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 .
Priority Claim
The instant application, filed on 24 August, 2023 claims domestic benefit to US provisional application no. 63/373,629 filed on 26 August 2022.
Status of Application, Amendments, and/or Claims
The response filed on 11 May, 2026 has been entered in full. The response is an amendment to a Non-Final Rejection to the claim set filed on 30 November, 2023. In the amendment claims 1-20 are cancelled, and claims 21 and 26 - 29 are amended. Therefore, claims 21-30 are pending and are the subject of this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 13 December, 2023 has been considered by the examiner.
Status of Objections and Rejections
In the office action of 02/11/2026
The specification was objected to for not being descriptive, the amendment to the name over comes this objection.
Claims 21-26, and 30 were rejected under 35 U.S.C. 103 over Wang et al. in view of Aftab et al. and Morgan et al. The amendment of claims 21 and 26 necessitates a new 103 rejection over Wang et al. in view of Xu et al. and Morgan et al.
Claims 27- 29 were rejected under 35 U.S.C. 103 over Wang et al. in view of Aftab et al. and Morgan et al., and further in view of Robinson and Schluns, and Miyazaki et al. The amendment of claims 21 and 27-29 necessitates a modified 103 rejection over Wang et al. in view of Xu et al. and Morgan et al., and further in view of Robinson and Schluns, and Miyazaki et al.
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.
Claims 21 - 26, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (2018) CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia Journal of Hematology & Oncology (11) 7 (hereafter Wang) in view of Xu et al. (2016) Multiparameter comparative analysis reveals differential impacts of various cytokines on CART cell phenotype and function ex vivo and in vivo Oncotarget (7) 50 82354-82368 (hereafter Xu) and Morgan et al. (2020) Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR-T and CAR-NK Cells Front. Immunol. (11) 1965 (hereafter Morgan).
In regards to claim 21 and 30 Wang teaches a CLL-1 targeting CAR-T cell which showed strong anti-leukemic activity in vivo (abstract).
In regards to claim 24 Wang teaches the use of healthy donor cells (pg.10 col 2, lines 29-30).
Wang fails to teach the in vivo expansion of the CLL-1 targeting CAR-T between 6 and 13 days post-administration by contact with an exogenous IL-15 agent of claim 21, the knockout of the expression of the genes TRAC and β-2microglobulin (β2m) with CRISPR/Cas9 of claims 22 and 23, the use of allogeneic immune cells of claim 25, and the administration of IL-15 sequentially after CAR administration of claim 26.
Xu, however, in regards to claims 21 and 26 teaches the administration of exogenous IL-15 in conjunction with C4-27z CAR-T cells (pg.82362, col 1, lines 3-8/ Figure 7A). The IL-15 was delivered interperitoneally subsequent to suboptimal administration of the CAR T cells on the same day (pg.82362, col 1, lines 3-8/ Figure 7A). Further Xu teaches continued administration of IL-15 over the course of a week (7 days) to facilitate anti-tumor response and expansion (pg.82362, col 1, lines 3-13/ Figure 7A/ Figure 7G). Xu demonstrates this delivery of the exogenous IL-15 was one of the more effective cytokines in cytokine expansion, and further lowered tumor size overtime (Figure 7G/ Figure 7B). Further Xu teaches that IL-15 has been reported to promote the induction and expansion of human memory stem cell line T cell subsets that were able to engraft, expand and mediate enhanced activity in a xenogeneic transplant model of graft vs host disease (pg.82355, col 1, lines 17-22).
Xu fails to teach the knockout of expression of the genes TRAC and β2m with CRISPR/Cas9 of claims 22 and 23 and the use of allogeneic immune cells of claim 25. Morgan, however, teaches the knockout of TRAC and β2m with CRISPR/Cas9 in combination with lentiviral delivery of an anti-CD19 CAR into allogeneic T cells resulted in a universal CAR T cells (pg.7 col 2 lines 45-48). Further Morgan teaches allogeneic cells are a beneficial source for CAR T cells because they reduce the time to treatment for patient with infectious or rapidly progressing cancer compared to autologous cells, lower the risk of genetically modifying and re-infusing cancer cells, and allow for “off-the-shelf” cell sources for greater flexibility in treatment and lower cost (pg.4, col 1, lines 7-21 ).
Thus, Wang discloses a CAR-T cell which targets CLL-1 derived from healthy donors, Xu teaches the administration of exogenous IL-15 subsequent to CAR T cell therapy causes in vivo cell expansion and further improves the CAR T cells anti-tumor efficacy, and Morgan teaches the use of allogeneic cell sources and the knockout of TRAC and β2m with CRISPR/Cas9 allows for the development of universal CAR-T cells. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Wang, Xu, and Morgan with a reasonable expectation of success to develop a method for expanding CAR-T cells in vivo with exogenous IL-15 to improve their clinical efficacy, and wherein the CAR-T cells are allogenic and/or from a healthy donor, target CLL-1, and have knocked out TRAC and β2m expression to create a universal CAR-T cell for better flexibility in clinical procedures.
Claims 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Wang in view of Xu and Morgan as applied to claim 21 above, and further in view of Robinson and Schluns (2017) The potential and promise of IL-15 in immune-oncogenic therapies Immunology Letters (190) 159-168 (hereafter Robinson and Schluns) and Miyazaki et al. (2021) NKTR-255, a novel polymer conjugated rhIL-15 with potent antitumor efficacy Journal for ImmunoTherapy for Cancer (9) e002024 (hereafter Miyazaki).
Wang in view of Xu and Morgan fails to teach the IL-15 as an agonist and further fails to teach the IL-15 agent being selected from a group consisting of a pegylated IL-15, an IL-15 fusion protein, and an IL-15 heterodimeric complex.
Robinson and Schluns, however, in regards to claims 27 and 28 teach the delivery of IL-15 by an IL-15 agonist including a fusion protein (pg.163 col 2, lines 51-52), and a heterodimeric complex (pg.163 col 2, lines 8-12) to increase IL-15 availability (pg.163 col 2, lines 4-6).
Robinson and Schluns fail to teach a pegylated IL-15 agent of claim 28 and 29, however Miyazaki teaches a pegylated IL-15 agent which retains receptor affinity, signaling, and leukocyte degranulation and had a longer half-life and reduced clearance (abstract).
Thus, Wang in view of Aftab and Morgan discloses a method to expand CAR cells targeting CLL-1 in vivo by administering IL-15, Robinson and Schluns teach the common IL-15 agonist administration methods of fusion proteins or heterodimeric complexes to increase IL-15 availability, and Miyazaki teaches the delivery of a pegylated IL-15 for enhanced half-life and decreased clearance. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Wang in view of Aftab and Morgan, with the teachings of Robinson and Schluns, and Miyazaki with a reasonable expectation of success to develop a method to expand CAR immune cells in vivo with IL-15 using known delivery methods, for increased availability, and/or increased half-life and decreased clearance.
Response to Arguments
Applicant's arguments filed 05/11/2026 have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (Remark 05/11/2026, pg.6, line 20-22), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant’s argument that the rejection relies on the applicant specification and “the office stiches together the teaching of several other references which are no more related to Wang than simply being other references in the field of cell therapy” (Remarks 05/11/2026, pg.6, lines 24-27), the examiner recognizes that although the claims are interpreted in light of the specification, limitation from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). No embodiments, or suggested limitations discussed in the specification are relied upon for the rejection of the claims. Motivations for combining references are not limitations, rather rationales which would have rendered the combination of references obvious to try and thus whether stated in the specification or not (See MPEP 716.06(f)), advantages are not imparting limitations on the claims and the specification can evidence the prior art (See MPEP 2143(1)E, Example 2).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references (Remarks 05/11/2026, pg. 6, lines 27-29), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Wang teaches a CAR-T cell which binds specifically to CLL-1, while Morgan teaches the knockout of TRAC and β2m with CRISPR/Cas9 to generate universal CAR-T cells. The motivation to combine these reference is a stated to be the knockout of TRAC and β2m for the development of a universal CAR-T cell which could bind to CLL-1. As highlighted within Morgan, and further known by a person of ordinary skill in the art at the time of the effective filing date universal CAR-T cells are an obvious method to try as to improve clinical flexibility.
In regards to the motivation to combine Aftab those arguments were directed to the previously stated non-final rejections, and they are moot because the present final rejection no longer relies on Wang in view of Aftab, but instead the current obviousness analysis instead relies on Wang in view of Xu.
Conclusion
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 DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday - Thursday from 8am to 6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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