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 without traverse of claims 2, 5-7, 9-11, 13-14, 16-20, 22-35, 69-80, and 89-90 with species election of SEQ ID NO: 1, D52R, a destabilized domain, and SEQ ID NO: 73 in the reply filed on March 10, 2026 is acknowledged.
Status of Claims
Claims 2, 5-7, 9-11, 13-14, 16-20, 22-35, 69-81, 84, and 89-90 are currently pending in the instant application. Claims 11, 13-14, 16-20, 24-25, 33-34, 81, and 84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Accordingly, claims 2, 5-7, 9-10, 22-23, 26-32, 35, 69-80, and 89-90 are under examination on the merits in the instant application.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on April 25, 2022 and December 27, 2022. It is noted, however, that applicant has not filed a certified copy of the PCTCN2022089053 and PCTCN2022142467 applications as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 27, 2023 has been considered by the examiner. Note that all foreign language documents are considered only insofar as the English language title and abstract as submitted by applicant.
Specification
1. The title of the invention is not descriptive. Note that the word “Novel” is not descriptive of an invention. A new title is required that is clearly indicative of the invention to which the claims are directed.
2. The disclosure is objected to for containing sequence rule non-compliant subject matter. See page 77. Appropriate correction is required as instructed below.
Drawings
The drawings are objected to because it contains sequence rule non-compliant subject matter. See Figures 2D, 2I, 4F, 5A, 5B, 6L, 7B, 7C, 7D, 9C, 10D, 10E, 12B, 13, 16B, 17, 18D, and 22. Corrected drawing sheets in compliance with 37 CFR 1.121(d) or amended specification are required in reply to the Office action to avoid abandonment of the application as instructed below. 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, see Figures 2D, 2I, 4F, 5A, 5B, 6L, 7B, 7C, 7D, 9C, 10D, 10E, 12B, 13, 16B, 17, 18D, and 22, 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.
Specific deficiency – The nucleotide sequence appearing in the specification, see page 77, is not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Claim Rejections - Improper Markush Grouping
Claims 2, 5-7, 9, 22-23, 26-32, 35, 69-80, and 89-90 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP §706.03(y).
The Markush grouping of SEQ ID NOs:1-34 is improper because the alternatives defined by the Markush grouping do not all share a substantially similar amino acid sequence. For instance, applicant’s elected SEQ ID NO:1 shares very little (about 13%) amino acid sequence homology with SEQ ID NO:2 when the two SEQ ID NOs are aligned with 15 amino acid residues shifted in relation to each other such that amino acid position 95 of SEQ ID NO:1 is aligned with amino acid position 80 of SEQ ID NO:2.
The Markush grouping of “functional domain” recited in claim 22 is improper because the alternatively recited species do not all share a common structural similarity, nor do they all share a common activity.
The Markush grouping of scaffold sequences of SEQ ID NOs:73-106 is improper because the alternatives defined by the Markush grouping do not all share a substantially similar nucleotide sequence. For instance, applicant’s elected SEQ ID NO:73 shares very little (about 10%) nucleotide sequence homology with SEQ ID NO:74 when the two SEQ ID NOs are aligned with 7 nucleotides shifted in relation to each other such that nucleotide position 68 of SEQ ID NO:73 is aligned with nucleotide position 75 of SEQ ID NO:74.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
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 2, 5-7, 9-10, 22-23, 26-32, 35, 69-80, and 89-90 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.
Claim 2 recites “(e.g., at least about 65%,…, or 100%)” and “(optionally any one of…, and 32)”, which render the claim indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claims 5-6 each recite “(on target)” and “(optionally any one of…, and 32)”, which render the claims indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention.
Claim 9 recites the phrase "such as", which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. Further, the parenthetical limitation itself also renders the claim indefinite because it is unclear whether it is part of the claimed invention. See MPEP § 2173.05(d).
Claims 10 and 28 each recite “(e.g., at least about 80%,…, or 100%)”, which render the claims indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claims indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 22 recites “(e.g., VP64 or VPR)”, “(e.g., KRAB moiety or SID moiety)”, “(e.g., T5E)”, “(e.g., destabilized domains (DD) of E. coli dihydrofolate reductase (ecDHFR))”, “(e.g., FokI)”, “(e.g., fluorescent)”, “(e.g., GST,…, BFP)”, “(e.g., MBP, Lex A, DBD, Gal4 DBD)”, “(e.g., His,…, etc)”, “(e.g., from O-GlcNAc transferase)”, and “(e.g., a functional truncation)”. It is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d). In addition, it is unclear what is encompassed by “etc” in “(e.g., His,…, etc)”.
Claim 23 recites “(e.g., destabilized domains (DD) of E. coli dihydrofolate reductase (ecDHFR))” and “(e.g., at least about 80%,…, or 100%)”. It is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 26 recites “e.g., a single guide RNA”. The phrase “e.g.,” renders the claims indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 29 recites “(optionally…, and 104).” It is unclear whether the parenthetical limitations are part of the claimed invention.
Claim 30 recites “(e.g., at least about 65%,…, or 100%)” and “(optionally any one of…, and 104)”, which render the claim indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 31 recites “(on target)” and “(optionally any one of…, and 32)”, which render the claims indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. Claim 31 also recites “e.g., an increase”. The phrase “e.g.,” renders the claims indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 32 recites “(e.g., a A-U base pair or a mismatched base pair)”, which renders the claims indefinite because it is unclear whether the parenthetical limitations are part of the claimed invention. In particular, the phrase “e.g.,” renders the claims indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 35 recites “(e.g., SEQ ID NO: 226)” and other similar limitations, which renders the claim indefinite as it is unclear whether the parenthetical limitations containing “e.g.,” are part of the claimed invention.
Claim 69 recites “e.g., about or at least…” and “e.g., from about 16…”. The phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 71 recites “e.g., about or at least…” and “e.g., in a length of from about 16…”. The phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 72 recites “100% (fully)”. It is unclear how “(fully)” is different from “100%”.
Claim 74 recites “e.g., a gene in a eukaryotic cell.” The phrase “e.g.,” renders the claim indefinite because it is unclear whether the recitation following the phrase is required or merely exemplary. See MPEP § 2173.05(d).
Claim 77 recites “(vector genome)”. It is unclear whether the parenthetical limitation is required or merely exemplary. See MPEP § 2173.05(d).
Claim 90 recites the limitation "a repeat sequence". It is unclear what is meant by the “repeat sequence” that is linked to a tracrRNA. It is noted that neither the specification nor the claim clearly defines the “repeat sequence”. It is also noted that the specification exemplifies SEQ ID NO:145 as being one possible repeat sequence. Hence, solely in the interest of compact prosecution, the “repeat sequence” will be interpreted as SEQ ID NO:145.
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 2, 5-7, 9-10, 22-23, 26-32, 35, 69-79, and 89-90 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kong et al. (Nature Communications, published online on April 11, 2023, 14:2046).
Applicant cannot rely upon the foreign priority benefit claim. As noted above, there is no certified copy, let alone an English language-translation of such copy, has been made of record in accordance with 37 CFR 1.55.
Kong discloses a CRISPR-Cas12f1 system/AAV vector comprising a Cas12f polypeptide (“OsCas12f1”) that is modified to comprise D52R mutation and an sgRNA targeting a target DNA of at least 20 nucleotides in length followed by a PAM sequence, wherein the Cas12f polypeptide is fused “with the destabilized domains (DD) of E. coli dihydrofolate reductase (ecDHFR).” See the entire reference including Figures 2 and 6; page 8.
Kong discloses the amino acid sequence of “OsCas12f1” in Supplementary Figure 6b, which is 100% identical to SEQ ID NO:1 claimed in the instant case.
Kong discloses that the sgRNA comprises the scaffold RNA comprising tracrRNA and crRNA that are linked via a 4-mer linker GAAA, wherein the scaffold RNA sequence is an RNA counterpart that is identical in sequence to the DNA sequence of SEQ ID NO:73 claimed in the instant case, wherein the tracrRNA is linked to the 12-mer RNA counterpart that is identical in sequence to the DNA sequence of SEQ ID NO:145, wherein the scaffold RNA can comprise a “C-G substitution”. See Figure 2d.
Kong teaches that the gRNA can have “3’ poly-uridine (U) overhang”. See page 3.
Kong teaches that the system can comprise two sgRNAs such as “5’sgRNA” and “3’sgRNA” targeting the same target DNA. See Figure 6a.
Since all structural limitations of the system of Kong fully satisfy those claimed in the instant case, it necessarily follows that Kong’s system would inherently possess the functionality recited in claim 6 and claim 31, absent objective evidence to the contrary.
Accordingly, claims 2, 5-7, 9-10, 22-23, 26-32, 35, 69-79, and 89-90 are described by Kong et al.
Claims 2, 5-6, 22, 26-27, 29-31, 69-72, and 74-80 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rabuka et al. (US 2026/0015598 A1).
Rabuka teaches making a system/an AAV vector/lipid nanoparticles (LNPs) comprising a CRISPR Type V Cas12f-like nuclease comprising SEQ ID NO:132 and a gRNA comprising a 20-mer sequence complementary to a target nucleic acid adjacent to a PAM sequence and a region that associated with the nuclease, wherein the gRNA “is encoded by a CRISPR RNA (crRNA)” and may be “a single guide RNA (sgRNA)” comprising “crRNA/tracrRNA” comprises SEQ ID NO:291, wherein the nuclease is fused to a nuclear localization sequence (NLS). See paragraphs 0030, 0051, 0110-0117, 0119-0120, 0226; Table 4.
It is noted that Rabuka’s SEQ ID NO:132 is 100% identical to SEQ ID NO:1 claimed in the instant case.
It is noted that Rabuka’s SEQ ID NO:291 is at least 60% identical to SEQ ID NO:73 claimed in the instant case.
Rabuka teaches that the nuclease can comprise one or more amino acid substitutions, which can improve editing efficiency. See paragraphs 0087-0089.
Since all structural limitations of the system of Rabuka fully satisfy those claimed in the instant case, it necessarily follows that Rabuka’s system would inherently possess the functionality recited in claim 6 and claim 31, absent objective evidence to the contrary.
Accordingly, claims 2, 5-6, 22, 26-27, 29-31, 69-72, and 74-80 are described by Rabuka et al.
Claims 2, 5-6, 22, 26-29, 31, 69-80, and 89 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Kim et al. (US 2025/0215457 A1).
Kim teaches making a system or “a ribonucleoprotein (RNP)” or an AAV vector comprising an endonuclease comprising SEQ ID NO:213 and an engineered guide RNA comprising a tracrRNA and an crRNA, which “are connected by a linker”, wherein the guide RNA comprises a “scaffold region”, which “can interact with a molecule called endonuclease”, wherein the system has a function of gene editing, which “involves nucleic acid cleavage of double-stranded DNA”, wherein the system is encapsulated in a lipid nanoparticle (LNP). See paragraphs 0012-0015, 0036, 0090-0095, 0342, 0346, 0634,
Kim’s SEQ ID NO:213 is 100% identical to SEQ ID NO:1 claimed in the instant case.
Kim teaches that the guide sequence has “a length of 17 to 25 nucleotides” and that the “guide sequence may comprise a combination of two guide sequences capable of hybridizing with one target sequence selected from the upstream and one target sequence selected from the downstream.” See paragraphs 0164-0165.
Kim teaches that the engineered gRNA can comprise “5-UUUUU” sequence at the 3’ end. See paragraphs 0188 and 0190.
Since all structural limitations of the system of Kim fully satisfy those claimed in the instant case, it necessarily follows that Kim’s system would inherently possess the functionality recited in claim 6 and claim 31, absent objective evidence to the contrary.
Accordingly, claims 2, 5-6, 22, 26-29, 31, 69-80, and 89 are described by Kim et al.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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