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 .
Election/Restrictions
Applicant's election with traverse of Group I, encompassing amended claims 1, 4, 11, 13-15, and 19 in the reply filed on 02 March 2026 is acknowledged. The traversal is on the ground(s) that Dai does not teach or suggest an HDR cassette including both (1) a desired CAR for expression AND (2) a crRNA targeting a host cell gene. Applicants’ assessment it correct. However, the combination of Dai and Fuller as discussed below provides a rationale to include both (1) a desired CAR for expression AND (2) a crRNA targeting a host cell gene in an HDR cassette. Therefore, the claimed invention is not recognized to have an advantage effect that cannot be predicted by a skilled artisan, and the group of inventions do not relate to a single general inventive concept because the technical feature is not a special technical feature since it does not make a contribution over the prior art over Dai in view of Fuller.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election without traverse of sgRNA of SEQ ID NO: 2388 in the reply filed on 02 March 2026 is acknowledged.
Claims 2-3, 5-6, 11, 20-22, 26, 36, 40-42, and 49 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 4, 11, 13-15, and 19 are being examined on the merits.
Priority
This application is a 371 of PCT/US2021/045882 filed 08/13/2021 which claims priority to application 63/065,194 filed 08/13/2020.
Information Disclosure Statement
The information disclosure statements filed 12/09/2024, 10/22/2025, and 11/13/2025 have been considered.
Drawings
The drawings are objected to because figures 1, 2, 3, 4, and 6 contains words and figure legends that are not clear and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings, fig. 4, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 26. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term Gene Forge, Aptagen, Illumina, TriLink BioTechnologies, ThermoFisher, Biologend, Lucigen, company named on pages 68-73, Gibson assembly, Lonza, Epicentre, QIAquick, New England BioLabs, Takara, Qiagen, Millipore, Miltenyi Biotec, Nextera, PerkinElmer, Roche, and PerkinElmer, to name a few, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. A cursory review of the specification has revealed these trademarks or names. It would be remedial to check the specification for additional trademarks or names and amend all upon amendment.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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, 11, 13-15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Dai (Dai et al. Nature Methods, Vol 16, 2019, 247-254, previously cited) in view of Fuller (Fuller et al. J. Cell Biol. 2020 Vol. 219 No. 6 e201910210).
Regarding claim 1, Dai teaches an AAV-delivered crRNA and HDR template (AAV–Cpf1), comprising a 5' homology arm, a crRNA expression cassette, a chimeric antigen receptor (CAR) expression cassette, and a 3' homology arm, wherein the CAR expression cassette is positioned between the 5' and 3' homology arms, wherein the 5' and 3' homology arms are homologous to a target site, wherein the crRNA expression cassette independently encodes a first guide RNA and a second guide RNA, wherein the first guide RNA targets the TRAC loci, and wherein the second guide RNA targets the PDCD1 locus [Fig. 1; pg. 247, last paragraph - pg. 249, first paragraph; Fig. 3].
Regrading claim 11, Dai teaches that the 5' and 3' homology arms are homologous to the TRAC locus [Fig. 3a].
Regarding claims 13-15, Dai teaches that the AAV vector that allows for one-step generation of TRAC knock-in CD19 and CD22-specific CAR-T cells with PDCD1, a key inhibitory receptor that drives T-cell exhaustion during chronic infections and cancer, disruption [pg. 251, col. 1, para 2 – col.2, para 2]. Dai teaches the integration of anti-CD19/CD22 CAR (CAR19/CAR22), CARs that are known to target the CD19 and CD22 protein on cancerous B cells, into TRAC can improve preclinical efficacy in leukemia, and specific knockouts can reduce T-cell exhaustion [pg. 251, col. 1, para 2 – col.2, para 2].
Regarding claim 19, Dai teach a population of cells comprising the AAV vector [pg. 252, col. 2].
Regarding claim 1, Dai does not teach that the crRNA expression cassette and CAR expression cassette are positioned between the 5' and 3' homology arms.
Fuller teaches the integration of a crRNA into a genome using homologous recombination where the crRNA is in a PCR cassette flanked by a 5’ and 3’ homology arm [Fig. 1; pg. 2, col. 2, para 2]. Fuller teaches that methods relying on HR are more flexible in terms of target sites, enabling highly precise genomic modifications [pg. 1, col. 2, para 2]. Fuller teaches that if cassettes are not or rarely incorporated into the genome, they are unlikely to be stable [pg. 5, col. 1, para 4].
It would have been to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Dai by placing the crRNA cassette within the 5’ and 3’ arms. One of ordinary skill would be motivated to make the modification for the advantage of stably integrating the crRNA expression cassette into the genome for stable guide RNA expression thereby equipping the cells with stable CAR expression and PDCD1 disruption thereby stably reducing T-cell exhaustion.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Dai (Dai et al. Nature Methods, Vol 16, 2019, 247-254, previously cited) in view of Fuller (Fuller et al. J. Cell Biol. 2020 Vol. 219 No. 6 e201910210) as applied to claim 1, and further in view of NG_029115.1 (Homo sapiens PR/SET domain 1 (PRDM1), RefSeqGene on chromosome 6, 7/5/2020) and Dong (Dong et al. Oncotarget, 2017, Vol. 8, (No. 2), pp: 2171-2186).
The teachings od Dai and Fuller are discussed above as applied to claim 1 and similarly apply to claim 4.
Dai or fuller do not teach wherein one or more sequences encoding the first and/or second guide RNAs is SEQ ID NO: 2388.
NG_029115.1 teaches a human PRDM1 gene sequence. NG_029115.1 teaches that this gene encodes a protein that acts as a repressor of beta-interferon gene expression and binds specifically to the PRDI (positive regulatory domain I element) of the beta-IFN gene promoter.
Dong teaches that B lymphocyte-induced maturation protein 1 (Blimp-1), which is encoded by the prdm1 gene, represses PD-1 gene expression through a feed-forward repressive circuit [pg. 2174, col. 1, para 2]. Dong teaches that blockade of PD-1 enhances
both proliferation of memory B cells and expansion of virus-specific CD8 T cells during chronic simian immunodeficiency virus (SIV) infection in macaques; and blockade of the PD-1/PD-L1 inhibitory pathway in infected mice lacking CD4 T-cell help had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines,
kill infected cells, and decrease the viral load [pg. 2171, col 1, para 2]. Dong teaches that blockade of the PD-1 pathway has achieved good effect on restraining tumor [pg. 2172, col. 1, para 3].
It would have been to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method as taught and suggested by Dai Fuller by replacing either the crRNA array targeting the TRAC or PDCD1 loci with a crRNA of SEQ ID NO: 2388. One of ordinary skill would be motivated to make the substitution for the advantage of targeting the knocking in the CAR in to the PRD1 locus while simultaneously enhancing
both proliferation of memory B cells and expansion of specific CD8 T cells to to undergo proliferation, secrete cytokines, kill infected cells as taught by Dong.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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