DETAILED ACTION
Receipt of Arguments/Remarks filed on April 22 2026 is acknowledged. Claims 4-5 were/stand cancelled. Claims 1-3, 6-7, 10-11 and 13-15 were amended. Claims 16-17 were added. Claims 1-3 and 6-17 are pending.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 18 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections/Rejections
The amendments filed April 22 2026 are sufficient to overcome the objection to the drawings and nucleotide sequence issues identified in the drawings.
The amendments filed April 22 2026 are sufficient to overcome the objection of claim 7 and 15. The extra comma was removed and the recitation a was changed in an.
The amendments and arguments filed April 22 2026 are sufficient to overcome the rejection of claims 1-15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
The amendment to claim 1 is sufficient to clarify that the complementary strand of the dstna is the strand complementary to a spacer sequence in the gRNA and it is this complementary strand is the strand that it is edited.
The cancellation of claim 4 has rendered the rejection moot.
The amendment of claim 6 clarifies the scope and removes the exemplary language.
The arguments are sufficient to overcome the rejection of claim 8.
The amendment of claim 15 has removed the indefinite language. The examiner notes that new claim 16 includes limitations previously presented in claim 15. This claim is interpreted as requiring the Cas nuclease is fused to both an adenine deaminase and a cytidine deaminase albeit at different ends of the Cas nuclease.
The amendments filed April 22 2026 are sufficient to overcome the rejection of claims 1-2, 8, 10-14 under 35 U.S.C. 102(a)(1) over Zhou (CN112126637A). The claims as amended requires that the Cas nuclease is cleavage-deficient and comprises less than 600 amino acid residues distinguishing the instant claim from Zhou.
The amendments filed April 22 2026 are sufficient to overcome the rejection of claim(s) 1-3 and 8-15 under 35 U.S.C. 102(a)(1) over Kim (USPGPUB No. 20180258418). The claims as amended requires that the Cas nuclease is cleavage-deficient and comprises less than 600 amino acid residues distinguishing the instant claim from Kim.
The amendments filed April 22 2026 are sufficient to overcome the rejection of claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Kim as applied to claims 1-3 and 8-15 above and in view of Liu et al. (USPGPUB No. 20190367891). The claims as amended requires that the Cas nuclease is cleavage-deficient and comprises less than 600 amino acid residues distinguishing the instant claim from Kim.
The amendments/arguments filed April 22 2026 and the references cited on the IDS filed May 18 2026 are sufficient to overcome the rejection of claims 5 and 7 under 35 U.S.C. 103 over Kim in view of Karvelis et al. (Nucleic Acids Research, 2010, cited on PTO Form 1449). The claims as amended require the Cas nuclease is cleavage deficient and less than 600 amino acid residues and requires that the editing occurs on the strand complementary to the spacer in the gRNA. This is not expressly taught in Karvelis et al. Karvelis et al. teaches the use of Un1Cas12f1, a Cas12f nuclease, which contains 500 amino acid residues (see supplementary Table S1). Swartjes et al. (reference submitted with IDS filed May 18 2026) teaches that Un1Cas12f1 does not result in editing of the target DNA strand (see summary). Therefore, the amendments/arguments and reference submitted with the IDS are sufficient to overcome this rejection.
Specification
The disclosure is objected to because of the following informalities: upon review of the response, the examiner noticed that in the PGPUB of the instant application (US20240110163), Table 1-2 include numerous instances of ? indicating that the tables are not printing correctly. On October 27 2024 there was an amendment to correct the tables but this amendment is confusing. There are two specifications submitted, one which is marked which crosses out some not only the title of the table but there are only lines through part of table 1. But then the unmarked copy includes not only the heading but all the parts of the table. Applicants are required to review these tables and improve the clarity of the tables.
Appropriate correction is required.
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 specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Specifically there are sequences in Table 1 with more than 10 specifically enumerated nucleotides and thus must be associated with a SEQ ID.
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.
New Rejections Necessitated by the Amendments filed April 22 2026
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 6-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a method for base-editing which provides A to G editing and/or C to T editing of the complementary strand of dstna (i.e. the strand that is complementary to a spacer sequence in a gRNA) by providing a CRISPR-based system comprising a gRNA and a cleavage-deficient CRISPR-associated (Cas) nuclease that is less than 600 amino acid residues or a nucleotide molecule which allows for A to G editing and/or C to T editing of the complementary strand with a Cas nuclease that is cleavage deficient and comprises less than 600 amino acid residues. None of the claims recite a specific structure of the Cas nuclease. The claims encompass genus of Cas nuclease such as C2c4 or Cas1F nuclease.
The specification discloses chemicals, such as AsCas12fl fused to TadA8e, Cas12u1 with TadA8e_eng which meet the written description and enablement provisions of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, claim(s) 1-3 and 6-17 is(are) directed to encompass any cleavage-deficient Cas with less than 600 amino acids and any deaminase which only correspond in some undefined way to specifically instantly disclosed chemicals.
Looking to the art, Swartjes et al. (iScience, 2025, cited on IDS filed May 18 2026) teaches that Un1Cas12f1, which as evidenced by Karvelis et al. (see supplemental table S1) has 429 amino acids, does not achieve editing of the target strand (summary, Figure 4) This is in contrast to AsCas12f1, which as evidenced by Karvelis et al. has 422 amino acid, which does achieve editing of the target strand (see summary). To complicate matters further, Swartjes et al. shows in Figure 3, that AsCas12f1-ABE editing on the E. coli gene results in target strand editing, but there is an absence of target strand (TS) editing for CBE. As stated by Swartjes et al., “These differences in editing efficiency and positional outcomes likely reflect intrinsic differences in the protein structure between the AsCas12f1 and Un1Cas12f1 variants. Previous studies of Un1Cas12f ABE in mammalian cells have reported efficient A-to-G editing on position 3 and 4. However, these base editors used a different version of the TadA and fused it to the N terminus of Cas12f. Similarly, an N-terminal fusion Un1Cas12f CBE showed a broad editing window and editing efficiency of up to 50% in mammalian cells. While we have not observed TS editing for Un1Cas12f BEs in the current study, a recent publication does report TS editing with a CBE using an engineered version of Un1Cas12f1. This suggests that the details of protein and protein fusion design affect editing efficiency and DNA strand preference.”.
Another reference, Lei et al. (Nature 2021) is directed to detect-seq reveals out-of-protospacer editing and target-strand editing by cytosine base editors. Lei et al. teaches that “to understand the mechanism of out-of-protospacer and target-strand editing, we performed in-depth analysis of the Detect-seq data. We found stronger Detect-seq signals at the PAM distal side than the PAM proximal side for both out-of-protospacer and target-strand edits (Fig. 4d). This observation hinted at a potential link with a certain property of the PAM distal side. We speculated that its DNA secondary structure may play a role. Results of ridge linear regression analysis illustrated that out-of-protospacer edits at the PAM distal side were highly correlated with mismatch numbers in the first 5–8 bp of the pRBSs (Fig. 5a); both counts of mismatches in PAM distal and proximal regions contributed to target-strand edits (Fig. 5b). It was anticipated that these mismatches would lead to imperfect pairing of sgRNA at the off-target DNA loci as well as a destabilized duplex structure at the PAM distal side, with strands unwound as single-strand DNA that could serve as substrates of APOBEC1. Indeed, we found a clear TC motif for out-of-protospacer edits and target-strand edits (Fig. 5c,d). In principle, to preserve the edited cytosines on the target strand, the resynthesis of target strand by the BE3-induced mismatch repair should not occur; thus, CBE may behave like a BE2 in generating target-strand editing (Fig. 5e).” “Despite the association with instability of the RNA/DNA hybrid, it is not sufficient to predict out-of-protospacer and target-strand edits. Not all typical Cas9-dependent off-target sites are accompanied with out-of-protospacer or target-strand edits, while the on-target sites, which are supposed to form a stable R-loop structure29, all possess proximal off-target mutations. Although those edits that occurred were more likely at the 5′ flanking region of pRBS, an evident pattern to ensure which cytosine was edited was lacking for different pRBSs or individual DNA molecules (Fig. 5f, Extended Data Fig. 5b and Supplementary Figs. 16 and 17). Even for a given locus with such edits, only a subset of cytosines embedded in the TC context were edited. In addition, the CBE editing can vary between different cell lines even for the same sgRNA. Not only can typical Cas9-dependent off-target sites be different between HEK293T and MCF7 cells (Fig. 5g and Supplementary Fig. 14), but conserved Cas9-dependent off-target sites can also be surrounded by differential out-of-protospacer edits (Fig. 5h and Supplementary Fig. 14a–d). Take a newly identified Cas9-dependent off-target site as an example, we observed a highest editing ratio of roughly 8.5 and 22.9% within the editing window in HEK293T and MCF7 cells, respectively, whereas a reverse trend (roughly 5.3 and 1.7% efficiency) was found for the highest out-of-protospacer edit (Supplementary Fig. 14c). In addition, target-strand edits can differ by greater than tenfold in the two cell lines (Supplementary Fig. 14d). Altogether, these observations reveal that off-target edits are influenced by various factors and prediction of off-target occurrence remains challenging.” (page 649-650, emphasis added). Again suggesting unpredictability in determining which Cas nuclease and which deaminases would allow for target strand editing.
The other reference submitted in the response filed April 22 2026 and the IDS filed May 18 2026, Wu et al., which Applicants indicate in the response states that the compact size of nucleases such as Cas12m and Cas12f1 results in a distinct base-editing window. However, looking to Wu et al., while Wu et al. does state that Cas12m-cytidine deaminase has a distinct C to T base editing window (highlights), looking at Figure 7A, this does not show editing on the target strand but the non-target strand (i.e. the strand that is not complementary to the gRNA). Therefore, this reference does not appear to support that smaller Cas nucleases necessarily result in editing of the complementary (e.g. target strand) strand.
The data in the specification (see example 2) seems to suggest that AsCas12f fused to TadA83 achieved A to G base editing of the target strand which is confirmed by Swartjes et al. Example 3 states Cas12f-CBE editing of the target strand. This appears to be specifically the AsCas12f fused to a specific cytidine deaminase using two different linkers. Since this result is in contrast to the results shown with Swartjes et al. (i.e. it allows for CBE editing), the specification fails to describe what structure is responsible for achieving the target strand editing. Is it the specific cytidine deaminase or the linkers or a specific structure associated with the nuclease? The actual description of what is required to achieve the purported unexpected base editing is critical to practicing the invention.
Karvelis et al. shows in supplementary Table S1 (see below) various different Cas12f proteins which meet the amino acid length requirement set forth in the claims. These Cas nucleases are taught as recognizing and cleaving dsDNA. Therefore, their use with gRNA in order to cleave and edit is already suggested (see abstract). Thus, the written description must distinguish between a mere recognition of latent properties/unappreciated property vs. an unexpected effect. Note MPEP 2112 and 2143.
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The recitation cleavage-deficient Cas with less than 600 amino acids does not appear to be of sufficient description to result in editing of A to G or C to T on the target strand. This recitation fails to meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, due to lacking chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. Since Swartjes et al., as provided by Applicants, make it clear that the design of the protein and protein-fusion design is critical to editing efficiency and strand preference, Lei et al. also supports unpredictability in predicting target strand editing and the specification does not describe what specific structural components are required to achieved the claimed editing, the specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163. As indicated above, merely having a cleavage-deficient Cas nuclease with less than 600 amino acids is not sufficient.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed Cas nuclease which achieves the claimed editing, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003).
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
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 ABIGAIL VANHORN whose telephone number is (571)270-3502. The examiner can normally be reached M-Th 6 am-4 pm EST.
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/ABIGAIL VANHORN/ Primary Examiner, Art Unit 1636
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