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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 26NOV2025 has been entered.
Claim Status
Applicant’s claims received 26NOV2025 are acknowledged.
Claims 2-3, 34-41, and 44 have been canceled.
Claims 1, 10, and 25-26 have been amended.
Claims 46-47 are new.
Claims 1, 4-33, 42-43, and 45-47 (i.e., Claims 1, 10, and 25-26 are independent) are pending in the instant application.
Claims 31-33 remain withdrawn.
Claims 1, 4-30, 42-43, and 45-47 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/JP2019/051311, filed 26DEC2019, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of JP2018/242733 filed on 26DEC2018 has been received and is acknowledged.
Specification
Applicant’s arguments, see p 17, Specification section, filed 26NOV2025, with respect to objections to the specification for minor informalities have been fully considered and said objections to the specification have been withdrawn in view of amendments to the specification filed as part of said response.
Claim Objections
Claims 4 and 6 are objected to because of the following informalities:
Claim 4, sections a2 and a4, appear to recite a Markush group, but the group of alternatives are not closed, and should be updated so that an “and” replaces the “or” between 1 and 2 in line 16 of the claim. Claim 4, section a4 has the same issue.
Claim 6 contains a typographical error in line 17, wherein the “[[90%]]” has inadvertently not been removed. Examiner notes that all other edits have been made to previously presented claim 6 with exception of this error. Appropriate correction is required.
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 11-13, 18-20, and 28 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.
Claims 11-13 recite the limitation “The modified TCR according to claim 1,” and then go on to reference proportions of cell populations or properties following introduction of the modified TCR into a specific cell; however, claim 1 solely references the TCR structure and does not recite proportions of cell populations or properties following introduction of the modified TCR into a specific population of cells. Therefore, there is insufficient antecedent basis for this limitation in the claim. Examiner notes, making claims 11-13 dependent on claim 10 would obviate the rejection.
Claim 18 recites the limitation “The modified TCR according to claim 1 for the expression in” various cell populations; however, in claim 1 the modified TCR comprises polypeptide chains and therefore claim 18 implicitly claims the vectors that encode the protein for expression in the specific cell population. In this instance, the polynucleotides or vectors are not referenced in claim 1 and therefore the claim lacks sufficient antecedent basis for the limitation in the claim. Claims 19-20 are also rejected since they depend upon claim 18 but do not remedy this deficiency.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Applicant’s arguments, see p 17, Claim rejection under 35 USC §112, written description section, filed 26NOV2025, with respect to the rejection(s) of claim(s) 10-17 under 35 USC §112(a) – written description have been fully considered and said rejections of claims 10-17 have been withdrawn in view of the claim amendments filed as part of said response.
Enablement
Applicant’s arguments, see p 17-19, Claim rejections under 35 USC §112, enablement section], filed 26NOV2025, with respect to the rejection(s) of claim(s) 1-30, 42-43, and 45 (claims 2-3 have been cancelled) under 35 USC §112(a) - enablement have been fully considered and said rejections of claims 1, 4-30, 42-43, and 45 have been withdrawn in view of the claim amendments filed as part of said response.
Applicant’s claims received as part of the 26NOV2025 response have necessitated the following new grounds of rejection.
Claims 22-26 and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The nature of the invention, drawn to any cell that expresses the modified TCR, a pharmaceutical composition comprising any cell which expresses the modified TCR, methods of producing the modified TCR in any cell, and a pharmaceutical composition comprising a nucleic acid encoding the modified TCR is not fully enabled. The instantly claimed invention is not fully enabled because the specification and working examples lack support for the expression of the modified TCR in any cell apart from cells which do not express mature TCRα and TCRß (i.e., a specific cell type rather than any generic host cell) and pharmaceutical compositions thereof. The specification and working examples further lack support for the use of any nucleic acid that encodes the modified TCR in any cell apart from the use of a vector that comprises the nucleic acid that encodes the modified TCR in a cell that do not express mature TCRα and TCRß and pharmaceutical compositions thereof. Therefore, it would require one of ordinary skill in the art undue experimentation to use the modified TCR in any cell, use a generic nucleic acid which encodes the modified TCR, or use either the cell or nucleic acid in a pharmaceutical composition (i.e., for administration).
The specification discloses that the modified TCR of the invention comprises a first and second polypeptide which when expressed in a T cell in which the endogenous TCR expression has been inhibited or eliminated, a T cell which is capable of responding to stimulation through a modified TCR/CD3 complex without causing the antigen responsiveness can be produced (¶0016). Furthermore, the specification teaches that a gene of the invention can be introduced by incorporating the gene in a viral vector such as a retrovirus, lentivirus, and adenovirus and infecting a cell into which the gene is introduced or using a nonviral vector and introducing the gene to the cell by physical or chemical methods and examples of the cells into which the modified TCR is introduced include a pluripotent stem cell, a HSPC, an endogenous TRAC and TRBC gene-knockdown or knockout T cell and the like (i.e., undifferentiated cells, immature precursor cells, or modified T cells) (¶0068 and ¶0072). The experimental data teach that a specific set of cells are used for the successful expression of the modified TCR which can then be differentiated into T cells and while the gene encoding the modified TCR is compact, the modified TCR is considered to be able to fit all formats for gene introductions, such as through vectors or genome editing technology (¶0193-0194). Although, this example supports that a vector is required for genetically modifying cells, that cells which do not express endogenous TCRα/ß are able to express the modified TCR which can then be differentiated into T cells, and that a pharmaceutical composition comprising i) a vector which comprises a nucleic acid for expression of the modified TCR in cells which do not express endogenous TCRα/ß or ii) a cell which expresses the modified TCR in which the cell does not express endogenous TCRα/ß, it is unclear whether the same results could be observed with a generic nucleic acid or with any cell as currently claimed. Therefore, there is no guidance for making the modified TCR in any generic host cell (i.e., wild-type CHO, E. coli, etc.) or as a nucleic acid which encodes the modified TCR and then using said product in a pharmaceutical formulation.
Thus, one skilled in the art would be unable to use the modified TCR expressed in any cell, use the pharmaceutical composition of the modified TCR expressed in any cell, use the pharmaceutical composition of the nucleic acid which encodes the modified TCR. Therefore, the implementation of the invention in view of the lack of support in the specification and working examples, would require undue experimentation for one of ordinary skill in the art to use the modified TCR as currently claimed.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see p 19-20, Claim rejection under 35 USC §102 section, filed 26NOV2025, with respect to the rejection(s) of claim(s) 1-30, 42-43, and 45 (claims 2-3 have been cancelled) under 35 USC §102 have been fully considered and are fully persuasive because of the claim amendments which add limitations not taught in the cited art. As such, said rejection of claims 1, 4-30, 42-43, and 45 under 35 USC §102 have been withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Applicant’s arguments, see 20-21, Double patenting section, filed 26NOV2025, with respect to the rejection of claim(s) 1, 14, 22, 25, and 42-43 under provisional non-statutory double patenting have been fully considered. Applicant has asked that the provisional nonstatutory double patenting rejections be held in abeyance until the indication of otherwise found allowable subject matter. The Applicant has amended the claims of the instant application to provide additional limitations, which has resulted in said rejections of claims 1, 14, 22, 25, and 42-43 being withdrawn. Upon further consideration of the amended claims received 26NOV2025 and because the Applicant has not filed terminal disclaimers, the following new grounds of provisional non-statutory double patenting rejection is necessitated.
Claims 1, 4-9, 14-17, 42-43, and 46-47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of co-pending Application No. 17/416859, herein referred to as “reference application” as evidenced by Lefranc, et al., (The T cell Receptor FactsBook, 2001, 1-397), herein referred to as “Lefranc.” Although the claims at issue are not identical, they are not patentably distinct from each other because the TCR variant of the reference application anticipates the modified TCR of the instant application. Specifically, both TCRs comprise two polypeptides wherein the constant regions of the TCRα and TCRß chains are expressed and the variable regions of the TCRα and TCRß chains are not expressed and there is no antigen recognition site.
The co-pending claims of the reference application recite: A variant of a T-cell receptor comprising a combination of two polypeptides comprising a constant region of a T cell receptor chain selected from the group consisting of α chain, ß chain, γ chain, and δ chain, wherein the variant of the T-cell receptor does not comprise any of the following (a)-(c): (a) a complementarity determining region (CDR) of the T cell receptor chain from which the constant region derives, (b) a complementarity determining region (CDR) of the α chain, and (c) a complementarity determining region (CDR) of the ß chain, and wherein the variant of the T-cell receptor does not have an antigen recognition site (i.e., claim 1). The variant according to claim 1, wherein one of the polypeptides comprises a constant region of the TCR α chain or ß chain and the other comprises a constant region of the TCR α chain or ß chain (i.e., claim 2). A nucleic acid molecule encoding the variant according to claim 1 (claim 4); a vector comprising the nucleic acid molecule according to claim 4 (claim 5); a method for producing a cell, comprising a step of introducing the vector according to claim 5 (claim 6); and a cell expressing the variant according to claim 1 (claim 7). A nucleic acid molecule encoding the variant according to claim 2 (claim 9). In this instance, the TCR variant (i.e., modified TCR) of the reference application comprises the constant regions of the TCRα and TCRß chains and no CDRs or antigen recognition site (i.e., antigen recognition region), wherein the polypeptide amino acid sequences of TRAC and TRBC2 are evidenced by Lefranc and are a 100% query match to SEQ ID NOs: 2 and 12 of the instant application (see OA.APPENDIX and Lefranc, p 372).
In this instance, because the TCR variant polypeptide sequences of the TCRα and TCRß constant regions (i.e., without any variable region or antigen recognition site) of the reference application are known sequences as evidenced by Lefranc, and SEQ ID NOs: 2 and 12 of the instant application consist of the TCRα and TCRß constant regions, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
Although the reference application is silent with regard to the modified TCR or TCR variant is able to hold a CD3 subunit on the cell membrane, transmitting TCR/CD3 related signal into the cytoplasm via the CD3 subunit and thus activates a T cell as in claims 14-17, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the TCR variant taught by the reference application would have the claimed properties recited in claims 14-17.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10-13, 18-23, and 25-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of co-pending Application No. 17/416859, herein referred to as “reference application” as evidenced by Lefranc, et al., (The T cell Receptor FactsBook, 2001, 1-397), herein referred to as “Lefranc” as applied to claims 1, 4-9, 14-17, 42-43, and 46-47 and in further view of Smith, et al., (Stem Cells, 2015, 33, 3174-3180), herein referred to as “Smith.”
The co-pending claims of the reference application recite: A variant of a T-cell receptor comprising a combination of two polypeptides comprising a constant region of a T cell receptor chain selected from the group consisting of α chain, ß chain, γ chain, and δ chain, wherein the variant of the T-cell receptor does not comprise any of the following (a)-(c): (a) a complementarity determining region (CDR) of the T cell receptor chain from which the constant region derives, (b) a complementarity determining region (CDR) of the α chain, and (c) a complementarity determining region (CDR) of the ß chain, and wherein the variant of the T-cell receptor does not have an antigen recognition site (i.e., claim 1). The variant according to claim 1, wherein one of the polypeptides comprises a constant region of the TCR α chain or ß chain and the other comprises a constant region of the TCR α chain or ß chain (i.e., claim 2). A nucleic acid molecule encoding the variant according to claim 1 (claim 4); a vector comprising the nucleic acid molecule according to claim 4 (claim 5); a method for producing a cell, comprising a step of introducing the vector according to claim 5 (claim 6); and a cell expressing the variant according to claim 1 (claim 7). A nucleic acid molecule encoding the variant according to claim 2 (claim 9). In this instance, the TCR variant (i.e., modified TCR) of the reference application comprises the constant regions of the TCRα and TCRß chains and no CDRs or antigen recognition site (i.e., antigen recognition region), wherein the polypeptide amino acid sequences of TRAC and TRBC2 are evidenced by Lefranc and are a 100% query match to SEQ ID NOs: 2 and 12 of the instant application (see OA.APPENDIX and Lefranc, p 372).
However, they do not claim: introduction of the modified TCR to pluripotent stem cells, or HSPCs and differentiation to T cells.
Nevertheless, Smith teaches a review of in vitro T cell generation from HSPCs and induced pluripotent stems cells (i.e., derived from fibroblast or lymphoid cells) providing a self-renewing source of T cells that can be readily genetically modified to express designer TCRs (i.e., modified TCR) which do not require MHC match between the donor and recipient or the disruption of the endogenous TCR, permitting universal application (see entire document, specifically see abstract and conclusion sections).
It would have been obvious to artisans to modify the co-pending TCR variant for expression in a generic cell line as claimed by the reference application by expressing the TCR variant in a pluripotent cell for differentiation into a T cell as claimed by Smith. This is because Smith teaches that induced pluripotent stems cells provides a self-renewing source of T cells that can be readily genetically modified and do not require MHC match between the donor and recipient or the disruption of the endogenous TCR permitting universal application. One would have been motivated to do so, given the direction by the reference application that the TCR variant can be produced by being expressed in a generic cell. There would have been a reasonable expectation of success, given the knowledge that by modifying the TCR variant produced by expression of the TCR variant in a generic cell taught by the reference application by expressing the TCR variant in a iPSC and differentiating the iPSC to a T cell would provide a nearly unlimited supply of modified T cells, which could be used for immunotherapy to express designer TCRs, as taught by Smith.
Although the reference application and Smith are silent with regard to the modified TCR or TCR variant wherein the proportion of CD3 positive cells in pluripotent stem cells, etc. into which the modified TCR has been introduced is 1% or more; or two times or more higher than the proportion of CD3 positive cells in corresponding cells into which the modified TCR has not been introduced in claims 10-11, or wherein the pluripotent stem cells, etc. into which the modified TCR has been introduced exhibits an equivalent or higher T cell differentiation capacity as compared to that of a corresponding cell into which the full-length TCR has been introduced as in claim 12, or wherein the alloreactivity of a non-T cell derived pluripotent stem cell, etc. into which the modified TCR has been introduced is lower than that of ta corresponding cell into which the full-length TCR has been introduced as in claim 13, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the TCR variant taught by the reference application would have the claimed properties recited in claims 10-13.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641