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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/1/2026 has been entered.
Applicant’s amendment of claims 51, 82, 86 and 91, in the paper of 7/1/2026, is acknowledged. Applicants' arguments filed on 7/1/2026, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 51-91 are still at issue and are present for examination.
Terminal Disclaimer
The terminal disclaimer filed on 4/5/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US 11,739,308 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Election/Restrictions
Applicant's election without traverse of Group I, claims 51-83, drawn to a composition comprising a Cas13b effector protein, in the paper of 12/6/2024, is acknowledged.
Applicant's election without traverse of the following species:
Species Group 1): SEQ ID NO: 32;
Species Group 2): R116A:
Species Group 3): (GGGGS)3-11;
Species Group 4): MS2;
Species Group 5): huADAR and
Species Group 6): HIV Rev NES
in the paper of 12/6/2024, is acknowledged.
Claims 84-90 are withdrawn from further consideration by the examiner, 37CFR 1.142(b), as being drawn to a non-elected invention.
Claim Rejections - 35 USC § 101
The rejection of claims 51-53, 61, 76-78, under 35 USC § 101is withdrawn based upon applicants amendment of the claims and applicants arguments presented in the paper of 8/27/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 91 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 pre-AIA the applicant regards as the invention.
Claim 91 recites the limitation "the CRISPR-Cas13b effector protein" in 51. There is insufficient antecedent basis for this limitation in the claim.
Appropriate comment/amendment is required.
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.
Claim(s) 51-83 and 91 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim(s) 51-83 and 91 are directed to all possible engineered compositions for modifying a target RNA sequence, said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence. The specification, however, only provides the representative species of compositions comprising the Cas13b effector proteins of SEQ ID NOs: 31-38, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The diversity of CRISPR-Cas systems has resulted in multiple rounds of classification and nomenclature evolution and there are currently two major classes distinguished by single versus complexed effector proteins (Barrangou and Gersbsch, Molecular Cell, 65, pp 582-584, Feb 2017). The specification also fails to describe additional representative species of these the Cas13b effector proteins by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicants arguments presented in the paper of 1/28/2026 in response to a similar rejection have been considered, however, are not found persuasive in overcoming the rejection as applied to applicants newly amended claims.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 51-83 and 91 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that composition comprising the Cas13b effector proteins of SEQ ID NOs: 31-38, does not reasonably provide enablement for all possible engineered compositions for modifying a target RNA sequence,said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claim(s) 51-83 and 91 are so broad as to encompass all possible engineered compositions for modifying a target RNA sequence,said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence. The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of recombinant Cas13b effector proteins and a functional variant thereof, a homologue or an orthologue thereof broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the Cas13b effector proteins and a functional variant thereof, a homologue or an orthologue thereof encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to those compositions comprising the Cas13b effector proteins of SEQ ID NOs: 31-38.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible engineered compositions for modifying a target RNA sequence,said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence, because the specification does not establish: (A) regions of the Cas13b effector protein which may be modified effecting the Cas13b effector protein activity; (B) the general tolerance of Cas13b effector proteins to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an enzyme of the Cas13b effector protein with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required Cas13b effector protein activities and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g, Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those Cas13b effector proteins and variants thereof.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any engineered compositions for modifying a target RNA sequence,said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those Cas13b effector proteins having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Applicants arguments presented in the paper of 1/28/2026 in response to a similar rejection have been considered, however, are not found persuasive in overcoming the rejection as applied to applicants newly amended claims.
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.
Claim(s) 51-53, 55-58, 73-83 and 91 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Abudayyeh et al. (US Patent No. 10,266,886).
Abudayyeh et al. (US Patent No. 10,266,886) disclose a nucleic acid detection system comprising: a CRISPR system comprising an effector protein and one or more guide RNAs designed to bind to corresponding target molecules; an RNA-based masking construct; and optionally, nucleic acid amplification reagents to amplify target RNA molecules in a sample. Abudayyeh et al. disclose a number of Cas effector proteins including the Cas effector of Table 4a isolated from Prevotella intermedia having the amino acid sequence of SEQ. I.D. NO. 338, which is 100% identical to instant SEQ ID NO:32. Abudayyeh et al. further teach compositions for modifying a target RNA sequence comprising the Cas effector protein of SEQ ID NO:338, a guide sequence and a heterologous functional domain, wherein the guide molecule comprises a guide sequence and a direct repeat sequence (see Table 4a, claims and supporting text). Abudayyeh et al. further teach the above compositions comprising the Cas effector protein of SEQ ID NO:338, mutated such that it is catalytically inactive and comprises a heterologous functional domain (see Table 4a, claims and supporting text).
Thus, claim(s) 51-53, 55-58, 73-83 and 91 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Abudayyeh et al. (US Patent No. 10,266,886).
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 51-83 and 91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,266,886. Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 51-83 and 91, drawn to an engineered composition for modifying a target RNA sequence, said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence are anticipated/obvious by claims 1-16 of U.S. Patent No. 10,266,886 drawn to a system for detecting the presence of a nucleic acid target sequence in an in vitro sample, comprising: reagents for amplifying the target sequence; a Cas13; at least one guide polynucleotide comprising a guide sequence that hybridizes with the target sequence, and designed to form a complex with the Cas13; and an RNA-based masking construct comprising a non-target sequence; and wherein the Cas13 exhibits collateral RNase activity and cleaves the non-target sequence of the RNA-based masking construct once activated by the target sequence.
Further, U.S. Patent No. 10,266,886 teaches that the Cas13 effector protein can be that disclosed in Table 4a, Prevotella intermedia (SEQ. I.D. NO. 338) which is 100% identical to instantly taught SEQ ID NO:32. Thus the claims 1-16 of U.S. Patent No. 10,266,886 drawn to a system for detecting the presence of a nucleic acid target sequence in an in vitro sample, comprising: reagents for amplifying the target sequence; a Cas13; at least one guide polynucleotide comprising a guide sequence that hybridizes with the target sequence, and designed to form a complex with the Cas13; and an RNA-based masking construct comprising a non-target sequence; and wherein the Cas13 exhibits collateral RNase activity and cleaves the non-target sequence of the RNA-based masking construct once activated by the target sequence make obvious the above system comprising the Cas13 protein of SEQ. I.D. NO. 338 and thus an engineered composition for modifying a target RNA sequence, said engineered composition comprising: (a) a Cas 13b effector protein comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO: 31-38, (b) an engineered guide molecule capable of forming a complex with the Cas13b effector protein, and (c) one or more heterologous functional domains, wherein the one or more functional domains are heterologous to the Cas 13b effector protein, wherein the engineered guide molecule comprises i) a guide sequence, and ii) a direct repeat sequence, wherein the engineered guide RNA molecule can direct sequence-specific binding of the complex to the new target sequence (instant claims 51-83 and 91).
Remarks
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
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rgh
9/15/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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