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 .
Claims 49-50 and 52-69, of record 2/27/2026, are pending and subject to prosecution. Claims 49, 60, 63, and 66 are amended. Claims 68-69 are newly added. Claim 51 is cancelled.
Status of Prior Objections/Rejections
RE: Objection to the specification:
The submission of a substitute specification is effective to obviate the objection. The objection is withdrawn.
RE: Objection to claims 49, 51, and 60:
The cancellation of claim 51 renders the objection thereto moot.
The amendment to claims 49 and 60 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 49-67 are rejected under 35 U.S.C. 112(a):
The cancellation of claim 51 renders the rejection thereto moot.
The amendment to claim 49 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claim 51 is rejected under 35 U.S.C. 112(b):
The cancellation of claim 51 renders the rejection thereto moot.
New Objections/Rejections
Claim Objections
Claims 62-63 are objected to because of the following informalities:
In line 1 of claim 62, “a step of” should be deleted.
In lines 1-2 and line 6 of claim 63, “the following steps” and “the step” should be deleted. In line 5, the comma should be replaced with “and”.
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 66 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 66 recites the limitation “the nucleic acid encoding the T cell antigen receptor according to claim 49” in lines 3-4. There is insufficient antecedent basis for this limitation in the claim.
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.
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 49-50, 52-56, 58-61, 63, and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Stauss et al. (US 20130045221 A1).
Regarding claims 49-50, 54, 56, and 58-61: Stauss et al. teach a CMV pp65-specific TCR wherein the α chain comprises CDR1α (SSNFYA, which reads on “an amino acid sequence comprising SEQ ID NO: 4”) and CDR3α (ARNTGNQFYFGTGTSLTVIPN, which reads on “an amino acid sequence comprising SEQ ID NO: 12”), and the β chain comprises CDR1β (MNHEY, which reads on “an amino acid comprising SEQ ID NO: 18”), CDR2β (SVGAGI, which reads on “an amino acid sequence comprising SEQ ID NO: 23”), and CDR3β (ASSFQTGASYGYTFGSGTRLTVL, which reads on “an amino acid sequence comprising SEQ ID NO: 28”) (See ¶0023-0025 and 0080 and alignments below).
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The TCR is specific for the pp65 epitope NLVPMVATV, which is identical to instant SEQ ID NO 1 (See Abstract and alignment below).
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The α and β chains of the TCR are linked via disulfide bond (which reads on “linked directly or indirectly”) (See fig. 1). The TCR is encoded by a nucleotide sequence which can be expressed in a T cell (which reads on “immune cell”) from a CMV-seronegative donor (which reads on “derived from a subject”) or a stem cell (See ¶0030, 0039, and 0041). A vector encoding the TCR can be used to transfect or transduce the cell (See ¶0040-0041 and 0150).
Stauss et al. do not expressly teach CDR2α as SEQ ID NO 8 (MTLNGDE). However, Stauss et al. teach CDR2α as having the sequence MTLNGD (See alignment below), and this sequence is immediately followed by a glutamic acid residue in a TCR construct, CMVa18-p2A-Vb13, which also comprises instant SEQ ID NOs 4, 12, 18, 23, and 28 (See ¶0080).
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One of ordinary skill in the art would reasonably expect that the sequence MTLNDG in the CDR2α loop of this construct, immediately followed by a glutamic acid residue, would be structurally and functionally equivalent to the claimed CDR2α comprising instant SEQ ID NO 8. The TCR taught by Stauss et al. therefore renders obvious the claimed TCR.
Regarding claim 52: Following the discussion of claims 49-50, 54, 56, and 58-61, Stauss et al. teach the sequence of the TCR construct CMVa18-p2A-Vb13 as comprising SEQ ID NO 8, which comprises amino acid sequences having 86.1% local similarity to instant SEQ ID NO 247 and 81.3% local similarity to instant SEQ ID NO 253 (which reads on “having at least 80% homology to any one of SEQ ID NOs: 247-252” and “having at least 80% homology to any one of SEQ ID NOs: 253-258”) (See ¶0079-0080 and alignments below (first 120 aa displayed)).
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Regarding claim 55: Following the discussion of claims 49-50, 54, 56, and 58-61, Stauss et al. teach the sequence of the TCR construct CMVa18-p2A-Vb13 as comprising SEQ ID NO 8, which comprises amino acid sequences having 86.1% local similarity to instant SEQ ID NO 36 (which reads on “having at least 80% homology to any one of SEQ ID NOs: 36…”) (See ¶0079-0080 and alignments below (first 120 aa displayed)).
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Regarding claim 63: Following the discussion of claims 49-50, 54, 56, and 58-61, Stauss et al. teach that the TCRα and TCRβ genes of the TCR construct were derived from HLA-A*0201 restricted CMV pp65-specific CTL clones (which reads on “a positive T cell clone” (See ¶0201). The TCR genes were transduced into donor T cells that were isolated from peripheral blood and cultured in vitro for seven days (which reads on “separating, culturing a primary T cell” and “delivering the nucleic acid”) (See ¶0202 and 0208).
Regarding claim 64: Following the discussion of claims 49-50, 54, 56, and 58-61, Stauss et al. teach the analysis of CMV-specific TCR expression on the cell surface using peptide-MHC tetramers (which reads on “multimeric complex, comprising the T cell antigen receptor”) (See ¶0203 and fig. 2).
Regarding claims 66-67: Following the discussion of claims 49-50, 54, 56, and 58-61, Stauss et al. teach that the TCR, a nucleotide or vector encoding the TCR, or a cell comprising the TCR can be used for a medicament for use in treating or preventing a disease associated with CMV in a subject (See ¶0054, 0150-0151, and 0158). Stauss et al. do not expressly teach administering “an effective amount”, however, treatment or prevention of a CMV-associated disease would inherently require that an effective amount be administered.
Claims 49-50, 52-56, 58-64, and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Stauss et al. (US 20130045221 A1) in view of Legut et al. (Blood, 2018).
The teachings of Stauss et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 62: Following the discussion of claims 49-50, 52-56, 58-61, 63-64, and 66-67, Stauss et al. render obvious a CMV pp65-specific TCR and its expression in T cells but do not teach knocking out an endogenous TCR.
Legut et al. teach that endogenous TCR knockout improves the expression and activity of transduced replacement TCRs (See Abstract).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Stauss et al. to comprise endogenous TCR knockout along with TCR transduction. One would have been motivated to make this modification because Legut et al. teach that endogenous TCR knockout increases the efficacy of the transduced TCR in T cells (See Abstract). There would be a reasonable expectation of success in doing so because Legut et al. demonstrate that the knockout and transduction can be performed simultaneously (See fig. 1).
Claims 49-50, 52-56, 58-61, 63-64 and 66-67 are rejected under 35 U.S.C. 103 as being unpatentable over Stauss et al. (US 20130045221 A1) in view of Altman et al. (Science, 1996).
The teachings of Stauss et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 65: Following the discussion of claims 49-50, 52-56, 58-61, 63, and 66-67, Stauss et al. render obvious a multimeric complex comprising a CMV pp65-specific TCR and peptide/MHC tetramer but do not teach expressly teach the composition of the tetramer.
Altman et al. teach the generation of peptide-MHC tetramers for phenotypic analysis comprising monomers comprising a biotinylated HLA-A2 heavy chain (which reads on “an α-chain extracellular domain of an MHC molecule”), β-2-microglobulin, and a peptide antigen (See page 94, col. 2, ¶1). The tetramers were formed by mixing monomers with fluorescently-labeled avidin molecules (which reads on “the monomer is conjugated to the biotin molecule binding to the… avidin molecule”) (See page 94, col. 2, ¶1 and page 95, col. 1, ¶1).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the MHC tetramer taught by Altman et al. for that of Stauss et al. for use with a CMV peptide. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Allowable Subject Matter
Claims 57 and 68-69 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
A nucleic acid having at least 80% homology to SEQ ID NOs 37, 39, 41, 43, 45, or 47 appears to be free of the prior art.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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