DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 2 2026 has been entered.
Receipt of Arguments/Remarks filed on February 2 2025 is acknowledged. Claims 1-2, 6, 10 and 12 were amended. Claims 16-17 were added Claims 1-17 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 .
Withdrawn Objections/Rejections
The submission of the sequence listing on 12/29/2025 is sufficient to overcome the objection to the sequence disclosure.
The amendments and arguments filed February 2 2026 are sufficient to overcome the rejection of claim(s) 1-7 and 10-15 is/are under 35 U.S.C. 102(a)(1) over Fukuda et al. (USPGPUB No. 20180208924, cited on PTO Form 1449) and claims 1-15 under 35 USC 103 over Fukuda et al. The arguments, see page 7, are persuasive.
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 16-17 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.
Claims 16 depends from claim 1 and claim 17 depends from claim 6 and both recite the same limitations. The claims recite “wherein the at least one base pair contained in the target RNA and the second oligonucleotide”, it isn’t clear what “base pair” applicants are referring to. Looking to claim 1, for example, the claims recites the target-corresponding nucleotide residue does not form a base pair with the adenosine residue to be edited. Claim 1 also recites the first oligonucleotide has a base sequence complementary to the target RNA which would indicate base pairing as well. Since the claim is merely reciting a single base, specifically C, U or G, it isn’t clear what structure the claim is supposed to recite. It isn’t clear if the C, U or G are supposed to be the base opposite the A to be edited, are suppose to indicate that the oligonucleotide must contain one of those bases in the complementary region or something else. The response filed February 2 2026 does not aid in determining the scope as the response merely indicates support for the new claims can be found in the examples. In the interest of compact prosecution, the examiner is interpreting that one of the bases in the mismatch either at the A site to be edited or between the target RNA and the second oligonucleotide must be a C, U or G.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-17 is/are rejected under 35 U.S.C. 102(a)(1) or 102(a)(2) as being anticipated by Zhang et al. (WO2019005884).
The instant application claims an oligonucleotide that induces site-specific editing of a target RNA, comprising a first oligonucleotide that identifies the target RNA, and a second oligonucleotide linked to the 5' side of the first oligonucleotide, wherein the first oligonucleotide consists of: a target-corresponding nucleotide residue that corresponds to an adenosine residue in the target RNA, wherein the target-corresponding nucleotide residue does not form a base pair with the adenosine residue to be edited, a 10 to 24 residue oligonucleotide linked to the 3' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and a 3 to 6 residue oligonucleotide linked to the 5' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA; and wherein the second oligonucleotide has 2 to 10 residues and forms a complementary strand with the target RNA, and (a)the target RNA and the second oligonucleotide contain at least one base pair that does not contain the adenosine residue to be edited and that does not form a stable base pair; or (b) at least one base is inserted in the target RNA and/or the second oligonucleotide.
The instant application claims a method for site-specific editing of a target RNA, comprising contacting an oligonucleotide with the target RNA in the presence of adenosine deaminase 1,wherein the oligonucleotide comprises a first oligonucleotide that identifies the target RNA, and a second oligonucleotide linked to the 5' side of the first oligonucleotide, wherein the first oligonucleotide consists of: a target-corresponding nucleotide residue that corresponds to an adenosine residue in the target RNA, wherein the target-corresponding nucleotide residue does not form a base pair with the adenosine residue to be edited, a 10 to 24 residue oligonucleotide linked to the 3' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and a 3 to 6 residue oligonucleotide linked to the 5' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA; and wherein the second oligonucleotide has 2 to 10 residues and forms a complementary strand with the target RNA, and (a) the target RNA and the second oligonucleotide contain at least one base pair that does not contain the adenosine residue to be edited and that does not form a stable base pair or(b) at least one base is inserted in the target RNA and/or the second oligonucleotide.
Zhang et al. is directed to CRISPR/CAS-Adenine Deaminase based composition, systems and method for targeted nucleic acid editing. Claimed is a method of modifying an adenine in a target RNA sequence of interest comprising delivery to said target RNA, a catalytically inactive (dead) Cas13 protein; a guide molecule and an adenosine deaminase protein wherein the guide sequence is capable of hybridizing with a target sequence comprising said Adenine wherein said guide sequence comprises a non-pairing cytosine at a position corresponding to said adenine resulting in an A-C mismatch in the RNA duplex formed (claim 1). The guide sequence has a length of about 20-53 nucleotides capable of forming said RNA duplex with the target (claim 12). The distance between said non-pairing C and the 5’ end of the guide is 20-30 nucleotides (claim 14). The adenosine deaminase protein can be a mutated hADAR1d (claim 18). The target RNA is within a eukaryotic cell (claim 24). The target locus of interest is within an animal (i.e. subject) (claim 28). Deamination of Adenine in the target RNA of interest remedies a disease (claim 42). Hereditary diseases are claimed (claim 43). Adenosine deaminase is (hu)ADAR1 (claim 70). The guide sequence comprises more than one mismatch, each comprising a mismatch corresponding to different adenosine sites in the target RNA (claim 13). Numerous guide RNA are exemplified include those with ADAR1 which includes guides of 30, 50, 70 and 84 bases (page 460). It is specifically taught that a C mismatch is known to create a bubble at the site of editing which is favored by the ADAR catalytic domain (paragraph 01178). Results suggest that A's opposite C's in the targeting window of the ADAR deaminase domain are preferentially edited over other bases. Additionally, A's base-paired with U's within a few bases of the targeted base show low levels of editing by Casl3b-ADAR fusions, suggesting that there is flexibility for the enzyme to edit multiple A's. See e.g. FIG. 18. These two observations suggest that multiple A's in the activity window of Casl3b-ADAR fusions could be specified for editing by mismatching all A's to be edited with C's. Accordingly, in certain embodiments, multiple A:C mismatches in the activity window are designed to create multiple A:I edits. In certain embodiments, to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's. (paragraph 0277; Fig 14; sequences in paragraph 01182). Addition of gRNA mismatches to the distal end of the gRNA can demonstrate enhanced specificity. The introduction of unprotected distal mismatches in Y or extension of the gRNA with distal mismatches (Z) can demonstrate enhanced specificity. This concept as mentioned is tied to X, Y, and Z components used in protected gRNAs. The unprotected mismatch concept may be further generalized to the concepts of X, Y, and Z described for protected guide RNAs (paragraph 0556). According to particular embodiments the guide sequence further comprises mismatches appended to the end of the guide sequence, wherein the mismatches thermodynamically optimize specificity (paragraph 0557).
Therefore, Zhang et al. exemplify oligonucleotides that contain mismatches and induce site-specific editing of a target RNA. Zhang et al. exemplify combining the guide with an ADAR and administering to cells (eukaryotic) as well as in a subject with hereditary diseases. ADAR1 and gRNA are exemplified. Furthermore, as claimed by Zhang et al. the number of ADAR is finite and one skilled in the art would immediately envision utilizing ADAR1. Note: MPEP 2131.02. Mismatches with the adenosine to be edited is expressly taught. Since distal mismatches are taught and exemplified, they read on a mismatch in the second oligonucleotide. Furthermore Zhang et al. teaches that non-target A’s are paired
Regarding the claimed length of the oligonucleotide, claims 1 and 6 recite: An oligonucleotide…comprising a first oligonucleotide and a second oligonucleotide. While the claims recites that the first oligonucleotide consists of, this does not limit the totality of the claimed oligonucleotide to be limited to this length but merely that the first oligonucleotide is limited to 10 to 24 residue oligonucleotides to the 3’ side of the garget-corresponding nucleotide, 3 to 6 residues linked to the 5’ side of the target corresponding nucleotide and the second oligonucleotide has 2 to 10 residues and is linked to the 5’ side of the first. Thus, additional bases/nucleotides are allowed to be included and still fall within the scope claimed.
Regarding claim 3 and 11, the claim recites “at least one nucleotide” is inserted which the examiner interprets as referring to the “at least one base” is inserted in part (b) of claim 1 or claim 6. Since insertion of at least one base is not required in either claim 1 or claim 6 and claims 3 and 11 do not require part (b) merely that when part (b) occurs the at least base is inserted into the second oligonucleotide. Thus, Zhang et al. anticipates (a) and therefore would still anticipate claims 3 and 11.
Regarding claims 14-15, paragraph 0054 of the instant specification teaches that it is the mismatch that is inserted into the model target RNA. Zhang et al. expressly teaches mismatched nt in the 3’side of the target RNA portion complementary suggesting the instantly claimed limitations.
Regarding claims 16-17, Zhang et al. teaches It is specifically taught that a C mismatch is known to create a bubble at the site of editing which is favored by the ADAR catalytic domain (paragraph 01178). Results suggest that A's opposite C's in the targeting window of the ADAR deaminase domain are preferentially edited over other bases. Additionally, A's base-paired with U's within a few bases of the targeted base show low levels of editing by Casl3b-ADAR fusions, suggesting that there is flexibility for the enzyme to edit multiple A's. See e.g. FIG. 18. These two observations suggest that multiple A's in the activity window of Casl3b-ADAR fusions could be specified for editing by mismatching all A's to be edited with C's. Accordingly, in certain embodiments, multiple A:C mismatches in the activity window are designed to create multiple A:I edits. In certain embodiments, to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's. (paragraph 0277; Fig 14; sequences in paragraph 01182). Suggesting C as the base pair with the A to be edited or G as the base pair with A when it is a non-target A.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 3 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO2019005884).
Applicant Claims
The instant application claims wherein the at least one nucleotide is inserted in the second oligonucleotide. While the examiner of the position this is not required since insertion is recited in the alternative (i.e. (a) or (b)). However, when interpreted more narrowly and the claims are interpreted as at least one nucleotide is inserted in the oligonucleotide is required.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Zhang et al. are set forth above. Zhang et al. teaches the 5’-handle of the guide is modified. The loop can be modified to have a deletion, an insertion, a spilt or chemical modification. The loop comprises 3, 4 or 5 nucleotides (paragraph 0353).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Zhang et al. suggests insertion into the guide RNA, Zhang et al. does not expressly teach a sequence with a mismatch in the second oligonucleotide and at least one nucleotide inserted in the second oligonucleotide.
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to insert bases into the gRNA. One skilled in the art would have been motivated to insert at least one base as Zhang et al. teaches that bases can be inserted into the gRNA and that gRNA contains a loop and that the loop comprises 3, 4 or 5 nucleotides. Since Zhang et al. teaches mismatches at additional A’s in the target mRNA and specifically teaches that to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's (which result in a mismatch). Thus, one skilled in the art would have been motivated to form the claimed oligonucleotide.
Response to Arguments
Applicants’ arguments filed August 25 2025 have been fully considered but they are not persuasive.
Applicant argues that (1) independent claims 1 and 6 have been amended to clarify that the target RNA and second oligonucleotide contain at least one base pair that does not contain the adenosine residue to be edited and does not form a stable base pair or at east one base is inserted in the target RNA and/or second oligonucleotide. It is argued that Zhang does not disclose or suggest that the target RNA and the second oligonucleotide contain at least one base pair that does not contain the adenosine residue to be edited and that does not form a stable base pair at least one base is inserted in the target RNA and/or second oligonucleotide. This modification renders the double-strand of the nucleotide unstable. A person of ordinary skill would have no reason to introduce such a base pair. Zhang teaches guide sequences that comprise more than one mismatch, e ach comprising a mismatch corresponding to different adenosine sites in the target RNA. The guide sequence does not contain any mismatch which is not to be edited.
Regarding Applicant’s first argument, Zhang et al. expressly teaches to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's which is also shown in Fig. 14). This necessarily results in a mismatch between the target RNA and the second oligonucleotide that does not include the A to be edited. Since this is an express teaching in Zhang et al. the examiner cannot agree that one skilled in the art would not have been motivated to add a mismatch and have that mismatch not include an A which is not to be edited.
Applicants argue that (2) the Office Action states that the distance between the non-pairing C and the 5’ end of the guide is 20-30 nucleotides. In the present claim 1, a 3 to 6 residue oligonucleotide is linked to the 5’ side of the target-corresponding nucleotide residue and a second oligonucleotide of 2 to 10 residues is linked to the 5’ side of the first oligonucleotide so that the distance between the target-corresponding nucleotide residue and the 5’ end of the second oligonucleotide is 16 at maximum. Thus the distance between target-corresponding nucleotide residues and the 5’-end of the guide is different.
Regarding Applicants’ second argument, the examiner cannot agree that the claims limit the distance between the 5’ end and target-corresponding nucleotide residue of the guide. Claims 1 and 6 recite: An oligonucleotide…comprising a first oligonucleotide and a second oligonucleotide. While the claims recites that the first oligonucleotide consists of, this does not limit the totality of the claimed oligonucleotide to be limited to this length but merely that the first oligonucleotide is limited to 10 to 24 residue oligonucleotides to the 3’ side of the garget-corresponding nucleotide, 3 to 6 residues linked to the 5’ side of the target corresponding nucleotide and the second oligonucleotide has 2 to 10 residues and is linked to the 5’ side of the first. These recitations do not even limit the second oligonucleotide being linked directed to the 5’ end of the first. Thus, additional bases/nucleotides are allowed to be included at the 5’ end, 3’ end of both the first and second oligonucleotide and still fall within the scope claimed.
Applicants argue that (3) with regards to present claim 3, the phrase the at least one nucleotide is inserted in the second oligonucleotide while keeping the complementary strand as is. Even if the claim is given its broadest possible interpretation, introduction of a nucleotide at the complementary position does not mean inserting a nucleotide in an oligonucleotide.
Regarding Applicants’ third argument, this argument has been carefully considered. Firstly, as set forth above, claims 3 and 11 do not require (b) to be present but that when (b) is present a base is inserted in the second oligonucleotide. Thus, Applicants arguments with respect to a mismatch not necessarily being an inserted base since the complementary strand is not changed, the requirement for a base to be inserted into second oligonucleotide is now rejected under 103. Zhang et al. teaches that the gRNA can include an inserted base and specifically teaches a loop with 3 to 5 nucleotides rendering obvious insertion of at least one base. Since the loop is not complementary to the complementary strand but in addition, it reads on the inserted base.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 18265756 (USPGPUB No. 20240093227). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims an oligonucleotide that induces site-specific editing of a target RNA, comprising a first oligonucleotide that identifies the target RNA, and a second oligonucleotide linked to the 5' side of the first oligonucleotide, wherein the first oligonucleotide consists of: a target-corresponding nucleotide residue that corresponds to an adenosine residue in the target RNA wherein the target-corresponding nucleotide does not form a base pair with the adenosine residue to be edited, a 10 to 24 residue oligonucleotide linked to the 3' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA, and a 3 to 6 residue oligonucleotide linked to the 5' side of the target-corresponding nucleotide residue and having a base sequence complementary to the target RNA; and wherein the second oligonucleotide has 2 to 10 residues and forms a complementary strand with the target RNA, and (a) the target RNA and the second oligonucleotide contain at least one base pair that does not contain the adenosine residue to be edited and does not form a stable base pair or (b) at least one base is inserted in the target RNA and/or second oligonucleotide.
Copending ‘756 claims an oligonucleotide, or a pharmaceutically acceptable salt thereof, comprising:
a first oligonucleotide identifying a target RNA; and a second oligonucleotide linked to the 5'-side of the first oligonucleotide,
wherein the first oligonucleotide consists of a target-corresponding nucleotide residue corresponding to an adenosine residue in the target RNA, an oligonucleotide of 10 to 24 residues, linked to the 3'-side of the target- corresponding nucleotide residue and having a base sequence complementary to the target RNA, and an oligonucleotide of 3 to 6 residues, linked to the 5'-side of the target- corresponding nucleotide residue and having a base sequence complementary to the target RNA, the second oligonucleotide has no nucleotide residue corresponding to a nucleotide residue of the target RNA or has a nucleotide residue which does not form a complementary pair with a nucleotide residue of the target RNA (i.e. it contains a mismatch) at the 3'-end thereof, a number of residues in the second oligonucleotide is 2 to 10, and at least the nucleotide residues other than at the 3'-end form a double-stranded structure complementary to the target RNA, a counter region consisting of the target-corresponding nucleotide residue and each one residue at the 3'-side and the 5'-side thereof is contained, the nucleotide residue linked to the 3'-side of the target-corresponding nucleotide residue is a 2'-deoxynucleotide residue, the third nucleotide residue counted in the 3'-direction from the target-corresponding nucleotide in the oligonucleotide linked to the 3'-side of the target-corresponding nucleotide residue is a 2'-deoxy-2'-fluoronucleotide residue, and the oligonucleotide, or a pharmaceutically acceptable salt thereof induces site-specific editing for the target RNA (claim 1). The number of residues in the second oligonucleotide is 4 to 8 (claim 2). Site-specific editing is due to adenosine deaminase 1 (claim 4).
Therefore, the scopes of the copending claims and the instant application overlap and thus they are obvious variants of one another.
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of copending Application No. 18265756 (USPGPUB No. 20240093227) as applied to claims 1-5 above in view of Zhang et al. (WO2019005884). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant application claims a method for site-specific editing of a target RNA, comprising contacting the oligonucleotide with the target RNA in the presence of adenosine deaminase 1.
The claims of copending ‘756 are set forth above. While copending ‘756 claims the editing is due to an enzyme reaction by adenosine deaminase 1, copending ‘756 does not expressly claim contacting an oligonucleotide with the target RNA in the presence of adenosine deaminase 1, a eukaryotic cell or in a subject. However, these deficiencies are cured by Zhang et al.
Zhang et al. is directed to CRISPR/CAS-Adenine Deaminase based composition, systems and method for targeted nucleic acid editing. Claimed is a method of modifying an adenine in a target RNA sequence of interest comprising delivery to said target RNA, a catalytically inactive (dead) Cas13 protein; a guide molecule and an adenosine deaminase protein wherein the guide sequence is capable of hybridizing with a target sequence comprising said Adenine wherein said guide sequence comprises a non-pairing cytosine at a position corresponding to said adenine resulting in an A-C mismatch in the RNA duplex formed (claim 1). The guide sequence has a length of about 20-53 nucleotides capable of forming said RNA duplex with the target (claim 12). The distance between said non-pairing C and the 5’ end of the guide is 20-30 nucleotides (claim 14). The adenosine deaminase protein can be a mutated hADAR1d (claim 18). The target RNA is within a eukaryotic cell (claim 24). The target locus of interest is within an animal (i.e. subject) (claim 28). Deamination of Adenine in the target RNA of interest remedies a disease (claim 42). Hereditary diseases are claimed (claim 43). Adenosine deaminase is (hu)ADAR1 (claim 70). The guide sequence comprises more than one mismatch, each comprising a mismatch corresponding to different adenosine sites in the target RNA (claim 13). Numerous guide RNA are exemplified include those with ADAR1 which includes guides of 30, 50, 70 and 84 bases (page 460). It is specifically taught that a C mismatch is known to create a bubble at the site of editing which is favored by the ADAR catalytic domain (paragraph 01178). Results suggest that A's opposite C's in the targeting window of the ADAR deaminase domain are preferentially edited over other bases. Additionally, A's base-paired with U's within a few bases of the targeted base show low levels of editing by Casl3b-ADAR fusions, suggesting that there is flexibility for the enzyme to edit multiple A's. See e.g. FIG. 18. These two observations suggest that multiple A's in the activity window of Casl3b-ADAR fusions could be specified for editing by mismatching all A's to be edited with C's. Accordingly, in certain embodiments, multiple A:C mismatches in the activity window are designed to create multiple A:I edits. In certain embodiments, to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's. (paragraph 0277; Fig 14; sequences in paragraph 01182). Addition of gRNA mismatches to the distal end of the gRNA can demonstrate enhanced specificity. The introduction of unprotected distal mismatches in Y or extension of the gRNA with distal mismatches (Z) can demonstrate enhanced specificity. This concept as mentioned is tied to X, Y, and Z components used in protected gRNAs. The unprotected mismatch concept may be further generalized to the concepts of X, Y, and Z described for protected guide RNAs (paragraph 0556). According to particular embodiments the guide sequence further comprises mismatches appended to the end of the guide sequence, wherein the mismatches thermodynamically optimize specificity (paragraph 0557).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘756 and Zhang et al. and contact the target RNA with the oligonucleotide of ‘756 in the presence of adenosine deaminase 1 (ADAR1). One skilled in the art would have been motivated to contact the target RNA with the oligonucleotide of ‘756 in the presence of ADAR1 in order to edit the target RNA. One skilled in the art would have a reasonable expectation of success as copending ‘756 claims the site-specific editing is due to ADAR1 and Zhang et al. suggests guide oligonucleotides like the one in copending ‘756 can be used in combination with ADAR1 to induce editing.
Regarding claims 7-9, Zhang et al. suggests the editing can be in eukaryotic cells or in subjects in need thereof and that the subject can have a hereditary disease. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of copending ‘756 and Zhang et al. and utilize the oligonucleotide anywhere editing is desired. Since Zhang et al. teaches editing in eukaryotic cells or in subjects there is a reasonable expectation of success.
Regarding claims 14-15, paragraph 0054 of the instant specification teaches that it is the mismatch that is inserted into the model target RNA. Zhang et al. expressly teaches mismatched nt in the 3’side of the target RNA portion complementary suggesting the instantly claimed limitations.
Regarding claims 16-17, copending ‘756 clearly claims the second oligonucleotide has a nucleotide residue which does not form a complementary pair with a nucleotide residue of the target RNA. Copending ‘756 is just silent to the base. Zhang et al. teaches It is specifically taught that a C mismatch is known to create a bubble at the site of editing which is favored by the ADAR catalytic domain (paragraph 01178). Results suggest that A's opposite C's in the targeting window of the ADAR deaminase domain are preferentially edited over other bases. Additionally, A's base-paired with U's within a few bases of the targeted base show low levels of editing by Casl3b-ADAR fusions, suggesting that there is flexibility for the enzyme to edit multiple A's. See e.g. FIG. 18. These two observations suggest that multiple A's in the activity window of Casl3b-ADAR fusions could be specified for editing by mismatching all A's to be edited with C's. Accordingly, in certain embodiments, multiple A:C mismatches in the activity window are designed to create multiple A:I edits. In certain embodiments, to suppress potential off-target editing in the activity window, non-target A's are paired with A's or G's. (paragraph 0277; Fig 14; sequences in paragraph 01182). Suggesting C as the base pair with the A to be edited or G as the base pair with A when it is a non-target A.
Response to Arguments
Applicants’ arguments filed February 2 2026 have been fully considered but they are not persuasive.
Applicants argue that the present application has an earlier effective filing date. As set forth in the MPEP once the other objections and rejections are withdrawn and the only other remaining issue is the double patenting the ejection can be withdrawn in the earlier filed application.
Regarding Applicants arguments, the patent term filing date of the instant application is September 25 2020 and the patent term filing date of the copending application is December 8 2021. Therefore, Applicants are correct that the instant application is earlier filed. Therefore, as long as the copending application remains unpatented, then once the instant claims are indicated as free of prior art, the double patenting rejection can be withdrawn as set forth in MPEP 804.
Conclusion
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636