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 .
Status of Application, Amendments and/or Claims
1. Claim 1 has been amended as requested in the amendment filed February 18, 2026. Following the amendment, claims 1-2, 5, 7-8, 10-13 and 38 are pending and under examination in the present application.
Information Disclosure Statement
2. The information disclosure statement (IDS) filed 02/18/2026 has been considered and the references therein are of record.
Withdrawn Claim Rejections
3. The terminal disclaimer filed on February 18, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,344,578 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Accordingly, the nonstatutory double patenting rejection over the claims of this patent has been overcome.
4. The rejection of claims 1-2, 5, 7-8, 12-13 and 38 under 35 U.S.C. 103 as being unpatentable over Liu et al. (2015) in view of Delconte et al. (2016) as evidenced by Nandagopal (2014), as discussed at section 5 of the 12/03/2025 office action, is withdrawn in view of applicant’s amendments to the claims to delete the limitation of the claimed engineered cells having essentially no CISH expression.
5. The rejection of claims 10-11 under 35 U.S.C. 103 as being unpatentable over Liu et al. (2015) in view of Delconte et al. (2016) as evidenced by Nandagopal (2014), and further in view of Moriarty et al. (US 2017/0067021) as discussed at section 6 of the 12/03/2025 office action, is withdrawn in view of applicant’s amendments to the claims to delete the limitation of having essentially no CISH expression.
New Claim Rejections, Necessitated by 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.
6. Claim(s) 1-2, 5, 7-8, 10-13 and 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Blood, 2015, 126(23):3091; Abstract 703; listed on 07/25/2023 IDS) in view of Busser et al. (WO 2018/073391 A1; pub 26 Apr 2018, filed 19 Oct 2017 with priority to earlier filing date), and as evidenced by Nandagopal et al. (Front. Immunol. 2014, 5, Article 187, pp. 1-12; listed on 10/26/2020 IDS).
Liu et al. teach cord blood derived natural killer (NK) cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD19 and expressing IL-15. Such teachings are on point to the NK cell of claims 1-2, 5 (derived from cord blood), and 8 (the CAR has antigenic specificity for CD19). Lui teaches that umbilical cord blood (CB) derived NK cells were used because of their availability as “off-the-shelf” frozen products and their potent preclinical activity against leukemia cells, which addresses claim 7 (the cord blood has previously been frozen). According to Liu, incorporation of the IL-15 gene enhanced NK cell proliferation and survival. Given that human CB-derived NK cells were used, one of skill in the art would implicitly understand that the IL-15 expressed by these cells would be human IL-15 (hIL-15), as in claim 1. And with respect to claim 12, Nandagopal evidences that IL-15 stimulation of NK cells induces mTOR signaling.
Regarding claim 38, Liu discloses that the CAR.CD19.IL-15-transduced CB NK cells were infused into a mouse model of lymphoma, which provides for a pharmaceutical composition comprising a population of the NK cells.
However, Liu does not teach that the NK cells were engineered to have essentially no expression of glucocorticoid receptor (GR) and/or TGF-beta receptor 2 (TGFbRII) as in amended claim 1.
Busser et al. disclose methods for engineering immune cells to improve the therapeutic potential of the cells (p. 13 line 9), and the engineered immune cells produced thereby, such as immune cells engineered to express a chimeric antigen receptor (CAR+ cells) (p. 6 lines 35-36). Busser teaches that an immune cell can be an NK cell (p.13 lines 31-32). Busser indicates that the immune cells can be differentiated from stem cells, such as cord blood stem cells, bone marrow stem cells, or induced pluripotent stem cells (iPSCs) (p. 14 lines 21-24), which is on point to claim 5 and is consistent with the teachings of Liu (i.e., NK cells derived from cord blood).
Also consistent with Liu, Busser discloses that the therapeutic potential of immune cells can be enhanced by, for instance, having the cells express IL-12 or IL-15 (p. 27 lines 3-5) in CAR positive immune cells, such as NK cells for treating tumors (p. 28 lines 1-3; p. 37 lines 26-28). Busser further teaches that in addition to insertion of immune enhancing genes or sequences, such as the addition of CAR and cytokines such as IL-12 and IL-15, immune cell therapeutic potential may be enhanced by inactivating endogenous genomic sequences (p. 44 lines 8-9), such as by the inactivation of checkpoint receptors and inhibitory pathways (p. 44 lines 36). For example, Busser teaches that the immune cell can be engineered with an exogenous coding sequence(s) to have the effect of reducing or preventing the expression of TGFBRII (Uniprot: P37173; i.e., TGF-beta receptor 2) (p. 46 lines 1-2 and 11; Table 3 at p. 47) to inhibit suppressive cytokine signaling by TGF-beta. Busser explicitly suggests that “preference is given to engineered immune cells in which a sequence encoding IL-2, IL-12 or IL-15 replaces the sequence of at least one of the above endogenous genes”, which genes include TGFbRII (p. 47 lines 8 and 11-12).
Further, Busser teaches that the immune cells may be engineered by inserting exogenous coding sequences that reduce or prevent the expression of glucocorticoid receptors, so as to make the engineered immune cells resistant to glucocorticoids (p. 48 lines 5-10). See also claims 8, 10, 13, 38-39, 49, 52, 56, 61 and 67-68 at pp. 122-127, which collectively provide for immune cells, such as NK cells (claim 61), that are engineered (claim 56) to express a CAR (claim 38), such as CAR directed against a CD22 antigen (claim 39), IL-12 or IL-15 (claims 8 and 10), and have essentially no expression of TGFbRII (claim 49) or glucocorticoid receptors (claim 52), and pharmaceutical compositions comprising a population of said engineered immune cells (claims 67-68).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of filing to have engineered the NK cells of Liu to also have a deletion of TGFbRII or glucocorticoid receptors (GRs) as taught by Busser, as well as to express a second cytokine such as IL-12 as taught by Busser, and thereby arrive at the presently claimed invention. The motivation to do so comes from Busser, who indicates that inactivation of the genes encoding for TGFbRII or GR, or insertion of a immune stimulating cytokine such as IL-21, can enhance the therapeutic potential of engineered immune cells and thus their anti-tumor activity. Given the demonstrated success of both Liu to engineer NK cells and the state of the art in general to introduce or delete expression of selected genes within a cell, as taught by Busser, the artisan would have had a reasonable expectation that the CAR.CD19.IL-15-transduced CB NK cells of Liu could be successfully engineered to have essentially no expression of TGFbRII or GRs as claimed, as well as to also express IL-12 as claimed.
Finally, with respect to claim 13, the engineered NK cells according to the combined prior art teachings would be expected to necessarily have increased JAK/STAT signaling absent evidence to the contrary. Given that the claims are directed to a product, and not a method, there is nothing in claim 13 that would require the detection of such signaling. And because all of the elements of claim 1 have been rendered obvious by the combination of prior art references, then these engineered cells would have increased JAK/STAT signaling as claimed.
Conclusion
7. No claims are allowed.
8. 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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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