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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/24/2023 and 12/01/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group 1 drawn to method of transfecting or transducing T-cells with plurality of nucleic acid molecules in the reply filed on 11/25/2025 is acknowledged.
Claim 22 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-21 are pending and under exam.
Claim Objections
Claim 2 is objected to because of the following informalities: the claim required sequencing T-cells when cells cannot be sequenced. Appropriate correction is required. For the sake of prosecution, the claim is interpreted to read on sequencing nucleic acid encoding TCRs.
Claim 3 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 14. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 13 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 2. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 17 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 7. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 18 and 19 are objected to under 37 CFR 1.75 as being a substantial duplicate of claims 8 and 9 respectively. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 20 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 11. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 5 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 5 which is a dependent claim on claim 4 and claim 1 requires substituted TCRs which is an optional embodiment of claim 1. As such the claim fails to "particularly point out and distinctly claim" the invention. Appropriate clarification is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 8-9, 13-14 and 18-19 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chen et al (WO2021101956A1; Published May 27, 2021; hereinafter “Chen;” See PTO-892).
Regarding claim 1: Chen disclosed a method of identifying a TCR by providing a plurality of T cells expressing a plurality of TCRs, wherein each T cell of the plurality of T cells expresses a cognate pair of a TCR of the plurality of TCRs; contacting the plurality of recipient cells with one or more antigens, thereby activating a marker in a subset of the plurality of recipient cells; wherein the one or more antigens are represented on one or more antigen presenting cells (APCs), MHC tetramers, nanoparticles or any combination thereof. (See claims 1 and 11 of Chen). The method of identifying activated T-cells is interpreted to read on the method for identifying TCR reactive to peptide as the method inherently involves activating T-cells expressing the TCRs. Additionally, claim 27 of Chen disclosed “selecting the TCR identified in (i) from the TCR repertoire of the plurality of recipient cells or the TCR repertoire of the subset of the plurality of recipient cells.” It is noted that [0029] of Chen indicated that “[t]he terms “enriching,” “isolating,” “separating,” “sorting,” “purifying,” “selecting” or equivalents thereof can be used interchangeably and refer to obtaining a subsample with a given property from a sample. As such, Chen disclosed the claimed sorting for T-cells with activated TCRs. The claim is anticipated.
Regarding claims 2 and 13: Chen disclosed sequencing TCR repertoire of recipient cells (See Chen claim 1h).
Regarding claim 3 and 14: Claim 29 of Chen disclosed that the polynucleotide pair encoding TCR delivered to the T-cells comprises a barcode.
Regarding claim 4: [0032] of Chen indicated that “the TCR-programmed recipient cells can be contacted with one or more antigens (e.g., one or more antigens in complexed with MHCs). Subsequent to contacting with the one or more antigens, the TCR-programmed recipient cells can be subject to selection (e.g., using fluorescence-activated cell sorting (FACS), magnetic activated cell sorting (MACS), panning or other method) to obtain post-selection TCR- programmed recipient cells.“
Regarding claims 8-9 and 18-19: Claim 26 of Chen disclosed that the antigen is upregulated in cancer cells and claim 23 disclosed that the antigen can be NY-ESO-1 antigen.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 5-7, 10-12, 15-17, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al (WO2021101956A1; Published May 27, 2021; hereinafter “Chen;” See PTO-892) in view of Chervin et al (Gene Ther. 2013 Jun; hereinafter "Chervin;" See PTO-892), and as evidenced by Yeung et al., (PNAS, published online August 18, 2014; hereinafter “Yeung”; See PTO-892).
Regarding claims 5 and 12: The teachings of Chen are set forth above. It is noted that Chen does not teach or suggest systematic CDR substitutions and comparing activation levels among substituted TCRs. Chervin is directed to “high-throughput platform of “reverse biochemistry” whereby a library of TCRs with a wide range of binding properties to the same antigen is introduced into T cells and adoptively transferred into mice with antigen-positive tumors. Extraction of RNA from tumor-infiltrating lymphocytes or lymphoid organs allowed high-throughput sequencing to determine which TCRs were selected in vivo. The results showed that CD8+ T cells expressing the highest affinity TCR variants were deleted in both the tumor infiltrating lymphocyte population and in peripheral lymphoid tissues. In contrast, these same high-affinity TCR variants were preferentially expressed within CD4+ T cells in the tumor, suggesting they played a role in antigen-specific tumor control.” (See Chervin Abstract). Chervin created libraries of TCR variants based on known TCRs (2C and m33). The variants included single-amino acid substitutions at key CDR positions, generating a range of binding affinities. The variants were transduced into T cells from mice. (See Chervin p. 2-3, last para p. 2 to first para p. 3). The transduced T cells were stimulated under multiple conditions such as in the presence of anti-CD3, SIY-pulsed antigen-presenting cells, null peptide OVA-pulsed T2-Kb cells and control cells. The peptide specific T-cell activation was measured. (See Chervin p. 7 para 3-5) The assays of Chervin allowed side-by-side comparison of functional activation among TCR variants with different substitutions and affinities. As such it is submitted that Chervin taught comparing activation levels of TCRs as required by the claim.
It would have been obvious for a person of ordinary skill in the art to modify the method of Chen by incorporating the CDR-substituted TCR variants and comparative functional activation analysis taught by Chervin thereby comparing the activation levels of substituted TCRs in the Chen activation based screening and sorting system. Such a combination represents the use of known techniques (CDR substitution and functional comparison of TCR variants) within a known screening framework (Activation based T-cell sorting) to achieve the predictable result of identifying TCR variants with improved or altered activation profiles. The person would have been motivated to combine Chen and Chervin as CDR substitutions are known to effect TCR-peptide-MHC interactions and functional T-cell activation was a standard and accepted metric for evaluating T-cell performance, as taught by Chervin. Applying Chervin’s substituted TCR variants to Chen’s activation based screening method would have been expected to yield predictable and informative differences in activation levels, enabling identification of desirable TCR variants.
Regarding claim 6 and 16: As indicated above, Chen taught measurement of TCR activation by FACS. It is noted that as evidenced by Yeung et al, see PTO-892 Fig. 7, the measurement of fluorescence in FACS is equivalent to comparing MFI.
Regarding claims 7, 10 and 17: Chervin disclosed sequencing the transcripts of TCR variants that were capable of controlling tumor growth were sequenced and the amino acid frequencies at position 46β were determined (See Chervin p. 5, last para). Chervin also disclosed that 46β is present in beta subunit CDR2 of β chain as required by claim 10.
Regarding claims 11 and 20: Chervin disclosed that they “used the 2C TCR and its high-affinity variant m33 (with affinity-increasing mutations in CDR3α). These TCRs bind with known affinity to the foreign peptide SIYRYYGL (SIY) and the structurally similar self-peptide EQYKFYSV (dEV8), both restricted by Kb” (See Chervin p. 3, para 2). As such Chervin taught that generating TCR variants with single amino acid substitutions confined to single CDR and expressing such TCRs in T cells, stimulating the T cells with peptide presenting antigen-presenting cells and evaluation of the functional activation of T cells expressing the substituted TCRs. Chervin particularly taught the placement of single amino acid substitution in CDR3 in the alpha chain. It would have been obvious for a person of ordinary skill in the art to modify the method of Chen by placing the single amino acid substitution in CDR3 as taught by Chervin in order to generate and evaluate TCR variants with altered functional properties. A person of ordinary skill would have been motivated to do so because Chervin taught that CDR3 substitutions are known to significantly affect TCR binding and activation and that single CDR substitutions can be functionally evaluated in T cells using activation based assays.
Regarding claim 15: [0032] of Chen indicated that “the TCR-programmed recipient cells can be contacted with one or more antigens (e.g., one or more antigens in complexed with MHCs). Subsequent to contacting with the one or more antigens, the TCR-programmed recipient cells can be subject to selection (e.g., using fluorescence-activated cell sorting (FACS), magnetic activated cell sorting (MACS), panning or other method) to obtain post-selection TCR- programmed recipient cells.”
Regarding claim 21: The teachings of Chen in view of Chervin are set forth above. It is noted that Chen taught delivering the TCRs to the T cells by viral transduction. For example [0039] of Chen taught that “[t]he TCR can be expressed from a vector such as plasmid, transposon (e.g., Sleeping Beauty, Piggy Bac), and a viral vector (e.g., adenoviral vector, AAV vector, retroviral vector and lentiviral vector).” As such Chen including paragraph [0039] taught expression of TCRs from viral vectors, co-culture with antigen presenting cells and identification and sorting of activated cells as explained above. Chervin taught expression of TCR variants in T-cells via retroviral vectors (See Chervin p. 3, para 3) and functional evaluation of substituted TCRs. It would have been obvious to a person of ordinary skill in the art to combine these teachings to transfect T-cells with viral vectors encoding TCRs or TCR variants, co-culture with peptide presenting APCs and sort activated T-cells, as each step was routine and yields predictable results.
Conclusion
No claim is allowed.
No claim is free of art.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633