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 .
Applicant’s response filed on 12/15/2025 is acknowledged and has been entered into the application file.
Election/Restrictions
Applicants have previously elected without traverse Group I, drawn to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a population of double negative T (DNT) cells that have been genetically modified to bind to one or more target antigens, in the reply filed on 07/25/2025.
Claims 1, 4, 10, 13-14, 16, 20, 23, 32, 35, 38, 42, 44, 49, 51-52, 54-55, and 57 are pending in the instant application. Claim 36 is cancelled. Claims 49, 51-52, 54-55, and 57 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/25/2025. Therefore, claims 1, 4, 10, 13-14, 16, 20, 23, 32, 35, 38, 42, and 44 are under examination in the instant application.
Status of Prior Objections/Rejections/Response to Arguments
RE: Objection to claim 20 for minor informalities:
Applicants have amended claim 20 to add “(a)” as suggested. The objection is therefore withdrawn.
RE: Rejection of claims 20, 32, 35-36, 38, 42, and 44 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ),
second paragraph:
Applicants have amended claim 20 to remove the exemplary language “such as”.
Applicants have also amended claim 32 to recite “a method of treating cancer expressing CD4” to clarify the previously claimed recitation “CD4+ cancer”.
Applicants’ amendments filed 12/15/2025 are effective to overcome the indefiniteness rejection. The rejection is therefore withdrawn.
RE: Rejection of claims 1, 4, 10, 13-14, 16, 20, 23, 32, 35-36, 38, 42, and 44 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Zakrzewski et al.:
Applicants have traversed the rejection asserting that claim 1 has been amended to clarify that the DNT cells are genetically modified to express a nucleic acid sequence encoding a CAR that binds to a target antigen, wherein the DNT cell is CD4-, CD8-, CD3+ γδ-TCR and/or CD4-, CD8-, CD3+, αβ-TCR+. Applicants specifically argue that Zakrewski et al. uses immature T cell precursors which are different from the fully matured DNT cells used in the presently claimed invention. T cell precursors are not functional T cells. They lack functional T cell receptor (TCR) meaning that they areCD3+ CD4- CD8-, but are negative for mature αβ-TCR and γδ-TCR. In contrast, the claimed cells are DNT cells that express functional αβ-TCR.
Applicants have specifically amended claim 1 to recite that the population is ex vivo expanded double negative T (DNT) cells, which was not claimed at the time of mailing the office action on 09/25/2025.
Applicant’s amendments and argument, filed 12/15/2025, with respect to at least independent claim 1 have been fully considered and are persuasive. The rejection of claims 1, 4, 10, 13-14, 16, 20, 23, 32, 35-36, 38, 42, and 44 has been withdrawn. However, applicant's amendment necessitated the new ground(s) of rejection (please see the rejection below under Claim Rejections - 35 USC § 103).
Claim Interpretation
Double negative T cells (DNTs) are mature peripheral T lymphocytes that express the CD3-TCR complex,
but do not express CD4, CD8 or NKT cell markers (See ¶0005 of as-filed specification).
Claim 32 is directed to “a method of treating cancer expressing CD4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a population of ex vivo expanded DNT cells that have been genetically modified to bind to a CD4 antigen…”. Independent claim 32 as currently amended does require the DNT cells to bind to the CD4 antigen.
New Grounds of Rejection
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 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.
Claim(s) 1, 4, 10, 13-14, 16, 20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Zakrzewski et al. (The US Patent Application Publication US20170049818A1, filed on 01/30/2009, and published on 02/23/2017), in view of Achita et al. (Achita et al., “Infusion of ex‐vivo expanded human TCR‐αβ+ double‐negative regulatory T cells delays onset of xenogeneic graft‐versus‐host disease”. Clin Exp Immunol. 2018 Sep;193(3):386-399).
Regarding claim 1, Zakrzewski et al. teaches methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, wherein said T-cell precursor comprises a nucleic acid sequence which encodes for a chimeric antigen receptor which is capable of expression in said T-cell precursor (Abstract and claim 1 of Zakrzewski et al.) and wherein said T-cell precursor expresses a chimeric antigen receptor which is specific for an antigen of a target cancer cell (claim 2 of Zakrzewski et al.). Zakrzewski et al. further teaches that the T-cell precursor cell is selected from the group consisting of one or more CD4−CD8− double negative precursor cell lineages, or a combination thereof (paragraph 0084).
However, Zakrzewski et al. fails to teach that the double negative T cells are ex vivo expanded DNT cells, wherein the DNT cell is CD4-, CD8-, CD3+ γδ-TCR and/or CD4-, CD8-, CD3+, αβ-TCR+.
However, Achita et al. teaches that ex‐vivo‐expanded DN Tregs suppress proliferation of polyclonally stimulated autologous T and B cells in vitro through direct cell‐to‐cell contact. Also, in vivo, authors have demonstrated that infusion of human DN Tregs delayed an onset of xenogeneic graft‐versus‐host disease (GVHD) significantly in a humanized mouse model. Furthermore, preincubation of ex‐vivo‐expanded DN Tregs with a mechanistic target of rapamycin (mTOR) inhibitor rapamycin enhanced their immune regulatory function further. Achita et al. teaches that human TCR‐αβ+ double‐negative regulatory T cells can be expanded ex vivo to therapeutic numbers highlighting the potential clinical use of DN Tregs to mitigate GVHD (Title and Abstract). Achita et al. further teaches that double-negative (DN) Tregs have been shown to have regulatory properties. DN Tregs express T cell receptor (TCR)- αβ+, are natural killer (NK) lineage marker-negative and lack CD4 and CD8 co receptors on their cell surface (page 386, column 2, last paragraph).
Therefore, it would have been prima facie obvious to have used the ex vivo expanded DNT cells of Achita et al. in the method of treating a T-cell deficiency of Zakrzewski et al. with a reasonable expectation of success. One would have been motivated to have done so since ex vivo expanded DNT cells can suppress proliferation of T and B cells and attenuate GVHD, which makes it effective for a variety of uses including treating cancer as taught by Achita et al.
Regarding claim 4: Following discussion of claim 1 above, Achita et al. teaches that the ex‐vivo‐expanded DN T cells attenuate GVHD (Abstract). This reads on the population of genetically modified DNT cells does not induce graft-versus-host disease (GvHD) in the subject or induces less GvHD in the subject relative to conventional T cells.
Regarding claim 10: Following discussion of claim 1 above, Zakrzewski et al. further teaches that the treatment method does not comprise co- or post-administration of immunosuppressive compositions in any sense (paragraph 0091). This reads on that the subject a) does not receive immunosuppressive therapy following administration of the population of genetically modified DNT cells.
Regarding claim 13: Following discussion of claim 1 above, Zakrzewski et al. further teaches T-cell precursor comprises a nucleic acid sequence which encodes for a chimeric antigen receptor which is capable of expression in said T-cell precursor (Abstract and claim 1 of Zakrzewski et al.).
Regarding claim 14: Following discussion of claim 1 above, Zakrzewski et al. further teaches that the DNT cells are genetically engineered to stably express a chimeric antigen receptor, which consists of an extracellular antigen-binding domain targeting human CD19, derived from an anti-CD19 antibody, and an intracellular signal transduction domain derived from human CD3-ζ (paragraph 0143, lines 8-14).
Regarding claim 16: Following discussion of claim 1 above, Zakrzewski et al. further teaches that the teaches that the DNT cells are genetically engineered to stably express a chimeric antigen receptor, which consists of an extracellular antigen-binding domain targeting human CD19 (paragraph 0143, lines 8-14).
Regarding claim 20: Following discussion of claim 1 above, Zakrzewski et al. further teaches that the T-cell deficiency is selected from the group consisting of leukemia such as acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, lymphoma such as Non-Hodgkin's lymphoma (paragraph 0101).
Regarding claim 23: Following discussion of claim 1 above, Zakrzewski et al. further teaches in Table 1 that solid tumors such as neuroblastoma, breast, ovarian Renal cell carcinoma are conditions treatable with this treatment method.
Claim(s) 32, 35, 38, 42, 44 are rejected under 35 U.S.C. 103 as being unpatentable over Zakrzewski et al. (The US Patent Application Publication US20170049818A1, filed on 01/30/2009, and published on 02/23/2017), in view of Achita et al. (Achita et al., “Infusion of ex‐vivo expanded human TCR‐αβ+ double‐negative regulatory T cells delays onset of xenogeneic graft‐versus‐host disease”. Clin Exp Immunol. 2018 Sep;193(3):386-399) and Pinz et al. (Pinz et al., “Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells”. Leukemia. 2016 Mar;30(3):701-7).
Regarding claim 32, Zakrzewski et al. teaches methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, wherein said T-cell precursor comprises a nucleic acid sequence which encodes for a chimeric antigen receptor which is capable of expression in said T-cell precursor (Abstract and claim 1 of Zakrzewski et al.) and wherein said T-cell precursor expresses a chimeric antigen receptor which is specific for an antigen of a target cancer cell (claim 2 of Zakrzewski et al.). Zakrzewski et al. further teaches that the T-cell precursor cell is selected from the group consisting of one or more CD4−CD8− double negative precursor cell lineages, or a combination thereof (paragraph 0084). Zakrzewski et al. further teaches that the DNT cells are genetically engineered to stably express a chimeric antigen receptor, which consists of an extracellular antigen-binding domain targeting human CD19 (paragraph 0143, lines 8-14).
However, Zakrzewski et al. fails to teach that the double negative T cells are ex vivo expanded DNT cells that have been genetically modified to bind to a CD4 antigen, wherein the DNT cell is CD4-, CD8-, CD3+ γδ-TCR and/or CD4-, CD8-, CD3+, αβ-TCR+.
However, Achita et al. teaches that ex‐vivo‐expanded DN Tregs suppress proliferation of polyclonally stimulated autologous T and B cells in vitro through direct cell‐to‐cell contact. Also, in vivo, authors have demonstrated that infusion of human DN Tregs delayed an onset of xenogeneic graft‐versus‐host disease (GVHD) significantly in a humanized mouse model. Furthermore, preincubation of ex‐vivo‐expanded DN Tregs with a mechanistic target of rapamycin (mTOR) inhibitor rapamycin enhanced their immune regulatory function further. Achita et al. teaches that human TCR‐αβ+ double‐negative regulatory T cells can be expanded ex vivo to therapeutic numbers highlighting the potential clinical use of DN Tregs to mitigate GVHD (Title and Abstract). Achita et al. further teaches that double-negative (DN) Tregs have been shown to have regulatory properties. DN Tregs express T cell receptor (TCR)- αβ+, are natural killer (NK) lineage marker-negative and lack CD4 and CD8 co receptors on their cell surface (page 386, column 2, last paragraph).
Also, Pinz et al. teaches in the Abstract that CD4 CAR T cells efficiently eliminated a CD4+ leukemic cell line. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of Peripheral T-cell lymphomas (PTCLs).
Therefore, it would have been prima facie obvious to have engineered the ex vivo expanded DNT cells of Achita et al. into CAR4-DNT cells according to Pinz et al. and used them in the method of treating a T-cell deficiency of Zakrzewski et al. with a reasonable expectation of success. One would have been motivated to have done so since ex vivo expanded CAR4-DNT cells can suppress proliferation of T and B cells and attenuate GVHD, and suppress the growth of lymphoma cells while also significantly prolonging survival, which makes it effective for a variety of uses including treating cancers, such as CD4 cancer as taught by Achita et al. and Pinz et al.
Regarding claim 35: Following discussion of claim 32 above, Zakrzewski et al. further teaches that the T-cell deficiency is acute lymphoblastic leukemia (paragraph 0101).
Regarding claim 38: Following discussion of claim 32 above, Zakrzewski et al. further teaches the T-cell precursor isolated from an allogeneic donor, wherein said T-cell precursor comprises a nucleic acid sequence which encodes for a chimeric antigen receptor which is capable of expression in said T-cell precursor (Abstract and claim 1 of Zakrzewski et al.)
Regarding claim 42: Following discussion of claim 32 above, Zakrzewski et al. further teaches that the treatment method does not comprise co- or post-administration of immunosuppressive compositions in any sense (paragraph 0091). This reads on that the subject a) does not receive immunosuppressive therapy following administration of the population of genetically modified DNT cells.
Regarding claim 44: Following discussion of claim 32 above, paragraph 0101 of Zakrzewski et al. discloses many examples of T-cell deficiencies that are relapsing cancers, such as acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia that are negative for the CD4 target antigen.
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 HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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