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 .
Status of Claims
Claims 1-3, 5, 7, 9-17, 20, 24-27 and 29 are currently pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-3, 5, 7, 9-17, a composition comprising a CRISPR system, in the reply filed on 01/07/2026 is acknowledged.
Applicant's election with traverse of the following species: Genus A - composition of Ai/Aii, and Genus B - tRNA fusion, in the reply filed on 01/07/2026 is acknowledged.
The traversal is on the ground(s) that the shared technical feature identified in the restriction requirement requires a Cas13 protein fused to both a nuclear localization signal (NLS) and a nuclear export signal (NES), and that Cheng et al. does not disclose fusion of both signals together. However, this argument misapprehends the basis of the restriction requirement. Claim 1 recites alternative embodiments; one embodiment requires fusion of the Cas13 protein with both an NLS and an NES, while another embodiment requires fusion with at least one localization signal, i.e., an NLS or an NES. Accordingly, the feature common to the alternative embodiments of claim 1 is not the simultaneous presence of both localization signals, but rather the presence of at least one (NLS or NES) associated with a Cas13 protein in combination with a guide RNA. The restriction requirement identified this shared technical feature as a CRISPR-Cas13 composition comprising a Cas13 protein (or nucleic acid encoding the protein) associated with a localization signal (NLS and/or NES) and a guide RNA. Cheng et al. teaches engineered CRISPR systems comprising a Cas protein complexed with a guide RNA and further teaches fusion of localization factors, including nuclear localization signals and nuclear export signals, to Cas proteins for intracellular targeting. Thus, Cheng et al. discloses the shared technical feature relied upon in the restriction requirement.
Additionally, applicant’s assertion that lack of search burden negates restriction is not persuasive. Unity of invention is determined by whether the claimed inventions share a common special technical feature making a contribution over the prior art, independent of claim dependency or search burden considerations. The claims remain directed to distinct statutory inventions including compositions, nucleic acids, vectors, host cells, kits, and methods of use and manufacture.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-14, 20, 24-27, and 29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claim.
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.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/21/2021 and 01/07/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claims 2-3 are objected to because of the following informalities:
In the interest of maintaining consistency throughout the claims, the recitation of “where in” in claims 2 and 3, should be amended to recite “wherein in”.
Claim 10 is objected to because of the following informalities:
Claim 10 includes the recitation of “(a)”, suggesting the presence of multiple separately enumerated elements when only a single limitation is presented. It is suggested that the “(a)” is deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 2-3 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 2 and 3 are indefinite due to the recitation of “said Cas13 protein” and “the Cas13 protein”, respectively. In claim 1, limitation Ai encompasses two Cas13 protein embodiments: (a) the CRISPR-associated protein 13 itself and (b) the Cas13 protein encoded by a nucleotide sequence. Therefore, in both claims 2 and 3, which depend on claim 1, it is unclear as to which Cas13 protein embodiment they are referring to. In one interpretation, “said protein” and/or “the protein” is referring to the encoded Cas13 protein. In another interpretation, they are referring to the Cas 13 protein itself. In the interest of advancing prosecution, the examiner is interpretating “said protein” and “the protein” as referring to the Cas13 protein itself.
Appropriate response and amendment is requested.
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.
Claims 1, 5, 7, 9-12, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hsu and Konermann (US2019062724, herein “Hsu”, cited in PTO-892).
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 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).
It is noted that the limitation “Ai” of claim 1, under the broadest reasonable interpretation, recites alternatively either: (1) at least one CRISPR-associated protein 13 (Cas13); or (2) a nucleotide sequence encoding said Cas protein fused with at least one nuclear localization signal fused to at least one nuclear export sequence. Because claim 1 is drafted in the alternative using the disjunctive “or”, satisfaction of either alternative meets the limitation of Ai. Accordingly, disclosure in the prior art of a Cas 13 protein itself satisfies limitation Ai without requiring disclosure of a nucleotide sequence encoding the Cas13 protein or fusion of such nucleotide sequence to localization signals. Likewise, the limitation of “Aii” recites alternatively either: (1) at least one guide RNA (gRNA); or (2) a nucleotide sequence encoding said gRNA capable of hybridizing with one or more target RNA molecules, and satisfaction of either alternative meets the limitation of Aii. Claim 11 and 12 further recite limitations directed specifically to the nucleotide sequence embodiment of claim 1. Accordingly, disclosure in the prior art of a Cas 13 protein itself satisfies limitation Ai, and disclosure of a gRNA satisfies limitation Aii, without requiring disclosure of a nucleotide sequence encoding the Cas13 protein, fusion of such nucleotide sequence to localization signals, or disclosure of a nucleotide sequence encoding the gRNA. However, because these claims depend from claim 1 and claim 1 encompasses the Cas13 protein and gRNA embodiments independently of their respective nucleotide sequence embodiments, the additional nucleotide sequence limitations do not restrict the scope of claim 1 when the claim is met by disclosure of a Cas13 protein and gRNA. Therefore, upon a showing in the prior art of a composition comprising a Cas13 protein and a guide RNA as recited in claim 1, claims 11 and 12 are likewise anticipated.
Thus, claims 1, 5, 7, 9-12, and 15-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hsu and Konermann (US2019062724, herein “Hsu”, cited in PTO-892).
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 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu, as applied to claim 1 above, and further in view of Gootenberg et al. (US2020231975, cited in PTO-892).
The teachings of Hsu, as it applies to claim 1, have already been discussed above. Briefly, Hsu discloses a composition comprising Cas13d and a guide RNA.
Hsu teaches fusion proteins wherein the Cas13d includes a subcellular localization signal, including a nuclear localization signal (NLS) (para 0382 and Example 4), thereby demonstrating that Cas13d proteins were conventionally modified with localization sequences to control intracellular distribution. Hsu 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). Hsu does not expressly disclose a Cas protein fused with at least one NLS fused to at least one NES via a linker, or fused to two NLS fused to one NES.
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 a. disclose each structural element of the claimed fusion architecture, differing only in the explicit combination of the localization signals on the Cas13d protein, which would have been an obvious design choice to control intracellular localization of the RNA-targeting complex.
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 in the art would have been motivated to incorporate the dual localization signal architecture taught by Gootenberg et al. into the Cas13d-guide RNA composition of Hsu, in order to regulate subcellular localization of the RNA-targeting complex. 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.
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.
Claims 1 and 9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18564684 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘684 claims anticipate and/or render obvious the instant claims.
Claim 2 of application ‘684 recites a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA; further bound to a target RNA molecule having a sequence that is at least 90% complementary to said guide RNA.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/ Examiner, Art Unit 1652
/RICHARD G HUTSON/ Primary Examiner, Art Unit 1652