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 species A, claims 1-15, Species 1A: E173Q + H145D corresponding to the first polypeptide domain: SEQ ID NO:13; Species 2A: SEQ ID NO:50; Species 3A: fusion of first domain to second domain; Species 4A: NLS linker; and Species 5A: SEQ ID NO: 74 in the reply filed on 11/10/2025 is acknowledged.
Claims 10-12 and 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/10/2025.
Species 5A for claim 15 is withdrawn.
Claims 1-20 are pending. Claims 1-9 and 13-15 (claim set filed 11/10/2025) are examined on the merits herein.
Priority
This application is a 371 of PCT/SG2020/050599 filed 10/19/2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on SINGAPORE 10201909733W filed 10/18/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/21/2025 complies with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-9 and 13-15 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the limitation for the first polypeptide domain to have at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1, the limitation for the second polypeptide domain to have at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 2 or at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 3 wherein the first polypeptide domain is fused to the second polypeptide domain or inserted into the second polypeptide domain. The polypeptide is designed to have RNA-targeting and editing activity as described in the specification (p. 1, lines 9-10). The first domain is described as adenosine deaminase and the second as Cas domains which are inactivated and do not cut the RNA, however, provide targeting function (p. 10, lines 39-40, p. 11, lines 1-2). Claim 1 is interpreted as directed to the polypeptide wherein 10% or less of the sequence of the first domain vary from SEQ ID NO: 1 and 10% or less of the sequence of the second domain vary from either SEQ ID NO:2 or SEQ ID NO:2. and the polypeptide retains function of its domains.
Thus, claim 1 broadly encompasses genus of the first polypeptide domain with 90% or more sequence identity to SEQ ID NO: 1, genus of the second polypeptide domain with 90% or more sequence identity to SEQ ID NO: 2 or SEQ ID NO: 3 and genus of the polypeptide composed of the polypeptide domains. This would represent large pools of variant amino acid sequences encoding the respective polypeptides which are functional. At the same time proteins can have 10% or less of sequences that can differ from SEQ ID NO: 1-3. The Specification does not provide structure function correlation for the first and the second polypeptide domains and does not describe domains and/or amino acid residues essential for the function of polypeptide in RNA targeting and editing and domain and/or amino acid residues which can be modified without loss of RNA targeting and editing function. Further, applicants have not shown possession of a representative number of species for the functional polypeptide as Specification provides examples of substitution of 17 amino acid residues of SEQ ID NO:1 and their combinations (p. 17), that represents only 4.4% of the 385 total number of amino acids. The Specification describes inactivating substitutions of 4 amino acid residues of SEQ ID NO:2 and two amino acid residues of SEQ ID NO:3 recited in claim 1 and substitution of additional critical residue, K942L of SEQ ID NO:2 (p. 12, line 31). The specification mentions that polypeptides can be further modified not affecting the described mutations, however, the specification does not describe which amino acids besides recited can be modified without affecting the function of the polypeptide (p. 27, lines 32-38).
Therefore, one of ordinary skill in the art would not be able to identify which polypeptide sequences that have 90% identity to SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 encode for functional polypeptide domains. One of ordinary skill in the art would conclude based on the lack of representative number of species and the lack of describing the domains or amino acid residues of SEQ ID NO: 1-3 critical for the function of the polypeptide domains, that the Applicant was not in possession of the claimed genera and that the specification fails to satisfy the requirements of written description under 35 U.S.C. 112 (a). Therefore, claim 1 is rejected.
Claims 2-9 and 13-15 do not resolve the issues mentioned above and are rejected.
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 1-9 and 13-15 is 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 1 recites: “(hADAR2dd)” in line 9. First, since the identifier is in parenthesis, it is not clear whether hADAR2d in parentheses is included in the scope of the claim. Second, it is not clear if hADAR2dd refers to the SEQ ID NO:1 or SEQ ID NO: 1 including amino acid substitutions recited in (ii) and (iii). The specification describes: “The polypeptide consisting of the amino acid sequence set forth in SEQ ID NO:1 is also referred to as "hADAR2dd" or "ADAR2'' herein.” (p. 15, lines 16-17). However, description “hADAR2dd” appears in claim 1 after recitation of amino acid substitutions and not after the first recitation of SEQ ID NO:1 in line 4.
Claim 1 recites: “(dCasRx)” in line 13. First, since the identifier is in parenthesis, it is not clear whether dCasRx in parentheses is included in the scope of the claim. Second, it is not clear if dCasRx refers to SEQ ID NO:2 since the identifier is positioned after recitation of SEQ ID NO:2 or to SEQ ID NO:2 with amino acid substitutions 239A, 244A, 858A and 863A. The specification does not clarify the issue because the specification refers SEQ ID NO:2 to CasRx (p. 15, line 21) and dCasRx (p. 15, line 24) wherein dCasRx is described as deactivated CasRx (p. 3, line 7) and inactivation is achieved by the recited substitutions: “This means that the CasRx domain is inactivated by including the mutations 239A, 244A, 858A, and 863A relative to SEQ ID NO:2” (p. 24, lines 39-40). It is unclear how the same identifier can refer to different sequences.
Claim 1 recites: “(dCas13b)” in line 16. First, since the identifier is in parenthesis, it is not clear whether dCas13b in parentheses is included in the scope of the claim. Second, it is not clear if dCas13b refers to SEQ ID NO:3 since the identifier is positioned after recitation of SEQ ID NO:3 or to SEQ ID NO:3 with amino acid substitutions 133A and 1058A. The specification does not clarify the issue because the specification refers SEQ ID NO:3 to Cas13b (p. 15, line 21) and dCas13b (p. 15, line 25) wherein dCas13b is described as deactivated Cas13b (p. 2, line 33) and inactivation is achieved by the recited substitutions: “inactivating mutations 133A and 1058A” (p. 15, line 40). It is unclear how the same identifier can refer to different sequences.
The scope and boundaries of claim 1 are not certain making claim 1 indefinite.
Claims 2-9 and 13-15 do not resolve the issues mentioned above and are rejected.
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 1-5, 8, 9 and 13 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Zhang (WO 2019005884 A1 on record in IDS).
Regarding claim 1, Zhang teaches systems, methods and compositions for targeting and editing nucleic acids (Abstract). The system comprises adenosine deaminase protein or catalytic domain thereof fused to catalytically inactive Cas13 protein (paragraphs 0010). Zhang discloses human adenosine deaminase domain, hADAR2d, comprising mutation E488Q (paragraph 0016). The sequence of hADAR2d with SEQ ID NO:650 (Figure 4) has 99.7% sequence identity to instant SEQ ID NO: 1 and has E488Q substitution corresponding to instant 173Q substitution. Zhang identified Cas13b ortholog from Prevotella sp. PO5-125 (PspCas13b) as the most efficient and specific for mammalian cells application (paragraph 01196). The sequence of PspCas13b of Zhang teaching with SEQ ID NO: 82 (p. 215-216, Table 3) is 100% identical to instant SEQ ID NO:3. Zhang describes that PspCas13b was made catalytically inactive via two histidine to alanine mutations: H133A and H1058A, corresponding to instant limitation (paragraph 01204). Zhang provides a working example of a polypeptide composed of PspCas13b containing inactivating mutations (dCas13b) fused to hADAR2d with E488Q mutation (paragraph 01230). Thus, Zhang teaches a polypeptide composed of the fist polypeptide domain of adenosine deaminase having 99.7% sequence identity to instant SEQ ID NO:1 and comprising instant amino acid substitution 173Q fused to the second polypeptide of Cas13b having 100% sequence identity to instant SEQ ID NO:3 and inactivating amino acid substitutions 133A and 1058A. Besides, the described polypeptide does not have substitutions recited in the last line of claim 1 correlating with claim 1 limitation. Therefore, Zhang teaching anticipates claim 1.
Regarding claims 2-5, Zhang teaches mutagenesis of ADAR2 to improve specificity using polypeptide dCas13b containing inactivating mutations fused to hADAR2d with E488Q mutation (paragraph 0099). The dCas13b-ADAR2dd(E488Q) is referred by Zhang as REPAIRv1: “… we chose dCas13b-ADAR2DD(E488Q) for further characterization and designated this approach as RNA Editing for Programmable A to I Replacement version 1 (REPAIRv1)” (paragraph 01231). One of the mutations is mutation H460D (paragraph 0242) that corresponds to instant H145D as confirmed by the specification: “the mutation H460D (H145D using the positional number of SEQ ID NO:1” (p. 12, lines 16-17). Figure 88 shows results of the evaluation of dCas13b-ADAR2dd(E488Q) polypeptides with various mutations including H460D mutation in comparison with REPAIRv1 polypeptide. As can be seen that mutation increases specificity (on-target versus non-target editing) while retaining high editing activity. As described above hARAD2d sequence with SEQ ID NO: 650 of Zhang corresponds to instant SEQ ID NO: 1 plus E488Q (E173Q) mutation. The instant SEQ ID NO: 13 (elected species) corresponds to instant SEQ ID NO:1 with E173Q and H145D substitutions. Therefore, the ADAR2dd of the Cas13b-ADAR2dd(E488Q) polypeptide of Zhang teaching with H460D mutation is identical to instant SEQ ID NO:13. Thus, Zhang teaching anticipated claims 2-5.
Regarding claims 8 and 9, Zhang teaches that hADAR2 domain (first instant polypeptide) is fused on the C-terminal of catalytically inactive dCas13b (second instant polypeptide domain) (paragraph 01204). Thus, Zhang teaching anticipates claims 8 and 9.
Regarding claim 13, Zhang teaches that hADAR2 domain is fused to the C-terminus of dCas13b via GS or GSGGGGS linkers (paragraph 01204). Thus, Zhang teaching anticipates claim 13.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2019005884 A1 on record in IDS) as evidenced by Behrens (Behrens et al. J. Virol., 2017, 91, e02107-16, 1-19).
The teaching of Zhang has been set forth above.
Regarding claim 14, as described above, Zhang teaches a polypeptide composed of the first polypeptide domain of adenosine deaminase having 99.7% sequence identity to instant SEQ ID NO:1 and comprising instant amino acid substitution 173Q fused to the second polypeptide of Cas13b having 100% sequence identity to instant SEQ ID NO:3 and inactivating amino acid substitutions 133A and 1058A (paragraph 01230). Zhang teaches that it is advantageous to provide either adenosine deaminase domain or Cas protein or both with nuclear localization sequences (NLS) for improved targeting of the polypeptide to nucleus (paragraph 0615). Zhang describes the NLS-tagged Cas13 fused to adenosine deaminase domain (paragraph 01163). However, since Zhang does not explicitly teach addition of NLS tag to the polypeptide composed of human ADAR2 domain with 173Q substitution and catalytically inactive Cas13b with 133A and 1058A substitutions corresponding to instant domains, 103 rejection of claim 14 is made.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add NLS-tag to the polypeptide composed of hADAR2 domain having 99.7% sequence identity to instant SEQ ID NO:1 and comprising instant amino acid substitution 173Q fused to Cas13b having 100% sequence identity to instant SEQ ID NO:3 and inactivating amino acid substitutions 133A and 1058A taught by Zhang. One would have been motivated to do that with reasonably expected success since Zhang describes that NLS improves targeting of the polypeptide and its components to nucleus. Thus, Zhang teaching renders claim 14 obvious.
Regarding claim 15, the amino acid sequence of SEQ ID NO: 58 is composed of dCas13b domain with amino acid substitutions 133A and 1058A, amino acid sequence of hADAR2 domain with 173Q and 145D substitutions and linkers in between these domains. The linkers are: GS; nuclear export sequence, NES (LQLPPLERLTL); and GSGGGGS. As described above, Zhang teaches a polypeptide comprising dCas13b having 100% sequence identity to instant SEQ ID NO:3 and inactivating amino acid substitutions 133A and 1058A, that corresponds to the N-terminal domain of SEQ ID NO: 58, fused at C-terminal to dADAR2 domain having 99.7% sequence identity to instant SEQ ID NO:1 and comprising instant amino acid substitution 173Q (paragraphs 01204, 01230). Zhang discloses dCas13b-ADAR2dd(E488Q) with additional 145D substitution (paragraph 0242, 01231, Figure 88) in which ADAR2dd corresponds to the C-terminal domain of SEQ ID NO: 58. Zhang describes that dCas13b domain and ADAR2dd domain can be linked via GS or GSGGGGS linkers (paragraph 01204) and mentions that: “the linker is used to separate the targeting domain and the adenosine deaminase by a distance sufficient to ensure that each protein retains its required functional property.” (paragraph 0201). Zhang teaches that the targeting domain, which is dCas13b domain, can comprise nuclear export signal (NES) which is preferably HIV Rev NES and preferably of C-terminal (paragraph 0042). Figure 57E shows construction of polypeptides composed of dCas13b with NES of C-terminus connected via GS or GSGGGGS linker to ADAR2d (E173Q). The HIV Rev NSE has sequence “LQLPPLERLTL” as evidenced by Behrens (p. 3, 4th paragraph). The polypeptide of Figure 57E with additional 145D substitution and NSE connected via GS at its N-terminal and GSGGGGS on its C-terminal will correspond to instant polypeptide with SEQ ID NO:58.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use dCas13b-ADAR2dd(E488Q/H460D corresponding to E173Q/H145D) polypeptide of Zhang teaching and add HIV Rev NES-tag (LQLPPLERLTL) connected via GS to the C-terminus of dCas13b and via GSGGGGS tag to the N-terminus hADAR2 domain. One would have been motivated to do that with reasonably expected success since Zhang shows that H145D mutation increases specificity (on-target versus non-target editing) while retaining high activity of adenosine deaminase, the NES will facilitate targeting of the polypeptide to nucleus and linkers will ensure that each protein domain and the NES retain their required functional property. Additionally, one would have been motivated to select either GS or GSGGGGS linker for connection of dCas13b with NES and NES with ADAR2dd since both linkers were used by Zhang to connect dCas13b and ADAR2dd (paragraph 01204) and to connect NSE to ADAR2dd (Figure 57E). Thus, Zhang teaching renders claim 15 obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2019005884 A1 on record in IDS) in view of Konermann (Konermann et al. Cell, 2018, 173, 665-676 on record in IDS).
The teaching of Zhang has been set forth above.
Zhang does not teach the second polypeptide with SEQ ID NO: 50 (elected species).
Regarding claim 7, Konermann teaches CasRx derived from Ruminococcus flavefaciens with robust activity in human cells (Abstract). The CasRx family was designated as Cas13d (p. 666, right column, last paragraph). The sequence of RfxCas13d from Konermann teaching presented in Table S5 (1st entry) has sequence with 100% identity to instant SEQ ID NO:2 for CasRx. Konermann describes modification of Cas13d sequence to make it catalytically inactive with substitutions 239A, 244A, 858A and 863A (Table S5, 2nd entry) corresponding to instant substitutions. The sequence of modified Cas13d, dCas13Rx, of Konermann has instant sequence with SEQ ID NO: 50. Konermann describes CasRx: “as a programmable RNA-binding module for efficient targeting of cellular RNA, enabling a general platform for transcriptome engineering and future therapeutic development” (Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Zhang and Konermann teachings and use catalytically inactive RfxCas13d from Konermann teaching containing 239A, 244A, 858A and 863A substitutions and comprising instant SEQ ID NO:50 as alternative to Cas13b from Zhang teaching fused to adenosine deaminase for RNA editing. One would have been motivated to make this combination since Konermann teaches catalytically inactive CasRx with efficient targeting of RNA and mentions that it can be used for therapy. A skilled artisan would have reasonably expected success in this combination because Zhang and Konermann teach RNA editing involving Cas13 proteins for RNA targeting. Thus, Zhang and Konermann teachings render claim 7 obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila G Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653