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
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1, 5-13, 15-16, 25-26, 28 and 31-42, drawn to an engineered T cell comprising a modified invariant CD3-immunoglobulin superfamily (invariant CD3-IgSF) chain locus comprising a nucleic acid sequence encoding a mini chimeric antigen receptor (miniCAR), in the reply filed on 02/17/2026 is acknowledged.
Claims 44, 71, 74-77, 83, 98-99, 102, 111 and 122 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant further elects the species of a modified CD3 epsilon (CD3E) locus encoding a CD3e chain in claim 6 and the target antigen of CD19 in claim 33.
Claim Status
Claims 1, 5-13, 15-16, 25-26, 28, 31-42, 44, 71, 74-77, 83, 98-99, 102, 111 and 122 are pending.
Claims 44, 71, 74-77, 83, 98-99, 102, 111 and 122 are withdrawn.
Claims 1, 5-13, 15-16, 25-26, 28 and 31-42 are considered on the merits.
Priority
This application is a 371 of PCT/US2021/057937 (filed on 11/03/2021), which claims benefit from provisional application 63/109,858 (filed on 11/04/2020). The priority claim of the instant application has been granted and the earliest benefit date is 11/04/2020 from the application 63/109,858.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/08/2023 and 02/17/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claims 9 and 15-16 are objected to because of the following informalities:
Claim 9, line 2, recites “a sequence of nucleotides encoding the heterologous antigen-binding domain”. Since claim 1 has recited “a sequence encoding the antigen-binding domain”, the phrase in claim 9 is recommended to change to “the sequence …”.
Similarly, claim 15, lines 2-3, the phrase “a sequence of nucleotides encoding the antigen-binding domain and a sequence of nucleotides encoding the linker” is recommended to change to “the sequence of … and the sequence of …”.
Similarly, claim 16, line 2, the phrase “a sequence of nucleotides” is recommended to change to “the sequence …”.
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.
Claim 37 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 37 recites “the TCR/CD3 complex” in line 2. There is insufficient antecedent basis for this limitation because base claim 1 is silent on a TCR/CD3 complex.
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 1, 5-9, 11-13, 15-16, 28 and 31-42 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle et al., (Nat Commun. 2019 May;10(1):2087, p. 1-12) in view of Roth et al., (WO2020/186219, published 2020 September).
With respect to claim 1, it is noted that the term “mini chimeric antigen receptor (miniCAR)” is examined as being defined by the claim which recites “wherein the miniCAR is a fusion protein comprising a heterologous antigen-binding domain and an endogenous invariant CD3 chain”.
Baeuerle teaches TRuC-T cells, i.e., T cells comprising T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits (e.g., abstract). Specifically, Baeuerle teaches the anti-CD19 scFv is tethered to the N-terminus of full-length CD3γ, CD3δ, or CD3ε TCR subunits via a flexible glycine serine linker (see e.g., p. 2, “Results” section, para 1 “Design of TRuCs and lentiviral expression in human T cells”, also see Fig 1 and legend). Thus, Baeuerle teaches an engineered T cell (i.e., a TRuC-T cell), comprising a nucleic acid sequence encoding a miniCAR (i.e, TRuC) wherein the miniCAR is a fusion protein comprising a heterologous antigen-binding domain (e.g., an anti-CD19 scFv) and a wildtype full-length invariant CD3-IgSF chain (e.g., full-length CD3γ, CD3δ, or CD3ε TCR subunits), wherein the nucleic acid sequence comprises an in-frame fusion of (i) a transgene comprising a sequence encoding the antigen-binding domain and (ii) an open-reading frame of the invariant CD3-IgSF chain gene encoding the invariant CD3-IgSF chain (see e.g., Fig 1a for schematic diagram of the T cell receptor fusion constructs attached).
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However, Baeuerle is silent on the cell comprising a modified invariant CD3-IgSF chain locus comprising in-frame fusion of the transgene encoding the antigen-binding domain with the endogenous invariant CD3-IgSF chain locus.
Nevertheless, Baeuerle teaches the TRuCs are able to integrate into natural TCR/CD3 complexes in place of their corresponding native counterparts (see e.g., p. 2, right col, section “Unlike CARs, TRuCs become an integral part of the TCR”, also see Fig 1b for schematic diagram of the TRuC-containing receptor complexes and Fig 2a for western blots analysis). Thus, Baeuerle suggests the TRuCs (i.e., miniCARs) can replace the corresponding endogenous invariant CD3-IgSF chains.
Regarding modifying invariant CD3-IgSF chain locus comprising in-frame fusion of heterologous domains, Roth teaches a method of targeted genomic insertion in a cell to obtain engineered cells expressing heterologous polypeptides under the control of endogenous loci (e.g., abstract). Roth teaches several approaches to generate Genetically Engineered Endogenous Proteins (GEEPs) to combine synthetic elements with endogenous sequences, including inserting a synthetic product under a particular endogenous promoter, replacing receptor specificity by targeting a sequence encoding a novel extracellular domain to the exon encoding the transmembrane domain, and altering the signaling of a receptor by knocking-in new signaling domains (e.g., [88], p. 19-beginning of p. 20, see Fig 2a). Roth teaches examples such as (1) targeting an insert encoding tNGFR to the N-terminal coding region of PD1 such that tNGFR would be expressed with PD1 under the regulation of the PD1 promoter (e.g., p. 20, example (c)); (2) knocking-in the 1G4 TCR receptor in-frame into the endogenous TRAC locus to alter TCR specificity using endogenous TRAC component (e.g., p. 20, example (d)); and (3) knocking-in additional signaling domains in-frame to the C-terminus of one of the CD3 subunits, e.g., CD3 epsilon, to create synthetic signaling cascades together with endogenous full length CD3 epsilon (e.g., p. 20, example (e)).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered T cell comprising a nucleic acid sequence encoding a heterologous antigen-binding domain tethered to the N-terminus of full-length CD3γ, CD3δ, or CD3ε TCR subunits disclosed by Baeuerle, by substituting the nucleic acid sequence with knocking-in the sequence encoding the heterologous antigen-binding domain in-frame to the endogenous N-terminal coding region of CD3γ, CD3δ, or CD3ε TCR subunits so as to obtain T cells comprising a modified CD3 locus as suggested by Roth with a reasonable expectation of success. Since Baeuerle suggests the TRuCs (i.e., having a heterologous antigen-binding domain tethered to the N-terminus of full-length CD3γ, CD3δ, or CD3ε TCR subunits) can replace the corresponding endogenous CD3γ, CD3δ, or CD3ε subunits (see above), and since Roth reduces to practice a method of targeted genomic insertion in a cell to generate genetically engineered endogenous proteins combining synthetic elements with endogenous sequences (e.g., [462]) and exemplifies knocking-in an insert to the N-terminal coding region of an endogenous gene locus and also exemplifies knocking-in additional signaling domains to the C-terminus of one of the CD3 subunits, e.g., CD3 epsilon gene locus to take advantage of the endogenous full length CD3 epsilon (see above), one of ordinary skill in the art would have had a reason to knock-in the sequence encoding the heterologous antigen-binding domain to the endogenous N-terminal coding region of CD3γ, CD3δ, or CD3ε TCR subunits gene loci so as to obtain T cells comprising a modified locus to express genetically engineered endogenous proteins combining synthetic elements with endogenous sequences (i.e., a miniCAR comprising the heterologous antigen-binding domain tethered to the N-terminus of endogenous CD3γ, CD3δ, or CD3ε TCR subunits) in order to obtain sustained expression (e.g., Roth, [138]) and to remove the need for a viral infection or random integration (e.g., Roth, [458]).
With respect to claim 5 and claim 6 directed to a modified CD3E locus encoding a CD3e chain, as stated supra, Baeuerle teaches the anti-CD19 scFv is tethered to the N-terminus of full-length CD3γ, CD3δ, or CD3ε TCR subunits (see e.g., p. 2, “Results” section, para 1, also see Fig 1 and legend), and Roth exemplifies knocking-in additional domains in-frame to the one of the CD3 subunits, e.g., CD3 epsilon (e.g., p. 20, example (e) and Fig 2b).
With respect to claim 7 directed to the antigen-binding domain comprising an antigen-binding fragment and claim 8 directed to a scFv, as stated supra, Baeuerle teaches an anti-CD19 scFv (see e.g., p. 2, “Results” section, para 1, also see Fig 1 and legend).
With respect to claim 9 directed to the order, claim 11 and claim 12 directed to a linker, claim 13 directed to the linker being 3’ to the antigen-binding domain, claim 15 and 16 directed to the order, as stated supra, Baeuerle teaches the anti-CD19 scFv is tethered to the N-terminus of full-length CD3γ, CD3δ, or CD3ε TCR subunits via a flexible glycine serine linker (see e.g., p. 2, “Results” section, para 1 “Design of TRuCs and lentiviral expression in human T cells”, also see Fig 1a attached above), thus teaches, in order from 5' to 3', a sequence of nucleotides encoding the heterologous antigen-binding domain and the endogenous invariant CD3-IgSF chain in claim 9, the antigen-binding domain and the invariant CD3-IgSF chain are linked indirectly via a linker in claim 11, the transgene further comprises a nucleic acid sequence encoding a linker in claim 12, the linker is positioned 3' to the antigen-binding domain in claim 13, in order from 5' to 3', a sequence of nucleotides encoding the antigen-binding domain and a sequence of nucleotides encoding the linker in claim 15, and in order from 5' to 3', a sequence of nucleotides encoding the antigen-binding domain, the linker, and the invariant CD3-IgSF chain in claim 16.
With respect to claim 28 directed to a full length mature invariant CD3-IgSF chain, as stated supra, Baeuerle teaches full-length CD3γ, CD3δ, or CD3ε TCR subunits (see e.g., p. 2, “Results” section, para 1 “Design of TRuCs and lentiviral expression in human T cells”) and teaches the TRuCs are able to integrate into natural TCR/CD3 complexes (see e.g., p. 2, right col, section “Unlike CARs, TRuCs become an integral part of the TCR”) and are functional (see e.g., Fig 3), thus teaches a full length mature invariant CD3-IgSF chain.
With respect to claim 31 directed to a target antigen associated with a disease, claim 32 directed to a tumor antigen, and claim 33 directed to an elected species CD19, as stated supra, Baeuerle teaches an antigen-binding domain being anti-CD19 scFv (see e.g., p. 2, “Results” section, para 1, also see Fig 1 and legend), thus teaches the target antigen being a tumor antigen CD19.
With respect to claim 34 and claim 35 directed to the miniCAR assembling into a TCR/CD3 complex in place of the endogenous CD3e chain, as stated supra, Baeuerle teaches the TRuCs, including CD3e-TRuC, are able to integrate into natural TCR/CD3 complexes (see e.g., p. 2, right col, section “Unlike CARs, TRuCs become an integral part of the TCR”, also see Fig 1b for schematic diagram of the TRuC-containing receptor complexes and Fig 2a for western blots analysis). It is noted that the assembled TCR complexes comprise the TRuCs in the place of the corresponding native counterparts (see e.g., Fig 2a for western blots analysis showing two CD3e-TRuC in the complexes and the schematic diagram in Fig 1b).
With respect to claim 36 directed to binding target antigen being capable of inducing antigen-dependent signaling, Baeuerle teaches TRuC-T cell has cytotoxicity and cytokine production when contacting with HeLa cells expressing the target antigen CD19 or contacting CD19 positive tumor cells (see e.g., Fig 3), thus teaches binding target antigen induces antigen-dependent signaling via the TCR/CD3 complex.
With respect to claim 37, claim 38 and claim 39 directed to the characteristics of the engineered T cell, MPEP 2145 (II) states that “mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”, and “the fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. In instant case, the prior art Baeuerle teaches the “ε-TRuC-T cells demonstrated superior tumor killing compared to both CD28ζ and BBζ CAR-T cells…This could relate to better tumor penetration, longer persistence, and/or less exhaustion by the tumor microenvironment” (p. 9, right col, last para – p. 10, para 1), thus teaches the engineered T cell exhibits increased persistence in claim 38 and increased cytolytic activity in claim 39. Thus, the fact that applicant has recognized another advantage (i.e., reduced tonic signaling recited in claim 37) cannot be the basis for patentability when the differences would otherwise be obvious over Baeuerle in view of Roth.
With respect to claim 40 directed to primary T cells from a subject, claim 41 directed to human, and claim 42 directed to a CD8+ T cell or a CD4+ T cell, Baeuerle teaches “Primary human T cells were isolated from leukapheresis product by magnetic bead separation using anti-CD4 and anti-CD8 microbeads” (e.g., p. 10, right col, para “Primary human T cell activation, transduction, and expansion”).
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.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle et al., (Nat Commun. 2019 May;10(1):2087, p. 1-12) in view of Roth et al., (WO2020/186219, published 2020 September), as applied to claim 1 above, and further in view of Eshhar et al., (Proc Natl Acad Sci U S A. 1993;90(2):720-724. IDS 12/08/2023).
Claim 10 is directed to the antigen-binding domain and the CD3-IgSF chain being directly linked.
However, Baeuerle teaches the antigen-binding domain and the CD3-IgSF chain are linked indirectly via a linker, but Baeuerle and Roth are silent on the antigen-binding domain and the CD3-IgSF chain being directly linked.
Eshhar teaches a chimeric scFvR comprising a single-chain Fv domain (scFv) of an antibody linked with a TCR chain, such as a CD3 gamma or zeta chains (e.g., abstract, see Fig 1 showing a scFv-CD3 gamma chain). Eshhar teaches the chimeric receptor could be expressed as functional surface receptors (e.g., Fig 2) in a cytolytic T-cell, could trigger interleukin 2 secretion (e.g., Fig 5) upon encountering antigen and mediate non-major-histocompatibility-complex-restricted hapten-specific target cell lysis (e.g., Fig 6, also see abstract). Eshhar teaches such chimeric receptors can be exploited to provide T cells with antibody-type recognition directly coupled to cellular activation (e.g., abstract). It is noted that in Eshhar’s chimeric scFvR, the antigen-binding domain and the CD3-IgSF chain are directly linked (see Fig 1 attached below).
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Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered T cell comprising an antigen-binding domain tethered to the N-terminus of CD3γ, CD3δ, or CD3ε TCR subunits via a linker suggested by Baeuerle in view of Roth, by substituting with the antigen-binding domain directly linked to the CD3-IgSF chain as suggested by Eshhar with a reasonable expectation of success. Since Eshhar reduces to practice the chimeric receptor in which the antigen-binding domain is directly linked to the CD3-IgSF chain and that is functional in inducing antigen-dependent signaling (see above), one of ordinary skill in the art would have had a reason to substitute with directly linking the antigen-binding domain to the endogenous CD3-IgSF chain in order to obtain a functional chimeric antigen receptor.
Furthermore, since Baeuerle’s nucleotide sequence having a linker and Eshhar’s nucleotide sequence without a linker are for the same purpose (i.e., to produce a chimeric antigen receptor), these nucleotide sequences 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 Eshhar’s nucleotide sequence without a linker for Baeuerle’s nucleotide sequence having a linker. See MPEP 2144.06.
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.
Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle et al., (Nat Commun. 2019 May;10(1):2087, p. 1-12) in view of Roth et al., (WO2020/186219, published 2020 September), as applied to claim 1 above, and further in view of Das et al., (J Virol Methods. 2004;117(2):169-77).
Claim 25 is directed to the transgene further comprising a nucleic acid sequence encoding an affinity tag. Claim 26 is directed to the affinity tag being a streptavidin binding peptide.
However, Baeuerle only teaches combining a GFP for detecting chimeric receptor (see Fig 1a and 1c), but Baeuerle and Roth are silent on the transgene encoding the scFv further comprising an affinity tag, or the affinity tag being a streptavidin binding peptide.
Das teaches development of a biotin mimic tagged ScFv antibody (see e.g., title and abstract, also see Fig 1), related to claim 25. Das teaches the biotin mimic tag is an 11 amino acid peptide that mimics biotin and it has affinity for streptavidin, related to claim 26, and these biotin mimics have been cloned successfully to different ScFv for use in immunoassay (e.g., p. 175, left col, para 1). Das teaches that the biotin mimic ScFv complexed with streptavidin horseradish peroxidase (St-HRPO) will be useful as a detector reagent in the ultrasensitive ELISA detection (see e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered T cell comprising an antigen-binding domain scFv fused to the endogenous CD3γ, CD3δ, or CD3ε TCR subunits suggested by Baeuerle in view of Roth, by combining a biotin mimic affinity tag to the antigen-binding domain scFv as suggested by Das with a reasonable expectation of success. Since Das teaches the biotin mimics have been cloned successfully to different ScFv for use in immunoassay (e.g., p. 175, left col, para 1 and abstract) and teaches the biotin mimic tagged scFv is functional (e.g., see Fig 6), one of ordinary skill in the art would have had a reason to combine a biotin mimic affinity tag to the scFv of Baeuerle in view of Roth in order to enable detection of the chimeric antigen receptor.
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.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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