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 .
Amendments Received
Amendments to the claims were received and entered on 06/23/2026.
Status of Claims
Claim 15 has been cancelled.
Claims 1, 3, 6-7, 10, 13-14, 17, 19-20, 23-24, 27, 29-31, 34, and 37 are currently pending.
Claims 1, 7, 10, 13-14 and 17 are under consideration, as claims 3, 6, 19-20, 23-24, 27, 29-31, 34, and 37 are withdrawn.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2022/022655 filed on 03/30/2022. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 32/169,425, filed on 04/01/2021. The present application and all claims are being examined with an effective filing date of 04/01/2021. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Objections
In view of Applicant’s amendments, the objection to claim 6 is hereby withdrawn.
Withdrawn Rejections
In view of Applicant’s cancellation of claim 15, all rejections of claim 15 are now moot and are hereby withdrawn.
In view of Applicant’s amendments, the rejection of claim 17 under 35 USC § 112(b) is hereby withdrawn.
In view of Applicant’s amendments, rejections of claims 1, 7, and 14 under 35 USC § 101 are hereby withdrawn.
In view of Applicant’s amendments, rejections of claims 1, 7, 10, and 13-14 under 35 USC § 103 over Carrell et al. and Hitchcock et al. are hereby withdrawn.
In view of Applicant’s amendments, the rejection of claim 17 under 35 USC § 103 over Carrell et al. and Hitchcock et al., further in view of Schutsky et al. is hereby withdrawn.
Maintained/Modified Rejections
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.
Claim 7 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 7 is indefinite due to the recitation in limitation (ii) of “an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% to the amino acid sequence of SEQ ID NO: 2.” It is unclear what characteristic is represented by the recited percentages, e.g., whether the percentages refer to sequence identity, sequence similarity, or another metric. Although claim 7 has been amended to remove the term “about,” the amendment does not clarify what characteristic is represented by the recited percentages in limitation (ii). For examination purposes, the Examiner is interpreting the recited percentages as referring to sequence identity to SEQ ID NO: 2.
Response to Arguments for Rejections under 35 USC § 112(b)
Regarding the rejection of claim 7 under 35 U.S.C. 112(b), Applicant’s amendment removing the term “about” has been considered. However, the amendment does not appear to address the previously noted indefiniteness. Specifically, limitation (ii) of claim 7 recites “at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% to the amino acid sequence of SEQ ID NO: 2,” without specifying whether the recited percentages refer to sequence identity, sequence similarity, or another metric. Accordingly, the rejection of claim 7 under 35 U.S.C. 112(b) is maintained.
The amendment to claim 17 resolves the previously noted indefiniteness. Accordingly, the rejection of claim 17 under 35 U.S.C. 112(b) is withdrawn.
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, 7, 10, 13-14, and 17 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 methods comprising contacting an isolated polynucleic acid molecule with a genus of SsdA functional fragments or derivatives having sequence-independent deamination activity, wherein the bacterial cytosine deaminase does not deaminate methylated cytosines in the isolated polynucleic acid. In particular, the recitation of “a functional fragment or derivative thereof having a sequence-independent deamination activity” is not limited to the specifically disclosed SsdA of SEQ ID NO: 2 or the specifically disclosed SsdA toxin-domain fragment, but encompasses SsdA-derived fragments and derivatives possessing the recited functional activity. Claim 7 has been broadly interpreted as further encompassing a genus of methods wherein the SsdA functional fragment or derivative comprises an amino acid sequence having at least 130 contiguous amino acids of SEQ ID NO: 2, an amino acid sequence having at least 80% sequence identity to 130 contiguous amino acids of SEQ ID NO: 2, or an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 2 in its entirety. Because claim 7 depends from claim 1, the SsdA functional fragments and derivatives encompassed by these structural alternatives must also possess the sequence-independent deamination activity recited in claim 1.
MPEP 2163 states that, to satisfy the written description requirement, the 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. For a genus defined in whole or in part by functional characteristics, possession may be demonstrated by disclosure of a representative number of species or by identifying characteristics, including structural features coupled with a known or disclosed correlation between structure and function.
Regarding claim 1, the claim recites that the bacterial cytosine deaminase is “SsdA, a functional fragment or derivative thereof having a sequence-independent deamination activity.” The specification discloses SsdA and expressly describes SsdA functional homologs, fragments, and derivatives. Specifically, paragraph [0037] describes SsdA from Pseudomonas species, including Pseudomonas syringae, and defines a functional homolog as an SsdA from another bacterial species having a common evolutionary origin that retains the core functional characteristic of selectively deaminating unmethylated cytosine residues. Paragraph [0038] further states that full-length SsdA is not required for functionality and describes a particular SsdA toxin-domain fragment as possessing selective deaminase functionality, with SEQ ID NO: 2 provided as a representative SsdA or functional fragment.
Thus, the issue is not whether the specification reasonably conveys possession of SsdA itself or the specifically disclosed functional toxin-domain fragment. Rather, claim 1 encompasses a broader genus of SsdA functional fragments and derivatives possessing the recited sequence-independent deamination activity. Although the specification states that an SsdA toxin-domain fragment possesses selective deaminase functionality, the specification does not identify the amino-acid boundaries or sequence of the demonstrated toxin-domain fragment or otherwise identify structural characteristics of that fragment that are sufficiently correlated with sequence-independent deamination activity to define the members of the broader claimed functional genus. Further, the specification does not disclose a representative number of SsdA functional fragments or derivatives reflecting the structural diversity encompassed by claim 1 and possessing the recited sequence-independent deamination activity.
Regarding claim 7, paragraph [0038] expressly describes SsdA functional fragments and derivatives according to these fragment-length and sequence-identity parameters. Thus, the issue is not whether the specification provides literal support for the recited sequence parameters. Rather, the specification does not identify which 130-amino-acid region corresponds to the demonstrated functional toxin domain, disclose representative functional variants spanning the structural diversity encompassed by the 80%-identity limitations, or establish which structural characteristics within these sequence ranges correlate with the sequence-independent deamination activity required through dependence from claim 1.
Moreover, while paragraph [0037] describes SsdA functional homologs as retaining the ability to selectively deaminate unmethylated cytosine residues and paragraph [0038] describes the SsdA toxin-domain fragment as possessing selective deaminase functionality, the specification defines selective deamination in terms of favoring unmethylated cytosine residues over methylated cytosine residues. These disclosures do not establish that the broadly described SsdA fragments and derivatives possess the sequence-independent deamination activity required by amended claim 1 or provide a sufficiently predictive structural correlation by which one of ordinary skill in the art would recognize the functional members possessing that activity throughout the claimed genus.
Although the specification further provides general guidance regarding conservative amino-acid substitutions, including groups of chemically similar amino acids, it does not identify which substitutions or sequence variations within SsdA are tolerated while retaining the claimed sequence-independent deamination activity. Accordingly, the disclosure does not provide a representative number of functional SsdA fragments and derivatives reflecting the structural diversity encompassed by claims 1 and 7 or a sufficiently predictive structure-function correlation to reasonably convey possession of the full scope of the claimed functional genus.
Claims 10, 13-14, and 17 depend directly or indirectly from claims 1 and/or 7 and are rejected for the same reasons.
Response to Arguments for Rejections under 35 USC § 112(a)
Applicant’s arguments regarding the rejection under 35 U.S.C. 112(a) have been fully considered but are not persuasive to overcome the rejection.
Regarding claim 1, Applicant argues that the claim is directed to a method rather than a composition claim encompassing an entire genus of bacterial cytosine deaminases and that the specification demonstrates possession through disclosure of SsdA (SEQ ID NO: 2), its biochemical activity, and a functional toxin-domain fragment. Applicant’s arguments regarding the previously claimed broader genus of bacterial cytosine deaminases are acknowledged. However, amended claim 1 now recites SsdA, or a functional fragment or derivative thereof having sequence-independent deamination activity. Thus, the issue is not whether the specification adequately describes SsdA itself or the specifically disclosed toxin-domain fragment, but whether the disclosure reasonably conveys possession of the full scope of functional SsdA fragments and derivatives encompassed by the amended claim. Recitation of the enzyme as an element of a method does not remove the requirement that the specification provide adequate written description of the full scope of that claimed element.
Applicant further relies on paragraphs [0037]-[0038] as support for SsdA functional homologs, fragments, and derivatives. Paragraph [0037] describes functional SsdA homologs as retaining the core functional characteristic of selectively deaminating unmethylated cytosine residues, while paragraph [0038] describes a particular SsdA toxin-domain fragment having selective deaminase functionality and expressly describes functional fragments and derivatives according to fragment-length and sequence-identity parameters. However, the specification does not identify the amino-acid boundaries of the demonstrated SsdA toxin-domain fragment, provide representative SsdA fragments or derivatives across the disclosed structural breadth that possess sequence-independent deamination activity, or establish a sufficiently predictive correlation between the disclosed structural characteristics and that particular activity throughout the claimed genus. Accordingly, the express description of SsdA functional fragments and derivatives in paragraphs [0037]-[0038] does not, by itself, reasonably convey possession of the full functional genus encompassed by amended claims 1 and 7.
Applicant’s reliance on de Moraes et al. has also been considered. Applicant relies on de Moraes et al. as evidence that SsdA is a member of the BaDTF2 family and that SsdA and related bacterial deaminases possess recognized structural and functional characteristics. While de Moraes et al. provides relevant information regarding SsdA and related bacterial deaminases, it does not disclose representative SsdA functional fragments or derivatives spanning the breadth encompassed by claims 1 and 7, including functional variants across the recited 80%-identity limitations. Nor does the reference establish that the identified family characteristics, conserved residues, or structural features provide a sufficiently predictive correlation with sequence-independent deamination activity throughout the breadth of the claimed functional genus.
Applicant further argues that one of ordinary skill in the art could determine the genus based upon sequence homology to SEQ ID NO: 2, ssDNA targeting, sequence-independent deamination, and retained cytosine-deaminase activity. However, the ability to identify candidate sequences and determine whether they possess the required function does not, by itself, establish that the original disclosure reasonably conveys possession of the claimed functional genus. Rather, the disclosure must provide sufficient representative species or identifying structural characteristics correlated with the required function such that one of ordinary skill in the art would recognize that Applicant possessed the claimed genus at the time of filing.
Regarding claim 7, Applicant’s amendment removing “about” from the sequence-identity limitation has been considered, and the previous interpretation encompassing sequences having as little as 72% identity is no longer applicable. Applicant’s reliance on the express disclosure of the fragment-length and sequence-identity ranges in paragraph [0038] has likewise been considered. The specification expressly provides these structural ranges. Nevertheless, because claim 7 depends from claim 1, the fragments and derivatives encompassed by these structural alternatives must also possess the sequence-independent deamination activity required by claim 1. Neither the specification nor de Moraes et al. provides representative functional variants reflecting the structural diversity encompassed by these alternatives or establishes a sufficiently predictive structure-function correlation by which one of ordinary skill in the art would recognize the functional members possessing sequence-independent deamination activity throughout the claimed sequence-defined genus.
Accordingly, Applicant’s arguments do not overcome the rejection of claims 1, 7, 10, 13-14, and 17 under 35 U.S.C. 112(a).
Relevant Art
Vaisvila et al. (EM-seq: Detection of DNA Methylation at Single Base Resolution from Picograms of DNA, bioRxiv 2019.12.20.884692, cited in PTO-892) teaches an in-vitro method of determining cytosine-methylation status in an isolated DNA molecule, including enzymatically deaminating unmodified cytosine residues to uracil with APOBEC3A and sequencing the treated DNA to detect resulting C-to-T transitions relative to the original sequence. Vaisvila further teaches that methylated and hydroxymethylated cytosines are protected from the APOBEC3A deamination step, such that their methylation status can be determined from whether a cytosine is converted or remains unconverted upon sequencing. However, Vaisvila et al. does not teach contacting the isolated polynucleic acid molecule with SsdA, a functional fragment thereof, or a derivative thereof having sequence-independent deamination activity; does not teach a bacterial cytosine deaminase that intrinsically does not deaminate methylated cytosines; and does not teach the claimed single-step method because Vaisvila et al. uses sequential TET2 oxidation and T4-βGT glucosylation to protect modified cytosines before APOBEC3A deamination.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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