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 05/26/2026, Applicant has amended claim 14, newly canceled claims 1-13 and 15-20, and added new claims 22-32.
Claim Status
Claims 14 and 22-32 are pending and are considered on the merits.
Withdrawn Claim Objections
The prior objection to claims 9, 11 and 14-15 because of grammatical errors is withdrawn in light of Applicant’s amendment to claim 14 and cancelation of other claims.
New Claim Objections
Claim 30 is objected to because of the following informalities:
Claim 30 recites the phrase “upstream and downstream of wherein the marker protein can be expressed” in line 5. It is recommended to change to “upstream and downstream of the marker protein wherein the marker protein can be expressed”.
Furthermore, claim 30 recites “further comprising the step of” in lines 5-6. It is recommended to change to “further comprises the step of”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 1-13 and 15-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in light of Applicant’s cancelation of the claims.
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 32 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 32 recites the limitation “the pluripotent stem cell” in line 1. There is insufficient antecedent basis for this limitation because base claim 14 is silent on a pluripotent stem cell. It is recommended to change the dependency to claim 31. It is examined as so.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-2, 4-7, 12-13 and 17-20 under 35 U.S.C. 103 as being unpatentable over Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) is withdrawn in light of Applicant’s cancelation of the claims.
The prior rejection of claims 3 and 8 under 35 U.S.C. 103 as being unpatentable over Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) in view of Eyquem et al., (Nature. 2017; 543(7643): 113-117) is withdrawn in light of Applicant’s cancelation of the claims.
The prior rejection of claims 9-11 under 35 U.S.C. 103 as being unpatentable over Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) in view of Eyquem et al., (Nature. 2017; 543(7643): 113-117), and further in view of Cao et al., (ClinicalTrials.gov ID NCT02903810, posted date 2016-10-12, p. 1-9) is withdrawn in light of Applicant’s cancelation of the claims.
The prior rejection of claims 14-16 under 35 U.S.C. 103 as being unpatentable over Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) in view of Eyquem et al., (Nature. 2017; 543(7643): 113-117) and Cao et al., (ClinicalTrials.gov ID NCT02903810, posted date 2016-10-12, p. 1-9) is withdrawn in light of Applicant’s amendment to claim 14 and cancelation of other claims.
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 14 and 22-32 are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) in view of Eyquem et al., (Nature. 2017; 543(7643): 113-117. Prior art of record) and Cao et al., (ClinicalTrials.gov ID NCT02903810, posted date 2016-10-12, p. 1-9. Prior art of record).
With respect to claim 14, Gong teaches a method for producing tumor antigen-specific T cells expressing a tumor antigen-specific TCR molecule using Dual-RMCE (dual-recombinase mediated cassette exchange) technology (see e.g. abstract), thus teaches a method for producing T cells which express a protein of a specificity-determining site (i.e., a tumor antigen-specific TCR).
In regard to the step of providing T cells comprising one cassette deck structure wherein the cassette deck structure comprises a cassette tape gene encoding a marker protein and a pair of recombinase target sequences placed upstream and downstream of the marker protein, Gong teaches Jurkat76 cells (a human T-lymphocyte cell line, and thus T cells) are transduced with retrovirus comprising an integration vector (e.g., [0053], the integration vector is equivalent to the claimed cassette deck structure). Gong teaches an integration vector pMP71-LGFPF plasmid which comprises a GFP gene that is flanked by LoxP and FRT sites (see e.g., p. 11, [0053] and Fig 1A, C. It is noted that the term “LGFPF” stands for LoxP-GFP-FRT), thus teaches the cassette deck structure (i.e., the integration vector) comprises a cassette tape gene encoding a marker protein (i.e., the GFP gene) and a pair of recombinase target sequences placed upstream and downstream of the marker protein (the LoxP and FRT sites flanking the GFP gene). Gong teaches Jurkat76 cells after transduction have GFP expression (e.g., [0031], see Fig 2L and Fig 2M), thus teaches the marker protein can be expressed in the cells.
However, Gong is silent on the cells comprising in their genome one cassette deck structure per one cell.
Nevertheless, Gong teaches multiple copies of the displacement substrate (equivalent to the claimed cassette deck structure) may reduce the displacement efficiency, and low/single-copy retrovirus cell clones are selected to improve the efficiency of Dual-RMCE (e.g., [0059]). Gong teaches using limiting dilution to obtain monoclonal cells with low/single-copy exchange components (i.e., low copies or one copy of cassette deck structure per one cell as claimed, see e.g., [0059], [0063]).
In regard to obtaining T cells comprising one copy of exogenous sequence in their genome per one cell, Eyquem teaches a method of targeted integration (e.g., the TRAC locus) of exogenous CAR into effector cells by CRISPR/Cas9 (see e.g., abstract). It is noted that by targeted integration into a specific gene locus, there would be only one copy of exogenous sequence in the genome per one cell as claimed in claim 14. Eyquem teaches targeted integration provides a safer therapeutic T cell by minimizing the risks of insertional oncogenesis and a better defined T cell by avoiding position-effect variegation and vector copy number variation (p. 117, para 1).
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 for producing T cells expressing a tumor antigen-specific TCR for immunotherapies disclosed by Gong, by substituting the retrovirus-mediated random integration with targeted integration as taught by Eyquem with a reasonable expectation of success. Since Gong acknowledges viral transduction (for introducing the cassette deck structure in the genome of T cells) is a process of multi-copy and random integration (e.g., [0007]) that may reduce the exchange efficiency, and teaches selecting low/single-copy cell clones to improve the efficiency of Dual-RMCE (e.g., [0059], [0063]), and since Eyquem teaches targeted integration provides a safer therapeutic T cell and a better defined T cell by avoiding position-effect variegation and vector copy number variation (p. 117, para 1), one of ordinary skill in the art would have had a reason to substitute targeted integration into a specific gene locus as taught by Eyquem for the retrovirus-mediated random integration of Gong so as to obtain T cells comprising only one cassette deck structure in their genome per one cell in order to obtain a safer and better defined cell with improved efficiency of Dual-RMCE.
In regard to the cassette deck structure not comprising an exogenous drug resistant gene, although Gong teaches a neomycin gene (i.e., an exogenous drug resistant gene) is comprised in the cassette deck structure (see e.g., Fig 1A), one of ordinary skill in the art would have understood that the drug resistance gene in the cassette would be neither necessary for the function of the cassette tape gene, nor sufficient for producing any unexpected results. Thus, omission of the exogenous drug resistant gene is obvious in the absence of any showing of unexpected results or criticality.
Gong teaches the cells comprising the integration vector are electroporated with a replacement vector comprising a TCR gene and a plasmid encoding Cre and FlpO recombinase (e.g., [0057], line 461) and after 10 days, cells fully express CD3 (from the exogenous TCR) and do not express EGFP, indicating that the EGFP gene is completely replaced by the TCR gene (e.g., [0059], from line 488), thus teaches exchanging the gene encoding the marker protein (i.e., the EGFP gene) in the T cells with a gene encoding a protein of the specificity-determining site (i.e., the TCR gene) to produce one type of T cells expressing a protein of a specificity-determining site.
However, Gong and Eyquem are silent on exchanging with genes encoding multiple proteins of the specificity-determining sites to produce multiple types of T cells each expressing a different protein of a specificity-determining site at the same time in claim 14.
Nevertheless, Gong teaches there are multiple tumor-associated antigens (e.g., [0005]), and a series of high-affinity tumor antigen-specific TCR genes have been isolated for use in tumors such as B-cell lymphoma (e.g., [0006]).
Cao teaches a clinical trial using combination transfer of two chimeric antigen receptor (CAR)-T cells for treating B cell malignancy (p. 1, Brief summary). Cao teaches because of the heterogeneity of the tumor, patients often carry tumor cells with various positive target antigens, thus Cao proposes infusion of a mixed population of CAR-T cells (CD19- and CD22-CAR-T cells) to eliminate tumor burden and inhibit the recurrence of tumor heterogeneity at the same time (see p. 1, Brief summary). Thus, Cao suggests multiple types of T cells (e.g., two types of CAR-T cells) each expressing a different protein of a specificity-determining site (e.g., a CD19-CAR or a CD22-CAR) at the same time (i.e., co-administration of two types of T cells) in claim 14.
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 for producing T cells expressing one tumor antigen-specific TCR by exchanging the marker gene with one donor TCR gene as suggested by Gong and Eyquem, by combining multiple genes encoding multiple proteins of the specificity-determining sites to produce multiple types of T cells each expressing a different protein of a specificity-determining site at the same time as suggested by Gong and Cao with a reasonable expectation of success. Since Gong teaches multiple tumor-associated antigens in tumors and isolation of a series of high-affinity tumor antigen-specific TCR genes for use in tumors such as B-cell lymphoma (e.g., [0005-0006]), and since Cao teaches treating B-cell malignancy with multiple types of T cells each expressing a different protein of a specificity-determining site (e.g., a CD19-CAR or a CD22-CAR) at the same time (i.e., co-administration of two types of T cells) to eliminate tumor burden and to inhibit the recurrence of tumor heterogeneity at the same time (see p. 1, Brief summary), one of ordinary skill in the art would have had a reason to combine and exchange with multiple genes encoding multiple proteins of the specificity-determining sites (e.g., a series of high-affinity tumor antigen-specific TCR genes) to produce multiple types of T cells each expressing a different protein of a specificity-determining site (a series of types of TCR-T cells) at the same time in order to co-administer the multiple types of TCR-T cells for eliminating tumor burden and inhibiting the recurrence of tumor heterogeneity.
With respect to claim 22, as stated supra, Gong teaches after 10 days, cells fully express CD3 (from exogenous TCR) and do not express EGFP, indicating that the EGFP gene is completely replaced by the TCR gene (e.g., [0059], from line 488), thus teaches the method further comprising a step of selecting the T cells that are negative for the marker protein (i.e., EGFP) so that the T cells expressing the protein of the specificity-determining site (i.e., the TCR) are selected.
With respect to claim 23 and claim 24 directed to the marker protein being a known rearranged TCR, although Gong does not specifically teach the marker protein being a TCR, Gong teaches after dual-RMCE, the TCR gene is exchanged with the EGFP gene and is expressed on the surface of the T cells (see e.g., [0059], from line 488 and see Fig 1C attached). It is noted that the new cassette comprises a pair of recombinase target sequences flanking the TCR gene, in the same manner as that in the integration vector flanking the EGFP gene.
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Since the cassette comprising an EGFP gene and the cassette comprising a TCR gene have the same flanking recombinase target sequences and can be used for the same purpose (i.e., as a starting cassette deck structure for dual-RMCE), these cassettes are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted the cassette comprising a TCR gene for the cassette comprising an EGFP gene so as to use the TCR gene as a marker gene to perform dual-RMCE. See MPEP 2144.06.
With respect to claim 25, as stated supra, Gong teaches the marker protein is a fluorescent protein (i.e., an EGFP protein, see e.g., Fig 1A).
With respect to claim 26, as stated supra, Gong in view of Eyquem and Cao make obvious the step of exchanging the gene encoding the marker protein in the T cells with genes encoding multiple proteins of specificity-determining sites. Gong teaches the exchanging is by using Dual-RMCE (dual-recombinase mediated cassette exchange) technology (see e.g. abstract).
With respect to claims 27 and 28, as stated supra, Gong teaches T cells fully express CD3 (from exogenous TCR) and do not express EGFP (e.g., [0059], from line 488, and see [0039] for the MAGEA1-specific TCR gene, thus rearranged TCR), thus teaches the proteins of specificity-determining sites to be expressed in the T cells are rearranged TCRs.
With respect to claim 29 directed to the TCRs being derived from tumor-infiltrating lymphocytes, it is noted that this claim is directed to a product-by-process claim. The applicant is reminded that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. In the instant case, the product itself, TCRs being derived from tumor-infiltrating lymphocytes (thus being tumor antigen-specific TCRs), is obvious from a product of the prior art, a series of tumor antigen-specific TCRs isolated from a human TCR-HLA humanized mouse model (see e.g., Gong, [0006]). Thus, claim 29 is unpatentable even though the prior product was made by a different process.
With respect to claim 30 directed to additional steps, in regard to step (1), Gong teaches mouse embryonic stem cells (ES14.1 cells) are electroporated with an integration vector pMP71-LGFPF plasmid (p. 11, [0053]), thus teaches step (1) providing material cells (i.e., ES cells) that have the cassette deck structure (i.e., the integration vector) with the cassette tape gene comprising the gene encoding a marker protein (i.e., the GFP marker protein) in their genome. Gong teaches in vivo differentiation of TCR-ES cells into T cells ([0070]-[[0073], see Fig 7), and teaches the T cells express the exogenous TCR incorporated by cassette exchange in place of the marker protein (see [0073] and Fig 7), thus teaches the material cells (i.e., the ES cells) can be differentiated into T cells, and the marker protein can be expressed in the T cells when the material cells are differentiated into the T cells (evidenced by the T cells expressing the exogenous TCR). It is noted that the exogenous TCR is under the same promoter as the marker protein after cassette exchange, thus the marker protein can be expressed in the differentiated T cells if the cassette exchange is not performed. It is also noted that the exogenous TCR can serve as a marker protein as discussed above, thus the marker protein (e.g., the exogenous TCR) can be expressed in T cells when the material cells are differentiated into T cells.
In regard to step (2), Gong teaches the mouse embryonic stem cells are cultured in a specific medium (see e.g., [0041], from line 337, and see Fig 2 for low-copy clones of ES cells after electroporation of the integration vector), thus teaches step (2) proliferating the material cells.
In regard to step (3), as stated supra, Gong teaches in vivo differentiation of TCR-ES cells into T cells (Example 3, [0070]-[[0073], see Fig 7), and also teaches both in-vivo and in-vitro cell differentiation technology can be used to produce a large amount of tumor antigen specific T cells (see e.g., abstract). Thus, Gong teaches step (3) differentiating the material cells (i.e., the ES cells) into the T cells.
It is noted that Gong’s exchanging the marker gene with the gene encoding a protein of a specificity-determining site happens in the ES cells before differentiating (see e.g., [0069], last line “3 ES cell clones also successfully underwent Dual-RMCE), while in the instant claims 14 and 30 the exchanging is in the T cells after differentiating the ES cells.
However, since performing the step of exchanging either before differentiating (i.e., Gong), or after differentiating the ES cells (i.e., instant invention) would lead to the same result, i.e., producing T cells expressing the protein of the specificity-determining site, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the step of exchanging after differentiating the ES cells into the T cells with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since MPEP 2144.04, section IV (C) directed to the order of steps citing In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) states that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.
Furthermore, since Gong has reduced to practice the step of exchanging in T cells (see RMCE performed in Jurkat76 cells which is a T cell line, e.g. [0059]), one of ordinary skill in the art would have had a reasonable expectation of success in performing the step of exchanging in the T cells differentiated from the ES cells.
With respect to claim 31 and claim 32, as stated supra, Gong teaches the material cell is an embryonic stem cell (e.g., [0053]) and induced pluripotent stem cell (iPS) (e.g., [0009] and [0028]).
Response to Traversal:
Applicant’s arguments filed on 05/26/2026 are acknowledged.
Applicant first argues that the term “known” in the new claims 23 and 24 is not indefinite because it is defined by surrounding claim language, the Specification and is understood by a person having skill in the art (Remarks, p. 6).
Applicant’s arguments have been fully considered and they are persuasive. Therefore, the prior rejection over the term “known” has been withdrawn (although the prior rejection becomes moot because of cancellation of the claims), and no new 112b rejection has been made on new claims 23 and 24.
Applicant further argues that in regard to amended claim 14, Gong teaches that retroviral transduction can result in multiple-copy integration, which reduces recombinase-mediated cassette exchange efficiency, and therefore teaches to "obtain low/mono-copy" cell clones "instead of multiple copied." Thus, Gong teaches away from Applicant's method comprising exchange of the marker gene with multiple genes encoding different proteins (Remarks, p. 9, para 2).
Applicant’s arguments have been fully considered but they are not persuasive.
Applicant is reminded that Gong’s teaching of the preference of mono-copy integration is directed to the integration of the integration vector (i.e., the claimed cassette deck structure), which is consistent with the claimed T cells comprising in their genome “one cassette deck structure per one cell” (see claim 14). In other words, both the instant invention and the method of prior art Gong in view of Eyquem are directed to one T cell has only one copy of cassette deck structure/integration vector. Thus, Gong does not teach away from Applicant's method.
Applicant further argues that Gong is describing introducing a TCR gene into T cells followed by expansion, which corresponds to introducing a selected gene and generating a corresponding cell population. This approach does not teach or suggest the simultaneous multi-gene exchange and concurrent generation of multiple distinct T cells or T progenitor cell types in a single cell population (Remarks, p. 9). Cao teaches producing two types of CAR-T cells separately and then combining the prepared cell populations to infuse into patients (Remarks, p. 10).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, it is noted that the features upon which applicant relies (i.e., simultaneous multi-gene exchange and concurrent generation of multiple distinct T cells or T progenitor cell types in a single cell population) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). See MPEP 2111.01 II. Specifically, the instant claim 14 only requires the multiple types of T cells or T progenitor cells each expressing a different protein of a specificity-determining site at the same time (underlined by examiner). Thus, the instant claim does not even require the multiple types of T cells or T progenitor cells being in a single population.
Additionally, as stated supra, Gong teaches there are multiple tumor-associated antigens (e.g., [0005]), and a series of high-affinity tumor antigen-specific TCR genes have been isolated for use in tumors (e.g., [0006]). Cao teaches the heterogeneity of tumors and teaches infusion of a mixed population of CAR-T cells (CD19- and CD22-CAR-T cells) to eliminate tumor burden and inhibit the recurrence of tumor heterogeneity (see p. 1, Brief summary). It is noted that in Cao’s mixed population of CAR-T cells, the two types of T cells each express a different CAR protein at the same time, as claimed in claim 14. Therefore, one of ordinary skill in the art would have combined multiple genes encoding multiple proteins of the specificity-determining sites to produce multiple types of T cells each expressing a different protein of a specificity-determining site at the same time as suggested by Cao in the method of Gong and Eyquem with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to co-administer the multiple types of TCR-T cells for eliminating tumor burden and inhibiting the recurrence of tumor heterogeneity as suggested by Cao.
Withdrawn Provisional Double Patenting Rejections
The prior provisional rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over copending claims 25, 4, 19, 26-29, 36 and 38-40 of copending Application No. 17/262,400 in view of Gong et al., and Cao is withdrawn in light of Applicant’s amendment to claim 14 and cancelation of other claims.
New Provisional 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 14 and 22-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 25, 4, 19, 26-29, 36 and 38-40 of copending Application No. 17/262,400 in view of Gong et al., (CN105316362A, published on 2016, English translation provided in IDS 07/27/2023) and Cao et al., (ClinicalTrials.gov ID NCT02903810, posted date 2016-10-12, p. 1-9. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a method for producing a cell that express an exogenous rearranged TCR or CAR, which comprises the steps of altering a non-rearranged TCR locus in a material cell genome so that it comprises a reporter gene or a known TCR or CAR gene (i.e., the instantly claimed marker gene in instant claims 14, 23 and 24), and replacing the gene with the exogenous TCR or CAR gene (reference claim 25, related to instant claims 14 and 27-29), the exogenous gene is introduced in the material cell by means of RMCE (reference claim 4, related to instant claims 14 and 26), the cassette comprises two target sequences for a recombinase and apply the recombinase (references claim 26 and 36, related to the upstream and downstream recombinase target sequences in instant claims 14), the method further comprises the step of differentiating the obtained cells into a T cell (reference claim 38, related to instant claims 30), and further comprises a step of removing the cell which was unsuccessfully exchanged with the TCR or CAR gene by an antibody (reference claim 40, related to instant claim 22). It is noted that since copending claims recite integration to a non-rearranged TCR locus, the material cell would have only one cassette structure in the genome per one material cell (related to instant claim 14).
However, the copending claims are silent on the reporter being a fluorescent protein in instant claim 25, the material cell being an ESC in instant claims 31-32, nor recite multiple cassette genes for exchange to produce multiple types of T cells in instant claim 14.
Gong teaches a method for producing tumor antigen-specific T cells expressing a tumor antigen-specific TCR using Dual-RMCE (see e.g. abstract). Gong teaches mouse embryonic stem cells are electroporated with an integration vector that comprises a fluorescent marker protein ([0053]) and the TCR-ES cells can be differentiated into T cells ([0070]-[[0073], see Fig 7). Thus, Gong teaches the reporter marker protein being a fluorescent protein in instant claim 25 and the material cell being an ESC in instant claims 31-32. Gong teaches there are multiple tumor-associated antigens (e.g., [0005]), and a series of high-affinity tumor antigen-specific TCR genes have been isolated for use in tumors such as B-cell lymphoma (e.g., [0006]).
Cao teaches a clinical trial using combination transfer of two chimeric antigen receptor (CAR)-T cells for treating B cell malignancy (p. 1, Brief summary). Cao teaches because of the heterogeneity of the tumor, patients often carry tumor cells with various positive target antigens, thus Cao proposes infusion of a mixed population of CAR-T cells (CD19- and CD22-CAR-T cells) to eliminate tumor burden and inhibit the recurrence of tumor heterogeneity at the same time (see p. 1, Brief summary). Thus, Cao suggests multiple types of T cells (e.g., two types of CAR-T cells) each expressing a different protein of a specificity-determining site (e.g., a CD19-CAR or a CD22-CAR) at the same time (i.e., co-administration of two types of T cells) in instant claim 14.
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 recited the method for producing T cells expressing exogenous TCRs or CARs, and have chosen fluorescent protein as marker protein and an ESC as a material cell for differentiating into T cells as taught by Gong, and have combined multiple genes encoding multiple proteins of the specificity-determining sites to produce multiple types of T cells each expressing a different protein of a specificity-determining site at the same time as suggested by Gong and Cao with a reasonable expectation of success. Since Gong reduces to practice a fluorescent marker protein and an ESC to differentiate into T cells, and teaches multiple tumor-associated antigens as well as a series of high-affinity tumor antigen-specific TCR genes for use in tumors such as B-cell lymphoma (e.g., [0005-0006]), and since Cao teaches treating B-cell malignancy with multiple types of T cells each expressing a different protein of a specificity-determining site (e.g., a CD19-CAR or a CD22-CAR) at the same time (i.e., co-administration of two types of T cells) to eliminate tumor burden and to inhibit the recurrence of tumor heterogeneity at the same time (see p. 1, Brief summary), one of ordinary skill in the art would have had a reason to choose a fluorescent marker protein and an ESC as a material cell as taught by Gong, and to combine and exchange with multiple genes encoding multiple proteins of the specificity-determining sites (e.g., a series of high-affinity tumor antigen-specific TCR genes) to produce multiple types of T cells each expressing a different protein of a specificity-determining site (a series of types of TCR-T cells) at the same time in order to co-administer the multiple types of TCR-T cells for eliminating tumor burden and inhibiting the recurrence of tumor heterogeneity.
Since the instant application claims are obvious over cited application claims, in view of Gong and Cao, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Response to Traversal:
Applicant’s arguments filed on 05/26/2026 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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JIANJIAN ZHU/Examiner, Art Unit 1631
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