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 .
Applicants’ reply to the February 19, 2026 Office Action, filed June 18, 2026, is acknowledged. Applicants previously canceled claim 2, and now cancel claims 3 and 5. Claims 6-10 remain withdrawn from consideration, as being directed to a non-elected invention. Applicants amend claim 1 and withdrawn claims 6-8 and 10. Claims 1, 4, and 6-10 are pending in this application, with claims 1 and 4 under examination. Any objection or rejection of record in the previous Office Action, mailed February 19, 2026, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments. This action is FINAL.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, no certified translation of the Chinese patent document has been received.
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:
Applicants filed a Sequence Listing under ST.26 rules on June 18, 2026, when the Sequence Listing should have been filed under ST.25 rules because the instant application is a U.S. national phase application with an international filing date before July 1, 2022.
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 and 4 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cowan et al. (U.S. Patent Application Publication No. 2019/0382798, published December 19, 2019 and claiming priority to PCT Patent Application No. PCT/IB2016/001709, published May 11, 2017 as WO 2017/077386, and cited in the Information Disclosure Statement filed November 6, 2025). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claim 1, Cowan discloses treatment of Glycogen Storage Disease type 1a (GSD1a) by modulating expression, function and or activity of glucose-6-phosphatase in a cell via editing (abstract). Cowan discloses that a donor template can be introduced into the cell to correct the G6PC gene, which is interpreted as a knock-out/knock-in gene targeted integration (paragraph [0041]). Cowan discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9 and Cpf1, which are able to provide for either single- or double-strand breaks (cleavage) (paragraphs [0041]-[0042]). Cowan discloses that the insertion of the new sequence can take place within or near a safe harbor locus, which includes AAVS1 (paragraphs [0030] and [0042]). Cowan discloses that polynucleotides encoding the DNA endonuclease and guide RNA can be introduced into the cell (paragraphs [0038]-[0040]). Cowan discloses that the polynucleotides can be introduced via a plasmid, transfection, conjugation, lipofection, electroporation, nucleofection, particle guns, micro-injection liposome-mediated transfection, which are non-viral methods of gene editing (paragraphs [00511], [00521], and [00523]). Cowan discloses guide RNAs that have the sequences of SEQ ID NOS: 740, 846, 775 and 848, which are the same as instant SEQ ID NOS: 3, 7, 8, and 9, respectively (Appendices I, V, VI, and VII, respectively). Cowan discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9 and Cpf1, which are able to provide for either single- or double-strand breaks (cleavage) (paragraph [0042]).
Regarding claim 4, Cowan discloses that the insertion of the new sequence can take place within or near a safe harbor locus, which includes AAVS1 (paragraphs [0030] and [0042]). Cowan discloses that a donor template can be introduced into the cell to correct the G6PC gene, which is interpreted as a knock-out/knock-in gene targeted integration (paragraph [0041]).
Cowan discloses each and every limitation of claims 1 and 4, and therefore, Cowan anticipates claims 1 and 4.
Claims 1 and 4 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Welstead et al. (PCT Patent Application Publication No. WO 2015/161276, published October 22, 2025). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claim 1, Welstead discloses treatment of cancer using CRISPR-Cas-related compositions by editing a target nucleic acid sequence (abstract and page 1, lines 16-19). Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28). Welstead discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9, which are able to provide for either single- or double-strand breaks (cleavage) (page 11, lines 5-20). Welstead discloses that the insertion of the new sequence can take place within or near the TRAC gene (page 3, lines 23-31). Welstead discloses that the DNA endonuclease and guide RNA can be introduced into the cell (page 11, lines 21-34, page 41, line 28 to page 42, line 16, and page 44, lines 21-33). Welstead discloses that the Cas9 and guide RNAs, and polynucleotides encoding them, can be introduced via non-viral methods of gene editing (page 339, lines 1-20). Welstead discloses guide RNAs that have the sequence of SEQ ID NOS: 464 and 462, which are the same as instant SEQ ID NOS: 4 and 5, respectively (Appendices III and IV respectively). Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28). Welstead discloses that the integration of the donor gene can be performed using CRISPR-Cas systems, including Cas9, which are able to provide for either single- or double-strand breaks (cleavage) (page 11, lines 5-20).
Regarding claim 4, Welstead discloses that the insertion of the new sequence can take place within or near the TRAC gene (page 3, lines 23-31). Welstead discloses that a donor template can be introduced into the cell to alter expression of T cell-expressed genes, and that T cell-expressed genes can be knocked out and an insertion being the alteration of the target site (page 3, line 32 to page 4, line 16 and , which is interpreted as a knock-out/knock-in gene targeted integration (page 4, line 31 to page 5, line 9 and page 56, line 19 to page 57, line 28).
Welstead discloses each and every limitation of claims 1 and 4, and therefore, Cowan anticipates claims 1 and 4.
Claims 1 and 4 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chen et al. (PCT Patent Application Publication No. WO 2017/093969, published June 8, 2017). This rejection is modified as necessitated by Applicants’ amendments.
Regarding claim 1, Chen discloses treatment of genome editing systems for immunological use (abstract). Chen discloses that simultaneous and sequential knockout of TRAC and B2M, and insertions can be indicated, which is interpreted as a knock-out/knock-in gene targeted integration (Example 8). Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28). Chen discloses that the insertion of the new sequence can take place within or near the B2M or TRAC loci (page 1, line 29 to page 2, line 2). Chen discloses that polynucleotides encoding the DNA endonuclease and guide RNA can be introduced into the cell (page 15, line 28 to page 16, line 2). Chen discloses that the polynucleotides can be introduced via non-viral vectors, including plasmids, minicircles, nanoplasmids, and RNA vectors (page 15, line28 to page 16, line 2). Chen discloses a guide RNA that has sequence of SEQ ID NO: 5498, which is the same as instant SEQ ID NO: 6 (Appendix IV). Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28).
Regarding claim 4, Chen discloses that the insertion of the new sequence can take place within or near the B2M or TRAC loci (page 1, line 29 to page 2, line 2). Chen discloses that simultaneous and sequential knockout of TRAC and B2M, and insertions can be indicated, which is interpreted as a knock-out/knock-in gene targeted integration (Example 8). Chen discloses a donor template can be inserted at or near a target sequence that has been modified by cleavage by a CRISPR system comprising guide RNAs (page 1, lines 23-28).
Chen discloses each and every limitation of claims 1 and 4, and therefore, Chen anticipates claims 1 and 4.
Response to Arguments
Regarding the rejections under 35 U.S.C. 102(a)(1) and 102(a)(2), Applicant's arguments have been fully considered but they are not persuasive.
Applicants assert that none of Cowan, Welstead, or Chen disclose that the site-directed cleavage and the site-directed knock-in are performed in a single step.
Applicants have provided no objective factually supported evidence that the cited prior art references (Cowan, Welstead, and Chen) fail to perform the site-directed cleavage and the site-directed knock-in in one step. Applicants have provided only arguments of counsel, and arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Here, each of the three cited prior art references discloses a method for performing single-step non-viral gene editing on a target site of a cellular genome.
Regarding Cowan, the reference discloses that gene editing can be performed either ex vivo or in vivo in order to create permanent changes to the genome of a cell. Specifically, Cowan discloses providing a Cas polypeptide and a guide RNA to a cell along with a donor for correction of a genetic defect. Cowan further discloses knock-in of a donor nucleic acid into a safe harbor locus by homology directed repair. By inducing double-stranded break with the CRISPR-Cas system along with a synthetic donor molecule, targeted changes can be made in the genome. Cowan specifically discloses “the step of introducing into the human cell one or more deoxyribonucleic acid (DNA) endonucleases to effect one or more single-strand breaks (SSBs) or double-strand breaks (DSBs) within or near a safe harbor locus that results in a permanent insertion of the G6PC gene, and results in restoration of G6Pase protein activity” (see paragraph [0014]). This is interpreted as being a single step protocol where site-directed cleavage and site-directed knock-in are performed in one step, as required by the claims.
Regarding Welstead, the reference discloses that gene editing can be performed either ex vivo or in vivo in order to create permanent changes to the genome of a cell. Specifically, Welstead discloses providing a Cas polypeptide and at least one guide RNA to a cell along with a donor for treatment of cancer. Welstead further discloses insertion of a donor nucleic acid into a safe harbor locus by homology directed repair. By inducing double-stranded break with the CRISPR-Cas system along with a synthetic donor molecule, targeted changes can be made in the genome. Welstead discloses that the targeting of one or more T-cell expressed genes can be mediated by any mechanism. Welstead specifically discloses “[e]xemplary mechanisms that can be associated with the alteration of one or more T cell-expressed genes, e.g., the FAS, BID, CTLA4, PDCD1,CBLB, PTPN6, TRAC and/or TRBC gene include but are not limited to, non-homologous end joining (e.g., classical or alternative), microhomology-mediated end joining (MMEJ), homology-directed repair (e.g., endogenous donor template mediated…” (see page 56, lines 13-16). This is interpreted as being a single step protocol where site-directed cleavage and site-directed knock-in are performed in one step, as required by the claims.
Regarding Chen, the reference discloses that gene editing can be performed in order to create permanent changes to the genome of a cell. Specifically, Chen discloses providing a Cas polypeptide and a guide RNA to a cell along with a donor template. Cowan further discloses knock-in of a donor nucleic acid into a safe harbor locus by homology directed repair. By inducing double-stranded break with the CRISPR-Cas system along with a synthetic donor molecule, targeted changes can be made in the genome. Chen specifically discloses “nuclease-induced homology directed repair (HDR) can be used to alter a target sequence and correct (e.g., repair or edit) a mutation in the genome. . . a plasmid donor can be used as a template for homologous recombination. . . Donor template-effected alteration of a target sequence depends on cleavage by a Cas9 molecule. Cleavage by Cas9 can comprise a double strand break or two single strand breaks” (see page 715 line 25 to page 716, line 3). This is interpreted as being a single step protocol where site-directed cleavage and site-directed knock-in are performed in one step, as required by the claims.
Regarding selection of the guide RNA, it is noted that each of the three cited prior art references lists a finite number of potential guide RNA molecules, each of which one of ordinary skill in the art would have understood to be available for use in the claimed invention of performing non-viral gene editing on a target site of a cellular genome.
Regarding Applicants’ assertion of unexpected results due to reciting that the gene editing is performed in a non-viral manner, it is noted that each of Cowan, Welstead, and Chen provide for gene editing using non-viral (e.g., plasmid) vectors to effect the knock-out, knock-in editing in a single step. And because the rejections are under 35 U.S.C. §§ 102(a)(1) and 102(a)(2), any assertion of unexpected results is not relevant. Thus, taking each of Cowan, Welstead, and Chen as a whole, each reference discloses single-step editing of a cellular genome using non-viral methods and the specifically claimed guide RNA molecules.
For all these reasons, and those listed above, the rejections under 35 U.S.C. §§ 102(a)(1) and 102(a)(2) are maintained, as set forth above.
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 NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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