DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, 17768632, US20240318135, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1, 2, 4, 8, 12, 14, 16, 19, 21, 22, 24, 25, 27, 28, 30, 33, 34, 36, 37, 38, 39, 44, 48, 49, 51, 52, 54, 56, 57, 58, 59, 60, 61, 62, 64, 65, are pending.
3. Claims 1, 2, 4, 8, 12, 14, 16, 19, 27, 28, 30, 33, 34, 36, 37, 38, 39, 44, 48, 49, 51, 52, 54, 56, 57, 58, 59, 60, 61, 62, 64, 65, are withdrawn for lack of unity.
4. Claims 21, 22, 24, 25, are examined and rejected.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 21, 22, 24, 25, in the reply filed on 9/10/2025, is acknowledged.
Applicant’s election without traverse of the species of CDR3b selected from the Markush Group of claim 51, TCR b selected from the Markush Group of claim 52, SEQ ID NO: 59, and SEQID NO: 261, in the reply filed on 9/10/2025 is acknowledged.
Priority
The filing receipt, mailed 6/21/2024, states that the Domestic Priority data as claimed by applicant states that this application is a 371 of PCT/EP2020/078954, filed 10/14/2020, and claims benefit to Foreign Application EUROPEAN PATENT OFFICE (EPO), 19202970.0, filed 10/14/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 7/20/2022, 4/25/2023, 6/27/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 22, 25 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claim(s) 22 and 25 are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 21 recites the broad recitation the DNA fragment comprising homology arms at the 3’ end, and the claim also recites , “in particular” wherein the DNA fragment “comprises a splice donor site that is located downstream of the most 3’ coding sequence of the DNA fragment and upstream of the 3’ homology arm,” which is the narrower statement of the range/limitation.”
Furthermore, claim 25 recites the a Markush group of introducing DNA fragments by homology methods and the claim also recites , “in particular” wherein the DNA fragment is introduced . . . through CRISPR-Cas9-mediated homology-directed repair, which is the narrower statement of the range/limitation.
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.
Claim(s) 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren, Clinical Cancer Research 2017 vol. 23, no. (9) pages 2255-2266, (of record, IDS).
Ren et al., 2017, uses CRISPR/Cas to target endogenous TCR alpha/beta constant region in primary human CD4/CD8 T-cells, resulting in CD3-negative cells. Afterwards, CD3-expression was restored by electroporation of TCR mRNA into the CD3-negative cells (p. 7, par. 2). Furthermore, via CRISPR/Cas, cells containing a TCR, B2M and PD1 triple disruption were generated.
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 21, 22, 24, 25 are interpreted as that the difference to most of the cited documents appears to be the introduction of a DNA fragment encoding a TCR alpha and beta variable domain and either a TCR alpha or beta constant domain.
1. Claim(s) 21, 24, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ren, Clinical Cancer Research 2017 vol. 23, no. (9) pages 2255-2266, (of record, IDS), and Welstead, US 20220143084, (priority at least to 62841066, see para [47]-[48], claims 29 and 36).
Ren et al., 2017, uses CRISPR/Cas to target endogenous TCR alpha/beta constant region in primary human CD4/CD8 T-cells, resulting in CD3-negative cells. Afterwards, CD3-expression was restored by electroporation of TCR mRNA into the CD3-negative cells (p. 2258, par. 1-2259, para 2). Furthermore, via CRISPR/Cas, cells containing a TCR, B2M and PD1 triple disruption were generated.
Ren does not explicitly teach T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and homologous recombination.
Welstead, US 20220143084, throughout the publication and abstract and at para [0019], [0045], [0053], teaches modified lymphocytes comprising rearranged endogenous T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and complete V-domain exons. Welstead, at para [0207], teaches replacement of a targeted region with all or part of the existing sequence with a homologous sequence. Welstead at para [0431] and [0480], teaches rearranged endogenous TCR locus (e.g., TCRα VJ and/or TCRf3 V(D)J section rearrangement & complete V-domain exons).
It would have been prima facie obvious before the effective filing date of the instant application for one of ordinary skill in the art to have combined T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements by homologous recombination, as taught by Welstead, in the method of expressing a TCR-CD3 complex on a cell surface, as taught by Ren.
One of ordinary skill in the art would have been motivated to have combined T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements by homologous recombination to restore TCR functionality after loss of function in the cell.
2. Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ren, Clinical Cancer Research 2017 vol. 23, no. (9) pages 2255-2266, (of record, IDS), and Welstead, US 20220143084, (priority at least to 62841066, see para [47]-[48], claims 29 and 36), as applied to claims 21, 22, 24 25 as above, and further in view of Brandt, 20210284709 A1 and .
Ren et al., 2017, uses CRISPR/Cas to target endogenous TCR alpha/beta constant region in primary human CD4/CD8 T-cells, resulting in CD3-negative cells. Afterwards, CD3-expression was restored by electroporation of TCR mRNA into the CD3-negative cells (p. 2258, par. 1-2259, para 2). Furthermore, via CRISPR/Cas, cells containing a TCR, B2M and PD1 triple disruption were generated.
Welstead, US 20220143084, throughout the publication and abstract and at para [0019], [0045], [0053], teaches modified lymphocytes comprising rearranged endogenous T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and complete V-domain exons. Welstead, at para [0207], teaches replacement of a targeted region with all or part of the existing sequence with a homologous sequence. Welstead at para [0431] and [0480], teaches rearranged endogenous TCR locus (e.g., TCRα VJ and/or TCRf3 V(D)J section rearrangement & complete V-domain exons).
Ren and Welstead do not explicitly teach T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and homologous recombination, wherein the DNA fragment further comprises a splice donor site that is located downstream of the most 3’ coding sequence of the DNA fragment and upstream of the 3’ homology arm.
Brandt, 20210284709 A1, teach template polynucleotides with flanking homology arms in the targeted insertion of a transgene. These targeting homology sequences target TRAC, TRBC1 and/or TRBC2 loci. The template polynucleotides can include additions sequences, such as splice donor sites. Brandt, at para [0955], states:
In some embodiments, a template polynucleotide having homology with sequences at or near one or more target site(s) in the endogenous DNA can be used to alter the structure of a target DNA, e.g., targeted insertion of the transgene. In some embodiments, the template polynucleotide contains homology sequences (e.g., homology arms) flanking the transgene, e.g., nucleic acid sequences encoding a recombinant receptor, for targeted insertion. In some embodiments, the homology sequences target the transgene at one or more of the TRAC, TRBC1 and/or TRBC2 loci. In some embodiments, the template polynucleotide includes additional sequences (coding or non-coding sequences) between the homology arms, such as a regulatory sequences, such as promoters and/or enhancers, splice donor and/or acceptor sites, internal ribosome entry site (IRES), sequences encoding ribosome skipping elements (e.g., 2A peptides), markers and/or SA sites, and/or one or more additional transgenes.
Brandt, 20210284709 A1, at para [0955], (emphasis added).
Laterza, US 20150306250, in describing mutation repair for Factor VIII to treat hemophilia, discusses donor sequences flanked by homology arms with identical sequence to the native chromosomal DNA 5’ and 3’ region flanking the break point, to allow very efficient homologous recombination. Laterza, at para [0059], states:
If a ds-DNA break occurs in the presence of a second nucleic acid, for example a cDNA-RS (a functional coding sequence) comprising a native FVIII 3′ splice acceptor site operably linked to a nucleic acid encoding a truncated FVIII polypeptide encoding exons 23-26 (i.e., a “donor plasmid (DP)” or donor sequence), which is flanked by a stretch of DNA with a left homology (HL) arm and right homology (HL) arm that have identical DNA sequences to that in the native chromosomal DNA 5′ and 3′ of the region flanking the break-point, homologous recombination (HR) occurs very efficiently. Following HR, the cDNA-RS segment between the left and right homology arms (which as shown in FIG. 2 contains a partial human F8 cDNA that contains, in-frame, all of exons 23-25 and the coding sequence of exon-26, with a functional 3′-splice site at its 5′-end) becomes permanently ligated/inserted into the chromosome.
Laterza, at para [0059] , (emphasis added).
It would have been prima facie obvious before the effective filing date of the instant application for one of ordinary skill in the art to have combined T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements by homologous recombination, as taught by Ren and Welstead, with the T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and homologous recombination, wherein the DNA fragment further comprises a splice donor site that is located downstream of the most 3’ coding sequence of the DNA fragment and upstream of the 3’ homology arm.
One of ordinary skill in the art would have been motivated to have combined T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements by homologous recombination with T-cell receptor (TCR) comprising TCRa VJ and/or TCR b V(D)J section rearrangements and homologous recombination, wherein the DNA fragment further comprises a splice donor site that is located downstream of the most 3’ coding sequence of the DNA fragment and upstream of the 3’ homology arm, because Brandt teaches sequences in addition to homology arms, that can include splice donor sites, and Laterza teaches recombination involving homology arm can lead to very efficient recombination. The instant specification does not point to any advantage particular to recombination involving a DNA fragment that further comprises a splice donor site that is located downstream of the most 3’ coding sequence of the DNA fragment and upstream of the 3’ homology arm. As such, this would appear to be an obvious design choice for the practitioner.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631