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, 4, 6, 8-11, 13, 16-17, 21-22, 24-25, 27-28, 30, 35, 40-41 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2022/080627 filed on 11/30/2022. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 63/284,858, filed on 12/01/2021. The present application and all claims are being examined with an effective filing date of December 1, 2021. 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 06/03/2024 and 12/02/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112(a)
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, 4, 6, 8, 10-11, 13, 16-17, 21-22, 24-25, 27-28, 30, 35, and 40-41 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.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow. Claim 1 has been broadly interpreted as encompassing a genus of non-naturally occurring OMNI-79 nuclease variants comprising an amino acid substitution at least one of positions I14, S1005, and E1050 relative to wild-type OMNI-79 SEQ ID NO: 1, while permitting an unknown number of additional amino acid substitutions, insertions, and/or deletions elsewhere in the sequence. This interpretation is consistent with the specification, which expressly contemplates OMNI-79 variants containing substitutions, insertions, or deletions, including mutations in addition to those specifically described herein. Thus, claim 1 does not require that the remaining amino acid sequence be identical, or even have any specified minimum degree of sequence identity, to SEQ ID NO: 1.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
In the instant case, the specification identifies wild-type OMNI-79 as SEQ ID NO: 1 and describes specific substitutions at positions I14, S1005, and E1050. For example, the specification identifies six substitutions at I14, twelve substitutions at S1005, and nine substitutions at E1050. However, the experimentally characterized variants are principally variants of SEQ ID NO: 1 containing only one or two amino acid substitutions. Table 4 identifies the tested single-substitution variants, and the disclosed variants include only I14L at position I14 and E1050K at position E1050, while a greater number of substitutions were tested at position S1005. Although the specification describes construction of a full-gene library containing combinatorial random mutations throughout the OMNI-79 open reading frame, the library contained an average of only 2.6 amino acid substitutions per open reading frame. The specification therefore does not provide representative species reflecting the substantially greater structural diversity encompassed by claim 1, nor does it identify structural characteristics that define which additional substitutions, insertions, and/or deletions throughout SEQ ID NO: 1 may be made while retaining an OMNI-79 nuclease within the claimed genus.
Thus, while the specification describes particular OMNI-79 variant species falling within the claimed genus, it does not sufficiently describe the structural features commonly possessed by members throughout the full scope of the genus or otherwise provide a representative number of species commensurate with the breadth of claim 1. Accordingly, one skilled in the art would not reasonably recognize that Applicant was in possession of the full scope of OMNI-79 nuclease variants encompassed by claim 1.
Claim 24 does not cure this deficiency. Claim 24 limits the OMNI-79 nuclease variant of claim 1 to variants having at least 80% sequence identity to wild-type OMNI-79 SEQ ID NO: 1. The specification similarly states that an OMNI-79 variant may have at least 80% sequence identity to SEQ ID NO: 1 and may contain one of the disclosed substitutions while the remaining sequence has at least 80% identity to SEQ ID NO: 1. However, a genus encompassing proteins having only 80% sequence identity to SEQ ID NO: 1 permits extensive sequence variation throughout the protein (~212 amino acids). The experimentally characterized variants do not reflect this degree of structural diversity but instead are substantially identical to wild-type OMNI-79 apart from a limited number of amino acid substitutions. The specification does not provide representative species spanning the claimed 80%-100% sequence-identity genus or identify structural characteristics sufficient to demonstrate possession of the members throughout that genus. Therefore, the limitation of claim 24 to at least 80% sequence identity does not remedy the written-description deficiency of the underlying genus.
Regarding claim 27 and claims dependent therefrom, claim 27 further requires that the claimed OMNI-79 nuclease variant, when complexed with a guide RNA molecule targeting a DNA target site, display increased on-target editing activity relative to a wild-type CRISPR system comprising wild-type OMNI-79 and the guide RNA molecule. The specification does not demonstrate possession of the full scope of this functionally defined genus. In particular, Applicant’s experimental results demonstrate that increased on-target editing activity is dependent upon the particular amino acid substitution employed. The specification reports that when the individual mutations of the V5570 and V5603 double-mutant variants were separately tested, only variants containing S1005R or S1005K showed higher editing activity relative to wild-type OMNI-79. Applicant subsequently tested ten additional substitutions at position S1005 and determined that positively charged amino acids R and K, as well as certain polar amino acids T, N, and Q, supported increased editing activity.
Thus, Applicant’s own experimental results demonstrate that merely possessing a (any) substitution at one of the positions encompassed by claim 1 does not establish the increased on-target editing activity required by claim 27. The specification does not provide representative species demonstrating the claimed increased activity across the structural breadth of the OMNI-79 variant genus, particularly considering the additional substitutions, insertions, and deletions encompassed by claim 1 and the sequence variation encompassed by claim 24. Nor does the specification establish a structure-function correlation sufficient to permit one skilled in the art to identify which members throughout the claimed structural genus would possess the required increased on-target editing activity.
Accordingly, the specification fails to reasonably convey to one skilled in the art that Applicant was in possession of the full scope of the functionally defined genus of CRISPR systems recited in claim 27. Claims 28, 30, 35, and 40-41 depend directly or indirectly upon and therefore encompass the insufficiently described genus and likewise fail to comply with the written description requirement.
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, 4, 6, 8, 10-11, 13, 16-17, 21-22, 24-25, 27-28, 30, 35, 40 and 41 are rejected under 35 U.S.C. 103 as being obvious over Izhar et al. (US20230122086A1, now US Patent No. 11946077B2, effectively filed on 06/04/2020, cited in PTO-892).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claims 1, 4, 6, 8, 10-11, 13, 16–17, 21–22, and 24, Izhar et al. teaches a non-naturally occurring “CRISPR nuclease having at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-8”, specifically an OMNI-79 CRISPR nuclease and provides the amino acid sequence of OMNI-79 as SEQ ID NO: 5 (Abstract, para 0010 and 0095). It is noted that SEQ ID NO: 5 of Izhar et al. is 100% identical to instant SEQ ID NO: 1 (see sequence alignment below). Izhar et al. further teaches that the characteristic targeted nuclease activity of OMNI-79 is imparted by the functions of its respective protein domains and identifies the OMNI-79 domains and their corresponding amino acid regions (para 0283-0292).As evidenced by Izhar et al., Domain A encompasses amino acids 1–40 and therefore encompasses residue I14, while Domain I encompasses amino acids 922–1062 and therefore encompasses residues S1005 and E1050. Izhar et al. further teaches that Domain A contains a nuclease active site that participates in DNA strand cleavage (para 0294) and Domain I is involved in providing PAM-site specificity to OMNI-79, including PAM-site interrogation and recognition, and further performs topoisomerase activity (para 0299). Izhar et al. also teaches utilizing amino acid sequences having similarity to an OMNI-79 domain in the design and manufacture of non-naturally occurring CRISPR nucleases so as to provide the advantageous features of the respective OMNI-79 domain activity (para 0301). Izhar et al. expressly contemplates substantial sequence variation within the OMNI-79 domains, including sequences having from 70% through 100% identity to an OMNI-79 domain (para 0302). Izhar et al. teaches “an amino acid sequence encoding any one of the domains of the OMNI-79 nuclease described herein in the peptide may comprise one or more amino acid substitutions relative to the original OMNI-79 domain sequence”. Izhar et al. further teaches that such amino acid substitutions may include conservative substitutions, semi-conservative substitutions, or substitution to another amino acid, and expressly recognizes that such substitutions may alter the activity relative to the original OMNI-79 domain function (para 0303).
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 arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Izhar et al. that individual amino acid residues within the OMNI-79 domains may be substituted, including by conservative, semi-conservative, or other amino acid substitutions, and that such substitutions may alter the activity of the corresponding OMNI-79 domain would have led a person of ordinary skill in the art to modify individual amino acid residues within the disclosed OMNI-79 domains, including residues I14 within Domain A and S1005 and E1050 within Domain I, to obtain OMNI-79 nuclease variants having altered domain activity. In particular, because Izhar et al. identifies Domain I as participating in PAM-site specificity, interrogation, and recognition, a person of ordinary skill in the art would have had reason to modify residues within this domain and evaluate the resulting variants for altered OMNI-79 nuclease properties. Likewise, because Izhar et al. identified Domain A as having a nuclease active site that participates in DNA strand cleavage, said practitioner would have been motivated to modify residues within this domain and evaluate the resulting variants for altered OMNI-79 nuclease properties. Selection of particular amino acid substitutions within the expressly identified functional domains and particular amino acid substitutions from the classes taught by Izhar et al. with the predictable result of producing non-naturally occurring OMNI-79 variants containing substitutions within the disclosed functional domains, would have been within the ordinary skill in the art.
Regarding claim 25, Izhar et al. teaches the nuclease described above comprising one or more nuclear localization sequences (para 0233).
Regarding claim 27, Izhar et al. teaches a CRISPR associated system comprising the CRISPR nuclease described above, and “one or more RNA molecules comprising a guide sequence portion linked to a direct repeat sequence, wherein the guide sequence is capable of hybridizing with a target sequence, or one or more nucleotide sequences encoding the one or more RNA molecules” (para 0011). Izhar et al. further teaches that the engineered nuclease “exhibits increased specificity to a target site compared to a SpCas9 nuclease when complexed with the one or more RNA molecules” (para 0165). Izhar et al. also teaches these nucleases having increased specificity and increased activity (para 0228-0229, and 0246), but does not expressly teach that the OMNI-79 variant displays increased on target activity relative to the corresponding wild-type OMNI-79 nuclease complexed with a guide RNA.
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 arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Izhar et al. that amino acid substitutions may be introduced into OMNI-79 functional domains to alter nuclease activity, together with its teaching that engineered CRISPR nucleases may exhibit increased activity and specificity, would have led a person of ordinary skill in the art to generate the OMNI-79 variants described above and evaluate their on-target editing activity relative to the wild-type OMNI-79 nuclease. Selection of variants exhibiting increased on-target editing activity would have been a predictable selection of variants having the desired enhanced nuclease activity from the variants expressly contemplated by Izhar et al.
Regarding claims 28, 30, 35, and 40-41, Izhar et al. teaches compositions comprising the CRISPR nucleases described above and methods for genome editing (para 0003, 0005-0006, and 0010). Specifically, Izhar et al. teaches a method of modifying a nucleotide sequence at a target site in the genome of a mammalian cell comprising introducing into the cell a composition comprising the engineered nuclease and DNA targeting RNA molecule described above. Izhar et al. also teaches that the cell may be a eukaryotic cell, and the eukaryotic cell may be a mammalian cell (para 0111-0113). Izhar et al. further expressly teaches modified cells obtained by the disclosed methods and a composition comprising the modified cells and a pharmaceutically acceptable carrier (para 0271-0272). Moreover, Izhar et al. teaches ex vivo gene-therapy applications in which cells are treated with nuclease systems such as CRISPR and subsequently reintroduced into a subject, and identifies suitable cells including peripheral blood mononuclear cells, hematopoietic stem cells (CD34+), and bone marrow-derived cells (para 0360-0363).
Allowable Subject Matter
Claim 9 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is condition for allowance.
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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