hereinafter “Dorand (October 2016)”). This is a new rejection necessitated by claim amendment.
The teachings of Graeber are recited in the 35 U.S.C. § 103 rejection above.
However, Graeber does not expressly teach detecting phosphorylation of at least one of serine 439, 440, and/or 443 on IRF2BP2.
The teachings of Dorand (July 2016) are recited in the 35 U.S.C. § 103 rejection above.
Dorand (October 2016) further describes the investigation of the role of Cdk5 in the ability of medulloblastoma (MB) to avoid immune detection. Dorand (October 2016) silenced expression of Cdk5 in murine MB cells and used a phosphoproteomics approach to measure altered phosphorylation of IRF2BP2. Dorand (October 2016) detected increased phosphorylation of serine 440 and serine 443 on IRF2BP2 in Cdk5-silenced medulloblastoma cells, relevant to claims 10 and 15-16. (Implicitly, it is understood that the observed increase in phosphorylation is compared to MB cells in which Cdk5 is not knocked down.) Dorand (October 2016) further teaches that increased phosphorylation of IRF2BP2 corresponded with a concomitant decrease in surface expression of PD-L1, and that inhibition of PD-L1 can lead to potent anti-tumor responses.
Based on the further teachings of Dorand (October 2016), it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate the step of measuring phosphorylation of Ser440 and/or Ser443 on IRF2BP2 to determine whether a subject’s cancer evades immune surveillance and to subsequently treat the subject using a Cdk5 inhibitor. The skilled artisan would have been motivated to do so because lower phosphorylation of IRF2BP2 is associated with greater tumoral expression of PD-L1, which would be recognized as a useful indicator of whether the tumor cells are more likely to be able to evade immune surveillance based on the teachings of Dorand (July 2016) and Dorand (October 2016). There would have been a reasonable expectation of success because it was recognized in the art at the time of filing that tumoral expression of PD-L1 is known to be involved in immune tolerance of tumors.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:00am - 5:30pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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