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
Claims 27-46 are presented for examination.
Acknowledgement is made of Applicant’s Track 1 Request for Prioritized Examination filed April 21, 2025, which was granted on May 20, 2025.
Applicant’s Amendment filed December 30, 2025 has been received and entered into the present application.
Claims 27-46 remain pending. Claims 27-42 are amended. Claim 46 is newly added.
Applicant’s arguments, filed December 30, 2025, have been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Error in Claim Listing of December 30, 2025
Applicant’s claim listing filed December 30, 2025 is improper for failing to comply with the stipulations of 37 C.F.R. §1.121(c) regarding the proper presentation of claims. 37 C.F.R. §1.121(c) states, “Each amendment document that includes a change to an existing claim, cancellation of an existing claim, or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously Presented), (New), and (Not entered).”
Applicant’s claim listing filed December 30, 2025 does not comply with the requirements of 37 C.F.R. §1.121(c) because it fails to present a complete listing of all claims ever presented with the proper status identifier. Here, Applicant presents claim 36 with the status identifier of “(Currently amended)”, which is incorrect as claim 36 is also withdrawn (and, thus, must be designated as “(Withdrawn – Currently Amended)”). For this reason, the claim listing is technically non-compliant for failing to comply with the provisions of 37 C.F.R. §1.121(c). In the interest of compact prosecution, however, the claim listing will be entered and treated on the merits solely because it does not affect the subject matter of the claims presently under examination.
Applicant is notified that any future submissions that do not explicitly comply with the requirements of 37 C.F.R. §1.121(c) may not be entered into the record at the discretion of the Examiner (and, if not entered, notice to this effect will be mailed to Applicant). Repeated submissions of non-compliant claim listings may delay substantive prosecution on the merits and may be considered non-bona fide attempts at reply.
Applicant is urged to review the requirements of 37 C.F.R. §1.121(c) prior to filing any claim listings in any future submission to ensure full compliance with this rule.
Requirement for Restriction/Election
Applicant is reminded of his election of the invention of Group II (original claims 1-18, 22-23), directed to a method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a hypoxia-activated prodrug (HAP) in combination with a therapeutically effective amount of an immunomodulator selected from inhibitors of PD-1, PD-L1, PD-L2 and agonists of 4-1BB, and the election of (i) pembrolizumab as the single disclosed species of immunomodulator, which Applicant specifically identifies as a PD-1 inhibitor antibody, and (ii) prostate cancer as the single disclosed species of cancer, to which examination on the merits has been confined, as stated in the reply filed May 10, 2022, which is still in effect over the claims.
As previously set forth in the previous Office Action dated July 1, 2025, instant claims 29-31, 34-36 and 39 are not directed to this originally elected subject matter and, thus, remain properly withdrawn from consideration pursuant to 37 C.F.R. §1.142(b) as being directed to non-elected subject matter.
Claims 27-28, 32-33, 37-38 and 40-45 remain, and newly added claim 46 is, drawn to the originally elected invention and species and are herein acted on the merits infra.
Information Disclosure Statement
Applicant’s Information Disclosure Statement filed December 30, 2025 has been received and entered into the present application. As reflected by the attached, completed copy of form PTO/SB/08a (three pages total), the Examiner has considered the cited references.
Status of Objections/Rejections in the July 1, 2025 Non-Final Action
In reply to the objection to claims 37 and 42 as set forth at p.4 of the previous Office Action dated July 1, 2025, Applicant amends claims 37 and 42 to now recite “anti-CTLA-4 antibody” consistent with claim 27 from which each claim depends. Accordingly, the objection is now hereby withdrawn.
In reply to the rejection of claims 27-28, 32-33, 37-38 and 40-45 under 35 U.S.C. §112(b) (pre-AIA second paragraph), as set forth at p.4-6 of the previous Office Action dated July 1, 2025, Applicant (i) amends claim 27 to clearly correlate the treatment of “a checkpoint insensitive tumor” to the subject that has “the checkpoint inhibitor insensitive tumor”, (ii) amends claim 27 to clarify that the subject is administered TH-302 in combination with an anti-CTLA-4 antibody and an anti-PD-1 antibody, and (iii) amends claims 27 and 37-38 to remove the limitations directed to “antigen binding fragments thereof”. Accordingly, these rejections are each now hereby withdrawn.
In reply to the rejection of claims 27-28, 32-33, 37-38 and 40-45 under 35 U.S.C. §103 as being unpatentable over Curd et al. (WO 2010/048330 A1; 2010, cited on the 08/09/22 PTO-892) in view of Patnaik et al. (“Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors”, Clin Cancer Res, 215; 21(19):4286-93, cited on the 08/09/22 PTO-892) and Gerritsen (“The Evolving Role of Immunotherapy in Prostate Cancer”, Annals of Oncology, 2012; 23(Supplement 8):viii22-viii27), as set forth at p.6-11 of the previous Office Action dated July 1, 2025, Applicant now amends claim 27 to specify that the tumor to be treated in the subject is “checkpoint insensitive” and further provides evidence of secondary considerations to support alleged nonobviousness in the December 30, 2025 submission. Accordingly, the rejection is now hereby withdrawn.
Upon further reconsideration of the claimed subject matter as amended in the December 30, 2025 claim listing, in addition to Applicant’s Information Disclosure Statement filed December 30, 2025, new grounds for rejection are necessitated and set forth infra.
Claim Rejections - 35 USC § 112(b) (Pre-AIA Second Paragraph)
(New Grounds of Rejection)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(1) Claims 27-28, 32-33, 37-38 and 40-46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicant’s claim 37 recites “[a] method of treating a checkpoint insensitive tumor” via “administering to a subject having the checkpoint insensitive tumor a therapeutically effective amount of TH-302 in combination with a therapeutically effective amount of an anti-CTLA-4 antibody and a therapeutically effective amount of an anti-PD-1 antibody”.
The limitation directed to “a checkpoint insensitive tumor” renders the claim indefinite because the degree of unresponsiveness of the tumor that underlies “checkpoint insensitivity” as claimed is not clearly set forth. The term “checkpoint insensitive tumor” is not defined either in the claim or the accompanying specification by providing a requisite standard to objectively identify what constitutes a “checkpoint sensitive” or “checkpoint insensitive” tumor, such that the ordinarily skilled artisan would have been reasonably apprised of the objective boundaries of the claimed subject matter by clearly distinguishing tumors that are subject to treatment via the claimed method from those that are not.
MPEP §2173.05(b)(IV) clearly states that “[c]laim scope cannot depend solely on the unrestrained subjective opinion of a particular individual purported to be practicing the invention (citing to Datamize LLC v. Plumtree Software, Inc., 417 F.3d 1342, 1350, 75 USPQ2d 1801, 1807 (Fed. Cir. 2005)).
Clarification is required.
It is additionally unclear if the “checkpoint insensitive tumor” is specifically insensitive to the forms of checkpoint inhibitors to be administered as part of the active step (i.e., anti-CTLA-4 antibody and/or anti-PD-1 antibody), or any checkpoint inhibitor.
Clarification is required.
As claims 28, 32-33, 37-38 and 40-46 do not clarify these points of ambiguity in claim 27, they must also be rejected on the same grounds.
For these reasons, the claims fail to meet the tenor and express requirements of 35 U.S.C. §112(b) (pre-AIA second paragraph) and are, thus, properly rejected.
Claim Rejections - 35 USC § 102 (New Grounds of Rejection)
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.
(2) Claims 27 and 43-45 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ai et al. (“Combination Hypoxia-Specific Chemotherapy and Immunotherapy”, Department of Immunology, The University of Texas MD Anderson Cancer Center, Poster, AACR Annual Meeting, April 5-9, 2014; cited by Applicant on the 12/30/25 IDS),
citing to Reagan-Shaw et al. (“Dose Translation from Animal to Human Studies Revisited”, FASEB J, 2007; 22:659-661) as factual evidence.
Ai et al. teaches an experimental study of the hypoxia-specific chemotherapy drug TH-302 used in conjunction with CTLA-4 and PD-1 antibody blockade (Poster, col.1, para.1). Ai et al. teaches the use of a Tramp-C2 prostate cancer mouse model for the experimental study, in which the mice were administered two cycles of TH-302 therapy (50 mg/kg, ip every day for 5 days) with a week of rest, with co-administration of CTLA-4 blocking antibody 9H10 and PD-1 blocking antibody RMP1-14 (ip at days 1, 4, 7 and days 13, 16 19) (Poster, col.3, Fig.4). Ai et al. teaches that antibody blockade of CTLA-4 and PD-1 in conjunction with TH-302 potentiated the antitumor effects of CTLA-4 and PD-1 in the Tramp-C2 prostate cancer murine model as evidenced by increased survival and decreased tumor size with the combination therapy as compared to untreated controls or those treated with the individual therapies (Poster, col.1, para.1; col.3, Fig.5). Ai et al. teaches that TH-302 functions to reduce tumor hypoxia, which are areas of the tumor resistant to immunotherapy, and yields enhanced tumor-specific T-cell expansion and anti-tumor T-cell response (Poster, col.1, para.1; col.4, “Conclusions”).
Claim 27 recites “[a] method of treating a checkpoint inhibitor insensitive tumor” via “administering to a subject having the checkpoint inhibitor insensitive tumor a therapeutically effective amount of TH-302” with an anti-CTLA-4 antibody and an anti-PD-1 antibody.
Ai et al. teaches the administration of TH-302 with anti-CTLA-4 antibody and anti-PD-1 antibody in a mouse with hypoxic Tramp-C2 prostate cancer. As explained by Ai et al., the hypoxic tumor regions of the tested mouse models are resistant to treatment with immunotherapies that allow for T-cell expansion (i.e., a form of T-cell checkpoint blockade), which establishes that the form of tumor treated in Ai et al. constitutes a “checkpoint inhibitor insensitive tumor” as instantly claimed.
Claim 43 recites that “TH-302 is administered in an amount of from about 320 mg/m2 to about 480 mg/m2”.
Claim 44 recites that “TH-302 is administered in an amount of from about 400 mg/m2 to about 480 mg/m2”.
Claim 45 recites that “TH-302 is administered in an amount of less than about 320 mg/m2”.
Ai et al. teaches that TH-302 was administered to the Tramp-C2 prostate cancer mouse in an amount of 50 mg/kg.
Reagan-Shaw et al. is cited as factual extrinsic evidence that a mg/kg dose is converted to a mg/m2 dose by multiplying the mg/kg dose by the species Km factor, which is 3 for a mouse (Table 2, p.660).
The 50 mg/kg dose of TH-302 administered in Ai et al. is equivalent to a 150 mg/m2 (50 mg/kg * 3 mouse Km factor = 150 mg/m2) dose, which directly meets the requirements of Applicant’s claim 45, as well as Applicant’s claims 43-44 absent any explicit definition of the amount of variation tolerated by the term “about” as used in such claims.
MPEP §2131.01 states that “[n]ormally, only one reference should be used in making a rejection under 35 U.S.C. 102”, but that it is proper to apply a second reference when the extra reference is cited for the purpose of “show[ing] that a characteristic not disclosed in the reference is inherent”.
Thus, instant claims 27 and 43-45 are properly anticipated under AIA 35 U.S.C. §102(a)(1).
Response to Applicant’s Arguments
In reply, Applicant traverses the previously applied rejections in view of the submitted amendments and arguments (Remarks, p.5-18).
Applicant’s traversal has been fully and carefully considered, and the previously applied objections and/or rejections have been withdrawn as indicated above.
However, upon further reconsideration of the claims as amended, as well as Applicant’s Information Disclosure Statement filed December 30, 2025, new grounds for rejection are necessitated and are set forth infra.
For these reasons supra, rejection of claims 27-28, 32-33, 37-38 and 40-46 is proper.
Conclusion
Rejection of claims 27-28, 32-33, 37-38 and 40-46 is proper.
Claims 29-31, 34-36 and 39 are withdrawn from consideration pursuant to 37 C.F.R. 1.142(b).
No claims of the present application are allowed.
Applicant is requested to specifically point out the support for any amendments made to the disclosure in response to this Office action, including the claims (M.P.E.P. §§ 714.02 and 2163.06). In doing so, applicant is requested to refer to pages and line (or paragraph) numbers (if available) in the as-filed specification, not the published application. Due to the procedure outlined in M.P.E.P. § 2163.06 for interpreting claims, other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Applicant is reminded that MPEP §2001.06(b) clearly states that “[t]he individuals covered by 37 C.F.R. 1.56 have a duty to bring to the attention of the examiner, or other Office official involved with the examination of a particular application, information within their knowledge as to other copending United States applications which are "material to patentability" of the application in question." See Armour & Co. v. Swift & Co., 466 F.2d 767, 779, 175 USPQ 70, 79 (7th Cir. 1972). MPEP §2001.06(b) clearly indicates that “if a particular inventor has different applications pending in which similar subject matter but patentably indistinct claims are present that fact must be disclosed to the examiner of each of the involved applications.” See Dayco Prod. Inc. v. Total Containment, Inc., 329 F.3d 1358, 1365-69, 66 USPQ2d 1801, 1806-08 (Fed. Cir. 2003).
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on December 30, 2025 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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 Leslie A. Royds Draper whose telephone number is (571)272-6096. The examiner can normally be reached Tuesday to Thursday (08:30 AM to 05:00 PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren can be reached at (571)-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Leslie A. Royds Draper/Primary Examiner, Art Unit 1629
May 5, 2026
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