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 .
Claims Status
The Amendment filed on 14Apr2026 is acknowledged in which claim(s) 2-3, 6, 8, 12-13, 16, 18, 22-23, 26-27, 29-30, 32, 34-38 were canceled by Applicant.
Claim(s) 1, 4-5, 7, 9-11, 14-15, 17, 19-21, 24-25, 28, 31 and 33 is/are presented for examination on the merits.
Response to Amendment
The objection(s) to the specification have been withdrawn in view of the Amendment filed on 14Apr2026.
All previous rejection(s) of claim(s) 2, 12 are moot in view of claim cancelation.
The previously set forth rejection(s) of claim(s) 7, 9, 17. 19 under 35 U.S.C. § 112(b), and of claim(s) 1, 4-5, 7, 9-11, 14-15, 17, 19-21, 24-25, 28, 31, 33 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 14Apr2026, which added new limitations to the claims, that were not considered in the previous rejections.
As all previously presented rejection(s) and/or objection(s) have been withdrawn, only Applicant arguments pertinent to new rejection(s)/objection(s) are addressed herein.
Rejections Maintained/Modified Rejections Necessitated by Claim Amendments
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1, 4-5, 7, 9-11, 14-15, 17, 19-21, 24-25, 28, 31 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0298340 A1 (hereinafter “US340”), in view of US 2020/0190191 A1 (hereinafter “US191”) as evidenced by Hanahan and Weinberg (Cell 144, March 4, 2011; hereinafter “Hanahan”), and Tran et al. (BLOOD, 21 May 2009, Vol. 113, No. 21; hereinafter “Tran”).
Regarding instant claim(s) 1, 4-5, 7, 9-11, 14-15, 17, 19-21, 24-25, 28, 31, US340 teaches methods for detecting and treating cancer comprising administering a composition comprising a logic-gated CAR T cell that binds two antigens [e.g., title; abstract; ¶ 0003-0006, 0009, 0079-0089, 0164, 0178-0179, 0352]. US340 further teaches the cancer is a solid tumor [e.g., ¶ 0082, 0089] and that the CAR is AND-gated (e.g., bifunctional switch requiring binding by both CARs to induce CAR T cell response) [e.g., ¶ 0164, 0178, 0351]. US340 further teaches AND-gated CAR T cell activation results in target cell death [e.g., ¶ 0126, 0132, 0158, 0159, 0164]. US340 further teaches the methods of the invention effectively treat (e.g., effective amount is administered to treat) diseases (e.g., solid tumor) with minimal side effects [e.g., ¶ 0178, 0199].
Regarding instant claim(s) 33, US340 further teaches detection of target cells comprising contacting tumor cells from a subject with the detectably labeled CAR cells of the invention, wherein binding is indicative of presence of the target cells [e.g., ¶ 0045-051, 0090-107, 0177, 0198, 0219, 0220; fig. 10; example 1].
US340 does not expressly teach (1) an AND-gated CAR T cell bind ICOS and IL-1R1, (2) a method treating cancer and/or depleting Tregs comprising administering an ICOS and IL1R1 directed AND-gated CAR T cell wherein (a) administration of the CAR T cells reduces immunosuppressive conditions, (b) the antigen binding domain(s) of the CAR(s) are conjugated to a toxin, or (c) an anti-cancer antibody is administered as a second therapeutic agent that improve immune response against the tumor; or (3) a method of detecting tumor infiltrating Tregs in the TME comprising contacting a sample comprising tumor cells from the subject with a detectably labeled ICOS and IL1R1 directed AND-gated CAR T cell wherein detecting binding to a cell in sample indicates the presence of tumor infiltrating Tregs.
Regarding claims 1-2, 4, 7, 9-12, 14, 17, 19, 28, 31, 33, US191 teaches a multispecific (e.g., bispecific) antibody that binds ICOS and a second antigen for the treatment of solid tumors [e.g., title; abstract; background]. US191 further teaches ICOS expression is higher in intratumorally Tregs (e.g., tumor-infiltrating Tregs) compared with CD4+ and CD8+ effector cells in the TME, and that depletion (e.g., killing) of Tregs using antibodies directed to ICOS has demonstrated strong anti-tumor efficacy [e.g., ¶ 0010]. Regarding claims 5, 15, US191 teaches antibody binding domain(s) may be conjugated to other molecules (e.g., payloads) such as toxins [e.g., ¶ 0058]. Regarding claim 10, US191 teaches ICOS+ Tregs are immunosuppressive (e.g., depleting these cells would naturally reduce immunosuppression) [e.g., ¶ 0017]. Regarding claims 20-21, 24-25, US191 teaches the administration of a second therapeutic agent wherein the second agent is an anti-tumor associated antigen (TAA) antibody or CAR T cell [e.g., ¶ 0100, 0527-0563].
Tran teaches that IL1R1 (CD121a) is expressed on activated Tregs but not on non-Treg cells [e.g., title, abstract; pg. 5127, col. 2, ¶ 2; fig. 2]. Tran teaches IL1R1 may serve as a biomarker of activated Tregs at sites of inflammation [e.g., pg. 5131, col 2., ¶ 1]. Inflammation is an enabling characteristic of cancer, as evidenced by Hanahan [e.g., fig. 3]. Tran further teaches antibodies that bind IL1R1 [e.g., pg.5126, “Methods”; fig. 2].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the generic antigen binding domains of the AND-gated CAR in the methods for detecting and/or treating solid tumors comprising the administration of AND-gated CAR T cells as taught by US340, with the ICOS directed antigen binding domain as taught by US191 and the IL-1R1 direct antigen binding domain as taught by Tran, to arrive at a method of treating solid tumors and/or depleting Tregs comprising administration of an ICOS and IL1R1 directed AND-gated CAR T cell. A PHOSITA would have been motivated to substitute the generic antigen binding domains of the AND-gated CAR in the methods for detecting and/or treating solid tumors comprising the administration of AND-gated CAR T cells as taught by US340, with the ICOS directed antigen binding domain as taught by US191 and the IL-1R1 direct antigen binding domain as taught by Tran, because US340 teaches the methods, the AND-gated CAR T structure, and that the CAR T can recognize any target antigen(s) selected [e.g., ¶ 0179, 0352], while US191 teaches that ICOS expression is higher in intratumoral Tregs and that depletion of Tregs using therapeutics directed to ICOS results in strong anti-tumor efficacy, and Tran further teaches that IL1R1 is a highly specific Treg marker not expressed on non-Tregs (and therefore a PHOSITA would be motivated to add this second antigen in addition to ICOS to decrease the potential for undesired cell targeting). There would have been a reasonable expectation of success for a PHOSITA to substitute the generic antigen binding domains of the AND-gated CAR in the methods for detecting and/or treating solid tumors comprising the administration of AND-gated CAR T cells as taught by US340, with the ICOS directed antigen binding domain as taught by US191 and the IL-1R1 direct antigen binding domain as taught by Tran because US340 teaches the methods and base CAR T cell, US191 and Tran collectively teach Treg-specific antigens, and US191 teaches the anti-cancer benefit of inhibiting and/or depleting intertumoral Tregs in solid tumors. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to further modify the modified methods of treating solid tumors and/or depleting Tregs comprising administration of an ICOS and IL1R1 directed CAR T cell of US340, US191, and Tran (see above) to include the that (a) the administration of the CAR T cells reduces immunosuppressive conditions, (b) the antigen binding domain(s) of the CAR(s) are conjugated to a toxin, or (c) an anti-cancer antibody is administered as a second therapeutic agent that improve immune response against the tumor as taught by US191, because US340, US191, and Tran teach the methods and administered CAR T cell composition, and US191 further teaches additional modifications to the composition as well as the administration of a second therapeutic agent for the treatment of solid tumors. There is an expectation of success for a PHOPSITA to substitute the modified methods of treating solid tumors and/or depleting Tregs comprising administration of an ICOS and IL1R1 directed CAR T cell as taught by US340, US191, and Tran to include the additional method and composition modifications as taught by US191, because US340, US191, and Tran teach the base methods and administered CAR T cell composition, and US191 further teaches additional modifications to the composition as well as the administration of a second therapeutic agent for the treatment of solid tumors. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified methods of detecting tumor infiltrating Tregs comprising administration of an ICOS and IL1R1 directed CAR T cell of US340, US191, and Tran (see above) to include a method of detecting tumor infiltrating Tregs in the TME comprising contacting a sample comprising tumor cells from the subject with a detectably labeled ICOS and IL1R1 AND-gated CAR T cell and detecting binding to a cell in sample to indicate the presence of target cells (e.g., Tregs) as taught by US340, because US340 teaches the base method, US340, US191, and Tran teach the modified ICOS and IL1R1 directed AND-gated CAR T cell composition, and US340 further teaches details of the method(s) for detection of target cells comprising administration of the CAR T cells. There is an expectation of success for a PHOPSITA to substitute the modified methods of detecting tumor infiltrating Tregs comprising administration of an ICOS and IL1R1 directed CAR T cell of US340, US191, and Tran with the additional method details for the detection of target cells as taught by WO340, because US340 teaches the base method, US340, US191, and Tran teach the modified ICOS and IL1R1 directed AND-gated CAR T cell composition, and US340 further teaches detailed method(s) for detection of target cells comprising administration of the CAR T cells. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
US340 does not provide guidance on which cell-surface antigens should be targeted in a CAR-T system. Stating US340 teaches the CAR T can recognize any target antigens desired is overstated because it doesn’t teach target antigens may be arbitrarily selected. In practice, selection of CAR targets is highly constrained by factors including antigen density, signaling compatibility and pattern of expression. a surface marker that identifies a cell population is not necessarily suitable as a target antigen in a CAR-T because it may be present at levels insufficient to trigger CAR signaling. US340 odes not teach nor suggest how to select Treg markers, and based on US3640 alone it would not have been obvious to substitute the antigen binding domains of the CAR, nor would there be motivation to do so due to lack of guidance on selecting a substituted target antigen.
In response, a skilled artisan would understand the constraints of target antigen(s) selection for CAR T cell construct design and select targets accordingly. Further, the selection of the ICOS and IL1R1 targets for the AND-gated CAR T cell were based on the teachings of US191 and Tran, respectively (see rejection above for details), not US340.
US191 does not disclose or suggest the use of IL1R1 as a target antigen, especially not as a potential partner antigen with ICOS. US191 identifies ICOS individually as a target for depeleting Tregs and discloses generally the use of ICOS with another target in a dual-binding antibody in particular focusing on PD1, PDL1, and other immune checkpoint inhibitors. However, like the US640, US191 does not provide guidance for selecting a second antigen to pair with ICOS. Based merely on the example antigens disclosed in the US191 application, it is unlikely that a skilled artisan would be able to identify a different antigen like IL1R1, which is not mentioned in US191 or US340. Thus, based on US191 alone or in combination with US340, it would not have been obvious to determine whether IL1R1 is compatible with ICOS as a second target antigen in a dual-antigen CAR-T cell.
In response, US191 and US340 were not relied upon to teach IL1R1 as the second antigen target. Rather, US340 was applied to teach the AND-gated CAR T cell, US191 taught ICOS as a Treg depleting target antigen, and Tran was relied upon to teach IL1R1 as the second antigen target (see rejection above for details).
Tran does dot disclose or suggest using IL1R1 as a therapeutic antigen target but rather reports IL1R1 as a marker associated with activated Tregs that can be used for purification or isolation of Tregs from cell populations. Tran identifies IL1R1 as a cell surface marker that distinguishes activated Tregs from non-Tregs and describes using it for cell sorting. As explained above, markers used for cell identification or purification may not be suitable as therapeutic antigen targets. While Tran identifies IL1R1 as a marker of activated Tregs, it does not disclose or suggest IL1R1 is an effective antigen target for use in a CAR-T cell. therefore, absent additional and extended experimentation, a person of ordinary skill would not have reasonable expectation of success in using IL1R1 in a CAR target based either on Tran individually or in combination with US340 and/or US191 which do not mention IL1R1.
In response, a skilled artisan would understand that the Treg specific expression of IL1R1 as taught by Tran could be employed with the AND-gated CAR-T of US340 and the ICOS target antigen for depleting Tregs as taught by US191 to decrease on-target, off-Treg killing (see the rejections above for details). Further, the killing of Tregs is based on the demonstrated killing of Tregs via ICOS targeting, as taught by US191, whereas the IL1R1 as taught by Tran was applied in the rejections above as a mechanism of refining/selectively activating killing by the AND-gated CAR-T cells on Tregs only (e.g., because Tran teaches non-Tregs don’t express IL1R1).
None of the cited references disclose or suggest combining ICOS and IL1R1 as dual target antigens for use in a CAR-T cell, nor do they provide a basis to suggest that such a combination would be effective in targeting Tregs. Proteins that may be suitable targets individually do not necessarily function effectively together because dual-target systems require compatible expression patterns and signaling properties. As such, cited references do not provide motivation or a reasonable expectation of success for selectively depleting Tregs.
In response, while no one reference teaches the instant invention, the invention is considered obvious over US340 in view of US191 and Tran. Briefly, US340 was applied to teach the AND-gated CAR-T cell, US191 was applied to teach ICOS as a target for Treg depletion, and Tran was applied to teach Treg selectivity in the AND-gated system of US340 (see rejections above for details).
The present application explicitly discloses the process of determining the presence of both ICOS and IL1R1 as unique cell surface protein markers of TIL Tregs that are not co-expressed by other immune population in the blood of tumor. Applicant disclosure provides evidence of extensive experimental analyses that ICOS and IL1R1 constitute a distinct and targetable subset of immune cells within the TME. In summary, the present application experimentally recognizes that ICOS and IL1R1 can function together as complementary targets in a logic-gated CAR-T cell requiring simultaneous binding of both antigens for activation.
In response, the Applicant disclosed experimentation does not negate the prior art teachings of US340, US1941, and Tran as recited above (please see responses and rejections above for details). Further, per MPEP2121 “PRIOR ART IS PRESUMED TO BE OPERABLE/ENABLING When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). See also MPEP § 716.07. See also In re Antor Media Corp., 689 F.3d 1282, 103 USPQ2d 1555 (Fed. Cir. 2012). Specifically, in In re Antor Media Corp., the court stated: "Consistent with the statutory framework and our precedent, we therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling. As long as an examiner makes a proper prima facie case of anticipation by giving adequate notice under § 132, the burden shifts to the applicant to submit rebuttal evidence of nonenablement. In re Antor Media Corp., 689 F.3d at 1289, 103 USPQ2d at 1559.”
Applicant arguments have been thoroughly reviewed but are not persuasive. The rejection(s) of claim(s) 1, 4-5, 7, 9-11, 14-15, 17, 19-21, 24-25, 28, 31 and 33 are maintained.
Conclusion
No claims are currently 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 AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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