DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
In the reply on 26 November 2025 Applicant has amended claims 2, 3, 17, 4 7, and 60. Claims 4, 5, 7-16, 18-39, 41-46, 48-59, 61-75, 78-86, 88, 90-96, 98, 99, 101-115, 117, 119-121, 123-125, 127, 128, 130, 132-135, 137-206, 208- 210, 212-214, 216, and 218-222 were previously cancelled. Claims 6, 76, 77, 87, 89, 97, 100, 116, 118, 122, 126, 129, 131, 136, 207, 211, 215, and 217 have been cancelled with this amendment and added new claims 223-239.
Therefore, claims 1-3, 17, 40, 47, 60, and 223-239 are herein pending.
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-3, 17, 40, 47, and 60, drawn to a cell expressing a chimeric antigen receptor (CAR), wherein the cell has reduced expression and/or a reduced biological activity of ZBTB32. in the reply filed on 26 November 2025 is acknowledged. The new claims 223-239 are within the scope of the elected invention.
Claims 76-77,87,89,97,100,116,118,122,126,129,131,136,207,211,215 and 217 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. However, applicant has cancelled the withdrawn claims in the reply filed on 26 November 2025.
Claims 1-3, 17, 40, 47, 60, and 223-239 are under current examination.
Priority
This application was filed 12/09/2022 and is a 371 application of PCT/US2021/037048 filed on 06/11/2021, which claims benefit to the Provisional Application 63037826 filed on 06/11/2020. Thus, the earliest possible priority for the instant application is 06/11/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/30/2023, and 11/26/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and the signed and initialed PTO Forms 1449 are mailed with this action.
However, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Title Objection
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. See MPEP 606.01
The following title is suggested:
CART cell with ZBTB32 Inhibitors and Uses Thereof.
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.
Claims 1, 3, 17, 40, 47, 60, and 223-239 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 draw to the cell has reduced expression and/or a reduced biological activity of ZBTB32. However, claim didn’t define the reference cell to compare the CART cell’s reduced expression of ZBTB32. In the instant SPEC discloses that the cell has reduced expression of ZBTB32, e.g., reduced by at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%, compared to a reference cell (see SPEC p. 6 lns 24-25), however, SPEC does not disclose the reference cell. Therefore, claim 1 is indefinite for failing to particularly point out reference cell. Dependent claims 3, 17, 40, 47, 60, and 223-239 are rejected as being dependent upon rejected base claim 1.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 40, 47, 60, 223-226, 229 and 235-239 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Busser et al (WO2019076486A1; cited in IDS filed 06/30/2023; hereinafter “Busser”).
With respect to claims 1-3, 223-226, and 229, Busser discloses CAR expressing T cells further comprising an exogenous sequence encoding an NK inhibitor integrated at the ZBTB32 locus (p. 29, lines 16 to 31 of Busser) via, the TALEN system or CRISPR-Cas9 (p. 17, lns 4-19 of Busser), and the medical use thereof for the treatment of cancer (claim 27 on p. 148 of Busser). Furthermore, Busser teaches that the exogenous sequence encoding NK inhibitor has been inserted by site directed gene editing for its expression during T-cell activation. Therefore, upon CART-cell activation the endogenous promoter (i.e., ZBTB32) under transcriptional control are down-regulated (p. 51 lns 5-9 of Busser). Alternatively, endogenous promoters are not expressed during immune cell activation without any adverse consequences on the genome (p. 4 lns 10-15 of Busser).
Regarding the Inherency and product claims MEPE 2112.01(I) and (II) states that “when the structure taught by the reference is identical or substantially identical to that of the claims, the claimed properties or functions are presumed to be inherent”. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). MPEP 2112 (II) also states that for composition of matter claims, if the composition is physically the same, it must have the same properties. In re Spada, 15 USPQ2d 1655, 1658 (Fed Cir 1990). Furthermore, MPEP 2112 (II) states that where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. "There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims. In here, in the cited prior art Busser discloses the same product CART cells comprising an exogenous sequence encoding an NK inhibitor is integrated at the ZBTB32 locus, that must necessarily inherent the same property of CART cell population that would include reduced/no detectable expression/biological activity of ZBTB32 or reduce level of ZBTB32 protein. Therefore, Busser’s is anticipating that the CART cell population has reduced/no detectable expression/ biological activity of ZBTB32 or reduce level of ZBTB32 protein.
With respect to claim 40, Busser teaches that the T cell is a human cell (p. 30 ln 8; p. 47 ln 15) and enhance survival and increase proliferation of CAR modified T cells. CARs have successfully allowed T cells to be redirected against antigens expressed at the surface of tumor cells from various malignancies including lymphomas and solid tumors (p. 3 lns 24-27 of Busser) Therefore, POSITA would have anticipated that CART cells with ZBTB32 inhibitor will enhance T cell-mediated anti-tumor response.
With respect to claims 47, and 236-237, Busser teaches that the cell is an immune effector CD4+ and CD8+ T cell or a population of immune effector CD4+ and
CD8+ T cells (p. 5 ln 10; p. 56 lns 15-20).
With respect to claim 60, Busser teaches that the antigen-binding domain binds to a tumor antigen selected from a group consisting of CD19, CD22, CD123, CS1, CL1, HSP70, GD3, and ROR1.
With respect to claim 235, Busser teaches that the antibody molecule comprises a single-domain antibody (sdAb) or nanobody that binds directed to against inhibitory peptides or proteins (i.e., a protein encoded by the ZBTB32 gene) (p. 28 lns 8-14).
With respect to claims 238-239, Busser teaches that the intracellular signaling domain comprises a primary signaling domain CD3 zeta or the Fc receptor gamma chains and costimulatory signaling domain selected from the group consisting of CD28, OX-40 (CD134), ICOS and 4-1BB (CD137) have (p. 3 lns 18-25).
Accordingly, Busser anticipates the instant claims 1-3, 40, 47, 60, 223-226, 229 and 235-239.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-3, 17, 40, 47, 60, 223-226, 229, 232 and 235-239 are rejected under 35 U.S.C. 103 as being unpatentable over Busser et al (WO2019076486A1; cited in IDS filed 06/30/2023; hereinafter “Busser”), in view of Shahi et al. (Proceedings of the National Academy of Sciences, 114(12), pp.3169-3174; cited in IDS filed 06/30/2023; hereinafter “Shahi”).
With respect to claims 1-3, 223-226, and 229, Busser discloses CAR expressing T cells further comprising an exogenous sequence encoding an NK inhibitor integrated at the ZBTB32 locus (p. 29, lines 16 to 31 of Busser) via, the TALEN system or CRISPR-Cas9 (p. 17, lns 4-19 of Busser), and the medical use thereof for the treatment of cancer (claim 27 on p. 148 of Busser). Furthermore, Busser teaches that the exogenous sequence encoding NK inhibitor has been inserted by site directed gene editing for its expression during T-cell activation. Therefore, upon CART-cell activation the endogenous promoter (i.e,. ZBTB32) under transcriptional control are down-regulated (p. 51 lns 5-9 of Busser). Alternatively, endogenous promoters are not expressed during immune cell activation without any adverse consequences on the genome (p. 4 lns 10-15 of Busser).
Regarding the Inherency and product claims MEPE 2112.01(I) and (II) states that “when the structure taught by the reference is identical or substantially identical to that of the claims, the claimed properties or functions are presumed to be inherent”. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). MPEP 2112 (II) also states that for composition of matter claims, if the composition is physically the same, it must have the same properties. In re Spada, 15 USPQ2d 1655, 1658 (Fed Cir 1990). Furthermore, MPEP 2112 (II) states that where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103. "There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102 and 103 rejection is appropriate for these types of claims as well as for composition claims. In here, in the cited prior art Busser discloses the same product CART cells comprising an exogenous sequence encoding an NK inhibitor is integrated at the ZBTB32 locus, that must necessarily inherent the same property of CART cell population that would include reduced/no detectable expression/biological activity of ZBTB32 or reduce level of ZBTB32 protein. Therefore, Busser’s is anticipating that the CART cell population has reduced/no detectable expression/ biological activity of ZBTB32 or reduce level of ZBTB32 protein.
Regarding claim 17, Busser is silent to the ZBTB32 inhibitor comprises a small interfering RNA (siRNA) or a small hairpin RNA (shRNA) targeting the ZBTB32 gene, however, such was known in the prior art.
With respect to claims 17 and 232, Shahi discloses that the ZBTB32 comprises with siRNAs is essential for downregulation of GATA3 (associates with breast cancer development) and promote cellular invasion via binding partner Zinc-finger elbow-related praline domain protein 2 (Zpo2) (abstract, p. 3171 right col. 1st ¶ and Fig. 3 on page 3172).
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the CAR T cell of Busser and include ZBTB32 comprises siRNAs with Zpo2 as taught by Shahi with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Shahi because it is essential for downregulation of GATA3 and promote cellular invasion (abstract, p. 3171 right col. 1st ¶ and Fig. 3 on page 3172 of Shahi). The POSITA would have had a reasonable expectation of success in combining the teachings of Busser and Shahi because each of these teachings both successfully generated CAR T cell with ZBTB32 inhibitor. Therefore, the products and method as taught by Busser et al. in view of Shahi et al. would have been prima facie obvious over the products and method of the instant application. In regard to the reasonable expectation of success in doing so, include ZBTB32 comprises siRNAs with Zpo2 of Shahi had a reasonable expectation of success since the steps thereof required no more than recombinant DNA technology and pipetting the appropriate Zpo2 concentration.
With respect to claim 40, Busser teaches that the T cell is a human cell (p. 30 ln 8; p. 47 ln 15).
With respect to claims 47, and 236-237, Busser teaches that the cell is an immune effector CD4+ and CD8+ T cell or a population of immune effector CD4+ and CD8+ T cells (p. 5 ln 10; p. 56 lns 15-20).
With respect to claim 60, Busser teaches that the antigen-binding domain binds to a tumor antigen selected from a group consisting of CD19, CD22, CD123, CS1, CL1, HSP70, GD3, and ROR1.
With respect to claims 230-231, Shahi discloses that the Zpo2 translocate to the nucleus and functions as a transcriptional repressor, suggesting that Zpo2 can interact and form complexes with other proteins. Furthermore, Zpo2 contains one zinc finger protein domain, it may lack DNA-binding ability (p. 3172 right-col 2nd ¶).
MPEP 2112.01 state that “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established,” In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the instant case Shahi discloses the cell with ZBTB32 inhibitor comprises a small interfering RNA (siRNA) and binding partners Zpo2, therefor, POSITA would have expected that the transcription repressor function of ZBTB32 is reduced and interaction between ZBTB32 and binding partners (Zpo2) is reduced.
With respect to claim 235, Busser teaches that the antibody molecule comprises a single-domain antibody (sdAb) or nanobody that binds directed to against inhibitory peptides or proteins (i.e., a protein encoded by the ZBTB32 gene) (p. 28 lns 8-14).
With respect to claims 238-239, Busser teaches that the intracellular signaling domain comprises a primary signaling domain CD3 zeta or the Fc receptor gamma chains and costimulatory signaling domain selected from the group consisting of CD28, OX-40 (CD134), ICOS and 4-1BB (CD137) have (p. 3 lns 18-25).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-3, 17, 40, 47, 60, 223-229 and 232-239 are rejected under 35 U.S.C. 103 as being unpatentable over Busser et al (WO2019076486A1; cited in IDS filed 06/30/2023; hereinafter “Busser”), and Shahi et al. (Proceedings of the National Academy of Sciences, 114(12), pp.3169-3174; cited in IDS filed 06/30/2023; hereinafter “Shahi”) as applied to claims 1-3, 17, 40, 47, 60, 223-226, 229, 232 and 235-239 above, and further in view of Coley et al., (F1000Research (2018) 7: 318; cited in IDS filed 06/30/2023; hereinafter “Coley”).
As stated above, Busser in view of Shahi discloses CAR expressing T cells further comprising an exogenous sequence encoding an NK inhibitor ZBTB32 integrated at the endogenous locus via, e.g., the TALEN system or CRISPR-Cas9 and the medical use thereof for the treatment of cancer.
Regarding claim 227, Busser is silent to the ZBTB32 genomic locus is altered, however, such was known in the prior art.
With respect to claims 227-228, 233-234, Coley discloses CRISPR gene editing systems targeting the ZBTB32 gene (Figure 1 on page 4). Furthermore, ZBTB32 gene is preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2+ DCs, and overexpression of ZBTB32 in islet-specific T cells inhibited the diabetes development by limiting T cell (abstract of Coley). The CRISPR/Cas9 technique was used to target exon 2 of the ZBTB32 gene directly in NOD mice, therefore, the loss of the ZBTB32 protein after CRISPR-mediated deletion was confirmed by Western blotting extracts from stimulated CD4+ splenocytes (Fig. 1 of Coley). Therefore, POSITA would have expected that the ZBTB32 genomic locus is altered.
MPEP 2143 (A) states that combining prior art elements according to known methods to yield predictable results. The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Accordingly, it would have been obvious to practice the CAR T cell of Busser and include CRISPR gene editing systems targeting the ZBTB32 gene as taught by Coley with a reasonable expectation of success. The POSITA would have been motivated at the time of filing to do so as taught by Coley because CRISPR can cause a frameshift mutation in the Zbtb32 gene, and validated the loss of the Zbtb32 protein therefore, the transcription repressor Zbtb32 reduced to play a critical role in the inhibition of T-cell mediated autoimmune T1D (p. 3 right-col 1st ¶). The POSITA would have had a reasonable expectation of success in combining the teachings of Busser and Coley because each of these teachings both successfully generated CAR T cell with ZBTB32 inhibitor. Therefore, the products and method as taught by Busser et al. in view of Coley et al. would have been prima facie obvious over the products and method of the instant application. In regard to the reasonable expectation of success in doing so, include CRISPR gene editing systems targeting the ZBTB32 gene of Coley had a reasonable expectation of success since the steps thereof required no more than recombinant DNA technology and cell culture technology.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MASUDUR RAHMAN whose telephone number is (571)272-0196. The examiner can normally be reached M-F 8-5 (EST).
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/MASUDUR RAHMAN/ Patent Examiner, Art Unit 1633
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684