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 05/20/2026, Applicant has amended claims 3, 11, 18, 25, 31 and 37, newly canceled claims 7, 8, 13, 17, 20, 22, 26, 28-30 and 33, and added new claims 110-113.
Claim Status
Claims 3-4, 6, 11, 18-19, 25, 31, 37, 100 and 110-113 are pending and are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/20/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Elvin Lauron on 05/20/2026 is insufficient to overcome the rejection of instant claims based upon 35 U.S.C 103 as set forth below.
Withdrawn Claim Objections
The prior objection to claims 18 and 37 is withdrawn in light of Applicant’s amendment to the claims.
New Claim Objections
Claim 3 is objected to because of the following informalities:
Claim 3 recites the term “the tumor” at the end of limitation (ii). since the preamble recites a cancer, it is recommended to change to “the cancer” to be consistent.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of claims 11 and 29-30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for insufficient antecedent basis is withdrawn in light of Applicant’s cancellation of claims 29-30 and amendment to claim 11.
New 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 31 and 37 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.
Claim 31 and Claim 37 both recite the limitation “the additional antigen binding protein”. There is insufficient antecedent basis for this limitation in the claims because the base claim 3 recites a CD70 binding protein and a second antigen binding protein, but is silent on an additional antigen binding protein. This limitation is examined as “the second antigen binding protein”.
Maintained Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 stands rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 recites the CD3ζ signaling domain comprises an amino acid sequence selected from a group of sequences, including SEQ ID NO: 587, which is directed to a CD27 intracellular domain (see specification Table 4 in p. 71). Thus, the SEQ ID NO: 587 fails to further limit the CD3ζ signaling domain of the base claim 3.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Traversal:
Applicant’s argument filed on 05/20/2026 is acknowledged.
Applicant argues that amended claim 11 now depends on claim 3 and limits the term thereof "CD3ζ signaling domain" to the variants of the CD3ζ signaling domain listed in Table 4 of the specification (Remarks, p. 6).
Applicant’s argument has been fully considered but it is not persuasive. As stated supra, the recited SEQ ID NO: 587 is directed to a CD27 intracellular domain (see specification, Table 4 in p. 71), thus fails to further limit the CD3ζ signaling domain.
Withdrawn Claim Rejections - 35 USC § 102
The prior rejection of claims 3-4, 6-7, 11, 13, 17-20, 22, 25, 28, 31, 33 and 100 under 35 U.S.C. 102 (a)(1) as being anticipated by Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), is withdrawn in light of Applicant’s cancellation of claims 7, 13, 17, 20, 22, 28 and 33 and amendment to claim 3 to recite new limitation that the CD70 binding protein does not comprise a costimulatory domain.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), and in view of Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025) is withdrawn in light of Applicant’s cancellation of claim 8.
The prior rejection of claim 26 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), and in view of Park et al., (N Engl J Med. 2018;378:449-459) is withdrawn in light of Applicant’s cancellation of claim 26.
The prior rejection of claims 29-30 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), and in view of Yang et al., (Theranostics. 2020; 10(17): 7622-7634. Cited in IDS 10/13/2025) is withdrawn in light of Applicant’s cancellation of claims 29-30.
The prior rejection of claim 37 under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), and in view of Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 10/13/2025) is withdrawn in light of Applicant’s amendment to claim 3 to recite new limitation that the CD70 binding protein 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 3-4, 6, 11, 18-19, 25, 31, 100 and 110-113 are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by McEarchern et al., (Blood. 2006; 108(11): 1728. P. 1-2), and in view of Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025).
With respect to claim 3, it is noted that the limitation “lymphodepletion" is interpreted as intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Thus, the limitation “a method of lymphodepletion” is reasonably interpreted as a method that is capable of performing lymphodepletion or that naturally results in lymphodepletion as recited in the preamble. Furthermore, in regard to the new limitation “a patient diagnosed with a cancer, wherein the cells of the cancer do not express CD70”, Applicant states that this amended new limitation of “a cancer that does not express CD70 for which support is found e.g., in paragraph [030] listing a number of cancers known to not express CD70” (Remarks, p. 5, section “Amendments to the claims”, para 1). Both the specification paragraph [030] and new claim 113 recite a number of cancers including glioma. Thus, for the purposes of search and examination, glioma is selected as a species of a cancer that does not express CD70. Accordingly, the new limitation in claim 3 is examined as “a patient diagnosed with glioma”, as it is “a cancer, wherein the cells of the cancer do not express CD70”.
Srinivasan teaches a method of treating cancers comprising administering to a subject in need thereof an effective amount of engineered immune cells expressing a CD70-specific CAR (e.g., [0081], [0079]).
In regard to the type of cancers, Srinivasan teaches “the disclosure is particularly useful for the treatment of cancer such as lymphoma, leukemia, glioma or Renal Cell Carcinoma” (e.g., [0003], [0076], [0081], also see reference claim 96), thus teaches the instantly claimed limitation of “a patient diagnosed with glioma” which, as discussed above, satisfies the limitation of “a cancer, wherein the cells of the cancer do not express CD70”.
In regard to the cells being allogeneic, Srinivasan teaches the engineered immune cell is obtained from a healthy donor (e.g., [0075]) and is suitable for allogeneic immunotherapy (e.g., [0294], [0406]).
In regard to the cells comprising or functionally expressing (i) a CD70 binding protein and (ii) a second antigen binding protein, Srinivasan teaches the engineered immune cell expresses (i) a CD70-specific CAR (i.e., a CD70 binding protein) and (ii) another CAR which is not specific for CD70 (i.e., a second antigen binding protein other than the CD70 binding protein) (e.g., [0072] and reference claims 76 and 77). Srinivasan further teaches combining CD70 CAR with the other heme targets offers opportunity to target or prevent tumor antigen escape (p. 72, right col, para 1), thus indicates that the second antigen binding protein recognizes an antigen on the cells of the tumor so as to prevent tumor antigen escape. Srinivasan teaches the CD70-specific CAR comprises an extracellular ligand binding domain (comprising a scFv binding to CD70, i.e., a CD70 binding domain), a transmembrane domain, and an intracellular signaling domain (e.g., [0086]) and examples of intracellular signaling domains used in the disclosure can include as those derived from TCRζ (i.e., a CD3ζ signaling domain) (e.g., [0198]).
In regard to Srinivasan’s method of administering allogeneic CD70-specific CAR T cells resulting in lymphodepletion and depleting non-cancerous CD70 positive T cells in the patient, McEarchern evidences that CD70 is expressed on activated lymphocytes and is important for generation of B and T memory and effector responses, and blockade of CD70 interaction with its receptor has been shown to inhibit cardiac allograft rejection in mice (p. 1, beginning of Abstract). McEarchern evidences that an antibody targeting CD70 (SGN-70) selectively depletes CD70+ activated T cells as SGN-70 treatment decreases the number of CD70+CD8+Vβ17+ cells by >80% and this depletion is dependent on the activity of CD16+ cells within the culture (i.e., via antibody-dependent cellular cytotoxicity) (see p. 1). Accordingly, McEarchern evidences that Srinivasan’s method of administering allogeneic CD70-specific CAR T cells would naturally result in lymphodepletion and would naturally deplete non-cancerous CD70 positive T cells in the patient.
However, Srinivasan and McEarchern do not specifically teach the CD70 binding protein comprises a CD3ζ signaling domain but does not comprise a costimulatory domain in the working example.
Nevertheless, 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 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 signaling domain (see Fig 1A, first row, in the cover page) and 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 method comprising administering an engineered immune cell expressing a CD70-specific CAR comprising a CD3ζ intracellular signaling domain in which a costimulatory domain is optional suggested by Srinivasan evidenced by McEarchern, by substituting with Brentjens’ intracellular signaling domain comprising only a CD3ζ signaling domain but not 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 only a CD3ζ intracellular signaling domain but not 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 4 directed to an anti-CD70 antibody scFv, as stated supra, Srinivasan teaches the CD70 binding domain comprises a single chain Fv fragment (scFv) binding to the extracellular domain of CD70 (e.g., [0086]).
With respect to claim 6 directed to a hinge domain, Srinivasan teaches the CAR comprises a stalk domain (i.e., a hinge domain) between the extracellular ligand-binding domain and the transmembrane domain, that is selected from the group consisting of a human CD8a hinge and others (e.g., [0062]).
With respect to claim 11 directed to the CD3ζ signaling domain comprising the sequence of SEQ ID NO: 272, Srinivasan teaches an exemplary CD70-specific CAR having a CD3ζ intracellular signaling domain (see Table 5 in p. 51, reference SEQ ID NO: 311) that comprises the sequence of instant SEQ ID NO: 272 (see below).
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With respect to claim 18 directed to a genomic modification of TCRa gene but not CD70 gene, Srinivasan teaches TCR is rendered not functional in the cells by disrupting or inactivating TCRa gene and/or TCRb gene(s) for treating patients against Host versus Graft (HVG) rejection and Graft versus Host Disease (GVHD) (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 comprise a genomic modification of TCRa gene but not CD70 gene such that the cells exhibit reduced level of TCRa expression.
With respect to claim 19 directed to the patient having or being expected to have a host v. graft rejection, as stated supra, Srinivasan teaches the engineered immune cell is obtained from a healthy donor (e.g., [0075]) and is suitable for allogeneic immunotherapy (e.g., [0294], [0406]), thus the patient is expected to have a host v. graft rejection. Additionally, Srinivasan teaches the method of treating patients in need thereof against Host versus Graft (HVG) rejection and Graft versus Host Disease (GVHD) (e.g., [0320]).
With respect to claim 25 directed to the patient being further administered a lymphodepleting agent before the engineered immune cells wherein the lymphodepleting agent is administered at a lower level compared to a patient receiving cells that do not express a CD70 binding protein, Srinivasan teaches the cell compositions of the disclosure are administered to a patient in conjunction with, e.g., following T cell ablative therapy using chemotherapy agents such as cyclophosphamide (e.g., p. 49, para 1, [0415]), thus teaches the patient is further administered a lymphodepleting agent before the engineered immune cells. As stated supra, McEarchern evidences that Srinivasan’s method of administering allogeneic CD70-specific CAR T cells would naturally result in lymphodepletion and would naturally deplete non-cancerous CD70 positive T cells in the patient (see above). Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen to administer the lymphodepleting agent at a lower level with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since McEarchern evidences that Srinivasan’s method of administering allogeneic CD70-specific CAR T cells would naturally result in lymphodepletion such that a lower level of the lymphodepleting agent would be sufficient to achieve lymphodepletion with less side effect.
With respect to claim 31, as stated supra, Srinivasan teaches the 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 the second antigen binding protein, other than the CD70 binding protein, is a 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 CAR comprises a CD3ζ signaling domain and a costimulatory domain (e.g., the 4-1BB costimulatory domain).
With respect to claim 100 directed to the dosage of the engineered immune cells, Srinivasan teaches the method comprises administration of about 104 to about 109 cells per kg body weight of the patient (e.g., [0409]), within the claimed range.
With respect to claim 110, it is noted that the cited SEQ ID NO: 592 is directed to a rituximab mimotope (see instant specification, Table 4 in page 71). Srinivasan teaches the same rituximab mimotope having the same sequence as cited in reference SEQ ID NO: 293 (see p. 44, left col). Srinivasan’s SEQ ID NO: 291 also comprises two copies (amino acids 1-9 and 40-48) of these rituximab mimotope sequences (see p. 44, right col). Srinivasan teaches “In some embodiments, the CAR-T cell comprises a polynucleotide encoding a suicide polypeptide….In some embodiments, the suicide polypeptide comprises the amino acid sequence shown in SEQ ID NO: 291” ([0328] in p. 44). Thus, since Srinivasan teaches only “in some embodiments” the CAR further comprises a suicide polypeptide comprising the reference SEQ ID NO: 291 (that comprises the instant SEQ ID NO: 592), one of ordinary skill in the art would have acknowledged that Srinivasan encompasses a CD70-specific CAR that does not comprise instant SEQ ID NO: 592.
With respect to claim 111 directed to the CD70 binding protein comprising SEQ ID NO: 594 but not SEQ ID NO: 596, it is noted that the cited SEQ ID NO: 594 is directed to an epitope recognized by antibody QBEND-10 (see instant specification, Table 4 in page 71) and the cited SEQ ID NO: 596 is directed to two copies of the same epitope linked by linker sequences (see instant specification, Table 4 in page 71). Srinivasan teaches the same epitope (“QBEND-10 Epitope 2”) having the same sequence as instant SEQ ID NO: 594 (reference SEQ ID NO: 295, p. 44, left col, see comparison of reference SEQ ID NO: 295 with instant SEQ ID NO: 594 below).
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Srinivasan teaches the method comprises in vitro sorting of a population of immune cells wherein a subset of the population of immune cells comprises engineered immune cells expressing the CD70-specific CARs comprising epitopes specific for monoclonal antibodies described herein (see p. 45, left col, section “Method for Sorting CAR-Positive Immune Cells”, [0334]-[0400]). Srinivasan teaches “the extracellular binding domain of the CAR comprises a mAb specific epitope of SEQ ID NO: 295 and the antibody used to contact the population of immune cells is QBEND-10” (e.g., [0336]). Srinivasan teaches the sorted population comprises at least 85% of CAR-expressing immune cells (e.g., [0338]).
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 method suggested by Srinivasan evidenced by McEarchern and in view of Brentjens, by combining a QBEND-10 mAb specific epitope having the claimed sequence of SEQ ID NO: 594 in the extracellular binding domain of the CAR as suggested by Srinivasan with a reasonable expectation of success. Since Srinivasan teaches combining an epitope enables in vitro sorting to obtain high-purity CAR-expressing immune cells (e.g., [0338]), one of ordinary skill in the art would have had a reason to combine an epitope having the instant SEQ ID NO: 594 to facilitate in vitro sorting to obtain purified CAR-T cells for administration. Furthermore, one of ordinary skill in the art would have acknowledged Srinivasan’s epitope-CAR comprising reference SEQ ID NO: 295 (the same as the instant SEQ ID NO: 594) would not comprise the instant SEQ ID NO: 596.
With respect to claim 112 directed to the CD70 binding protein comprising SEQ ID NO: 596, as stated supra, the cited SEQ ID NO: 596 is directed to two copies of the same QBEND-10 epitope flanked by GSGGGGS linkers (i.e., linker-epitope-linker-epitope, see instant specification, Table 4 in page 71, and see below).
GSGGGGSELPTQGTFSNVSTNVSPAKPTTTAGSGGGGSELPTQGTFSNVSTNVSPAKPTTTA
As stated supra, Srinivasan teaches the same epitope having the same sequence (reference SEQ ID NO: 295 that has the same sequence as that bolded in instant SEQ ID NO: 596 herein, p. 44, left col. Also see comparison above). Srinivasan further teaches “In some embodiments, two instances of the same epitope, separated by linkers, may be used in the CAR” (p. 46, para 1). Srinivasan teaches several arrangements of epitopes in the extracellular binding domain of the CAR, including “(L)x - Epitope1 - (L)x - Epitope2 - (L)x - V1 - L1 - V2” (e.g., [0352], in which L stands for linkers), thus teaches the claimed format of linker-epitope-linker-epitope. In the exemplary reference SEQ ID NO: 294, Srinivasan uses a linker sequence GSGGGGS (see p. 46, left col). In summary, Srinivasan suggests an arrangement of two copies of the same epitope (e.g., the QBEND-10 epitope “ELPTQGTFSNVSTNVSPAKPTTTA”) that has a linker GSGGGGS in the 5’ end and between the two copies, i.e., has the sequence of GSGGGGS – ELPTQGTFSNVSTNVSPAKPTTTA – GSGGGGS – ELPTQGTFSNVSTNVSPAKPTTTA, which is the same as the instant SEQ ID NO: 596.
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 method suggested by Srinivasan evidenced by McEarchern and in view of Brentjens, by combining an arrangement of two copies of the same QBEND-10 mAb epitope flanked by linkers having the claimed sequence of SEQ ID NO: 596 in the extracellular binding domain of the CAR as suggested by Srinivasan with a reasonable expectation of success. Since Srinivasan suggests that two instances of the same epitope, separated by linkers, may be used in the CAR (p. 46, para 1) and reduces to practice the QBEND-10 mAb epitope and the GSGGGGS linker, one of ordinary skill in the art would have had a reason to combine two copies of epitope flanked by linkers having the instant SEQ ID NO: 596 to facilitate in vitro sorting to obtain purified CAR-T cells for administration (e.g., [0338]).
With respect to claim 113 directed to the cancer being glioma, as stated supra, Srinivasan teaches “the disclosure is particularly useful for the treatment of cancer such as lymphoma, leukemia, glioma or Renal Cell Carcinoma” (e.g., [0003], [0076], [0081], also see reference claim 96), thus teaches the cancer is glioma.
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 argument and Dr. Elvin Lauron’s declaration filed on 05/20/2026 are acknowledged.
Applicant first argues amended claim 3 recites a method of lymphodepletion in a cancer patient wherein the cells of the cancer (the malignant cells) do not express CD70. Srinivasan is lacking this limitation as it expressly teaches targeting CD70-expressing cancer cells (Remarks, p. 7, para 2 and p. 8, last para).
Applicant’s argument has been fully considered but it is not persuasive. As stated supra, in regard to the new limitation “a patient diagnosed with a cancer, wherein the cells of the cancer do not express CD70”, Applicant states that this amended new limitation of “a cancer that does not express CD70 for which support is found e.g., in paragraph [030] listing a number of cancers known to not express CD70” (Remarks, p. 5, section “Amendments to the claims”, para 1). Both the specification paragraph [030] and new claim 113 recite a number of cancers including glioma. Thus, for the purposes of search and examination, glioma is selected as a species of a cancer that does not express CD70. Accordingly, the new limitation in claim 3 is examined as “a patient diagnosed with glioma”, as it is “a cancer, wherein the cells of the cancer do not express CD70” as argued by Applicant and supported by dependent claim 113. In the instant case, Srinivasan teaches “the disclosure is particularly useful for the treatment of cancer such as lymphoma, leukemia, glioma or Renal Cell Carcinoma” (e.g., [0003], [0076], [0081], also see reference claim 96), thus teaches the cancer is glioma and satisfies the new limitation in claim 3 and claim 113.
Applicant further argues, and Dr. Lauron declares that Zhao was unable to achieve lymphodepletion (Remarks, p. 7, last para, and Declaration, para 6, and Shariff et al., 2011).
Applicant's argument and Dr. Lauron’s declaration regarding Zhao become moot because the new ground of rejection does not rely on Zhao for any teaching or matter specifically challenged in the argument. As necessitated by amendment, prior art McEarchern is cited to evidence CD70 blockade would naturally result in direct depletion of non-cancerous CD70 positive T cells in the patient. See McEarchern evidencing that an antibody targeting CD70 (SGN-70) selectively depletes CD70+ activated T cells as SGN-70 treatment decreases the number of CD70+CD8+Vβ17+ cells by >80% and this depletion is dependent on the activity of CD16+ cells within the culture (i.e., via antibody-dependent cellular cytotoxicity) (see p. 1).
Applicant further argues, and Dr. Lauron declares that Srinivasan teaches 2nd generation anti-CD70 CAR T cells but does not produce anti-CD70 CAR T cells without a costimulatory domain and does not test their survival in the presence of alloreactive T cells. Brentjens only makes anti-CD19 CAR T cells and has no data on anti-CD70 CAR T cells. Thus, cited art contains no data and no teachings that could be used to form an expectation of success (Remarks, p. 9, Declaration para 10).
Applicant’s arguments and Dr. Lauron’s declaration have been fully considered but they are not persuasive. As a first matter, as stated supra, 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.
Furthermore, Regarding Brentjens only makes anti-CD19 CAR T cells and has no data on anti-CD70 CAR T cells, Applicant is reminded that a 35 U.S.C. § 103 based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, Srinivasan has already taught a method of administering anti-CD70 CAR T cells and has suggested a costimulatory domain in the CAR is optional. Brentjens is cited to teach the construction of a CAR that does not comprises a costimulatory domain and further assay the function and expression of that CAR construct. Brentjens teaches 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). Thus, one of ordinary skill in the art would have substituted with Brentjens’ CAR construct that comprises only a CD3ζ signaling domain but not a co-stimulatory domain to make Srinivasan’s anti-CD70 CAR with a reasonable expectation of success. Furthermore, McEarchern evidences CD70 blockade would naturally result in direct depletion of non-cancerous CD70 positive T cells in the patient. Thus, Srinivasan’s functional anti-CD70 CAR T cells would naturally deplete activated CD70 positive host T cells, and would thus survives better in the patient.
Applicant further argues, and Dr. Lauron declares that both the Brentjens reference and the state of the art point one of ordinary skill away from omitting costimulatory domains (Remarks, p. 10, para 1, Declaration, para 9).
Applicant’s arguments and Dr. Lauron’s declaration have been fully considered but they are not persuasive. As a first matter, declaration without specifically pointing to factually supported objective evidence in the record is insufficient to overcome a 103 rejection. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
Furthermore, 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) that 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 is actually 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). Thus, 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.
Applicant further argues, and Dr. Lauron declares unexpectedly improved properties that “the CAR T cells without the costimulatory domain consistently survived better than the CART cells with the costimulatory domain," (Affidavit, par. 4, Remarks, p. 10, para 2, and referring to instant Fig 6A and in the post-filing evidence in a recently accepted article in journal Nature Communications).
Applicant’s arguments and Dr. Lauron’s declaration have been fully considered but they are not persuasive. MPEP § 2145 states that a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). In the instant case, the instant Fig 6A is modified and attached below:
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As can be seen, the CD70 CAR T cells (a second-generation CAR comprising a 4-1BB costimulatory domain and a CD3ζ signaling domain, see specification, [0255] for designations) survive the best. Thus, the statement “the CAR T cells without the costimulatory domain consistently survived better than the CART cells with the costimulatory domain” is not supported by the factually supported objective evidence identified by Applicant.
Applicant further argues, and Dr. Lauron declares lack of success in the art ("failure of others") because although many antigens are known to be expressed on T cells, no CART-based lymphodepletion exists to date. Specifically for CD70, its use in allorejection has not been proposed by others until after the priority date (Affidavit, par. 8, Remarks, p. 10-11 and Verma et al., 2024).
Applicant’s arguments and Dr. Lauron’s declaration and Verma et al. have been fully considered but they are not persuasive. As stated supra, McEarchern specifically evidences that CD70 is expressed on activated lymphocytes and is important for generation of B and T memory and effector responses, and blockade of CD70 interaction with its receptor has been shown to inhibit cardiac allograft rejection in mice (p. 1, beginning of Abstract), thus evidences that CD70 blockade has been used in relieving allorejection. Furthermore, McEarchern evidences that an antibody targeting CD70 (SGN-70) selectively depletes CD70+ activated T cells as SGN-70 treatment decreases the number of CD70+CD8+Vβ17+ cells by >80% and this depletion is dependent on the activity of CD16+ cells within the culture (i.e., via antibody-dependent cellular cytotoxicity) (see p. 1). Accordingly, McEarchern evidences that Srinivasan’s method of administering allogeneic CD70-specific CAR T cells would naturally result in lymphodepletion and would naturally deplete non-cancerous CD70 positive T cells in the patient.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) as evidenced by McEarchern et al., (Blood. 2006; 108(11): 1728. P. 1-2), and in view of Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025), as applied to claim 3 above, and further in view of Lin et al., (Expert Opin Biol Ther. 2016;16(10):1265-75).
Brentjens teaches examples of cancer include glioma (e.g., p. 71, line 25) and teaches the tumor antigen is selected from the group including EGFRvIII (e.g., p. 25, line 10 and reference claim 16).
However, Srinivasan, McEarchern and Brentjens do not specifically teach targeting EGFRvIII for treating glioma.
Lin summarizes cellular immunotherapy for malignant gliomas, including CAR-T cell therapy (see e.g., abstract). Regarding administering anti-EGFRvIII CAR T cells for treating glioma, Lin refers to a clinical trial (NCT01454596, study name “CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII”) in which anti-EGFRvIII CAR-transduced PBL are administered to a patient diagnosed with aalignant gliomas expressing EGFRvIII (see p. 1268, Table 2, the fourth row from bottom, also see p. 1270, left col, last para).
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 method of administering engineered immune cells comprising an anti-CD70 CAR and a second CAR to a patient diagnosed with glioma suggested by Srinivasan evidenced by McEarchern and in view of Brentjens, by choosing the second CAR targeting EGFRvIII as suggested by Lin with a reasonable expectation of success. Since Lin summarizes a clinical trial using anti-EGFRvIII CAR T cells in glioma patients, one of ordinary skill in the art would have had a reason to choose EGFRvIII as the targeting antigen of the second CAR in order to perform combinatory therapy to target and prevent tumor antigen escape (Srinivasan, p. 72, right col, para 1).
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 argument and Dr. Elvin Lauron’s declaration filed on 05/20/2026 are acknowledged and have been discussed above.
Furthermore, Applicant's argument regarding Tu (Remarks, p. 12, para 1) becomes moot because the new ground of rejection does not rely on Tu for any teaching or matter specifically challenged in the argument.
Withdrawn Double Patenting Rejections
The prior rejection of Claims 3-4, 6-8, 11, 13, 17-20, 22, 25-26, 28-31, 33, 37 and 100 on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos: 11396551 (‘551) or 12152081 (‘081), in view of Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025), Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025), Park et al., (N Engl J Med. 2018;378:449-459), Yang et al., (Theranostics. 2020; 10(17): 7622-7634. Cited in IDS 10/13/2025) and Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 10/13/2025), is withdrawn in light of Applicant;s cancellation of claims 7, 8, 13, 17, 20, 22, 26, 28, 29, 30 and 33 and amendment to claim 3 to recite the new limitation that the engineered immune cells deplete non-cancerous CD70 positive T cells in the patient.
Withdrawn Provisional Double Patenting Rejections
The prior provisional rejection of Claims 3-4, 6-8, 11, 13, 17-20, 22, 25-26, 28-31, 33, 37 and 100 rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application NOs: 18/919,327, 18/361,056, 18/521,196, 19/420,431, 19/420,409 or 19/363,288 in view of Zhao et al., (Front. Immunol. 2021 February; 11:555996. P. 1-12), Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025), Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025), Park et al., (N Engl J Med. 2018;378:449-459), Yang et al., (Theranostics. 2020; 10(17): 7622-7634. Cited in IDS 10/13/2025) and Tu et al., (Front. Oncol. 2019;9:1350, p. 1-6. Cited in IDS 10/13/2025) is withdrawn in light of Applicant;s cancellation of claims 7, 8, 13, 17, 20, 22, 26, 28, 29, 30 and 33 and amendment to claim 3 to recite the new limitation that the engineered immune cells deplete non-cancerous CD70 positive T cells in the patient.
New 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 3-4, 6, 11, 18-19, 25, 31, 37, 100 and 110-113 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos: 11396551 (‘551) or 12152081 (‘081), in view of McEarchern et al., (Blood. 2006; 108(11): 1728. P. 1-2), Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025), Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) and Lin et al., (Expert Opin Biol Ther. 2016;16(10):1265-75). 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 (‘551, that can be obviously used in administering to a subject diagnosed with a cancer as instantly claimed), or a method of administering an engineered immune cells expressing a CD70 CAR for treating cancers including glioma (‘081), related to instant claims 3 and 113. Wherein the engineered immune cells further comprising another CAR which is not specific for CD70 (related to instant claims 3 and 37). The CD70 CAR comprises anti-CD70 antibody, a transmembrane domain (related to instant claims 3-4), a stalk domain (related to instant claim 6), and an intracellular domain, wherein the intracellular signaling domain comprises a CD3ζ signaling domain (related to instant claims 3 and 11). The immune cell is allogeneic to the subject (‘081, related to instant claim 3, and thus the patient expected to have a host v. graft rejection in claim 19), the method further comprises administering one or more additional therapies (related to instant claim 25).
However, the patented claims do not recite the method of lymphodepletion and depleting non-cancerous CD70 positive T cells in instant claim 3 and administering a lower level of lymphodepleting agent in instant claim 25, the CD70 CAR having no costimulatory domain in claim 3, the sequence of CD3ζ in claim 11, the cells comprising genomic modification of TCRa gene in claim 18, the second antigen binding domain is a CAR comprising a costimulatory domain in claim 31, the dosage of the immune cells in claim 100, the additional epitope sequience in the CAR in claims 110-112, or the other CAR binding tumor antigen EGFRvIII in claim 37.
McEarchern evidences that CD70 is expressed on activated lymphocytes and is important for generation of B and T memory and effector responses, and blockade of CD70 interaction with its receptor has been shown to inhibit cardiac allograft rejection in mice (p. 1, beginning of Abstract). McEarchern evidences that an antibody targeting CD70 (SGN-70) selectively depletes CD70+ activated T cells as SGN-70 treatment decreases the number of CD70+CD8+Vβ17+ cells by >80% and this depletion is dependent on the activity of CD16+ cells within the culture (i.e., via antibody-dependent cellular cytotoxicity) (see p. 1). Thus, McEarchern evidences blockade of CD70, such as anti-CD70 CAR T cells would have naturally resulted in lymphodepletion and depleting non-cancerous CD70 positive T cells in instant claim 3 and makes obvious administering a lower level of lymphodepleting agent in instant claim 25.
Brentjens encompass a CD70 CAR (e.g., p. 6, para 2). Brentjens teaches in certain embodiments, the CAR does not comprise a co-stimulatory signaling domain and reduces to practice a CD19 CAR having a CD3ζ intracellular signaling domain (see Fig 1A, first row, in the cover page) that does not comprise a co-stimulatory domain, related to instant claim 3.
Srinivasan teaches a method of administering CD70-specific CAR T cells to treat CD70 related diseases such as glioma in a subject (e.g., [0081] and Srinivasan claim 96). Srinivasan teaches an exemplary CD70-specific CAR having a CD3ζ intracellular signaling domain (see Table 5 in p. 51, reference SEQ ID NO: 311) that comprises the sequence of instant SEQ ID NO: 272 (related to instant claim 11). Srinivasan teaches disrupting or inactivating TCRa gene in the cells for treating patients against Host versus Graft (HVG) rejection and Graft versus Host Disease (GVHD) (e.g., [0320], also see Fig 5A, related to claim 18). 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 CAR comprises a CD3ζ signaling domain and a costimulatory domain (e.g., the 4-1BB costimulatory domain) in instant claim 31. Srinivasan teaches the method comprises administration of about 104 to about 109 cells per kg body weight of the patient (e.g., [0409], related to instant claim 100). Srinivasan teaches only “in some embodiments” the CAR further comprises a suicide polypeptide comprising the reference SEQ ID NO: 291 (that comprises the instant SEQ ID NO: 592) ([0328] in p. 44), thus suggests a CD70-specific CAR that does not comprise instant SEQ ID NO: 592 in instant claim 110. Srinivasan teaches an epitope (“QBEND-10 Epitope 2”) having the same sequence as instant SEQ ID NO: 594 (reference SEQ ID NO: 295, p. 44, left col) that is used for sorting CAR-T cells, related to instant claim 111. Srinivasan further teaches “In some embodiments, two instances of the same epitope, separated by linkers, may be used in the CAR” (p. 46, para 1) and teaches an arrangement of linker-epitope-linker-epitope ([0352]) and a linker sequence GSGGGGS (see p. 46, left col), thus suggests an epitope arrangement having the sequence of the instant SEQ ID NO: 596 in instant claim 112.
Lin summarizes cellular immunotherapy for malignant gliomas, including CAR-T cell therapy (see e.g., abstract). Regarding administering anti-EGFRvIII CAR T cells for treating glioma, Lin refers to a clinical trial (NCT01454596, study name “CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII”) in which anti-EGFRvIII CAR-transduced PBL are administered to a patient diagnosed with aalignant gliomas expressing EGFRvIII (see p. 1268, Table 2, the fourth row from bottom), related to instant claim 37.
Therefore, one of ordinary skill in the art would have expected that the claimed method of administering engineered immune cells expressing a CD70 CAR recited in the patent claims would have resulted in lymphodepletion in the patient diagnosed with glioma as taught by McEarchern. Furthermore, 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 and a method of administering the engineered immune cells expressing a CD70 CAR recited in the patented claims, by choosing a CAR structure that does not comprise a costimulatory signaling domain as suggested by Brentjens, by combining disruption of an endogenous TCRa gene to treat host v. graft rejection, and combining epitopes for sorting, and using the claimed dosage as suggested by Srinivasan, and by choosing the other CAR binding tumor antigen EGFRvIII as suggested by Lin 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 treat host v. graft rejection as suggested by Srinivasan, to obtain a CAR with the structure reduced to practice by Brentjens and to achieve a combination therapy with EGFRvIII for treating glioma as suggested by Lin.
Since the instant application claims are obvious over cited patent claims, in view of McEarchern, Brentjens, Srinivasan and Lin, said claims are not patentably distinct.
Response to Traversal:
Applicant’s argument and Dr. Elvin Lauron’s declaration filed on 05/20/2026 are acknowledged and have been discussed above.
New Provisional Double Patenting Rejections
Claims 3-4, 6, 11, 18-19, 25, 31, 37, 100 and 110-113 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of US Application NOs: 18/919,327, 18/361,056, 18/521,196, 19/420,431, 19/420,409 or 19/363,288 in view of McEarchern et al., (Blood. 2006; 108(11): 1728. P. 1-2), Brentjens et al., (WO 2019/099479 A1. Cited in IDS 10/13/2025), Srinivasan et al., (US 2019/0233528 A1. Cited in IDS 10/13/2025) and Lin et al., (Expert Opin Biol Ther. 2016;16(10):1265-75). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in the cited application ‘327 recite 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. The CD70 CAR comprises anti-CD70 antibody, a hinge, a transmembrane domain, and an intracellular domain, wherein the intracellular signaling domain comprises a CD3ζ signaling domain.
Copending claims in ‘056 recite a method of treating a condition in a subject comprising administering to the subject the CAR T cell, comprising an antigen binding domain and a CD70 binding protein wherein the antigen binding protein is a CAR and wherein the CAR T cell expresses one or more of the CAR, TCR and CD70 binding protein. The CAR T cell comprises a genomic modification of an endogenous TCRa and optionally wherein the cell further 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 a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of the 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, a hinge, a transmembrane domain and an intracellular domain comprising a CD3 signaling domain.
Copending claims of ‘431 recite a method of treating a disease or condition in a patient comprising administering to the patient a population of engineered immune cells comprising two CARs wherein the first CAR binds a target that is not CD70 and the second CAR binds CD70, the CARs comprising a hinge, a transmembrane domain, an intracellular domain, the cells comprising a genomic modification of endogenous TRAC gene or CD52 gene, but not CD70 gene, the cells are derived from a healthy volunteer.
Copending claims of ‘409 recite a method of extending expansion of allogeneic immune cells in a patient comprising introducing into the allogeneic immune cells a CD70-binding protein that comprises a CD70 binding domain and a transmembrane domain, the CD70 binding domain comprising an antibody, the CD70-binding protein further comprising a hinge domain, and an intracellular domain, the intracellular domain being CD3ζ signaling domain, the CD70-binding protein does not comprise a co-stimulatory domain, the immune cell also express a second antigen binding protein capable of binding a non-CD70 protein such as a CD19, the cells further comprises a genomic modification of an endogenous TCRa gene, the patient possesses alloreactive immune cells including activated T cells.
Copending claims of ‘288 recite a method of lymphodepletion in a patient in need thereof, comprising the step of administering the CD70 positive cells with engineered immune cells that comprises a CD70-binding protein that comprises a CD70 binding domain and a transmembrane domain, wherein the engineered immune cells inhibit proliferation of CD70 positive cells in the patient. The CD70 binding comprises an anti-CD70 antibody, further comprises a hinge, one or more intracellular signaling domain selected from CD3ζ signaling domain, and does not comprise a costimulatory domain, the CD70 positive cells are normal lymphocytes in the patient, the engineered immune cells are autologous or allogeneic to the patient, further comprise a genomic modification of an endogenous TCRa gene, the patient is expected to have host v. graft rejection, the patient is in need of bone marrow transplant or adoptive cell therapy, the patient is further administered a chemotherapy and is not administered fludarabine, the engineered immune cells have an additional antigen binding protein, the binding proteins are one protein a bispecific CAR, the target of interest is CD19, and the dosage of administering cells. It is noted that copending claims of ‘288 anticipate the claims in the instant application.
However, the patented claims do not recite the method of lymphodepletion and depleting non-cancerous CD70 positive T cells in instant claim 3 and administering a lower level of lymphodepleting agent in instant claim 25, the CD70 CAR having no costimulatory domain in claim 3, the sequence of CD3ζ in claim 11, the cells comprising genomic modification of TCRa gene in claim 18, the second antigen binding domain is a CAR comprising a costimulatory domain in claim 31, the dosage of the immune cells in claim 100, the additional epitope sequience in the CAR in claims 110-112, or the other CAR binding tumor antigen EGFRvIII in claim 37.
McEarchern evidences that CD70 is expressed on activated lymphocytes and is important for generation of B and T memory and effector responses, and blockade of CD70 interaction with its receptor has been shown to inhibit cardiac allograft rejection in mice (p. 1, beginning of Abstract). McEarchern evidences that an antibody targeting CD70 (SGN-70) selectively depletes CD70+ activated T cells as SGN-70 treatment decreases the number of CD70+CD8+Vβ17+ cells by >80% and this depletion is dependent on the activity of CD16+ cells within the culture (i.e., via antibody-dependent cellular cytotoxicity) (see p. 1). Thus, McEarchern evidences blockade of CD70, such as anti-CD70 CAR T cells would have naturally resulted in lymphodepletion and depleting non-cancerous CD70 positive T cells in instant claim 3 and makes obvious administering a lower level of lymphodepleting agent in instant claim 25.
Brentjens encompass a CD70 CAR (e.g., p. 6, para 2). Brentjens teaches in certain embodiments, the CAR does not comprise a co-stimulatory signaling domain and reduces to practice a CD19 CAR having a CD3ζ intracellular signaling domain (see Fig 1A, first row, in the cover page) that does not comprise a co-stimulatory domain, related to instant claim 3.
Srinivasan teaches a method of administering CD70-specific CAR T cells to treat CD70 related diseases such as glioma in a subject (e.g., [0081] and Srinivasan claim 96). Srinivasan teaches an exemplary CD70-specific CAR having a CD3ζ intracellular signaling domain (see Table 5 in p. 51, reference SEQ ID NO: 311) that comprises the sequence of instant SEQ ID NO: 272 (related to instant claim 11). Srinivasan teaches disrupting or inactivating TCRa gene in the cells for treating patients against Host versus Graft (HVG) rejection and Graft versus Host Disease (GVHD) (e.g., [0320], also see Fig 5A, related to claim 18). 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 CAR comprises a CD3ζ signaling domain and a costimulatory domain (e.g., the 4-1BB costimulatory domain) in instant claim 31. Srinivasan teaches the method comprises administration of about 104 to about 109 cells per kg body weight of the patient (e.g., [0409], related to instant claim 100). Srinivasan teaches only “in some embodiments” the CAR further comprises a suicide polypeptide comprising the reference SEQ ID NO: 291 (that comprises the instant SEQ ID NO: 592) ([0328] in p. 44), thus suggests a CD70-specific CAR that does not comprise instant SEQ ID NO: 592 in instant claim 110. Srinivasan teaches an epitope (“QBEND-10 Epitope 2”) having the same sequence as instant SEQ ID NO: 594 (reference SEQ ID NO: 295, p. 44, left col) that is used for sorting CAR-T cells, related to instant claim 111. Srinivasan further teaches “In some embodiments, two instances of the same epitope, separated by linkers, may be used in the CAR” (p. 46, para 1) and teaches an arrangement of linker-epitope-linker-epitope ([0352]) and a linker sequence GSGGGGS (see p. 46, left col), thus suggests an epitope arrangement having the sequence of the instant SEQ ID NO: 596 in instant claim 112.
Lin summarizes cellular immunotherapy for malignant gliomas, including CAR-T cell therapy (see e.g., abstract). Regarding administering anti-EGFRvIII CAR T cells for treating glioma, Lin refers to a clinical trial (NCT01454596, study name “CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII”) in which anti-EGFRvIII CAR-transduced PBL are administered to a patient diagnosed with aalignant gliomas expressing EGFRvIII (see p. 1268, Table 2, the fourth row from bottom), related to instant claim 37.
Therefore, one of ordinary skill in the art would have expected that the claimed method of administering engineered immune cells expressing a CD70 CAR recited in the patent claims would have resulted in lymphodepletion in the patient diagnosed with glioma as taught by McEarchern. Furthermore, 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 and a method of administering the engineered immune cells expressing a CD70 CAR recited in the patented claims, by choosing a CAR structure that does not comprise a costimulatory signaling domain as suggested by Brentjens, by combining disruption of an endogenous TCRa gene to treat host v. graft rejection, and combining epitopes for sorting, and using the claimed dosage as suggested by Srinivasan, and by choosing the other CAR binding tumor antigen EGFRvIII as suggested by Lin 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 treat host v. graft rejection as suggested by Srinivasan, to obtain a CAR with the structure reduced to practice by Brentjens and to achieve a combination therapy with EGFRvIII for treating glioma as suggested by Lin.
Since the instant application claims are obvious over cited application claims, in view of McEarchern, Brentjens, Srinivasan and Lin, 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 argument and Dr. Elvin Lauron’s declaration filed on 05/20/2026 are acknowledged and have been discussed above.
Applicant further requests that the double patenting rejections be held in abeyance until allowable subject matter is identified. This is not found persuasive therefore the rejections are maintained. Applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional. See MPEP 804.I.B.1.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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