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 .
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.
Status of the Claims
Claims 1-18 are pending. Claims 1, 7, 15 and 16 are amended. Claims 19 and 20 are cancelled. Claims 10-12 and 16-18 are withdrawn.
Claims 1-9 and 13-15 (claim set filed 04/01/2026) and are examined on the merits herein.
Withdrawal of Rejections
The response and amendment filed on 04/01/2026 are acknowledged. All of the amendment and arguments have been thoroughly reviewed and considered.
For the purposes of clarity of the record, the reasons for the Examiner's withdrawal and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner's response to arguments section.
The previous claims 1-9 and 13-15 rejection under 35 U.S.C. 112(b) has been withdrawn necessitated by amendment of claim 1.
The previous claims 1-5, 8, 9 and 13 rejection under 35 U.S.C. 102(a)(1) and (a)(2) has been withdrawn necessitated by amendment of claim 1.
Maintained/Modified Rejections
The following rejections are maintained and/or modified taking into consideration amendment to claims filed on 04/01/2026.
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 1-9 and 13-14 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 and the limitation for the second polypeptide domain to have at least 96% sequence identity to the amino acid sequence of SEQ ID NO: 2 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 domain which is inactivated and does 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 4% or less of the sequence of the second domain vary from either 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 96% or more sequence identity to SEQ ID NO: 2 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 and 4% or less of sequences that can differ from SEQ ID NO: 2. 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 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 at least 90% identity to SEQ ID NO:1 and at least 96% identity to SEQ ID NO:2 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 and 2 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 13-14, dependent on claim 1, do not resolve the issues mentioned above and are rejected.
Response to Arguments
Applicant's arguments filed 04/01/2026 have been fully considered but they are not persuasive.
Applicant argues (addressing p. 6-7 of the Remarks) that the level of sequence identity (90% and 96%) is sufficiently high and one of ordinary skill in the art can identify sequences based on common knowledge and guidance from the Specification and that significant sequence identity is sufficient to practice the subject matter of the present claims and does not constitute undue trial and error to reproduce the results of the invention. These arguments are not persuasive because:
The MPEP 2163 states: “The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.").”
In instant case, claim 1 encompasses a genus of the polypeptide composed of the first polypeptide domain with sequence identity of at least 90% to SEQ ID NO: 1 and the second polypeptide domain with the sequence identity of at least 96% to SEQ ID NO: 2. As recited by the Applicant, that provides 39 variant amino acid residues for the first polypeptide domain and 39 variant amino acid residues for the second polypeptide domain. Thus, the total variability of the fusion polypeptide is 78 amino acid residues with any possible substitutions that provides a very broad genus of the polypeptide composed of the first and second domains within the scope of claim 1. However, the specification does not describe structure function correlation for the polypeptides and provides examples of the limited number of a representative species as described in the rejection. Thus, one of ordinary skill in the art would not be able to elect proteins that will be functional without experimentation since election with the lack of written description can lead to unpredictable results. Thus, since the specification does not describe the domains and/or amino acid residues of SEQ ID NO: 1 and 2 essential for the polypeptide function and does not provide the representative species one would conclude that the Applicant does not have possession of the full scope of the claimed invention and therefore the 35 U.S.C. 112(a) rejection (written description) is maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-5, 7-9 and 13-15 are 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).
Regarding claim 1, Zhang teaches systems, methods and compositions for targeting and editing nucleic acids and in particular RNA (Abstract). The system comprises adenosine deaminase protein or catalytic domain thereof fused to catalytically inactive Cas13 protein (paragraph 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 describes that Cas3 protein is selected from Cas3a, Cas13b or Cas3c (paragraph 0009). 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 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.
Zhang does not teach the second polypeptide domain with at least 96% sequence identity to SEQ ID NO: 2 comprising amino acid substitutions 239A, 244A, 858A and 863A.
Regarding claim 1, 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) comprises sequence with 100% identity to instant SEQ ID NO:2. 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. Konermann suggests to use inactivated dCasRx for targeting specific coding and non-coding elements within a transcript to study and manipulate RNA (p. 672, left column, 3rd paragraph). 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 substitute catalytically inactive Cas13b in Zhang fusion protein for RNA targeting and editing with catalytically inactive RfxCas13d from Konermann teaching containing 239A, 244A, 858A and 863A substitutions. One would have been motivated to make this substitution since Konermann suggests to use catalytically inactive CasRx for specific 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 1 obvious.
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 and Konermann teachings render claims 2-5 obvious.
Regarding claim 7, Konermann teaches the inactivated Cas13d, dCas13Rx, comprising sequence with 100% identity to instant sequence with SEQ ID NO: 50.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use Cas13d comprising sequence with 100% identity to 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 do that with reasonably expected success since Konermann provides Cas13 inactivated with 239A, 244A, 858A and 863A substitutions with efficient targeting of RNA and Zhang teaches fusion proteins containing another Cas13, Cas13b and variant ADAR2dd polypeptides with editing activity and specificity for RNA (Figure 88). Thus, Zhang and Konermann teachings render claim 7 obvious.
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). Regarding claim 13, Zhang teaches that hADAR2 domain is fused to the C-terminus of dCas13b via GS or GSGGGGS linkers (paragraph 01204). Zhang mentions that linkers are used to separate the targeting domain and the adenosine deaminase domain to ensure that each protein retains its functional property (paragraph 0377).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Zhang guidance for fusion of hADAR2 domain to the C-terminal of dCas13 via linkers and apply that to fusion of ADAR2 with dCas13d based on combination of Zhang and Konermann teachings. One would have been motivated to do that with reasonably expected success since Zhang describes constructs with ADAR2 attached to C-terminal of Cas13b to be active and specific and for linker to provide flexibility and separate protein domains. Thus, Zhang and Konermann teachings render claims 8, 9 and 13 obvious.
Regarding claim 14, Zhang teaches that it is advantageous to provide either adenosine deaminase domain or Cas13 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). Konermann mentions that RfxCas13d-NLS fusion was more efficient in targeting than the wild-type RfxCas13d (p. 669, right column, 2nd paragraph).
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 and Cas13d based on Zhang and Konermann teachings. One would have been motivated to do that with reasonably expected success since Zhang describse that NLS improves targeting of the polypeptide and its components to nucleus and Konermann mentions NLS to improve RNA targeting. Thus, Zhang and Konermann teachings render claim 14 obvious.
Regarding claim 15, the amino acid sequence of SEQ ID NO: 59 is composed of dRfxCas13d domain with amino acid substitutions 239A, 244A, 858A, 863A, amino acid sequence of hADAR2 domain with 173Q and 145D substitutions and linkers before the dRfCas13d domain and in between domains. The linkers are: NLS at the beginning of dRfCas13d domain and GSG plus NLS plus XTEN linkers in between domains.
Zhang teaches dCas13 fused at the C-terminal to dADAR2 domain identical to instant SEQ ID NO:1 plus E173Q and H145D substitutions as described above for claim 5 (Figure 4, paragraph 00242). Konermann teaches sequence for RfxCas13d domain (NLS-dRfxCas13d-NLS-HA) with NLS sequence at the N-terminal and C-terminal of RfxCas13d (Table S5, 4th entry). Additionally, that sequence has GSG linker before the NLS on the C-terminal and HA sequence (used for purification or detection) after NLS. The sequence of NLS-dRfxCas13d-NLS-HA of Konermann is identical to part of the instant sequence with SEQ ID NO:59, i.e. NLS-dRfCas13d domain-GSG-NLS. Zhang teaches that it is advantageous to provide either adenosine deaminase domain or Cas13 protein or both with nuclear localization sequences (NLS) for improved targeting of the polypeptide to nucleus (paragraph 0615) and mentions that linkers are used to separate the targeting domain and the adenosine deaminase domain to ensure that each protein retains its functional property (paragraph 0201). Zhang describes that domains can be linked via different linkers including XTEN linker, SGSETPGTSESATPES (paragraph 01204). Modification of sequence of NLS-dRfxCas13d-NLS-HA from Konermann teaching by substitution of HA epitope (that is used as purification tag and not as linker) with dADAR2 domain of Zhang teaching with E173Q and H145D substitutions and connecting NLS and ADAR2 via XTEN linker will provide instant sequence with SEQ ID NO:59.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use ADAR2dd(E488Q/H460D corresponding to E173Q/H145D) polypeptide domain of Zhang teaching and attach it via XTEN linker to C-terminus of polypeptide domain NLS-dRfxCas13d-NLS-HA of Konermann teaching substituting HA epitope to obtain sequence corresponding to instant SEQ ID NO:59 for RNA editing. One would have been motivated to do that with reasonably expected success since Zhang shows that H145D mutation increases specificity of Cas13-ADAR2dd(E173Q) (on-target versus non-target editing) while retaining high activity of adenosine deaminase, Konermann provides Cas13 inactivated with 239A, 244A, 858A and 863A substitutions with efficient targeting of RNA, the NLS will facilitate targeting of the polypeptide to nucleus and linkers will ensure that each protein domain and the NLS retain their required functional property.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try different linkers suggested by Zhang and including XTEN linker for connection of NLS-dRfxCas13d-NLS to ADAR2dd(E173Q/H145D). One would have been motivated to do that with reasonably expected success since linker would provide separation of NLS on the C-terminal of dRfxCas13d and ADAR2 which is necessary for retaining of their functional properties and selection of the optimal linker is within the skills of the artisan in the field. Thus, Zhang and Konermann teachings render claim 15 obvious.
Response to Arguments
Applicant's arguments filed 04/01/2026 have been fully considered but they are not persuasive.
Since amended claim 1 requires fusion of ADAR2 to inactive CasRx (Cas13d) and Zhang does not teach dCasRx, the 35 U.S.C. 102 rejection was withdrawn and 35 U.S.C. 103 rejection was modified.
Applicant argues (addressing p. 8-11 of the Remarks) that the CasRx scaffold in combination with engineered ADAR2 variants improves editing window control and enhances overall specificity relative to prior Cas13b-based constructs. Applicant further argues that: “The demonstrated preservation of on-target efficiency alongside improved specificity constitutes an unexpected technical effect that could not be predicted based on the prior art.”. Applicant argues that Zhang does not disclose CasRx (Cas13d) and does not suggest to substitute Cas13b with CasRx. Konermann does not disclose fusion of CasRx to ADAR2 and does not suggest CasRx to be functionally interchangeable with Cas13b and that the rationale to combine them is based on hindsight reconstruction and that the improved balance between on-target activity and reduced off-target editing is not taught or suggested by Zhang and Konermann or expected in view of thereof. These arguments are not persuasive because:
First, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In instant case, Zhang teaches fusion protein consisting of adenosine deaminase with 173Q substitution and inactive Cas13 protein (paragraphs 0010, 0016). Konermann teaches another Cas13, i.e. catalytically inactive CasRx (Cas13d) with 239A, 244A, 858A and 863A substitutions and suggests to use it for specific targeting of RNA and RNA manipulation (p. 672, left column, 3rd paragraph) providing motivation to substitute catalytically inactive Cas13b in Zhang fusion protein for RNA targeting and editing with catalytically inactive CasRx (Cas13d). Although Cas13 of Zhang and Konermann teachings are different, they are perform the same function of specific RNA targeting.
Second, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” The combination of prior art of Zhang and Konermann provides fusion polypeptide of the same structure as instant fusion polypeptide, i.e. Zhang ADAR2dd with SEQ ID NO: 650 is identical to instant SEQ ID NO: 1 with 173Q substitution and Konermann CasRx comprises sequence identical to instant SEQ ID NO:2 with the recited substitutions (Table S5, 2nd entry), and hence that fusion polypeptide is expected to have the same properties as instant polypeptide. Besides, Zhang discloses variants of ADAR2dd such as 145D variant within the Cas13b-ADAR2dd polypeptide (Figure 88) with increased specificity (on-target versus non-target editing) while retaining high editing activity and Konermann discloses that CasRx represents a RNA-binding module for efficient targeting of cellular RNA and enabling a general platform for transcriptome engineering (Abstract). Thus, combination of modified ADAR2dd of Zhang and inactive CasRx (Cas13d) of Konermann is expected to provide high specificity and RNA editing activity.
Therefore, the combination of Zhang and Konermann teachings makes instant claims obvious and 35 U.S.C. 103 rejection is maintained and modified necessitated by claims amendment.
Conclusion
No claims are allowed.
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 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
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