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 .
Amendments Received
Amendments to the claims were received and entered on June 05, 2026.
Status of Claims
Claim 14 has been cancelled.
Claims 1-3, 5, 7, 9-13, 15-17, 20, 24-27 and 29 are currently pending.
Claims 1-3, 5, 7, 9-12, and 15-17, as claims 13, 20, 24-27 and 29 are withdrawn.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/086992 filed on December 21, 2021 and claims priority to foreign application LU102326, filed on 12/22/2020. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application and all claims are being examined with an effective filing date of December 22, 2020. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Objections
In view of Applicant’s amendments, objections to claims 2-3 and 10 are hereby withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments, rejections of claims 1, 5, 7, 9-12, and 15-17 under 35 USC § 102 are hereby withdrawn.
In view of Applicant’s arguments, clarifying that the recitation of “said Cas13 protein” and “the Cas13 protein”, the rejections of claims 2 and 3 under 35 USC § 112(b) are hereby withdrawn.
In view of Applicant’s amendments, the provisional double patenting rejection of claims 1 and 9 over copending Application No. 18564684 is hereby withdrawn.
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 1-3, 5, 7, 9-12, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu and Konermann (US2019062724, herein “Hsu”, cited in a previous office action) and Gootenberg et al. (US2020231975, cited in a previous office action).
Applicant amended claim 1 to expressly recite that the Cas13 protein is fused with at least one NLS that is fused to at least one NES. Because this amendment materially changes the scope of claim 1 relative to that previously examined, the anticipation rejection has been withdrawn and replaced with the present obviousness rejection.
Hsu discloses a CRISPR-Cas system comprising at least one Cas13d protein and at least one guide RNA “that hybridizes with the one or more target RNA molecules” (Specification, para 0008). Hsu teaches wherein the “gRNA can further include one or more spacer sequences specific for (e.g., is complementary to) the target RNA” (para 0017). Hsu further teaches fusion proteins wherein the Cas13d includes a subcellular localization signal, including a nuclear localization signal (NLS) (para 0382 and Example 4) and additionally identifies other localization signals, including nuclear export signals (NES), as known subcellular localization signals that may be incorporated into Cas13d fusion constructs (para 0382). Therefore, Hsu demonstrates that Cas13d proteins were conventionally modified with localization sequences, including NLS and NES. Additionally, Hsu teaches that the gRNA that hybridizes with the one or more target RNA molecules includes one or more direct repeat (DR) sequences, one or more spacer sequences, or one or more sequences comprising DR-spacer-DR-spacer, wherein the one or more DR sequences have at least 80% sequence identity to defined sequences (para 0355). Moreover, Hsu teaches that “an unprocessed guide RNA is 36 nt of DR followed by 30-32 nt of spacer…is processed (truncated/modified) by Cas13d itself or other RNases into the shorter “mature” form”. An unprocessed guide RNA, as taught by Hsu, is at least 30 nucleotides in length and a processed guide RNA is “about 44 to 60” nucleotides in length (para 0414). Hsu also teaches that “Cas13d protein could be targeted to the miRNA-122 binding site on the viral RNA to synergistically combat HCV infections by simultaneously reversing miRNA-122-mediated protection and directly degrading HCV RNA” and that “targeting AU-rich elements in the 3′ UTR of a target gene, a HEPN-mutated Cas13d can block binding of RNA-binding proteins…”. It is noted that “by using an Cas13d protein with a mutated or intact HEPN domain and a guide RNA containing at least one a spacer sequence specific for the target RNA, a target RNA can be masked from RNA-binding proteins or RNA-binding elements such as miRNAs” (para 0481-0482). It is also noted that Because Cas13d targeting of RNA occurs through sequence complementarity provided by the guide RNA spacer, the targeting of 3’ UTR of a target gene inherently involves hybridization of the guide RNA to that untranslated region. Regarding inactivation of bacterial or viral ssRNA, as recited in claim 16, in addition to the teachings described above regarding targeting viral DNA (HCV RNA), Hsu further teaches that Cas13d efficiently cleaves complementary target ssRNA in a guide-sequence dependent manner (para 0522 and Fig. 5A-5D). Hsu discloses compositions comprising Cas13d, guide RNA, RNP complex, nucleic acids, vectors, or cells, wherein such compositions may include pharmaceutically acceptable carriers expressly discloses said composition as a pharmaceutical composition (para 0020 and para 0312).
Hsu does not expressly disclose a Cas protein fused with at least one NLS fused to at least one NES as recited in claim 1, fused via a linker as recited in claim 2, or fused to two NLS fused to one NES as recited in claim 3.
Gootenberg et al. teaches systems, methods, and compositions for targeting nucleic acids. In particular, Gootenberg et al. discloses non-naturally occurring or engineered RNA-targeting systems comprising a novel RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA (Abstract). Gootenberg et al. teaches that the effector protein may be any member of the Cas13 family, including Cas 13d (Specification, para 0136), and wherein the CRISPR enzyme (e.g. Cas13d) is fused with a destabilization domain (DD). Gootenberg et al. further teaches wherein the fusion of the CRISPR enzyme with the DD comprises a linker between the DD and the CRISPR enzyme and further comprises at least one Nuclear Export Signal (NES) or at least one Nuclear Localization Signal (NLS) “in addition to an NES”. Additionally, Gootenberg et al. teaches that the localization signal may be incorporated within or form part of the linker joining the CRISPR enzyme and the fusion partner (para 0261). Because Gootenberg et al. expressly identifies Cas13d as a suitable CRISPR effector protein, the localization fusion architectures discloses therein are applicable to the Cas13d protein taught by Hsu. Accordingly, the combined teachings of Hsu and Gootenberg et al. disclose each structural element of the claimed fusion architecture, differing only in the explicit arrangement of the localization signals on the Cas13d protein. Although neither reference expressly discloses the precise arrangement of the localization signals recited in claim 1, neither Hsu nor Gootenberg et al. attributes any criticality to the relative arrangement of the NLS and NES. Rather, both references recognize these localization signals as conventional modular fusion elements for regulating intracellular localization. Accordingly, selecting one conventional arrangement, including the claimed Cas13-NLS-NES configuration, would have been an obvious matter of routine design choice that predictably performs the known functions of the localization signals.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Gootenberg et al. disclose RNA-targeting CRISPR systems comprising a CRISPR effector protein, including Cas13d, complexed with a guide RNA, wherein the CRISPR enzyme (Cas13d) may be fused to additional elements through a linker, and may further comprise at least one nuclear localization signal (NLS) and at least one nuclear export signal (NES), including configurations in which the NLS is in addition to an NES and forms part of the linker architecture. In view of Hsu, which discloses compositions comprising a Cas13d protein and a guide RNA, and further disclose that Cas13d proteins may be modified to include subcellular localization signals, including a nuclear localization signal (NLS) and nuclear export signal (NES), to control intracellular distribution, a person of ordinary skill would have been motivated to incorporate the dual localization architecture taught by Gootenberg into Hsu’s Cas13d construct to regulate nuclear import and export of the RNA-targeting complex, with a reasonable expectation of success. Given Gootenberg et al.’s explicit disclosure of CRISPR effector proteins fused to both NLS and NES sequences via a linker, a person of ordinary skill in the art would have reasonably expected that modifying the Cas13d construct of Hsu to include at least one, including two, NLS and one NES as part of a fusion configuration would have predictably yielded a Cas13d-guide RNA composition capable of controlled nuclear import and export. Such modification represents the predictable use of known localization elements according to their established functions to achieve a known objective, namely regulation of intracellular distribution of CRISPR effector complexes. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claims 1-3, 5, 7, 9-12, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu and Gootenberg et al.
Response to Arguments for Prior Art Rejections
In the response filed on 06/05/2026, Applicant argues that: (1) neither Hsu nor Gootenberg discloses a Cas13 protein fused to an NLS that is fused to an NES; (2) Gootenberg is directed to a different purpose and therefore would not have been combined with Hsu; (3) Gootenberg fails to disclose the claimed structural arrangement of the localization signals; (4) the claimed tandem NLS-NES configuration is critical to improved RNA knockdown efficiency; and (5) Gootenberg’s examples would have directed one of ordinary skill toward an NLS alone rather than the claimed tandem configuration. Applicant’s arguments have been fully considered but are not persuasive for the reasons set forth below.
Applicant’s argument that neither reference expressly discloses the claimed Cas13-NLS-NES fusion architecture is acknowledged. However, obviousness does not require that every aspect of the claimed combination be expressly disclosed in a single reference. As discussed above, Hsu teaches Cas13 proteins modified with localization signals, including NLS and NES, while Gootenberg expressly teaches Cas13 fusion constructs incorporating both NLS and NES localization signals. Although Gootenberg does not expressly identify the precise ordering of the NLS and NES localization signals, Gootenberg teaches that both localization signals may be incorporated into the fusion construct and does not limit their relative arrangement. Once both localization signals are selected for incorporation, their arrangement would have been one of a limited number of predictable configurations encompassed by Gootenberg’s disclosure. Accordingly, selecting the claimed arrangement would have represented no more than a routine design choice for one of ordinary skill in the art.
Applicant’s argument that Gootenberg is directed to regulation of Cas13 protein stability rather than improving RNA knockdown efficiency is likewise unpersuasive. The present rejection does not rely upon Gootenberg for its teachings regarding destabilization domains, ligand-dependent regulation, or protein stability. Rather, Gootenberg is relied upon solely for its express teaching that Cas13 fusion constructs may incorporate both NLS and NES localization signals. Hsu independently teaches modifying Cas13 proteins with localization signals, including NLS and NES, to regulate intracellular localization. Thus, the motivation for the proposed modification arises from Hsu’s recognition of the desirability of controlling Cas13 localization, while Gootenberg merely provides a known fusion architecture demonstrating that both NLS and NES were conventionally incorporated into Cas13 fusion constructs. Accordingly, Applicant’s characterization of Gootenberg’s primary objective does not undermine the rationale supporting the present obviousness rejection.
Applicant’s reliance on Examples 1 and 8 of Gootenberg is also unpersuasive. Although those examples evaluate particular Cas13 constructs and identify specific embodiments as effective, they do not criticize, discourage, or otherwise teach away from Gootenberg’s broader disclosure expressly teaching incorporation of both NLS and NES localization signals into Cas13 fusion constructs. Obviousness is evaluated based on the reference as a whole and is not limited to its preferred embodiments or working examples. Accordingly, the cited examples do not undermine the broader teachings of Gootenberg relied upon in the present rejection.
Finally, Applicant’s assertion that the claimed tandem NLS-NES arrangement provides improved RNA knockdown efficiency does not overcome the rejection. The present rejection is based upon the obviousness of the claimed structural configuration in view of the combined teachings of Hsu and Gootenberg. While Applicant alleges improved performance associated with the claimed arrangement, Applicant has not provided evidence demonstrating that any alleged improvement would have been unexpected relative to the teachings of the applied prior art or otherwise sufficient to outweigh the evidence supporting the conclusion of obviousness. Accordingly, Applicant’s arguments do not overcome the prima facie case of obviousness established above.
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 1-3, 5, 7, 9-12 and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 11, 14 , and 16 of copending Application No. 18879172 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘172 claims anticipate and/or render obvious the instant claims.
Claim 1 recites a clustered, regularly interspaced, short palindromic repeats (CRISPR) system comprising i) at least one nucleotide sequence encoding at least one CRISPR-associated protein 13 (Cas13); and ii) at least one guide RNA (gRNA) or at least one nucleotide sequence encoding said at least one gRNA capable of hybridizing with one or more viral target RNA molecules, wherein said system comprises a viral 5' untranslated region (UTR) or a nucleotide sequence encoding said 5' UTR and/or a viral 3' UTR or a nucleotide sequence encoding said viral 3' UTR, wherein a viral replicase recognition sequence is comprised in at least any one of said 5' UTR or in the nucleotide sequence encoding said 5' UTR, or said 3' UTR or in the nucleotide sequence encoding said 3' UTR, and wherein said system does not comprise a nucleotide sequence encoding a viral replicase and wherein said viral replicase recognition sequence is from the same RNA virus as the one or more viral target RNA molecules.
Claim 6 recites, in part, wherein said system further comprises at least one nucleotide sequence encoding at least one viral packaging signal which is comprised by said nucleotide construct of said system comprising said at least one nucleotide sequence encoding said at least one Cas13 protein, optionally wherein said at least one nucleotide sequence encoding said at least one viral packaging signal is also comprised by said construct comprising said at least one qRNA or said at least one nucleotide sequence encoding said at least one qRNA as defined by claim 5, and/or ii) said system inactivates viral ssRNA.
Claim 8 of application ‘172 recites, in part, wherein said Cas13 protein is a Cas13d protein.
Claim 11 recites, in part, wherein said at least one nucleotide sequence encoding said at least one Cas13 protein i) is fused with at least one nucleotide sequence encoding at least one nuclear localization signal (NLS) fused to at least one nucleotide sequence encoding at least one nuclear export sequence (NES), optionally via a nucleotide sequence encoding a peptide linker, or ii) is fused with at least one nucleotide sequence encoding at least one NLS or with at least one nucleotide sequence encoding at least one NES…wherein said at least one nucleotide sequence encoding said at least one Cas13 protein is fused with two nucleotide sequences both encoding a NLS fused to one nucleotide sequence encoding a NES.
Claim 14 recites, in part, wherein said gRNA has a length of at least about 23 nucleotides, optionally between about 26 to about 30 nucleotides.
Claim 16 recites, in part, wherein said gRNA has at least about 68% complementary sequence identity to said one or more viral target RNA molecules, and/or wherein said qRNA is capable of hybridizing to (a) 5'- and/or 3'-untranslated region(s) of said one or more viral target RNA molecules.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments for Double Patenting Rejections
In the response filed on 06/05/2026, Applicant states that because no claims have been allowed in either the instant application or copending applications, “it is premature to file arguments or a terminal disclaimer at this time”. Upon consideration of Applicant’s amendments, the examiner has determined that the provisional non-statutory double patenting rejections over copending application 18/564,684 is no longer applicable, and has therefore withdrawn that rejection. However, the provisional non-statutory double patenting rejections over copending application 18/879,172 is maintained.
Conclusion
No claim is in condition for allowance.
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 NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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