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 .
DETAILED ACTION
Amendments
In the reply filed 03/11/2026, Applicant has amended claims 65, 71, 72, 75, 80, 88 and 89, and newly canceled claims 3-4, 6-9, 11-22, 25-26, 28-37, 40-41, 44-45, 52-54, 56-64, 66-67, 69, 73, 83-85 and 107-109. It is noted that some of the above claims (i.e., claims 3-4, 6-7, 11-22, 25-26, 28-37, 40-41, 44-45, 52-54, 56-64) are identified as “(Withdrawn)” (see claim listing, page 1), however, the text of the claims are deleted. Therefore, those claims are examined as “(Canceled)” claims.
Claim Status
Claims 65, 71-72, 75-82, 88-96, 98, 100-101 and 104-106 are pending.
Claims 76, 78-79, 81, 90-96, 98, 100-101 and 104-106 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/24/2025.
Claims 65, 71-72, 75, 77, 80, 82 and 88-89 are considered on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/12/2026 and 03/11/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Withdrawn Claim Objections
The prior objection to claim 75 because of minor informalities is withdrawn in light of Applicant’s amendment to the claim.
New Claim Objections
Claims 3-4, 6-7, 11-22, 25-26, 28-37, 40-41, 44-45, 52-54, 56-65 are objected to because of the following informalities:
Amendments to instant claim have not been properly submitted. 37 C.F.R. 1.121. Manner of making amendments in application; Section (c) Claims (1)(ii) The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). In the instant case, claims 3-4, 6-7, 11-22, 25-26, 28-37, 40-41, 44-45, 52-54, 56-64 are identified as “(Withdrawn)” (see claim listing, page 1), however, the text of the claims are deleted. Therefore, those claims should be identified as “(Canceled)” and are examined as so.
Furthermore, claim 65 is listed twice: one identified as “(Withdrawn)” and the other identified as “(Currently amended)”.
Furthermore, claim 65 recites a list of target of interest in which “WT1” is listed twice. It is recommended to remove one.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 65, 71-72, 75, 77, 80, 82 and 88-89 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting a subjective phrase is withdrawn in light of Applicant’s amendment to claim 65 to recite a list of targets of interest to be selected from.
New Claim Rejections - 35 USC § 112
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.
Claim 88 is 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.
Claim 88 recites the limitation “The population of engineered immune cells of claim 82”. There is insufficient antecedent basis for this limitation in the claim because the base claim 82 recites “The engineered immune cell of claim 65”, but is silent on a population of engineered immune cells. It is recommended to change the limitation in claim 88 to “A population of engineered immune cells of claim 82”.
Withdrawn Claim Rejections - 35 USC § 101
The prior rejection of claims 65, 75, 82 and 89 under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more is withdrawn in light of Applicant’s amendment to claim 65 to recite new limitations of an engineered immune cell expressing a first CAR and a second CAR.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 65, 75, 82 and 89 under 35 U.S.C. 102 (a)(1) as being anticipated by Schiott et al., is withdrawn in light of Applicant’s amendment to claim 65 to recite new limitations of an engineered immune cell expressing a first CAR and a second CAR.
The prior rejection of claims 65, 71-72, 75, 77, 82 and 88-89 under 35 U.S.C. 102 (a)(1) as being anticipated by Srinivasan et al., is withdrawn in light of Applicant’s amendment to claim 65 to recite new limitations of a list of target of interest to be selected from, and the CD70 CAR does not comprise a costimulatory domain.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 65, 71-72, 75, 77, 82 and 88-89 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., in view of Tu et al., is withdrawn in light of Applicant’s amendment to claim 65 to recite new limitations of the CD70 CAR does not comprise a costimulatory domain.
The prior rejection of claims 65, 71-72, 75, 77, 80, 82 and 88-89 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., is withdrawn in light of Applicant’s amendment to claim 65 to recite new limitations of a list of target of interest to be selected from, and the CD70 CAR does not comprise a costimulatory domain.
New 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 65, 71-72, 75, 77, 80, 82 and 88-89 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US2019/0233528 A1. Cited in IDS 12/07/2022) in view of Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 12/07/2022) and Brentjens et al., (WO 2019/099479 A1. Prior art of record).
With respect to claim 65, Srinivasan teaches an engineered immune cell expressing at its cell-surface membrane a CD70-specific CAR and another CAR which is not specific for CD70 (e.g., [0072] and reference claims 76 and 77), thus teaches an engineered immune cell that functionally expresses a first CAR and a second CAR. Srinivasan teaches “in some embodiments the CARs disclosed herein comprise an scFv, CD8α human hinge and transmembrane domains, the CD3ζ signaling domain, and 4-1BB signaling domain” (see e.g., end of [0200] in the right column), thus teaches the first CAR (i.e., “another CAR”) specifically binds a target of interest (i.e., binds to an antigen that is not CD70, see above) and comprises a first transmembrane domain (e.g., CD8α transmembrane domain), a first intracellular signaling domain (e.g., the CD3ζ signaling domain) and a costimulatory domain (e.g., the 4-1BB signaling domain). Srinivasan teaches the CD70-specific CAR comprises an extracellular ligand-binding domain comprising a single chain FIT fragment (scFv) binding to the extracellular domain of CD70, a first transmembrane domain and an intracellular signaling domain (see e.g., [0009] and reference claim 56-59) and teaches the transmembrane domain comprises a CD8α chain transmembrane domain (e.g., reference claim 69) and the intracellular signaling domain comprises a CD3ζ signaling domain (e.g., reference claim 61), thus teaches the second CAR specifically binds CD70 (i.e., the CD70-specific CAR) and comprises an anti-CD70 scFv, and further comprises a second transmembrane domain (e.g., a CD8α chain transmembrane domain) and a second intracellular signaling domain (e.g., a CD3ζ signaling domain). Since Srinivasan suggests both the first transmembrane domain and the second transmembrane domain in the CARs may be a CD8α transmembrane domain (see e.g., end of [0200] and reference claim 69), Srinivasan suggests the first and the second transmembrane domains are the same transmembrane domain.
However, Srinivasan is silent on the other CAR, which is not specific for CD70, specifically binds a target of interest being CD19.
Nevertheless, Srinivasan teaches a method of treating a diffuse large-cell lymphoma expressing CD70 by administering the engineered immune cells (see e.g., [0076] and reference claim 96).
Tu teaches a method of combinatory CAR-T cell therapy comprising co-administering anti-CD70 CAR T cells and anti-CD19 CAR T cells to treat diffuse large B-cell lymphoma as a strategy to prevent relapse due to antigen escape (see e.g., abstract and p. 2, left col, “Background” para 1). Tu teaches the patient has maintained disease-free survival with more than 17 months of follow-up, indicating that combination of CD19- and CD70-specific CAR T-cells may effectively target diffuse large B-cell lymphoma and maintain disease-free survival (see e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cell expressing a CD70-specific CAR and another CAR specific for another target of interest for treating a cancer such as diffuse large-cell lymphoma suggested by Srinivasan, by choosing CD19 as the target of interest (i.e., a CD19-specific CAR) as suggested by Tu with a reasonable expectation of success. Since Srinivasan contemplates treatment of a diffuse large-cell lymphoma using the engineered immune cells expressing CD70-specific CAR and another CAR binding a target of interest (e.g., [0076] and reference claim 96), and since Tu teaches combination of CD19- and CD70-specific CAR T-cells effectively targets diffuse large B-cell lymphoma and prevents relapse due to antigen escape (see e.g., abstract and “Background” para 1), one of ordinary skill in the art would have had a reason to choose CD19 as the target of interest (i.e., a CD19-specific CAR) in combination with the CD70-specific CAR in the engineered immune cell of Srinivasan in order to effectively target diffuse large B-cell lymphoma and prevent relapse due to antigen escape as suggested by Tu.
However, Srinivasan does not specifically teach the CD70-specific CAR does not comprise a costimulatory domain in the working example.
Srinivasan teaches “In some embodiments, the intracellular signaling domain comprises a CD3 signaling domain….In some embodiments, the CAR further comprises a second intracellular signaling domain” (e.g., [0060]) and “in some embodiments the intracellular signaling domain of the CAR of the disclosure comprises a domain of a co-stimulatory molecule” ([0198]). Thus, since Srinivasan teaches only “in some embodiments” the CAR further comprises a second intracellular signaling domain (i.e., a domain of a co-stimulatory molecule), one of ordinary skill in the art would have acknowledged that Srinivasan suggests that a costimulatory domain is optional.
Brentjens teaches a CAR T cell that binds to an antigen (see reference claims 1 and 8), said antigen is a tumor antigen (reference claim 15) selected from the group including CD70 (e.g., p. 6, para 2). Brentjens teaches the CAR comprises an intracellular signaling domain. In certain embodiments, the CAR does not comprise a co-stimulatory signaling domain. In certain embodiments, the CAR is 19z (e.g., p. 5, last full para, also see reference claims 22-24). It is noted that the exemplary 19z comprises only one CD3ζ intracellular signaling domain (see Fig 1A, first row, in the cover page), that does not comprise a co-stimulatory domain.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CD70-specific CAR comprising a CD3 intracellular signaling domain in which a costimulatory domain is optional suggested by Srinivasan, by substituting with Brentjens’ intracellular signaling domain comprising a CD3ζ signaling domain but not comprising a co-stimulatory domain with a reasonable expectation of success. Since Srinivasan suggests a costimulatory domain is optional (e.g., [0060]), and since Brentjens reduces to practice a functional CAR comprising a CD3ζ intracellular signaling domain but not comprising a co-stimulatory domain (see e.g., “ah19mZ” in Fig 3 for tumor lysis and “ah19Z” in Fig 16 for expression), one of ordinary skill in the art would have had a reason to substitute with Brentjens’ intracellular signaling domain in Srinivasan’s CD70-specific CAR in order to obtain a functional CAR with expression and tumor lysis effect.
Furthermore, since Brentjens’ intracellular signaling domain and Srinivasan’s intracellular signaling domain are for the same purpose (i.e., to construct a functional CAR with expression and tumor lysis effect), these domains are art-recognized obvious equivalents to each other. This is evidenced by Brentjens’ teaching that the CAR comprising a CD3ζ intracellular signaling domain but without a costimulatory domain (i.e., ah19mZ or ah19Z) is functional in tumor lysis (see Fig 3) and is highly expressed in T cells (see Fig 16) as compared to a CAR comprising a CD3ζ intracellular signaling domain and a CD28 costimulatory domain (ah19m28Z or ah19h28Z) or a 41BB costimulatory domain (ah19hBBZ). It is noted that the tumor lysis effect of ah19mZ might be lower than that of ah19m28Z in Fig 3 (although the corresponding curves for each CAR are difficult to identify), but the expression level of ah19Z (93.8% CAR+ cells) is clearly higher than that of ah19h28Z (88.8% CAR+) or ah19hBBZ (64.2% CAR+) (see Fig 16 and Fig 16 continued). Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Brentjens’ intracellular signaling domain for Srinivasan’s intracellular signaling domain. See MPEP 2144.06.
With respect to claim 71 directed to a genomic modification of TCRa gene but not CD70 gene, and claim 72 directed to the genomic modification comprising a gene knockout, Srinivasan teaches TCR is rendered not functional in the cells by disrupting or inactivating TCRa gene and/or TCRb gene(s) (e.g., [0320], also see Fig 5A “4F11 TCR KO” and “P08F08 TCR KO” for cells expressing anti-CD70 CAR with TCRa KO alone without CD70 KO). Thus, Srinivasan teaches the engineered immune cells further comprise a genomic modification of TCRa gene but not CD70 gene and the genomic medication comprising TCRa knockout.
With respect to claim 75 directed to the cell comprising a first nucleic acid and a second nucleic acid encoding the CARs, and claim 77 directed to a first vector and a second vector comprising the nucleic acids, Srinivasan teaches a lentiviral vector comprising a nucleic acid encoding the anti-CD70 CAR is added to the T cells for transduction (see e.g., [0457]), thus teaches a nucleic acid and a vector. Srinivasan specifically recites in reference claim 90 “A method of engineering an immune cell, comprising: a) providing an immune cell; and b) introducing into the cell at least one polynucleotide encoding said CD70-specific CAR of claim 56” and in reference claim 91 “The method of engineering an immune cell of claim 90, further comprising introducing at least one other CAR which is not specific for CD70”. Thus, Srinivasan teaches an engineered immune cell that comprises a first vector comprising a first nucleic acid encoding one CAR (i.e., “one other CAR which is not specific for CD70” in reference claim 91) and a second vector comprising a second nucleic acid encoding the CD70 specific CAR (reference claim 90).
Claim 80 is directed to the first nucleic acid or the second nucleic acid being located within a disrupted TRAC locus or a disrupted CD52 locus.
However, Srinivasan does not specifically teach the CD70-specific CAR or another CAR being located within a disrupted TRAC or CD52 locus.
Nevertheless, Srinivasan teaches TCR is rendered not functional in the cells by disrupting or inactivating TCRa gene (e.g., [0320], also see Fig 5A “4F11 TCR KO” and “P08F08 TCR KO” for cells expressing anti-CD70 CAR with TCRa KO).
Regarding the method of inactivation of the genes, Srinivasan teaches “inactivation of a gene can be accomplished by introducing into the cells at least one rare-cutting endonuclease such that the rare-cutting endonuclease specifically catalyzes cleavage in a targeted sequence of the cell genome; and optionally, introducing into the cells an exogenous nucleic acid successively …; wherein the introduced exogenous nucleic acid inactivates a gene and integrates at least one exogenous polynucleotide sequence encoding at least one recombinant protein of interest. In some embodiments, the exogenous polynucleotide sequence is integrated within a gene encoding a protein selected from the group consisting of TCRA, TCRB, CD52” (see e.g., [0281]). Thus, Srinivasan teaches targeted integration of an exogenous nucleic acid to be located within a disrupted TRAC or CD52 locus in the genome.
Regarding engineering the immune cell with exogenous CAR polynucleotides, Srinivasan teaches stable transformation methods can be used to integrate the CAR polynucleotide construct into the genome of the cell (e.g., [0308]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cell comprising exogenous polynucleotides encoding a CD70-specific CAR and another CAR and comprising a disruption of endogenous TCRa or CD52 gene suggested by Srinivasan, by integrating the CAR polynucleotide within a TRAC or CD52 locus as suggested by Srinivasan with a reasonable expectation of success. Since Srinivasan teaches the CAR polynucleotide can be stably integrated into the genome of the cell ([0308]) and teaches introducing an exogenous nucleic acid sequence within the TCRA or CD52 locus can simultaneously inactivate the TCRA or CD52 gene and integrate the exogenous nucleic acid sequence (such as an exogenous CAR polynucleotide sequence) into the genome of the cell (see e.g., [0281]), one of ordinary skill in the art would have had a reason to integrate the exogenous CAR polynucleotide within a TRAC or CD52 gene locus as suggested by Srinivasan so as to obtain an engineered immune cell comprising the first or the second CAR nucleic acid being located within a disrupted TRAC or CD52 locus in order to simultaneously achieve stable integration of CAR polynucleotides in the genome and disruption of TRAC or CD52 gene that is particularly suitable for allogeneic immunotherapy ([0294]).
With respect to claim 82 directed to the immune cell being obtained from a healthy volunteer or from a patient, and claim 88 directed to a population of immune cells of claim 82 being obtained from a healthy volunteer or from a patient, Srinivasan teaches the engineered immune cells are obtained from a healthy donor, or in some embodiments, the engineered immune cells are obtained from a patient (e.g., [0075]).
With respect to claim 89 directed to a pharmaceutical composition comprising the engineered immune cells and a pharmaceutically acceptable carrier, Srinivasan teaches the CD70 CAR T cells are resuspended in serum-free RPMI and administered to mice (see e.g., Example 7 [0477], also see [0174] for pharmaceutically acceptable carriers), thus teaches a pharmaceutical composition.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant first argues that Srinivasan does not teach or suggest a CAR lacking a co-stimulatory domain or any rationale for or benefit of omitting a costimulatory domain. Tu teaches a fourth-generation CAR with not one but two costimulatory domains and the art teaches away from the invention because the invention comprises a CAR with no costimulatory domains at all. MPEP 2144 states that omission of an element with retention of the element's function is an indicium of non-obviousness (Remarks, p. 8-9).
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Srinivasan teaches an engineered immune cell that functionally expresses a CD70-CAR and another CAR. There are two differences between Srinivasan and the instant invention in that (1) Srinivasan is silent on the other CAR, the one that is not specific for CD70, specifically binds a target of interest such as CD19, and (2) Srinivasan does not specifically teach a CD70-specific CAR that does not comprise a costimulatory domain in the working example. Tu is cited to make obvious a combinatory therapy using CAR T cells that recognize multiple tumor associated antigens including CD19 and CD70 in order to prevent tumor escape. Brentjens is cited to reduce to practice a functional first-generation CAR design that does not comprise a costimulatory domain and to evidence the first-generation CAR and the second-generation CAR being art-recognized obvious equivalents to each other (see above). Although Tu uses a fourth-generation CAR with two costimulatory domains, Tu does not negate a first-generation CAR that does not comprise a costimulatory domain. Thus, Tu does not teach away a first-generation CAR encompassed by Srinivasan and reduced to practice by Brentjens. In regard to Applicant’s argument on omission of a costimulatory domain with retention of the CAR’s function, as stated supra, Brentjens demonstrates that the first-generation CAR that does not comprise a costimulatory domain can be highly expressed in T cells and have tumor lysis function (see above), thus renders the instant invention obvious.
Applicant additionally argues that Brentjens only uses the first generation CAR constructs as a baseline control. Results in Figure 3 clearly show that first generation CART produces lower level of tumor lysis compared to second generation CART. Brentjens teaches away from the invention: a costimulatory domain is "required for efficient response" according to Brentjens. The claimed invention omits an element of Brentjens while preserving the element's function (e.g., applicant's Figures 5-7) (Remarks, p. 10-11).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to Brentjens only using the first generation CAR constructs as a baseline control, Brentjens aims to enhance immune response of CAR-T cells by arming with IL-33 (e.g., abstract), so Brentjens indeed uses the first-generation CAR and the second-generation CAR as baseline controls. However, this does not negate Brentjens’ teaching that the first-generation CAR (lacking a costimulatory domain) is highly expressed (see e.g., Fig 16) and functional in tumor lysis (see e.g., Fig 3).
In regard to results in Figure 3 showing the first generation CART producing lower level of tumor lysis thus Brentjens teaches away by teaching a costimulatory domain is “required for efficient response”, Figure 3 of Brentjens is attached below.
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As can be seen, the corresponding curves for each CAR are difficult to identify, except that the two constructs using anti-mouse CD19 scFv (am19) do not lyse tumor cells expressing human CD19 antigen. Even assuming the first generation CART (ah19mZ) produces lower level of tumor lysis (see the gray line in the middle), it obtains 100% tumor lysis at a 1:1 ratio and 50+% tumor lysis at a 0.25:1 ratio to the tumor cells, thus is clearly functional (or highly functional). Furthermore, the expression level of the first generation CAR ah19Z (93.8% CAR+ cells) is clearly higher than that of the second generation CARs ah19h28Z (88.8% CAR+) or ah19hBBZ (64.2% CAR+) (see Fig 16 and Fig 16 continued). Brentjens does not negate a first-generation CAR (e.g., see p. 77, para 1 regarding Fig 3 that only discusses IL-33 improvement), thus does not teach away a first-generation CAR.
Furthermore, it is noted that Applicant’s quotation of Brentjens (Remarks, the bridging paragraph between p. 10-11) “As used herein, "co-stimulatory molecules'' refer to cell surface molecules other than antigen receptors or their ligands that are required for an efficient response of lymphocytes to antigen” (emphasis added) actually refers to the full-length cell surface co-stimulatory molecules, but not the specific intracellular costimulatory domain within a second generation CAR. Thus, Applicant’s argument that Brentjens states a costimulatory domain is “required for efficient response” (Remarks, p. 11) is not supported by Brentjens.
In regard to Applicant’s argument that the claimed invention omits an element of Brentjens while preserving the element's function (e.g., applicant's Figures 5-7), as stated supra, Brentjens demonstrates that the first-generation CAR (lacking a costimulatory domain) can be highly expressed in T cells and have tumor lysis function (see above), thus renders the instant invention obvious.
Applicant finally argues that the applicant's data demonstrates that in the claimed CAR-T cells expressing the CD70 CAR lacking a co-stimulatory domain are as active, fit and potent (or better) as CAR-T cells having a CD70 CAR with a co-stimulatory domain (see e.g., the applicant's Figures 5-7: in every experiment clones "z" only having the CD3ζ domain outperform clones "bbz" having the CD3ζ domain and the 4-1BB costimulatory domain) (Remarks, p. 9, last full para).
Applicant’s arguments have been fully considered but they are not persuasive.
In regard to the applicant's Figures 5-7: in every experiment clones "z" outperform clones "bbz", it is noted that also in Figures 5-7, in every experiment clones “QR3z” (a first-generation CAR comprising the QR3 safety switch and a CD3ζ signaling domain) underperform clones “CD70 CAR” (a second-generation CAR comprising a QR3 safety switch and a 4-1BB costimulatory domain and a CD3ζ signaling domain, see specification, [0255] for designations). Thus, Applicant’s data demonstrate that the first-generation CARs certainly do not always outperform the corresponding second-generation CARs in a side-by-side comparison.
In regard to the argument that Applicant demonstrates the claimed CAR-T cells (having the first-generation CAR) are as active, fit and potent (or better) as second-generation CAR-T cells, as stated supra, Brentjens demonstrates that the first-generation CARs can be highly expressed in T cells (e.g., Fig 16) and have tumor lysis function (e.g., Fig 3 attached above), thus renders the instant invention obvious.
Maintained Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 65, 71-72, 75, 77, 80, 82 and 88-89 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos: 11396551 or 12152081, in view of Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 12/07/2022), Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 12/07/2022) and Brentjens et al., (WO 2019/099479 A1. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims in the cited patents recite an engineered immune cells expressing a CD70 CAR, or a method of administering an engineered immune cells expressing a CD70 CAR, wherein the engineered immune cells further comprising another CAR which is not specific for CD70, a pharmaceutical composition comprising the engineered immune cells, a method of engineering an immune cell, comprising: a) providing an immune cell; and b) introducing into the cell at least one polynucleotide encoding the CD70-specific CAR of claim 1, and further comprising introducing at least one other CAR which is not specific for CD70. The CD70 CAR comprises anti-CD70 antibody, a transmembrane domain, and an intracellular domain, wherein the intracellular signaling domain comprises a CD3ζ signaling domain.
However, the patented claims do not recite disruption of an endogenous TCRa gene in instant claims 71-72 and 80, or the other CAR binding tumor antigen CD19 or the CD70 CAR does not comprise a costimulatory domain in instant claim 65.
Srinivasan teaches an engineered immune cell comprising a CD70 CAR and another CAR that is not specific for CD70. Srinivasan teaches the engineered cells comprise a disruption of one or more endogenous genes, including TCRa or CD52 (e.g., [0074], [0277], [0280]), and related to instant claims 71-72. Srinivasan teaches the engineered immune cell is obtained from a healthy donor, or in some embodiments, the engineered immune cell is obtained from a patient (e.g., [0075]), related to instant claims 82 and 88. Srinivasan teaches the exogenous polynucleotide sequence is integrated within a gene encoding a protein selected from the group consisting of TCRA, TCRB, CD52” (see e.g., [0281]). Thus, Srinivasan teaches targeted integration of an exogenous nucleic acid to be located within a disrupted TRAC or CD52 locus in the genome, related to instant claim 80.
Tu teaches a method of combinatory CAR-T cell therapy comprising co-administering anti-CD70 CAR T cells and anti-CD19 CAR T cells to treat refractory and relapsed diffuse large B-cell lymphoma after confirming the expression of both CD19 and CD70 on the tumor cells (see e.g., abstract), related to instant claim 65. Tu teaches combination of CD19- and CD70-specific CAR T-cells may effectively target diffuse large B-cell lymphoma and maintain disease-free survival (see e.g., abstract).
Brentjens teaches an isolated immunoresponsive cell comprising CAR binds to a tumor antigen such as CD19 or CD70 (e.g., p. 6, para 2). Brentjens teaches in certain embodiments the CAR does not comprise a co-stimulatory signaling domain and teaches an exemplary functional CD19 CAR (19z) comprising a CD19 scFv antibody and a CD3ζ intracellular signaling domain (see Fig 1A, first row, in the cover page), that does not comprise a co-stimulatory signaling domain, related to instant claim 65.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cells expressing a CD70 CAR and another CAR recited in the patented claims, by combining disruption of an endogenous TCRa gene to target integrate the CAR polynucleotide as suggested by Srinivasan, by choosing the other CAR binding tumor antigen CD19 as suggested by Tu and by choosing a CAR structure that does not comprise a costimulatory signaling domain as suggested by Brentjens with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make these modifications in order to produce CD70 CAR immune cells that are particularly suitable for allogeneic immunotherapy as suggested by Srinivasan (e.g., [0294]), to achieve a combination therapy with CD19 for a lymphoma expressing both CD19 and CD70 to prevent tumor escape as suggested by Tu, and to obtain a functional CAR with the structure reduced to practice by Brentjens.
Since the instant application claims are obvious over cited patent claims, in view of Srinivasan, Tu and Brentjens, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged.
Applicant argues that as stated in the preceding section, the amended claims recite a structure omitting an essential element present in the art. The art contains nothing to induce one of ordinary skill to omit a costimulatory domain (Remarks, p. 12).
Applicant’s arguments have been fully considered but they are not persuasive for the same reasons discussed above. Specifically, in regard to omitting an essential element, Brentjens reduces to practice a functional first-generation CAR that does not comprise a costimulatory domain (the same as claimed), and evidences that the first-generation CAR is highly expressed (e.g., Fig 16) and is functional in tumor lysis (e.g., Fig 3 attached above). Thus, Brentjens reduces to practice the claimed CAR structure, and evidences that the first-generation CAR and the second-generation CAR being art-recognized obvious equivalents to each other.
Provisional Double Patenting Rejections
Claims 65, 71-72, 75, 77, 80, 82 and 88-89 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application No: 18/919,327, 18/361,056 or 18/521,196, in view of Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 12/07/2022), Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 12/07/2022) and Brentjens et al., (WO 2019/099479 A1. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in the cited application ‘327 recite an engineered immune cells expressing a CD70 CAR, or a method of administering an engineered immune cells expressing a CD70 CAR, wherein the engineered immune cells further comprising another CAR which is not specific for CD70, a pharmaceutical composition comprising the engineered immune cells, a method of engineering an immune cell, comprising: a) providing an immune cell; and b) introducing into the cell at least one polynucleotide encoding the CD70-specific CAR of claim 1, and further comprising introducing at least one other CAR which is not specific for CD70. The CD70 CAR comprises anti-CD70 antibody, a transmembrane domain, and an intracellular domain, wherein the intracellular signaling domain comprises a CD3ζ signaling domain. Copending claims in ‘056 recite an engineered immune cells comprising an antigen binding domain and a CD70 binding protein wherein the antigen binding protein is a CAR and wherein the engineered immune cell expresses one or more of the CAR, TCR and CD70 binding protein. The engineered immune cell comprising a genomic modification of an endogenous TCRa and optionally wherein the cel lfurther comprises genomic modifications of an endogenous CD52 gene. The engineered immune cell is obtained from a healthy volunteer or a patient, or an iPSC. Copending claims of ‘196 recite an engineered immune cell comprising a CD70 binding protein and a CAR binding to Claudin 18.2, the CD70 binding protein comprising an anti-CD70 antibody and a transmembrane.
However, the copending claims do not recite disruption of an endogenous TCRa gene in instant claims 71-72 and 80, or the other CAR binding tumor antigen CD19 or the CD70 CAR does not comprise a costimulatory domain in instant claim 65.
Srinivasan teaches an engineered immune cell comprising a CD70 CAR and another CAR that is not specific for CD70. Srinivasan teaches the engineered cells comprise a disruption of one or more endogenous genes, including TCRa or CD52 (e.g., [0074], [0277], [0280]), and related to instant claims 71-72. Srinivasan teaches the engineered immune cell is obtained from a healthy donor, or in some embodiments, the engineered immune cell is obtained from a patient (e.g., [0075]), related to instant claims 82 and 88. Srinivasan teaches the exogenous polynucleotide sequence is integrated within a gene encoding a protein selected from the group consisting of TCRA, TCRB, CD52” (see e.g., [0281]). Thus, Srinivasan teaches targeted integration of an exogenous nucleic acid to be located within a disrupted TRAC or CD52 locus in the genome, related to instant claim 80.
Tu teaches a method of combinatory CAR-T cell therapy comprising co-administering anti-CD70 CAR T cells and anti-CD19 CAR T cells to treat refractory and relapsed diffuse large B-cell lymphoma after confirming the expression of both CD19 and CD70 on the tumor cells (see e.g., abstract), related to instant claim 65. Tu teaches combination of CD19- and CD70-specific CAR T-cells may effectively target diffuse large B-cell lymphoma and maintain disease-free survival (see e.g., abstract).
Brentjens teaches an isolated immunoresponsive cell comprising CAR binds to a tumor antigen such as CD19 or CD70 (e.g., p. 6, para 2). Brentjens teaches in certain embodiments the CAR does not comprise a co-stimulatory signaling domain and teaches an exemplary functional CD19 CAR (19z) comprising a CD19 scFv antibody and a CD3ζ intracellular signaling domain (see Fig 1A, first row, in the cover page), that does not comprise a co-stimulatory signaling domain, related to instant claim 65.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cells expressing a CD70 CAR and another CAR recited in the application claims, by combining disruption of an endogenous TCRa gene to target integrate the CAR polynucleotide as suggested by Srinivasan, by choosing the other CAR binding tumor antigen CD19 as suggested by Tu and by choosing a CAR structure that does not comprise a costimulatory signaling domain as suggested by Brentjens with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make these modifications in order to produce CD70 CAR immune cells that are particularly suitable for allogeneic immunotherapy as suggested by Srinivasan (e.g., [0294]), to achieve a combination therapy with CD19 for a lymphoma expressing both CD19 and CD70 to prevent tumor escape as suggested by Tu, and to obtain a functional CAR with the structure reduced to practice by Brentjens.
Since the instant application claims are obvious over cited application claims, in view of Srinivasan, Tu and Brentjens, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending applications have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged and have been discussed above.
Claims 65, 71-72, 75, 77, 80, 82 and 88-89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application No: 19/363,288, 19/420,409 and 19/420,431, in view of Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 12/07/2022). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in the applications recite a method of introducing into immune cells a CD70 binding protein that comprises a CD70 binding domain that is a CD70-binding CAR, comprising a CD70 binding scFv and a transmembrane domain, the CD70 binding protein comprises a CD3z signaling domain and does not comprise a costimulatory domain, the cells also express a second antigen-binding protein being a CAR capable of binding a non-CD70 protein, the CAR comprises an intracellular CD3z signaling domain and a co-stimulatory domain, the second antigen-binding protein binds a protein selected from a list, the cells further comprise a genomic modification of TCRa gene, the cells being allogenic from the patient. The copending claims recite the cells being for treatment, thus indicates a pharmaceutic composition.
However, the copending claims do not recite targeted integration of CARs into the disrupted TCRa gene locus in instant claim 80, or the transmembrane domains of the CARs being the same in instant 65, or the cells obtained from a healthy donor in claim 82 and 88.
Srinivasan teaches the engineered immune cell is obtained from a healthy donor (e.g., [0075]), related to instant claims 82 and 88. Srinivasan teaches the exogenous polynucleotide sequence is integrated within a gene encoding a protein selected from the group consisting of TCRA, TCRB, CD52” (see e.g., [0281]). Thus, Srinivasan teaches targeted integration of an exogenous nucleic acid to be located within a disrupted TRAC or CD52 locus in the genome, related to instant claim 80. Srinivasan suggests both the first transmembrane domain and the second transmembrane domain in the CARs may be a CD8α transmembrane domain (see e.g., end of [0200] and reference claim 69), thus suggests the first and the second transmembrane domains are the same transmembrane domain in instant claim 65.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cells expressing a CD70 CAR and another CAR recited in the application claims, by combining obtaining the cells from a heathy donor, combining targeted integration of CARs into disrupted TRAC locus, and choosing the same transmembrane domain in the CARs as suggested by Srinivasan with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to make these modifications in order to produce CD70 CAR immune cells that are particularly suitable for allogeneic immunotherapy as suggested by Srinivasan (e.g., [0294]).
Since the instant application claims are obvious over cited application claims, in view of Srinivasan, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending applications have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 03/11/2026 are acknowledged and have been discussed above.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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