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, 3, 6-7, 10, 13-15, 17, 19-20, 23-24, 27, 29-31, 34, and 37 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., a method of deaminating one or more unmethylated cytosine residues in a polynucleic acid molecule) and Genus A species: (single stranded DNA deaminase toxin A, or a functional fragment or derivative thereof, in the reply filed on 12/19/2025 is acknowledged.
Claims 3, 6, 19-20, 23-24, 27, 29-31, 34, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025.
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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/08/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claim 6 is objected to because of the following informalities:
Claims 6 recites “ contacted to the polynucleic acid” which should be “contacted with the polynucleic acid”.
Appropriate correction is required.
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.
Claims 7 and 17 are 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 of “at least 80%...to the amino acid sequence of SEQ ID NO: 2”. It is unclear whether the recited percentage refers to sequence identity, sequence similarity, or another metric. For examination purposes, the examiner is interpreting the claim as requiring at least 80% sequence identity to SEQ ID NO: 2.
Claim 17 recites in part, “comparing the sequence of the polynucleic acid with a reference polynucleic acid sequence obtained from a reference polynucleic acid that has not been contacted with the bacterial cytosine deaminase, and wherein the reference polynucleic acid is obtained from the same or similar biological sample as the polynucleic acid molecule contacted with the bacterial cytosine deaminase. The phrase “reference polynucleic acid sequence obtained from a reference polynucleic acid” is confusing and unclear as it recites obtaining a reference from a reference, thus rendering the claim indefinite.
Appropriate response and clarification for all of the above is requested.
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, 13-15, 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 a genus of polynucleic acid molecules with a genus of bacterial cytosine deaminases, wherein the genus of bacterial cytosine deaminases do not deaminate methylated cytosines. With respect to claim 7, as set forth in the specification, the term “about” is defined as encompassing variation of ±10%, such that the recited “about 80% identity” in claim 7 encompasses sequences having identity values significantly below 80% (i.e., 72%). The claim therefore encompasses a broad genus of SsdA fragments and variants defined predominantly by sequence identity and recited function. Accordingly, claim 7 has been broadly interpreted as encompassing a genus of methods comprising contacting a polynucleic acid molecule with a genus of bacterial cytosine deaminases, wherein the bacterial cytosine deaminase comprises a single-stranded DNA deaminase toxin A (SsdA), or a functional fragment or derivative of SsdA, comprising an amino acid sequence having at least 130 contiguous amino acids of SEQ ID NO: 2, or an amino acid sequence having at least 72% sequence identity to at least 130 contiguous amino acids of SEQ ID NO: 2, or an amino acid sequence having at least 72% sequence identity to SEQ ID NO: 2 in its entirety.
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 recitation of “a bacterial cytosine deaminase, wherein the bacterial cytosine deaminase does not deaminate methylated cytosines” in claim 1, defines the enzyme genus purely by functional capability rather than by specific structural features. However, the specification discloses only two specific enzymes set forth in SEQ ID NO: 1 and SEQ ID NO: 2, and does not identify structural characteristics common to bacterial cytosine deaminases that possess the claimed substrate selectivity, nor does it provide representative species across the breadth of bacterial cytosine deaminases encompassed by the claim. Accordingly, the instant disclosure does not reasonably convey possession of the full scope of the genus recited in claim 1.
With respect to claim 7, SEQ ID NO: 2 encodes an enzyme that is intended to have specific biological activity (i.e., catalyzes the deamination of unmethylated cytosine without deaminating methylated cytosines). As stated above, the specification discloses the specific sequence (SEQ ID NO:2), but fails to describe which regions are essential for catalytic function or how the structure-function relationship is maintained across sequences that share only 72% identity. Given that the primary amino acid sequence determines protein structure and function, the breadth of the claimed genus encompasses a wide range of possible structural variants throughout the molecule. The specification does not identify any essential or critical residues, nor does it describe which amino acid changes (substitutions, insertions, or deletions) can be made, and still result in a protein having the desired activity/function. As such, while the specification defines a single species falling within the genus, it fails to define any structural features commonly possessed by members of the genus that distinguish them from others.
The specification’s working Example 1 demonstrates the activity of one specific bacterial cytosine deaminase, namely DddA, using a purified active domain corresponding to a specific amino acid sequence (SEQ ID NO: 1) that catalyzes cytosine-to-uracil deamination in DNA, yields detectable C·G-to-T·A transitions upon sequencing, and exhibits reduced activity at methylated cytosines relative to unmethylated cytosines. There is no guidance that would allow a skilled artisan to predict which other sequences within the claimed scope would retain the required enzymatic function.
In the absence of such structural or functional characterization, one of ordinary skill in the art would not be able to visualize or recognize the identity of the members of the genus encompassed by at least 72% sequence identity of any 130 contiguous amino acids within SEQ ID NO: 2, or the broader genus of bacterial cytosine deaminases that do not deaminate methylated cytosines, without undue experimentation.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the full scope of the invention of claims 1, 7, 10, 13-15, and 17.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 7, and 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
In view of the 2019 PEG (“The 2019 Revised Patent Subject Matter Eligibility Guidance” (2019 PEG) found at https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf ), based upon an analysis with respect to the claims as a whole, claims 15 and 17 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
Claim 1 does not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more (these claims are interpreted in light of the most recent Guidelines (See “Subject Matter Eligibility” found at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility ; as well as Subject Matter Eligibility Examples: Life Sciences at https://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf )
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. In view of the Subject Matter Eligibility Test for Products and Processes and the Steps cited below (See flowchart at pages 10-11 at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf ), the claims are directed to a natural phenomenon as further detailed below.
In this case claim 1 recites or is directed to a process (Step 1) and recites the step of “contacting the polynucleic acid molecule with a bacterial cytosine deaminase, wherein the bacterial cytosine deaminase does not deaminate methylated cytosines in the polynucleic acid” which is directed to a judicial exception (in this case, a natural phenomenon)(Step 2A). As evidenced by Hitchcock et al., wild type bacterial cytosine deaminases, such as E. coli CodA, inherently possesses this substrate selectivity and perform cytosine to uracil deamination in vivo. wherein CodA efficiently deaminates cytosine, but does not accept and strongly discriminates against 5-methylcytosine as a substrate (Abstract). Claim 7 further limits the bacterial cytosine deaminase to a single stranded DNA deaminase toxin A or a function fragment or derivative thereof comprising SEQ ID NO: 2 or sequences having at least 80% identity thereto. SEQ ID NO: 2 corresponds to a naturally occurring cytosine deaminases from Pseudomonas syringaie. Claim 14 further recites “wherein deamination of the one or more cytosine residues in the polynucleic acid molecule results in a cytosine to uracil conversion. As discussed above, conversion of cytosine to uracil is the inherent biochemical results of cytosine deaminase activity and occurs in wild type E. coli CodA. Thus, the claims are directed to at least one exception (Step 2A: YES), which may be termed a natural phenomenon.
As to Prong 2 of Step 2A, the instant claims do not recite additional elements that integrate the judicial exception into a practical application. “Integration into a practical application’ requires an additional element(s) or combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception. Under the broadest reasonable interpretation, the term “contacting” encompasses the natural interaction that occurs within a bacterial cell between a wild type cytosine deaminase and the host genomic DNA. The claim does not require isolation of the enzyme, removal from its natural environment, or any specific non-natural manipulation. Therefore, the step of “contacting the polynucleic acid molecule with a bacterial cytosine deaminase” reads on the naturally occurring in vivo interaction between the enzyme and DNA and merely permits the enzyme to perform its inherent biochemical function.
Further, in view of Step 2B and the “No” pathway, the claims do not recite additional elements that amount to significantly more than the natural enzymatic activity itself. The method merely applies the naturally occurring property of the enzyme without imposing meaningful limitations beyond allowing the natural biochemical reaction to occur. Thus, the claims as a whole do not amount to significantly more than the exception.
Thus, it is asserted that the claims are directed to judicial exceptions without reciting more or additional elements that amount to significantly more than the judicial exception. Therefore, claims 1, 7, and 14 do not recite eligible subject matter under 35 U.S.C. 101 in view of the Subject Matter Eligibility Test for Products and Processes, and the claimed invention is directed to non-statutory subject matter.
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.
Claim 1, 7, 10, and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Carrell et al. (US 2011/0059446, cited in the IDS) and Hitchcock et al. (Discovery of a Bacterial 5‑Methylcytosine Deaminase, Biochemistry 2014, 53, 7426−7435, cited in PTO-892).
Carrell et al. teaches that the analysis of DNA methylation patterns in epigenetics has become an important tool in biomedical diagnostics, and that differential methylation of certain promoters has been correlated with various cancer types. Carrell et al. further teaches that the development of specific inhibitors of methyltransferases has become of great importance in the quest for novel antitumor agents. Specifically, “inhibition of methyltransferases has been shown to reactivate tumor-suppressor genes that were silenced by promoter hypermethylation”. Therefore, Carrell et al. teaches the need for analyzing DNA patterns. Carrell et al. discloses methods of selectively deaminating non-methylated cytosine to uracil, such as methods based on bisulfite treatment and hydrazine treatment (Specification para 0003 and 0007), in addition to other methods and reagent kits for determining methylation at cytosine (dC) residues in nucleic acids, such as DNA (Abstract). Specifically, Carrell et al. teaches a method for determining non-methylated cytosine residues in DNA, comprising: (a) providing a sample comprising a single-stranded DNA segment comprising at least one cytosine residue, (b) treating a fraction of the sample from step (a) with a first reagent that selectively reacts with non-methylated cytosine residues in said single-stranded DNA segment to obtain modified residues, and (c) detecting said modified residues (Specification, para 0019-0022). With respect to the reagent capable of selectively deaminating non-methylated cytosine in DNA, Carrell et al. teaches nucleophilic reagents, preferably reagents that comprise hydroxylamines and hydrazine species (para 0036). With respect to the DNA sample (single stranded DNA segment), Carrell et al. teaches it is preferably genomic DNA and that the sample “may be obtained by standard methods known in the art” (para 0027). It would have been obvious to a person of ordinary skill in the art to obtain such DNA by isolating it from cells using routine DNA extraction techniques, as “genomic DNA” must necessarily be isolated from cellular material prior to analysis. Carrell et al. does not expressly teach wherein the reagent is bacterial cytosine deaminase.
Hitchcock et al. teaches bacterial cytosine deaminases, including E. coli CodA, wherein CodA efficiently deaminates cytosine, but does not accept and strongly discriminates against 5-methylcytosine as a substrate (Abstract). It is well understood in the art, as also evidenced above by Carrell et al., that deamination of cytosine results in uracil as the reaction product (see also reaction diagram in Abstract section of Hitchcock et al.). Therefore, deamination of cytosine to uracil is inherent in the enzymatic activity of CodA disclosed by Hitchcock et al.
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 combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, Carrell et al. teaches the need for analyzing DNA methylation patterns as a tool in biomedical diagnostics and discloses the use of nucleophilic reagents capable of selectively reacting with non-methylated cytosine residues in DNA for methylation analysis. Combined with the teachings of Hitchcock et al., that the bacterial cytosine deaminase CodA inherently possess the ability to deaminate cytosine to uracil (claim 14) with strong discrimination against methylated cytosine, a person of ordinary skill in the art would be motivated to use CodA for selectively deaminating unmethylated cytosine residues in a DNA sample (claims 1 and 10), isolated using known methods in the art including extraction from a cell or plurality of cells (claim 13), for methylation analysis in epigenetics, as taught by Carrell et al., with a reasonable expectation of success. It would have been obvious to substitute Carrell’s chemical reagent with a known selective enzymatic reagent, capable of selectively deaminating unmethylated cytosine, including the CodA disclosed by Hitchcock et al. (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). Given that Hitchcock et al. demonstrates a successful method of selectively deaminating unmethylated cytosine using the bacterial cytosine deaminase CodA, said practitioner would have readily predicted that the combination of teachings would successfully result in a method for deaminating one or more unmethylated cytosine residues in a polynucleic acid molecule comprising contacting the polynucleic acid molecule with a bacterial cytosine deaminase, with a reasonable expectation of success. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 7 is included in this rejection because the claim recites that the bacterial cytosine deaminase is “single-stranded DNA deaminase toxin A (SsdA), or a functional fragment, or derivative thereof”, and further recites sequence identity limitations in alternative form. Because the sequence identity limitations are written in the alternative following “SsdA or a functional fragment or derivative of SsdA”, the claim does not clearly require that a derivative of SsdA satisfy the recited sequence identity limitations.
Claims 15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Carrell et al. and Hitchcock et al., as applied to claim 1 and 14 above, further in view of Schutsky et al. (APOBEC3A efficiently deaminates methylated, but not TET-oxidized, cytosine bases in DNA, Nucleic Acids Res. 2017 Jul 27;45(13):7655-7665, cited in the IDS).
The teachings of Carrell et al. and Hitchcock et al. as they apply to claims 1 and 14 have already been discussed above. Briefly, Carrell et al. discloses methods of selectively reacting with and deaminating non-methylated cytosine residues to uracil in a DNA sample using chemical reagents. Hitchcock et al. teaches the ability of bacterial cytosine deaminase, namely CodA from E. coli, to selectively deaminate nonmethylated cytosine, making its use in the method of Carrell et al. obvious. Carrell et al. also teaches detecting modified cytosine resides, after contacting the DNA sample with the chemical reagents, but neither Carrell nor Hitchcock expressly teach detecting the occurrence of deamination events by sequencing the treated sample and comparing it with an untreated similar sample.
Schutsky et al. teaches the use of a cytosine deaminase, APOBEC3A (A3A), to deaminate methylated cytosine to uracil in single stranded DNA, followed by amplification and sequencing of the treated DNA to detect cytosine deamination (C[Wingdings font/0xE0]U) events by sequencing, where the deamination product is read out as C:G [Wingdings font/0xE0]T:A transitions, compared to the starting (untreated) sequence. Specifically, Schutsky et al. teaches single stranded 636-mer DNA substrates were incubated with A3A, the reaction product was used as template for PCR amplification, amplification products were gel purified, clones, and transformed into cells, miniprepped and sequenced, wherein “deamination events were evidenced by C→T mutations, and local sequence context was recorded for each deamination event” (pg. 7657-7658, Materials and Methods). Specifically, Fig. 3 of Schutsky et al. sequences defined single-stranded DNA substrates following A3A treatment and quantifies C[Wingdings font/0xE0]T transitions. It would have been obvious to a person of ordinary skill in the art that the defined starting sequence of the substrate DNA, prior to A3A treatment, inherently serves as the reference polynucleic acid for comparison in order to determine the occurrence of deamination events.
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 combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Schutsky et al., which discloses a method of detecting deamination events, namely C[Wingdings font/0xE0]T transitions in a DNA sample, by sequencing said sample after cytosine deaminase (A3A) treatment, would have led said practitioner to incorporate the process of detecting deamination events taught by Schutsky et al., into the method of deaminating unmethylated cytosine in DNA, made obvious by Carrell et al. and Hitchcock et al. Said practitioner would have been motivated to modify Carrell and Hitchcock’s method because the detection method disclosed by Schutsky et al. is specific to detection of the deamination of cytosine residues in DNA. There is a reasonable expectation of success because Schutsky et al. demonstrates the successful sequencing and detection of C[Wingdings font/0xE0]T transitions in DNA treated with a cytosine deaminase. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652