DETAILED ACTION
Status of the Application
Claims 1-15 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claims 9-10, and amendments to the specification as submitted in a communication filed on 5/8/2026 is acknowledged.
Applicant elected without traverse Group 36, claims 9-11, drawn in part to a protein that comprises SEQ ID NO: 9, in a communication filed on 12/31/2025.
Claims 1-8, 12-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/31/2025.
Claims 9-11 are at issue and will be examined only to the extent they encompass the elected invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Specification
The objection to the disclosure due to the presence of an embedded hyperlink and/or other form of browser-executable code is hereby withdrawn by virtue of Applicant’s amendment.
The specification remains objected for not complying with sequence rules. While Figure 4 display nucleotide sequences, neither the drawings nor the Brief Description of the Drawings indicate the corresponding sequence identifiers. Applicant is required to insert the corresponding sequence identifiers in the Brief Description of the Drawings or amend the drawings to include the sequence identifiers in front of each sequence. See particularly 37 CFR 1.821(d). Appropriate correction is required.
Claim Objections
Claim 9 is objected to due to the recitation of “…endonuclease encoded by a nucleic acid molecule, wherein the nucleic acid molecule encodes the RNA-guided DNA nuclease, wherein the RNA…endonuclease comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9…endonuclease comprises one or more nuclear localization signals”. Since the claim is directed to a polypeptide, and the sequence recited is an amino acid sequence, to enhance clarity and simplify the language, the claim should be amended to recite “An RNA-guided DNA endonuclease that comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9, wherein the ….endonuclease comprises one or more nuclear localization signals”. Appropriate correction is required.
Claim Rejections – Improper Markush Grouping
Claims 10-11 were rejected on the basis that they contain an improper Markush grouping of alternatives. In view of Applicant’s amendment of claim 10, which is now directed to a composition comprising a protein, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 101
Claims 9-11 were rejected under 35 U.S.C. 101 because the claimed invention was directed to a product of nature without significantly more. In view of the amendment of claim 9, which now requires a protein that has one or more nuclear localization signals, and the fact that the naturally occurring protein of SEQ ID NO: 9 does not have a nuclear localization signal, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 9-11 were 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.
In view of Applicant’s amendment of claims 9-10, which no longer recite “preferably”, “more preferably”, and “most preferred”, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(d) or Fourth Paragraph (pre-AIA )
Claims 9-11 were rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
In view of the fact that claims 9-11 no longer depend from a claim directed to a nucleic acid molecule, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 9-11 remain 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.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant states that the written description rejection should be withdrawn in view of the claim amendments and the disclosure of the application as filed. Applicant states that amended claim 9 is focused on close variants of the disclosed BMC09 RNA-guided endonuclease and further requires an NLS. Applicant states that the specification discloses the protein of SEQ ID NO: 9 and describes that this protein is structurally distinct from known CRISPR-Cas systems. Applicant refers to Examples 5 as well as Figures 3 and 4 of the specification in support of the argument that the functionality of the protein of SEQ ID NO: 9 has been provided. Applicant states that the protein of SEQ ID NO: 9 is representative of the entire genus of variants required by the claims. Applicant states that the genus of proteins recited are closely related to the protein of SEQ ID NO: 9. Applicant states that while the calculation of 95% identity may theoretically permit a number of amino acid substitutions, this does not by itself establish lack of written description. Applicant states that the specification provides a representative sequence and identifying structural and functional features that define the claimed subject matter. Applicant states that the application further describes that the one or more NLSs may be located near or at the C- and/or N-terminus. Applicant states that claims 10-11 are supported because they depend from claim 9 and are limited to the proteins of claim 9.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the teachings of the specification and amendments made to claim 9 and agrees that the genus of proteins required are limited to those that are at least 95% sequence identical to the protein of SEQ ID NO: 9. The Examiner also agrees that the proteins now claimed require one or more NLSs. However, the examiner disagrees with Applicant’s contention that the entire genus of proteins required by the claims is adequately described.
With regard to the requirement of NLSs in the claimed variants, it is noted that the genus of NLSs required by the claims has not been found to lack adequate description. With regard to the argument that amended claim 9 is focused on close variants of the disclosed BMC09 RNA-guided endonuclease and further requires an NLS, it is reiterated herein that a polypeptide having at least 95% sequence identity with the polypeptide of SEQ ID NO: 9 allows for any combination of 64 amino acid modifications within SEQ ID NO: 9 (64 = 0.05x1274; SEQ ID NO: 9 has 1274 amino acids). Using the previously provided equation, the total number of variants of the polypeptide of SEQ ID NO: 9 that have at least 95% sequence identity to the polypeptide of SEQ ID NO: 9 that result solely from amino acid substitutions is 1274!x1964/(1274-64)!/64! or 5.87x10190 variants. While it is agreed that the specification has functionally characterized the protein of SEQ ID NO: 9, the specification fails to disclose which structural features can be modified in the polypeptide of SEQ ID NO: 9 and which ones have to be conserved for the variant to have the same function as that of the protein of SEQ ID NO: 9. No structure/function correlation has been provided so that one of skill in the art could determine a priori, from an essentially infinite number of variants, which structural variants of the polypeptide of SEQ ID NO: 9 having the required % sequence identity have endonuclease activity. While Applicant refers to Example 5 and Figures 3-4 as providing support to the entire genus of proteins required by the claims, it is noted that neither Example 5 nor Figures 3-4 provide those structural features that should be maintained and those that can be modified in the polypeptide of SEQ ID NO: 9 so that the resulting variant would display the same enzymatic activity as that of the polypeptide of SEQ ID NO: 9. Therefore, contrary to Applicant’s assertions, the claimed invention is not adequately described by the teachings of the specification and/or the prior art.
Claims 9-11 remain 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 the protein of SEQ ID NO: 9 and a composition comprising the protein of SEQ ID NO: 9, does not reasonably provide enablement for a protein which is a variant of the polypeptide of SEQ ID NO: 9, or a composition comprising said variant. 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/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant states that the enablement rejection should be withdrawn in view of the claim amendments and the disclosure of the application as filed. Applicant states that amended claim 9 encompasses close variants of the disclosed BMC09 RNA-guided endonuclease having an NLS. Applicant states that the specification enables the claimed subject matter because it discloses the protein of SEQ ID NO: 9 and provides working examples demonstrating the activity described above. Applicant states that the application also provides experimental procedures for evaluating DNA targeting and genome editing activity, citing Examples 4-5 and Figure 4. Applicant states that one of skill in the art with the disclosed BMC09 sequence and the experimental procedures described would be able to make and test the variants having the recited % sequence identity without undue experimentation. Applicant states that the added NLS feature does not create an enablement issue and refers to sections of the specification that refer to NLSs. Applicant states that claims 10-11 are enabled for the same reasons.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the teachings of the specification and amendments made to claim 9 and agrees that the scope of the claims is narrower. The Examiner also agrees that the proteins now claimed require one or more NLSs. However, the examiner disagrees with Applicant’s contention that the entire genus of proteins required by the claims is fully enabled by the teachings of the specification and/or the prior art.
The Examiner agrees with Applicant’s contention that the added NLS feature does not create an enablement. Instead, the issue in the instant case is that the enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements within the polypeptide of SEQ ID NO: 9 which are required and those which can be modified to obtain variants having RNA-guided DNA endonuclease activity as required by the claims.
With regard to the arguments that the specification enables the claimed subject matter because it discloses the protein of SEQ ID NO: 9, provides working examples demonstrating the recited activity, and provides experimental procedures for evaluating DNA targeting and genome editing activity, as shown in Examples 4-5 and Figure 4, while it is agreed that the specification discloses the activity of the protein of SEQ ID NO: 9 and provides an enzymatic assay, it is noted that the specification is silent with regard to the structural features in the polypeptide of SEQ ID NO: 9 that are essential for the desired enzymatic activity, such that one of skill in the art would know which amino acids should be conserved and which amino acids can be modified in the polypeptide of SEQ ID NO: 9 to obtain variants with the desired enzymatic activity. It is reiterated herein that total number of variants of the polypeptide of SEQ ID NO: 9 that have at least 95% sequence identity to the polypeptide of SEQ ID NO: 9 that result solely from amino acid substitutions is 1274!x1964/(1274-64)!/64! or 5.87x10190 variants. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find an RNA-guided DNA endonuclease. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and RNA-guided DNA endonuclease activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics. This is not deemed routine experimentation.
Guo et al. (PNAS 101(25):9205-9210, 2004) teach that the percentage of random single substitution mutations which inactivate a protein for the protein 3-methyladenine DNA glycosylase is 34% and that this number appears to be consistent with other studies in other proteins as well. Guo et al. further show in Table 1 that the percentage of active mutants for multiple mutants appears to be exponentially related to this by the simple formula (0.66)N x 100% where N is the number of mutations introduced. In the instant case, for a protein having 95% sequence identity to the protein of SEQ ID NO: 9, N is equivalent to 64 (64= 0.05x1274; SEQ ID NO: 9=1274 amino acids), and (0.66)64 X 100% or 2.82 x 10-10% of random mutants having 95% sequence identity to the polypeptide of SEQ ID NO: 9 would be active. In other words, the estimate of Guo et al. predicts that 1 in 3.54x1011 variants having 95% sequence identity to the polypeptide of SEQ ID NO: 9 would have activity (1/(0.66)N ). In view of this, one of skill in the art would expect that the vast majority of the species encompassed by the recited genus of proteins lack enzymatic activity. In the instant case, one of skill in the art would have to carry an immense amount of experimentation to find a single active mutant. Since there is an immense number of mutants that one of skill in the art would have to test to find one enzymatically active variant, one of skill in the art cannot possibly conclude that the amount of experimentation required with current techniques (i.e., high throughput mutagenesis and screening techniques) in the art is routine. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed. Such guidance has not been provided in the instant specification. Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the full scope of the claimed invention is enabled by the teachings of the specification and/or the prior art.
Conclusion
No claim is in condition for allowance.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a). A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
July 17, 2026
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