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 .
Election/Restrictions
Applicant’s election without traverse of an isolated cell comprising: 1) a chimeric receptor comprising: a) an extracellular domain that binds to CEACAM5; b) a CD8 hinge space; c) a CD28 transmembrane and d) a CD28 intracellular signaling domain and a CD3 zeta intracellular signaling domain and 2) an inhibitory chimeric receptor comprising: a) an extracellular binding domain that binds to VSIG2; b) a CD8 hinge spacer; c) a SIRPa transmembrane domain and d) a SIRPa intracellular inhibitory domain in the reply filed on 03/31/2026 is acknowledged.
Applicant’s elected species of an inhibitory chimeric receptor with an extracellular domain that binds VSIG2 is found free of the prior art.
The search was expanded to an inhibitory chimeric receptor with an extracellular domain that targets GPA33 which is not found free of the prior art.
Applicant’s elected inhibitory transmembrane and intracellular domains of SIRPa is not recited in the claim 2 which details the inhibitory chimeric receptor, therefore the transmembrane and intracellular domain examined herein are comprised of LAG-3.
Application Status
Claims 1-20 are pending and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 01/08/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. There is no copy attached of non-patent literature reference Li et al. 2017. It has been placed in the application file, but the information referred to therein has not been considered.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 81. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term nanobody™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 4 is objected to because of the following informalities:
In line 2: reads “one or more additional antigen is CECAM1”; should read “one or more additional antigen(s) is CEACAM1”;
In line 6: reads “one or more additional antigen is CECAM5”; should read “one or more additional antigen(s) is CEACAM5”;
In line 27: reads “one or more additional antigen is CECAM6”; should read “one or more additional antigen(s) is CEACAM6”;
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 2, the claim recites “the isolated cell of claim 0” which is a non-existent claim.
For the purpose of compact prosecution claim 2 will be examined as depending from claim 1.
Regarding claim 3, the recitation of “optionally wherein the CAR comprises a SIRPa domain” renders the claim as indefinite as it is unclear which domain within the CAR is meant to be a SIRPa domain chosen from the extracellular, hinge, transmembrane or intracellular domains contained therein. Further, If the intracellular signaling domain were from SIRPa this would act in opposition to the activating intracellular domains recited in claim 3 such as CD3 zeta and CD28, which renders the function of the CAR as indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cancer, does not reasonably provide enablement for preventing cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
Nature of the invention/ Breadth of the claims. The claims are drawn to a method of treating or preventing a cancer in a subject comprising
State of the prior art/ Predictability of the art. There is prior art demonstrating the effectiveness of combination CAR and inhibitory CAR treatment for cancer. Maryamchik (Cytometry. 2020;98:299–327; PTO-892) teaches that in addition to an activating tumor-specific CAR, inhibitory CAR T cells (iCARs) express an inhibitory chimeric receptor, in which antigen recognition domain specific for a normal tissue marker is fused with a signaling domain of an immunoinhibitory receptor, such as CTLA-4 or PD-1. Binding of the iCAR to the normal tissue temporarily inhibits its cytokine secretion, cytotoxicity, and proliferation, but this inhibition is reversed when the cell migrates into the tumor, which lacks the normal tissue marker. Maryamchik further teaches that in preclinical studies, iCAR was shown to selectively protect off-target cells without abrogating rejection of target cells (section 3.3.2).
There is also prior art with the specific components of the instant claims, but there are no working examples of prevention of cancer therein. Saqi (WO 2020/065406 A2; published 04/02/2020; IDS entered 04/08/2025) teaches a method for treating cancer in a patient having a tumor characterized by LQH, comprising administering to the patient a safe effector immune cell expressing the iCAR and aCAR according to any of claims 1 through 88 (claim 91), comprising an aCAR capable of inducing activation of an effector immune cell, wherein the aCAR is directed to CEACAM5; iii) expressing the iCAR or pCAR from step i) and the aCAR from step ii) in a population of cells (claim 1 and para 00711); wherein the gene comprising the extracellular polymorphic epitope is selected from the group consisting of…GPA33 (claim 20); Saqi further teaches that the target for use in the iCAR and/or pCAR is selected from the group consisting of…GPA33 (para 0094).
The state of the art does not recognize that administering an immune cell with an aCAR and an iCAR for immunotherapy would prevent cancer.
Working examples. There are no working examples provided in the instant disclosure for prevention of cancer. For example, the specification teaches [0421, Table 7] that colon cancer cells were inoculated intraperitoneally into mice five days prior to NK cell treatment in order to track tumor progression. However, this in vivo model is not reflective of a preventative or vaccine. See below for more guidance.
Guidance in the specification. The specification provides guidance towards the meaning of the term “prevent”.
The instant specification discloses that: An "anti-tumor effect" can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the present disclosure in prevention of the occurrence of tumor in the first place, such as in a prophylactic therapy or treatment (para 0153)
The instant disclosure also discloses that: In some embodiments, a further group of subjects are those having a genetic predisposition to a solid tumor disorder, but that have not yet evidenced clinical signs of the solid tumor. For example, women testing positive for a genetic mutation associated with a cancer of the female reproductive organs (e.g., breast cancer, ovarian cancer), but still of childbearing age, may benefit from receiving one or more of the cells of the present disclosure (e.g., immunoresponsive cells, e.g. NK cells) in treatment prophylactically to prevent the occurrence of said cancer of the female reproductive organs until it is suitable to perform preventive surgery (para 0388).
The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent.
Amount of experimentation necessary. An extensive amount of additional research is required in order to determine how effective administering a potent immune cell to a subject would be at preventing cancer and to determine to which population of subjects to administer the potent immune cells that could predictably prevent cancer as claimed in the instant claims 18 and 20.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Saqi (WO 2020/065406 A2; published 04/02/2020; IDS entered 04/08/2025).
Regarding claims 1, 4, 7, and 20, Saqi teaches a method of identifying an inhibitory chimeric antigen receptor (iCAR) or protective chimeric antigen receptor (pCAR)/activating chimeric antigen receptor (aCAR) target pair comprising: i) selecting an iCAR or a pCAR capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR or pCAR target is directed to a target extracellular polymorphic epitope from a gene selected from the group consisting of the 598 genes listed in Fig. 22; and ii) selecting an aCAR capable of inducing activation of an effector immune cell, wherein the aCAR is directed to a target non-polymorphic cell surface epitope of a protein selected from the group consisting of the 49 target proteins listed Fig. 23; iii) expressing the iCAR or pCAR from step i) and the aCAR from step ii) in a population of cells (claim 1); wherein the gene comprising the extracellular polymorphic epitope is selected from the group consisting of…GPA33 (claim 20); Saqi further teaches that the target for use in the iCAR and/or pCAR is selected from the group consisting of…GPA33 (para 0094) and aCAR targets CEACAM5 (para 00711).
Regarding claim 2, Saqi teaches an iCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be from PD1, CTLA-4, BTLA, or LAG3; the transmembrane can be from PD1, CTLA-4, BTLA, or LAG3; and the intracellular domain can be from PD1, CTLA-4, BTLA, or LAG3 (Fig 50-51).
Regarding claim 3, Saqi teaches an aCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be CD8; the first signaling domain can be 41BB or CD28; and the second signaling domain can be CD3zeta (Fig 50B).
Regarding claims 5 and 8, Saqi teaches that the effector immune cell is a T cell, a natural killer cell or a cytokine-induced killer cell (para 0085).
Regarding claim 6, Saqi teaches that care must be taken to ensure that the inhibitory signal transmitted by the iCAR is strictly and permanently dominant over the aCAR signal and that no cross-recognition between the iCAR and the aCAR occurs (para 0071), this capacity will be influenced by the relative affinities of the two recognition moieties for their respective target epitopes and the overall avidities of their interactions (para 00182).
Regarding claim 9, Saqi teaches a nucleic acid sequence encoding an iCAR and an aCAR (claim 101).
Regarding claim 10, Saqi teaches a vector comprising a nucleic acid or nucleic acid sequence composition (claim 103).
Regarding claim 11, Saqi teaches a safe effector cell comprising a nucleic acid or nucleic acid sequence composition of any one of claims 93 through 101 (claim 104).
Regarding claim 12, Saqi teaches pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients (para 0063).
Regarding claims 13-15 and 17, Saqi teaches a method for treating cancer in a patient having a tumor characterized by LQH, comprising administering to the patient a safe effector immune cell expressing the iCAR and aCAR according to any of claims 1 through 88 (claim 91). Saqi further teaches that upon binding to cognate antigen, a CAR can activate or inactivate the cytotoxic cell in which it is disposed, or modulate the cell's antitumor activity or otherwise modulate the cells immune response (para 0057).
Regarding claim 16, Saqi teaches a method of reducing tumor burden in a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00463).
Regarding claim 18, Saqi teaches wherein the tumor is selected from the group consisting of a breast tumor, a prostate tumor, an ovarian tumor, a cervical tumor, a skin tumor, a pancreatic tumor, a colorectal tumor, a renal tumor, a liver tumor, a brain tumor, a lymphoma, a leukemia, a lung tumor, and a glioma (claim 43).
Regarding claim 19, Saqi teaches a method of increasing survival of a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00464).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 7-9, 11-13, and 16-18 of copending Application No. 18/504,037 in view of Saqi (WO 2020/065406 A2; published 04/02/2020; IDS entered 04/08/2025).
This is a provisional nonstatutory double patenting rejection.
Regarding claims 1 and 20, the copending claims teach a chimeric protein comprising an antigen-binding domain specific for V-Set And Immunoglobulin Domain Containing 2 (VSIG2) and a heterologous molecule or moiety, wherein the antigen-binding domain comprises a heavy chain variable (VH) region and a light chain variable (VL) region (claims 1-3), wherein the chimeric protein is a chimeric antigen receptor (CAR), (claim 5), wherein the CAR is an inhibitory CAR (claim 6), wherein the cell or population of cells further comprises one or more tumortargeting chimeric receptors expressed on the cell surface, optionally wherein each of the one or more tumor-targeting chimeric receptors is a chimeric antigen receptor (CAR) or an engineered T cell receptor (claim 11).
Regarding claim 2, the copending claims teach wherein the antigen-binding domain comprises a single chain variable fragment (scFv) (claim 4).
Regarding claims 5 and 8, the copending claims teach wherein the cell or the population of cells is selected from the group consisting of: a T cell, a CD8+ T cell, a CD4+ T cell, a gamma-delta T cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a viral-specific T cell, a Natural Killer T (NKT) cell, a Natural Killer (NK)…(claim 12).
Regarding claims 7 and 10, the copending claims teach an expression vector comprising the engineered polynucleotide of claim 7 (claim 8).
Regarding claim 9, the copending claims teach an engineered polynucleotide encoding the chimeric protein of claim 1 (claim 7).
Regarding claim 11, the copending claims teach an isolated cell or a population of engineered cells comprising the chimeric protein of claim 1 (claim 9).
Regarding claim 12, the copending claims teach a pharmaceutical composition comprising an effective amount of the cell or the population of engineered cells of claim 9 and a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, or a combination thereof (claim 13).
Regarding claims 14-15, the copending claims a method of stimulating a cell-mediated immune response to a tumor cell in a subject, the method comprising administering to a subject having a tumor a therapeutically effective dose of the chimeric protein of the cell or the population of cells of claim 9 (claim 18).
Regarding claims 13 and 17, the copending claims teach a method of treating a subject having a tumor, the method comprising administering a therapeutically effective dose of the cell or the population of cells of claim 9 (claims 16-17).
The copending claims do not teach the target of the antigen binding domain of the aCAR; the specific transmembrane or intracellular domains of the inhibitory chimeric receptor; the benefits of treatment with the regimen.
Regarding claims 1, 4, 7, and 20, Saqi teaches a method of identifying an inhibitory chimeric antigen receptor (iCAR) or protective chimeric antigen receptor (pCAR)/activating chimeric antigen receptor (aCAR) target pair comprising: i) selecting an iCAR or a pCAR capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR or pCAR target is directed to a target extracellular polymorphic epitope from a gene selected from the group consisting of the 598 genes listed in Fig. 22; and ii) selecting an aCAR capable of inducing activation of an effector immune cell, wherein the aCAR is directed to a target non-polymorphic cell surface epitope of a protein selected from the group consisting of the 49 target proteins listed Fig. 23; iii) expressing the iCAR or pCAR from step i) and the aCAR from step ii) in a population of cells (claim 1); wherein the gene comprising the extracellular polymorphic epitope is selected from the group consisting of…GPA33 (claim 20); Saqi further teaches that the target for use in the iCAR and/or pCAR is selected from the group consisting of…GPA33 (para 0094) and aCAR targets CEACAM5 (para 00711).
Regarding claim 2, Saqi teaches an iCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be from PD1, CTLA-4, BTLA, or LAG3; the transmembrane can be from PD1, CTLA-4, BTLA, or LAG3; and the intracellular domain can be from PD1, CTLA-4, BTLA, or LAG3 (Fig 50-51).
Regarding claim 3, Saqi teaches an aCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be CD8; the first signaling domain can be 41BB or CD28; and the second signaling domain can be CD3zeta (Fig 50B).
Regarding claim 6, Saqi teaches that care must be taken to ensure that the inhibitory signal transmitted by the iCAR is strictly and permanently dominant over the aCAR signal and that no cross-recognition between the iCAR and the aCAR occurs (para 0071), this capacity will be influenced by the relative affinities of the two recognition moieties for their respective target epitopes and the overall avidities of their interactions (para 00182).
Regarding claim 16, Saqi teaches a method of reducing tumor burden in a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00463).
Regarding claim 18, Saqi teaches wherein the tumor is selected from the group consisting of a breast tumor, a prostate tumor, an ovarian tumor, a cervical tumor, a skin tumor, a pancreatic tumor, a colorectal tumor, a renal tumor, a liver tumor, a brain tumor, a lymphoma, a leukemia, a lung tumor, and a glioma (claim 43).
Regarding claim 19, Saqi teaches a method of increasing survival of a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00464).
It would have been obvious to one of ordinary skill in the art to use the established CAR targeting CEACAM5 and the intracellular portions of the iCAR as taught by Saqi in the cell comprising an inhibitory VSIG2 chimeric receptor and an activating chimeric receptor of the copending claims. The ordinary artisan would have been motivated to do so because the copending claims and Saqi are analogous arts with the same goal to improve CAR-T therapy by generating CAR-T cells with an off switch for healthy cells to limit off target cytotoxicity.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/128,245 in view of Saqi (WO 2020/065406 A2; published 04/02/2020; IDS entered 04/08/2025).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, the copending claims teach an isolated antibody or antigen binding fragment thereof that specifically binds to human V
set and Immunoglobulin Domain Containing 2 (VSIG2) comprising a heavy chain variable (VH) region and a light chain variable (VL) region (claims 1-5). The copending claims further teach a chimeric protein comprising an antibody or antigen binding fragment thereof of any one of claims 1-7 and a heterologous molecule or moiety, wherein the CAR is an inhibitory CAR comprising one or more intracellular inhibitory domains that inhibit an immune response (claim 8).
Regarding claim 2, the copending claims teach wherein the antigen binding fragment comprises a single chain variable fragment (scFV), optionally wherein the VH and VL of the scFv are separated by a peptide linker (claims 6-7).
Regarding claims 3, 5, and 7-8, the copending claims teach wherein the chimeric protein is recombinantly expressed, wherein each of the one or more tumor-targeting chimeric receptors is a chimeric antigen receptor (CAR) or an engineered T cell receptor, optionally wherein the cell or population of cells is selected from a regulatory T cell, a viral-specific T cell, a Natural Killer T (NKT) cell, a Natural Killer (NK) cell, a B cell, a tumor-infiltrating lymphocyte (TIL), an innate lymphoid cell, a mast cell, an eosinophil,…(claim 16).
Regarding claim 9, the copending claims teach an engineered nucleic acid encoding the antibody or antigen binding fragment of any one of claims 1-7 or the chimeric protein of claim 8 (claim 10).
Regarding claim 10, the copending claims teach an expression vector comprising the engineered nucleic acid of claim 10 (claim 11).
Regarding claim 11, the copending claims teach an isolated cell comprising the engineered nucleic acid of claim 10, the expression vector of claim 11, the composition of claim 12, the antigen binding fragment of any one of claims 1-7 or the chimeric protein of claim 8 (claims 13-15).
Regarding claims 12-13, the copending claims teach a pharmaceutical composition comprising an effective amount of the cell or population of engineered cells of claim 14, genetically modified cells expressing the antigen binding fragment of any one of claims 1-7, or the chimeric protein of claim 8 and a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, or a combination thereof, optionally wherein the pharmaceutical composition is for treating and/or preventing a tumor (claims 17, 12, and 9).
Regarding claim 14, the copending claims teach a method of stimulating a cell-mediated immune response to a tumor cell in a subject, the method comprising administering to a subject having a tumor a therapeutically effective dose of the composition of claim 9 or claim 12, or any of the cells of any one of claims 14, or the pharmaceutical composition of claim 17 (claim 18), wherein the method comprises administering to the subject any of the cell of claim 14, wherein the isolated cell or population of cells express the chimeric protein comprising the activating CAR of claim 8 (claim 19).
Regarding claim 20, the copending claims teach a kit for treating and/or preventing a tumor, comprising the chimeric protein of claim 8, the cell or population of cells, the engineered nucleic acid, vector, or composition, optionally wherein the kit further comprises written instructions for using the chimeric protein for producing one or more antigen-specific cells for treating and/or preventing a tumor in a subject (claim 20).
The copending claims do not teach the target of the antigen binding domain of the aCAR; the specific transmembrane or intracellular domains of the inhibitory chimeric receptor; the benefits of treatment with the regimen.
The copending claims do not teach the target of the antigen binding domain of the aCAR; the specific transmembrane or intracellular domains of the inhibitory chimeric receptor; the benefits of treatment with the regimen.
Regarding claims 1, 4, 7, and 20, Saqi teaches a method of identifying an inhibitory chimeric antigen receptor (iCAR) or protective chimeric antigen receptor (pCAR)/activating chimeric antigen receptor (aCAR) target pair comprising: i) selecting an iCAR or a pCAR capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR or pCAR target is directed to a target extracellular polymorphic epitope from a gene selected from the group consisting of the 598 genes listed in Fig. 22; and ii) selecting an aCAR capable of inducing activation of an effector immune cell, wherein the aCAR is directed to a target non-polymorphic cell surface epitope of a protein selected from the group consisting of the 49 target proteins listed Fig. 23; iii) expressing the iCAR or pCAR from step i) and the aCAR from step ii) in a population of cells (claim 1); wherein the gene comprising the extracellular polymorphic epitope is selected from the group consisting of…GPA33 (claim 20); Saqi further teaches that the target for use in the iCAR and/or pCAR is selected from the group consisting of…GPA33 (para 0094) and aCAR targets CEACAM5 (para 00711).
Regarding claim 2, Saqi teaches an iCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be from PD1, CTLA-4, BTLA, or LAG3; the transmembrane can be from PD1, CTLA-4, BTLA, or LAG3; and the intracellular domain can be from PD1, CTLA-4, BTLA, or LAG3 (Fig 50-51).
Regarding claim 3, Saqi teaches an aCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be CD8; the first signaling domain can be 41BB or CD28; and the second signaling domain can be CD3zeta (Fig 50B).
Regarding claim 6, Saqi teaches that care must be taken to ensure that the inhibitory signal transmitted by the iCAR is strictly and permanently dominant over the aCAR signal and that no cross-recognition between the iCAR and the aCAR occurs (para 0071), this capacity will be influenced by the relative affinities of the two recognition moieties for their respective target epitopes and the overall avidities of their interactions (para 00182).
Regarding claim 15 and 17, Saqi teaches a method for treating cancer in a patient having a tumor characterized by LQH, comprising administering to the patient a safe effector immune cell expressing the iCAR and aCAR according to any of claims 1 through 88 (claim 91). Saqi further teaches that upon binding to cognate antigen, a CAR can activate or inactivate the cytotoxic cell in which it is disposed, or modulate the cell's antitumor activity or otherwise modulate the cells immune response (para 0057).
Regarding claim 16, Saqi teaches a method of reducing tumor burden in a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00463).
Regarding claim 18, Saqi teaches wherein the tumor is selected from the group consisting of a breast tumor, a prostate tumor, an ovarian tumor, a cervical tumor, a skin tumor, a pancreatic tumor, a colorectal tumor, a renal tumor, a liver tumor, a brain tumor, a lymphoma, a leukemia, a lung tumor, and a glioma (claim 43).
Regarding claim 19, Saqi teaches a method of increasing survival of a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00464).
It would have been obvious to one of ordinary skill in the art to use the established CAR targeting CEACAM5 and the intracellular portions of the iCAR as taught by Saqi in the cell comprising an inhibitory VSIG2 chimeric receptor and an activating chimeric receptor of the copending claims. The ordinary artisan would have been motivated to do so because the copending claims and Saqi are analogous arts with the same goal to improve CAR-T therapy by generating CAR-T cells with an off switch for healthy cells to limit off target cytotoxicity.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/471,943 in view of Saqi (WO 2020/065406 A2; published 04/02/2020; IDS entered 04/08/2025).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1-4, the copending claims teach an isolated antibody or antigen binding fragment thereof that specifically binds to human V-set Immunoglobulin domain containing 2 (VSIG2) comprising a heavy chain variable (VH) region and a light chain variable (VL) region (claim 1), a chimeric protein comprising an antibody or antigen binding fragment thereof of claim 1 and a heterologous molecule or moiety, optionally wherein the chimeric protein is a chimeric antigen receptor (CAR), and wherein the heterologous molecule or moiety comprises a polypeptide selected from the group consisting of: a transmembrane domain, one or more intracellular signaling domains, a hinge domain, a spacer region, one or more peptide linkers, and combinations thereof, optionally wherein the CAR is an inhibitory CAR, optionally wherein the one or more intracellular inhibitory domains comprise an ICD derived from PD-I, CTLA4, TIGIT, BTLA, LIRI (LILRBI), TIM3, KIR3DL1, NKG2A , LAG3, LAIRI, SIRPa, KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL2, KLRG-1, CEACAMI, LIR2, LIR3, LIR5, SIGLEC-2, SIGLEC-10, PECAM-1, CD72, IRTA2, IRTA4, NKIR, TLTI, PCDHGC3, MPZLI, FCGR2B, SIGLEC-6, MPIG6B, SIGLEC-12, LIR8, IRTAI, KIR2DL4, KIR2DL5, SIGLEC-7, or FCRH3 (claim 4). The copending claims further teach an engineered expression system comprising a) a first nucleic acid sequence encoding a first CAR comprising: i) an ECD that binds to CEACAM5, CEA, CEACAM1, or CEACAM6, ii) a TM domain, and iii) one or more ICD signaling domains and b) a second nucleic acid encoding a second CAR wherein the second CAR comprises the antibody or antigen binding fragment of claim 1 (claims 5-7 and 9).
Regarding claims 5, 7-8, 11, the copending claims teach an isolated cell or population of engineered cells comprising the engineered nucleic acid of claim 14, optionally wherein the cell or population of cells is selected from the group consisting of: a T cell, a CD8+ T cell, a CD4+ T cell, a gamma-delta T cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a viral-specific T cell, a Natural Killer T (NKT) cell, a Natural Killer (NK) cell, a B cell, a tumor-infiltrating lymphocyte (TIL), … further comprises one or more tumor-targeting chimeric receptors expressed on the cell surface (claim 16).
Regarding claims 9-10, the copending claims teach the engineered expression system of claim 5, wherein the first and second nucleic acid sequences are comprised within a single expression vector or wherein the first nucleic acid sequence is comprised within a first expression vector and the second nucleic acid sequence is comprised within a second expression vector (claim 8).
Regarding claims 12-13 and 17, the copending claims teach a method of treating a subject having a tumor, the method comprising administering a therapeutically effective dose of the composition of claim 15 (claim 19). Administration to a patient necessitates formulation in a pharmaceutical composition.
Regarding claim 20, the copending claims teach kit for treating and/or preventing a tumor, comprising: the chimeric protein of claim 4 (claim 20).
The copending claims do not teach the relative avidity/ affinity of the CARs; the specific transmembrane or intracellular domains of the inhibitory chimeric receptor; the benefits of treatment with the regimen.
Regarding claim 2, Saqi teaches an iCAR construct comprising an scFv-hinge-transmembrane domain-signaling domain- (optional second signaling domain) wherein the hinge can be from PD1, CTLA-4, BTLA, or LAG3; the transmembrane can be from PD1, CTLA-4, BTLA, or LAG3; and the intracellular domain can be from PD1, CTLA-4, BTLA, or LAG3 (Fig 50-51).
Regarding claim 6, Saqi teaches that care must be taken to ensure that the inhibitory signal transmitted by the iCAR is strictly and permanently dominant over the aCAR signal and that no cross-recognition between the iCAR and the aCAR occurs (para 0071), this capacity will be influenced by the relative affinities of the two recognition moieties for their respective target epitopes and the overall avidities of their interactions (para 00182).
Regarding claims 14-15 and 17, Saqi teaches a method for treating cancer in a patient having a tumor characterized by LQH, comprising administering to the patient a safe effector immune cell expressing the iCAR and aCAR according to any of claims 1 through 88 (claim 91). Saqi further teaches that upon binding to cognate antigen, a CAR can activate or inactivate the cytotoxic cell in which it is disposed, or modulate the cell's antitumor activity or otherwise modulate the cells immune response (para 0057).
Regarding claim 16, Saqi teaches a method of reducing tumor burden in a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00463).
Regarding claim 18, Saqi teaches wherein the tumor is selected from the group consisting of a breast tumor, a prostate tumor, an ovarian tumor, a cervical tumor, a skin tumor, a pancreatic tumor, a colorectal tumor, a renal tumor, a liver tumor, a brain tumor, a lymphoma, a leukemia, a lung tumor, and a glioma (claim 43).
Regarding claim 19, Saqi teaches a method of increasing survival of a subject having a tumor characterized by LOH, comprising administering to the patient an effector immune cell as defined above (para 00464).
It would have been obvious to one of ordinary skill in the art to use the established intracellular portions of the iCAR as taught by Saqi in the cell comprising an inhibitory VSIG2 chimeric receptor and an activating CEACAM chimeric receptor of the copending claims. The ordinary artisan would have been motivated to do so because the copending claims and Saqi are analogous arts with the same goal to improve CAR-T therapy by generating CAR-T cells with an off switch for healthy cells to limit off target cytotoxicity.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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