DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1, 7-8, 11-15, 26, 29-30, 48 and 49 and Species Group A in the reply filed on 18 February 2026 is acknowledged. During a telephone conversation with Laura A Labeots on 3/27/2026 a provisional election was made without traverse to prosecute the invention of the genome editing system, wherein the polypeptide comprises an alanine at a position corresponding to position 43 of SEQ ID NO: 1; an alanine at a position corresponding to position 55 of SEQ ID NO: 55; and/or an alanine at a position corresponding to position 152 of SEQ ID NO: 1 (all substitutions), claim 12. Affirmation of this election must be made by applicant in replying to this Office action.
Claims 8, 13, 35, 39-40, 42-43 and 46-47 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention below. The search and examination has been extended to an amino acid modification or mutation that comprises adding an amino acid.
Claims 1, 7, 11-12, 14-15, 26, 29-30, 48 and 49 are being examined on the merits.
Priority
The application claims priority to application 63/365,281 filed 05/25/2022.
Information Disclosure Statement
The information disclosure statements filed 1/17/2024 and 12/03/2024 have been considered.
Drawings
The drawings are objected to because the drawing do not contain a Fig. 4H as indicated in the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term Novagen, Nacalai Tesque, Thermo Fisher Scientific, Millipore, Quantifoil, New England Biolabs, Beckman Coulter, Zymo Research, Invitrogen, Biotek, Addgene, Sigma Aldrich, and Applied Biosystems to name a few, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. A cursory review of the specification has revealed these trademarks or names. It would be remedial to check the specification for additional trademarks or names and amend all upon amendment.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites an alanine at a position corresponding to position 55 of SEQ ID NO:
55. SEQ ID NO: 55 in a nucleotide sequence with only 31 residues. It is unclear what sequence this limitation is referring to. For examination purposes, the other two mutations of the claim will be searched and examined.
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, 7, 11, 14-15, 26, 29-30, 48 and 49 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The claims are directed to a composition (or a genome editing system) comprising a polypeptide comprising an amino acid sequence at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4, a deaminase, and a guide RNA that hybridizes to the RNA target and the polypeptide. The claim require that the composition or system must be capable of cleaving a target RNA. Therefore, the claims require the provision of a genus of polypeptides with at least between 85-100% identity to any one of SEQ ID NOs: 1-4 that are defined by the function of being capable of cleaving a target RNA.
The specification teaches a Desulfonema ishimotonii (D.ishimotonii) Cas7-11 and its cleavage process [see Example 12]. The specification teaches that SEQ ID NO: 1-4 are human D.ishimotonii Cas7-11 proteins [Table 3]. The specification teaches a D.ishimotonii Cas7-11 double mismatch mutant with abolished target RNA cleavage and teach the cleavage of other Cas7-11 mutants [0293-294; Fig. 5E]. The specification also teaches that H43A, Y55A, and N152A Cas7-11 mutants are capable of target RNA cleavage [0289]. Therefore, the applicant has provided a limited genus of compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4 that is capable of cleaving a target RNA.
Ozcan (Ozcan et al. 2021 Nature Vol. 597, cited on the Information Disclosure statement filed 1/17/2024) teaches engineered D.ishimotonii mutants and their RNA knockdown mammalian editing efficiencies [abstract]. Ozcan teaches that Cas7-11 substitutions in several of the conserved acidic residues across all four Cas7 domains (D177, D429, D654, D745, D758, E959 and D998) led to impaired target cleavage [pg. 722, col.1, para 2]. Therefore, Ozcan teaches that not all compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4 is capable of cleaving a target RNA.
Accordingly, in view of the limited amount of guidance provided by the specification and the art, and the unpredictability of the art, one of ordinary skill in the art would conclude that Applicant was not in possession of all compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4 that are capable of cleaving a target RNA.
Claims 1, 7, 11, 14-15, 26, 29-30, 48 and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises an alanine at a position corresponding to position 43 of SEQ ID NO: 1; an alanine at a position corresponding to position 55 of SEQ ID NO: 1; and/or an alanine at a position corresponding to position 152 of SEQ ID NO: 1 (H43A, Y55A, and N152A Cas7-11 mutants) that can cleave a target RNA, does not reasonably provide enablement for any compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The claims are directed to a composition (or a genome editing system) comprising a polypeptide comprising an amino acid sequence at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4, a deaminase, and a guide RNA that hybridizes to the RNA target and the polypeptide. The claim require that the composition or system must be capable of cleaving a target RNA.
Breadth of the claims: The claims broadly encompass the provision or use of all single and multiple amino mutants of SEQ ID NOs: 1-4 that are capable of cleaving a target RNA. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification: The specification teaches a Desulfonema ishimotonii (D.ishimotonii) Cas7-11 protein and its cleavage process [see Example 12]. The specification teaches that SEQ ID NO: 1-4 are human D.ishimotonii Cas7-11 proteins [Table 3]. The specification teaches a D.ishimotonii Cas7-11 double mismatch mutant with abolished target RNA cleavage and teach the cleavage of other Cas7-11 mutants [0293-294; Fig. 5E]. The specification also teaches that H43A, Y55A, and Nl52A Cas7-11 mutants are capable of target RNA cleavage [0289].
Predictability and state of the art: Ozcan (Ozcan et al. 2021 Nature Vol. 597, cited on the Information Disclosure statement filed 1/17/2024) teaches engineered D.ishimotonii mutants and their RNA knockdown mammalian editing efficiencies [abstract]. Ozcan teaches that Cas7-11 substitutions in several of the conserved acidic residues across all four Cas7 domains (D177, D429, D654, D745, D758, E959 and D998) led to impaired target cleavage [pg. 722, col.1, para 2]. Therefore, Ozcan teaches that not all compositions comprising a polypeptide that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4 are capable of cleaving a target RNA.
Amount of experimentation necessary: A large amount of experimentation would be required to make and use the full scope of the claimed invention. One would be required to mutate every possible amino acid, using single or multiple mutations, of SEQ ID NOs: 1-4 and measure their cleavage activity while making sure the mutants are at least 85% identical to SEQ ID NOs: 1-4. This type of experimentation would require a large amount of inventive effort.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention.
Claim Rejections - 35 USC § 103
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, 7, 11, 14-15, 26, 29-30, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Catchpole (Catchpole et al. Mol Cell. 2021 November 04; 81(21): 4354–4356) in view of Cheng (US 2020/0299659 A1) and Genbank WP_124327589 (Desulfonema ishimotonii; Cas_III-E_gRAMP, 2018).
Regarding claim 1, 14-15, 30, and 48-49 Catchpole teaches that a Type III-E CRISPR-Cas systems has demonstrated applicability as highly-specific, programmable, all-in-one RNA-targeting systems [pg. 2, para 2; Fig. 1]. Catchpole teaches that Type III-E systems appear to be a fusion of canonical Type III Cas7 and Cas11 subunits into a single polypeptide, resulting in a polypeptide that is referred to as Cas7-11 or gRAMP (for giant repeat-associated mysterious protein) [pg. 2, para 2]. Catchpole teaches that Cas7-11 protein cleaves CRISPR array transcripts to generate mature crRNAs and uses these as guides to cleave RNAs at two sites in a sequence-specific manner [Fig. 1]. Catchpole teaches that Cas7-11 alone was able to target mRNAs in the heterologous contexts of E. coli and mammalian cells (regarding claim 30), and that sequence-specific targeting resulted in RNA knockdown and decreased protein expression [pg. 3, para 3]. Catchpole teaches that the specificity of the Cas7-11 system resulted in significantly fewer off-target effects in mammalian cells than the classical RNA interference using short hairpin RNAs, or the more recent Cas13 technologies, indicating that Cas7-11 may be a superior RNA knockdown method [pg. 3, para 3]. Catchpole teaches that fusion of Cas7-11 to an adenosine deaminase (ADAR2) (regarding claim 48) resulted in site-specific A-to-I modification of RNAs in vivo, albeit at low frequency (2%–8% of transcripts) [pg. 3, para 3]. Catchpole teaches that
Catchpole does not teach that the Cas7-11 comprises an amino acid sequence at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises at least one amino acid modification or mutation relative to the amino acid sequence of SEQ ID NO: 1-4.
Cheng teaches non-naturally occurring, engineered Type III-E CRISPR-Cas systems, components, and methods for targeted modification of DNA, RNA, and protein substrates [abstract]. Cheng teaches a Type III-E CRISPR-Cas system that includes an effector protein, RNA guides, and RAMP domains [0010]. Cheng teaches targeting of a target nucleic acid by the Type III-E CRISPR-Cas effector protein and Type III-E RNA guide that results in a modification in the target nucleic acid where the modification of the target nucleic acid can be a cleavage event [0016]. Cheng teaches that the CRISPR enzymes can comprise functional domains [0094]. Cheng teaches SEQ ID NO: 16 which is identified by the name WP 124327589.1 that is 100% identical to the current application’s SEQ ID NO: 1. Genbank WP 124327589.1 teaches that SEQ ID NO: 16 is a type III-E CRISPR-associated gRAMP effector Cas7-11. Cheng teaches that various mutations can be introduced into CRISPR enzymes to improve specificity and/or robustness [0112].
Regarding claim 26, Cheng teaches nucleic acid molecules thereof, or nucleic acid molecules encoding or providing components thereof of the CRISPR system [0199].
Regarding claim 29, Chen teaches vectors comprising the CRISPR system components where the vector can be a viral vector [0199].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the system of Catchpole by substituting the Cas7-11 with the Cas7-11 of Cheng. The modification would amount to a simple substitution of one Cas7-11 protein for another. One of ordinary skill would be further motivated to try to introduce a mutation or amino acid modification into the Cas7-11 protein for the advantage of improve genome editing specificity. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Catchpole and Cheng teaches Type III-E CRISPR-Cas genome editing.
Regarding claim 7 and 11, Cheng teaches that CRISPR enzymes can comprise or be associated with one or more functional domains (e.g., via fusion protein, linker peptides, "GS" linkers, etc.) [0094]. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the that the system as taught and suggested by Catchpole and Cheng to compris an addition as the amino acid modification, which can be a GS linker (two amino acid modification). One of ordinary skill would be motivated to make the modification for the advantage of linking a functional domain, such as the deaminase as taught by Catchpole, to the CRISPR enzyme.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: Claim 12 contains allowable subject matter. A polypeptide comprising an amino acid sequence at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4 wherein the amino acid sequence of the polypeptide comprises an alanine at a position corresponding to position 43 of SEQ ID NO: 1; an alanine at a position corresponding to position 55 of SEQ ID NO:1; and/or an alanine at a position corresponding to position 152 of SEQ ID NO: 1 is free of the art.
The instant specification teaches that Cas7-11 H43A, Y55A and N152A mutants are capable of target RNA cleavage even though they exhibit reduced or no pre-crRNA processing activities [0289; Fig. 4]. The closet prior art is Catchpole as discussed above. Catchpole nor the prior art as a whole teaches or provides a reasonable rationale to mutate the Cas7-11 protein where the mutation is H43A, Y55A or N152A.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637