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 .
1. The Amendment filed December 3, 2025 in response to the Office Action of September 3, 2025, is acknowledged and has been entered. Claims 1, 2, 4-8, 10, 12, 13, 15, 17-19, 21, 23, 25, 27, 29, and 33 are now pending. Claims 1 and 15 are amended. Claim 33 is new. Claims 10, 17, 19, 25 remain withdrawn. Claims 1, 4-8, 12, 13, 15, 18, 21, 23, 27, 29, and 33 are currently being examined as drawn to the elected species of:
(A) antigen binding regions that comprise an scFv;
(B) antigen binding molecule is scFv-Fc;
(C) immune cells that are Vδ2+ ɣδ T cells;
(D) specificity of the antigen binding region for GD2; and
(E) immune cells containing only one encoded antigen binding molecule.
Claim 1 is amended and altered in scope to require the immune cell capable of ADCC to comprise a nucleic acid sequence encoding a secretable antigen binding molecule that is capable of binding to a Fc receptor. The amendments necessitate new rejections stated below.
Claim Objections
2. Claim 23 is free of the art but is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Each of the VH and VL sequences, SEQ ID NOs: 20 and 18, and SEQ ID NO:17 are novel.
3. Claim 15 is objected to because of the following informalities: There appears to be a typo for the protein “gp1OO” where the capital letter O’s should be changed to zeros to recite “gp100”. Appropriate correction is required.
New Rejections
(necessitated by amendments)
Claim Rejections - 35 USC § 102
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
4. Claim(s) 1, 4-7, 12, 13, 15, 18, 27, 29, and 33 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 12,042,515, Qian et al, claiming priority to 2017.
Qian teaches an immune cell, that is an NK cell or γδ T cell capable of ADCC, and comprises a nucleic acid sequence encoding and expressing a secretable antibody;
wherein the secretable antibody comprises an Fc region that is capable of binding to a Fc receptor, and comprises an scFv binding region (scFv-Fc) (Figures 1, 11, 19, and 27; col. 3, lines 5-46; col. 4, lines 9-37; col. 6, lines 24-43; col. 9, lines 3-25; col. 9, lines 34-41; col. 9, lines 52-60; col. 13-17; col. 19, lines 4-28; Examples 13-20);
wherein the secretable antibody binds to a tumor antigen that is GD2 (col. 3, lines 47-51; col. 8, lines31-42; col. 9, lines 3-11; claims 1-8);
wherein immune cell can also express a chimeric antigen receptor (CAR) and/or express a protein that acts as a molecular brake and is targeted by known antibody therapeutics, thereby encompassing immune cells that do not express a CAR (Figures 1, 11, 19, and 27; col. 4, lines 9-37; col. 13, lines 7 to col. 14, line 36).
Qian teaches a method of producing the immune cell by introducing nucleic acid sequence encoding the antibody into the immune cell, wherein the nucleic acid sequence is comprised in a recombinant expression vector or viral vector (col. 4, lines 38-42; col. 14, lines 21-46; col. 18, lines 1-28; Example 13).
Qian teaches a method of treating cancer in an individual, comprising administering to the individual a therapeutically effective number of the immune cells, wherein the cancer is a solid tumor (col. 4, lines 47-61; col. 7, lines 32-34; col. 17, lines 47-59; claims 9-14; Example 19; Figure 17).
Qian demonstrates the NK immune cells “highly efficiently mediate ADCC effect” (Example 20). Quian teaches the advantage of immune cells expressing anti-tumor antibody (col. 2, lines 23-43):
Therefore, if the cellular immunity effector cells keep the cell killing toxicity while being able to efficiently express antibody with anti-tumor activity, the problems that the immune treatment effect of cells is insufficient and a macromolecular antibody is difficult to enter into solid tumors will be simultaneously overcome, with the treatment cost reduced. Under the effect of chemokines, the cells with both cell killing toxicity and high-level expression of antibodies can actively enter into tumor tissue via cytomorphosis, so that local high-level expression of antibody in the tumor tissue can be achieved, and the side effects caused by systemic administration can be avoided. Meanwhile, due to the co-existence of the antibody and the cytotoxic cell killing immune cells, the antibody acting on the immune cells (such as HER2 antibody Herceptin) can induce strong ADCC effect and CDC effect to efficiently kill tumor cells. Moreover, the antibody acting on T cells (such as PD1 antibody Keytruda) can prevent the inhibitory effects of tumor microenvironment on the re-infused effector T cells, making them continuously exert a therapeutic effect.
Qian teaches (col. 9, lines 3-8):
In other embodiments, the antibody is antibody acting on tumor cells, which after being expressed by killer cells such as NK cells, can, through guidance of the antibody, produce a synergistic ADCC effect with the killer cells. In some embodiments, the antibody is a secretory antibody.
Qian teaches: (col. 19, lines 4-28):
The present invention overcomes the deficiencies of the present commonly used gene transfection vector system (low transfection efficiency for killer cells, and low expression level of antibody), so that the immune killer cells can stably express high level of antibodies comprising full-length human Fc segment. The present invention overcomes the difficulty of insufficient cellular immune-therapy effect and the difficulty of macromolecular antibodies entering into solid tumors. In addition, the present killer cells can remain the cytotoxic while they can also stably express antibodies comprising human Fc segment at high levels, or stably express antibodies comprising human Fc segment, or stably express the antigen-binding fragment of the antibodies of interest and CAR. In addition, in order to prevent the proliferation of immune cells stably expressing antibodies in vivo which may lead to over-expression of the antibodies and in turn systemic toxicity and autoimmune disease, a molecular brake system (such as a CD20-Rituxan molecular brake system, CD20BR) is introduced. Using the commercially available monoclonal antibody (such as Rituxan), killing cells integrated with antibody expression cassette will be rapidly removed via the ADCC effect and CDC effect mediated by the monoclonal antibody, and thus the safety for therapy is effectively improved.
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.
5. Claim(s) 1, 7, and 8 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 12,042,515, Qian et al, claiming priority to 2017; in view of WO 2020/021045, Quintarelli et al, claiming priority to 2018.
Quian teaches an immune cell, that is an NK cell or γδ T cell capable of ADCC, and comprises a nucleic acid sequence encoding and expressing a secretable antibody;
wherein the secretable antibody comprises an Fc region, and methods of administering the cells to treat cancer, as set forth above.
Qian does not teach the γδ T cells comprise Vδ2+ cells.
Quintarelli also teaches modified NK cells or γδ T cells for the treatment of cancer, and teaches γδ T cells can comprise Vδ2+ cells and methods of isolating the cells to make a therapeutic composition (p. 8, 11, 13, 15, 22-23, 31-33, 35, 43-44; Examples; claims 70, 72, 93-95, 139, 149-150), wherein the NK or γδ T cells can be engineered to comprise a nucleic acid encoding an antibody that binds a tumor antigen such as dinutuximab (anti-GD2), or encoding a CAR targeting GD2 (p. 12-13, 16-17, 39).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize Vδ2+ cells as the γδ T immune cell of Qian. One would have been motivated to and have a reasonable expectation of success to because: (1) both Qian and Quintarelli teach modifying γδ T cells to express an anti-tumor antibody, including anti-GD2 antibody, or express a CAR, and to administer the modified γδ T cells for cancer therapy; (2) Quintarelli teaches these γδ T cells include Vδ2+ cells; and (3) Quintarelli teaches known methods for isolating and modifying Vδ2+ cells.
6. Claim(s) 1 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent 12,042,515, Qian et al, claiming priority to 2017; in view of WO 2018/183888, Lynn et al; and US Patent Application Publication 2018/0100016, Song.
Quian teaches an immune cell, that is an NK cell or γδ T cell capable of ADCC, and comprises a nucleic acid sequence encoding and expressing a secretable antibody;
wherein the secretable antibody comprises an scFv and Fc region, and binds to tumor antigen GD2, for the treatment of cancer, as set forth above.
Qian does not teach the sequences of the anti-GD2 antibody comprise instant VH and VL SEQ ID NOs:4 and 5.
Lynn teaches an anti-GD2 scFv antibody comprising SEQ ID NO:44 that comprises 100% of instant SEQ ID NOs:4 and 5 (p. 29 and 38) (see sequence alignments below). Lynn teaches the antibody can be expressed by an immune cell in a CAR construct and used for the treatment of cancer (p. 6, Figure 1; p. 14, 32, 44, 58-60).
Song teaches transfecting an NK cell to express a CAR (NK-CAR) comprising an anti-tumor scFv antibody, such as an anti-GD2 scFv antibody comprising variable heavy chain region SEQ ID NO:16 that is 100% identical to instant SEQ ID NO:4, and comprising variable light chain region SEQ ID NO:14 that comprises 100% of instant SEQ ID NO:5 (see sequence alignment in previous office action), and wherein the anti-tumor scFv is fused to an IgG CH2-CH3 Fc region (claims 5-12; [17]; [20]; [37-38]; Figure 3; [59-60]; Example 1). Song teaches administering the transformed NK cell to a patient to treat cancer or a tumor, wherein the anti-GD2 antibody of the NK cell binds to tumor cells expressing GD2 (claims 13-15; [10];[22]; [32]; [88-90]). Song teaches NK cells are naturally capable of ADCC ([6]; [11]).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the anti-GD2 scFv antibody of Lynn and Song as the anti-GD-2 scFv-Fc antibody expressed by the immune cell of Qian. One would have been motivated to and have a reasonable expectation of success to because Qian, Lynn, and Song teach utilizing anti-GD2 antibody for the same purpose of targeting and treating cancer (functionally equivalent); and Lynn and Song teach the known sequences of the anti-GD2 antibody for recombinant expression in an immune cell.
Instant anti-GD2 VH domain SEQ ID NO:4 aligned with Lynn SEQ ID NO:44:
RESULT 3
BFS45894
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
ID BFS45894 standard; protein; 244 AA.
XX
AC BFS45894;
XX
DT 29-NOV-2018 (first entry)
XX
DE Anti-GD2 scFv antibody (14G2a), SEQ 44.
XX
KW GD2 protein; acute lymphoblastic leukemia; cancer; cell exhaustion;
KW cell signaling; cell therapy; cytostatic; expression; glioblastoma;
KW glioma; hodgkins disease; immune stimulation; neuroblastoma;
KW osteosarcoma; sarcoma; single chain antibody; t-lymphocyte; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2018183888-A2.
XX
CC PD 04-OCT-2018.
XX
CC PF 30-MAR-2018; 2018WO-US025459.
XX
PR 31-MAR-2017; 2017US-0479930P.
XX
CC PA (STRD ) UNIV LELAND STANFORD JUNIOR.
XX
CC PI Lynn R, Mackall C, Wandless TJ, Weber E;
XX
DR WPI; 2018-77552Y/71.
DR N-PSDB; BFS45893.
XX
CC PT New chimeric antigen receptor (CAR) comprises extracellular ligand-
CC PT binding domain, transmembrane domain, cytoplasmic domain, and regulatable
CC PT destabilization domain, for treating or delaying the progression of
CC PT cancer in patient.
XX
CC PS Disclosure; SEQ ID NO 44; 126pp; English.
XX
CC The present invention relates to a novel chimeric antigen receptor (CAR),
CC useful for treating cancer. The CAR comprises an extracellular ligand-
CC binding domain, transmembrane domain, cytoplasmic domain having signaling
CC domains, and regulatable destabilization domain (RDD). The invention
CC further claims: (1) a genetically modified T cell comprising an isolated
CC nucleic acid sequence encoding the CAR; (2) a method for improving and/or
CC prolonging a T lymphocyte cell (T cell) effector function in a mammal;
CC (3) a method for treating a mammal suffering from cancer by introducing a
CC T cell comprising the CAR into the mammal; (4) a method for stimulating a
CC T cell-mediated immune response to a target cell population or tissue in
CC a mammal; (5) a method for providing an anti-cancer immune response in a
CC mammal; (6) a method for treating or delaying the progression of cancer
CC in a patient; and (7) a therapeutically effective amount of a composition
CC comprising genetically modified T cells for expressing CAR. The CAR is
CC useful for preparing a composition for treating or delaying the
CC progression of cancer in the patient; improving and/or prolonging T cell
CC effector function in the mammal; treating mammal suffering from cancer;
CC stimulating T cell-mediated immune response to the target cell population
CC or tissue in the mammal; and providing the anti-cancer immune response in
CC the mammal, where cancer is selected from neuroblastoma, glioblastoma,
CC midline glioma, osteosarcomas, sarcoma, B lineage acute lymphoblastic
CC leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's
CC lymphoma, leukemia and lymphoma, acute lymphoblastic leukemia, Hodgkin's
CC lymphoma, and childhood acute lymphoblastic leukemia. The CAR is useful
CC for maintaining the functionality under conditions in which unmodified
CC CAR T cells display exhaustion; and inhibiting or reversing CAR T cells
CC exhaustion by modulating CAR surface expression for enhancing CAR T cell
CC function. The invention is useful for treating T cell exhaustion by
CC inhibiting or modulating T cell receptor signaling. The present sequence
CC is a anti-GD2 single chain variable fragment (scFv) antibody, which can
CC be useful for preparing a CAR construct for treating cancer in the method
CC of the present invention.
XX
SQ Sequence 244 AA;
Query Match 100.0%; Score 593; Length 244;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVKLQQSGPSLVEPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 132 EVKLQQSGPSLVEPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSY 191
Qy 61 NQKFKGRATLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 192 NQKFKGRATLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS 244
Instant anti-GD2 VL domain SEQ ID NO:5 aligned with Lynn SEQ ID NO:44:
RESULT 6
BFS45894
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
ID BFS45894 standard; protein; 244 AA.
XX
AC BFS45894;
XX
DT 29-NOV-2018 (first entry)
XX
DE Anti-GD2 scFv antibody (14G2a), SEQ 44.
XX
KW GD2 protein; acute lymphoblastic leukemia; cancer; cell exhaustion;
KW cell signaling; cell therapy; cytostatic; expression; glioblastoma;
KW glioma; hodgkins disease; immune stimulation; neuroblastoma;
KW osteosarcoma; sarcoma; single chain antibody; t-lymphocyte; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
CC PN WO2018183888-A2.
XX
CC PD 04-OCT-2018.
XX
CC PF 30-MAR-2018; 2018WO-US025459.
XX
PR 31-MAR-2017; 2017US-0479930P.
XX
CC PA (STRD ) UNIV LELAND STANFORD JUNIOR.
XX
CC PI Lynn R, Mackall C, Wandless TJ, Weber E;
XX
DR WPI; 2018-77552Y/71.
DR N-PSDB; BFS45893.
XX
CC PT New chimeric antigen receptor (CAR) comprises extracellular ligand-
CC PT binding domain, transmembrane domain, cytoplasmic domain, and regulatable
CC PT destabilization domain, for treating or delaying the progression of
CC PT cancer in patient.
XX
CC PS Disclosure; SEQ ID NO 44; 126pp; English.
XX
CC The present invention relates to a novel chimeric antigen receptor (CAR),
CC useful for treating cancer. The CAR comprises an extracellular ligand-
CC binding domain, transmembrane domain, cytoplasmic domain having signaling
CC domains, and regulatable destabilization domain (RDD). The invention
CC further claims: (1) a genetically modified T cell comprising an isolated
CC nucleic acid sequence encoding the CAR; (2) a method for improving and/or
CC prolonging a T lymphocyte cell (T cell) effector function in a mammal;
CC (3) a method for treating a mammal suffering from cancer by introducing a
CC T cell comprising the CAR into the mammal; (4) a method for stimulating a
CC T cell-mediated immune response to a target cell population or tissue in
CC a mammal; (5) a method for providing an anti-cancer immune response in a
CC mammal; (6) a method for treating or delaying the progression of cancer
CC in a patient; and (7) a therapeutically effective amount of a composition
CC comprising genetically modified T cells for expressing CAR. The CAR is
CC useful for preparing a composition for treating or delaying the
CC progression of cancer in the patient; improving and/or prolonging T cell
CC effector function in the mammal; treating mammal suffering from cancer;
CC stimulating T cell-mediated immune response to the target cell population
CC or tissue in the mammal; and providing the anti-cancer immune response in
CC the mammal, where cancer is selected from neuroblastoma, glioblastoma,
CC midline glioma, osteosarcomas, sarcoma, B lineage acute lymphoblastic
CC leukemia, B-cell chronic lymphocytic leukemia, B-cell non-Hodgkin's
CC lymphoma, leukemia and lymphoma, acute lymphoblastic leukemia, Hodgkin's
CC lymphoma, and childhood acute lymphoblastic leukemia. The CAR is useful
CC for maintaining the functionality under conditions in which unmodified
CC CAR T cells display exhaustion; and inhibiting or reversing CAR T cells
CC exhaustion by modulating CAR surface expression for enhancing CAR T cell
CC function. The invention is useful for treating T cell exhaustion by
CC inhibiting or modulating T cell receptor signaling. The present sequence
CC is a anti-GD2 single chain variable fragment (scFv) antibody, which can
CC be useful for preparing a CAR construct for treating cancer in the method
CC of the present invention.
XX
SQ Sequence 244 AA;
Query Match 100.0%; Score 589; Length 244;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DILLTQTPLSLPVSLGDQASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DILLTQTPLSLPVSLGDQASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRF 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK 113
7. All other rejections recited in the Office Action mailed September 3, 2025 are hereby withdrawn in view of amendments. The claim amendments exclude the prior art previously of record.
8. Conclusion: Claim 23 is objected to. Claims 1, 4-8, 12-13, 15, 18, 21, 27, 29 and 33 are rejected.
Conclusion
9. 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Laura B Goddard/Primary Examiner, Art Unit 1642