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 .
Please note: The examiner handling this application has changed. The new examiner on this case is Kailey Cash in AU1683. Any correspondence relating to the instant application should be directed to this examiner.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 7, 8, 11, 14, 17, 18, 27, 28, 33, 36, and 37) and the species of 5pyC, biotin-streptavidin, a chemical agent (specifically bisulfite), and deamination resistant dCTP analogs in the reply filed on 7/6/2026 and 7/16/2026 is acknowledged. Applicant acknowledges that they do not agree with the Examiner’s position but does not offer specific arguments regarding the lack of unity of invention. Therefore, this reply is being treated as “without traverse”.
Applicant’s amendment to the claims, submitted on 7/16/2026, incorporate limitations from non-elected claims 1 and 3 into the elected invention. The species requirement made in the Office Action dated 5/5/2026 and the elections of 5pyC and biotin-streptavidin are now relevant to claims 7 and 17. These claims will be examined insofar as they require the species of 5pyC within the oligonucleotide adapter and biotin-streptavidin as the specific binding pair.
The species election requirement as it pertains to the choice between unmodified dCTP analogs, non-deamination resistant dCTP analogs, and deamination-resistant dCTP analogs (species requirement made in Offfice Action of 5/5/2026, number 3c) is partially withdrawn to include unmodified dCTP analogs. Claims 14, 24, and 33 are being examined insofar as they require deamination-resistant dCTP analogs or unmodified dCTP analogs for polymerase being used at step (b). The election of a chemical agent to be used at step a) or c) (see claim 8), means that step b) is the only step which may allow for addition of a polymerase separate from the election made in claim 8.
Although amended, claim 40 is directed to a product as set forth in the restriction requirement dated 5/5/2026 and is withdrawn from consideration as being drawn to a non-elected invention.
Claims 1-3, 7-8, 11, 14, 17-18, 24, 27-28, 33, 36-37, and 40 are pending.
Claims 1-3, 11, 18, 28, and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
In the species election made in Applicant’s reply, species election 3 required the election of either an enzyme (glucosyltransferase, methyltransferase, polymerase, TET) or a chemical agent (claim 8). Applicant elected a chemical agent. Although claim 8 has subsequently been amended to recite “and, or a chemical agent”, this recitation now encompasses each of the elements in the alternative, any particular combination of the elements in the alternative, or all of the elements. Claims 11, 18, and 28, requiring an enzyme (glucosyltransferase, methyltransferase, polymerase, TET) or the combination of an enzyme and a chemical agent are withdrawn from further consideration as being drawn to non-elected species.
Claims 7-8, 14, 17, 24, 27, 33 and 36-37 are being examined on the merits.
The species being examined are:
1) the oligonucleotide adapter comprises 5pyC (relevant to claim 7, 17, 27);
2) a specific binding pair of streptavidin-biotin (relevant to claim 7, 17, 27);
3) a chemical agent (relevant to claim 7, 8); and
3b) bisulfite (relevant to claim 8).
4) unmodified dCTP analogs or deamination-resistant dCTP analogs (relevant to claim 14, 24, 33).
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (e.g., see pages 49-52). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities: the specification contains references to colors in the figures (pg 39, “red” and “blue”). The drawings are only provided in black and white. Therefore, please refrain from referencing particular features with colors to avoid any confusion.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pg 34, ln 15). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms “MiSeq” and “NextSeq” (pg 35, ln 20), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
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.
The examples above are not an exhaustive list of unmarked trade names or marks used in commerce throughout the specification. Please carefully read through and properly notate each instance.
Claim Objections
Claims 7, 8, 14, 17, 24, 27, and 33 are objected to because of the following informalities:
Claim 7 b)-e) and claim 27 ci) and civ) recite the term “a specific-binding pair complex” and also “specific binding pair complex. Use of a hyphen between “specific” and “binding” is different throughout the claim. Please choose a single way to write this claim term and keep it consistent throughout the claims.
Claim 7 c) reads “the oligonucleotide of step b)” and should read “the oligonucleotide adapter of step b)” to maintain consistent claim terminology.
Claim 7 c)-e) reads “containing specific binding member pair complex” and should read “containing the specific binding member pair complex” to make it clear that this is the same specific binding member pair complex as defined in step b) and maintain proper grammar.
Claims 8, 14, 24, and 33 contain the phrase “and, or”. This should be amended to read “and/or” to more clearly indicate that these are alternatives of each other.
Claim 17 c) and d) read “single stranded DNA” and should read “[[single stranded]]single-stranded DNA”.
Claim 17 d) reads “contacting the single stranded DNA of step d)” and should read “contacting the single stranded DNA of step [[d)]]c)”
Claim 24, lines 8-9, reads “copied by a polymerase with deamination-resistant dCTP analogs in a copy strand of the target DNA” and should read “copied by a polymerase with deamination-resistant dCTP analogs [[in]]to generate a copy strand of the target DNA”.
Claim 27 c) reads “performed any operable order” and should read “performed in any operable order”.
Claim 27 ci) and civ) reads “containing specific binding member pair complex” and should read “containing the specific binding member pair complex” to make it clear that this is the same specific binding member pair complex as defined in step b) and maintain proper grammar.
Claim 27 ciii) reads “a first library of constructs comprising a first set of barcode, for identifying 5mC and 5hmC present in said sequence” and should read “a first library of constructs comprising a first set of barcodes, for identifying 5mC and 5hmC present in said sequences”.
Claim 27 civ) reads "for identifying 5mC and 5hmC present in said sequence” and should read “for identifying 5hmC present in said sequences”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 7-8, 14, 17, 24, and 36-37 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 a method directed to the “assessment of the methylation state of a DNA molecule via enzymatic or a combination of chemical and enzymatic deamination of an immobilized target molecule” (emphasis added). The steps of claim 7 do not contain a step which explicitly involves a chemical deamination or an enzymatic deamination step, and certainly does not contain both. It is unclear how the cited purpose of the claim can be achieved given the lack of explicitly enzymatic or explicitly chemical and enzymatic steps. Relevant to this, claim 7 step e) involves contacting the single-stranded DNA with at least one deaminase. Is this generic to any agent for deamination or is it specifically reciting that an enzyme which deaminates is applied to the sample? For purposes of examination, the deaminase in step e) is being treated as a deaminating enzyme. Therefore, step 7 does not comprise any chemical deamination steps and cannot achieve a combination of chemical and enzymatic deamination. Clarification is required.
Claim 7 recites “the DNA” for the first time in line 4. This term is indefinite, given that 4 different claim terms that could be what is being referred to occur before this recitation. Is “the DNA” referring to “a DNA molecule” (line 1-2), “an immobilized target DNA molecule” (line 2-3), “a nucleic acid sample” (line 4), or “methylated DNA” (line 4)? For the purposes of examination, “the DNA” is being interpreted as all of the DNA in the nucleic acid sample (which comprises methylated DNA and possibly other types of DNA). However, further clarification is required to avoid confusion as to what DNA the steps of the method are being applied to. “[T]he DNA” or “said DNA” claim terms also appear in claims 8, 14, 27, 33, 36, and 37 and would need to be corrected if any amendments are made to clarify the term in claim 7.
Claims 8, 14, 36, and 37 depend from claim 7, inherit these deficiencies, and are rejected on the same basis. Claim 27 recites all the limitations of claim 7 and thus also inherits these deficiencies, as does claim 33 which depends from claim 27.
Claim 14 recites “wherein said DNA in step b) or c) is copied by a polymerase”. However, it is unclear in step b) whether said copying is performed before or after the conjugation of the oligonucleotide adapter to the DNA molecule. This makes it unclear whether or not the adapter would be copied as well. The lack of definition as to when this copying occurs in the context of step b) makes it unclear as to what type of DNA molecule would result from said copying and as such renders the scope of this claim indefinite.
Claim 17 is a method directed to the “assessment of the methylation state of a DNA molecule via enzymatic or a combination of chemical and enzymatic deamination of an immobilized target molecule” (emphasis added). The steps of claim 17 do not contain a step which explicitly involves a chemical deamination or an enzymatic deamination step, and certainly does not contain both. It is unclear how the cited purpose of the claim can be achieved given the lack of explicitly enzymatic or explicitly chemical and enzymatic steps. Relevant to this, claim 17 step d) involves contacting the single-stranded DNA with at least one deaminase. Is this generic to any agent for deamination or is it specifically reciting that an enzyme which deaminates is applied to the sample? Clarification is required.
Claim 17 recites “the DNA” for the first time in line 4. This term is indefinite, given that 4 different claim terms that could be what is being referred to occur before this recitation. Is “the DNA” referring to “a DNA molecule” (line 1-2), “a target DNA molecule in solution” (line 2-3), “a nucleic acid sample” (line 4), or “methylated DNA” (line 4)? For the purposes of examination, “the DNA” is being interpreted as all of the DNA in the nucleic acid sample (which comprises methylated DNA and additionally other types of DNA). However, further clarification is required to avoid confusion as to what DNA the steps of the method are being applied to. “[T]he DNA” claim term also appears in claim 24 and would need to be corrected if any amendments are made to clarify the term in claim 17.
Claim 17 recites the limitation "said duplex DNA" in step c). There is insufficient antecedent basis for this limitation in the claim. For the purposes of examination, said duplex DNA is being interpreted to mean “the DNA” as first recited in line 4 and which itself is being interpreted as all of the DNA in the nucleic acid sample (see above). Further clarification is required.
Claim 24 depends from claim 17, inherits these deficiencies, and is rejected on the same basis.
Claim 24 recites “wherein said DNA in step b) is copied by a polymerase”. However, it is unclear in step b) whether said copying is performed before or after the conjugation of the oligonucleotide adapter to the DNA molecule. This makes it unclear whether or not the adapter would be copied as well. The lack of definition as to when this copying occurs in the context of step b) makes it unclear as to what type of DNA molecule would result from said copying and as such renders the scope of this claim indefinite.
Claim 27 recites the limitation "the DNA sample" in step c). There is insufficient antecedent basis for this limitation in the claim. the only sample defined in claim 7 (which is incorporated into claim 27 in its entirety) is “a nucleic acid sample”. For the purposes of examination this is being treated as the same sample, however further clarification is required.
Claim 36 is directed to the method of claim 7, “wherein said DNA is obtained from tissue, tumor cell, blood…aspirate, swab, and nasal secretion” (emphasis added). It is unclear if this is really intended to be a combination of all sources of DNA (as in, samples are taken from every single source type and pooled together) or if this is an error. The specification provides these sample types in the alternative (pg 7) and there is not indication as to how this combination would be achieved or examples exhibiting combination of all sample types in the disclosure. Therefore, the scope of this claim is indefinite. For purposes of examination, the claim is being interpreted as “wherein said DNA is obtained from one of the following:”. In other words, the DNA is obtained from one type of sample for analysis. Further clarification is required.
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.
Claims 7, 8, 14, 17, 24, 27, 33, 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Schutsky (Schutsky et al., Nature Biotechnology 2018; cited on IDS of 7/6/2026) in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026), Ariazi (Ariazi et al., WO 2020/243609 A1; cited on IDS of 7/6/2026), and Zatopek (Zatopek et al., US 2020/0325533 A1).
Claim 7 and 17: Schutsky teaches a method termed ACE-seq for determining the methylation state of a DNA molecule via an enzymatic method. Schutsky teaches providing a nucleic acid sample comprising methylated DNA in which the DNA was sheared gDNA (claim 7 and 17, step a), denaturing the DNA (claim 7d, claim 17c), contacting the single-stranded DNA with A3A (reads on at least one deaminase; claim 7e, claim 17d), PCR amplifying the deaminase-treated DNA (library preparation, claim 7f, claim 17e), and performing sequencing on the PCR amplicons to generate methylation profiles for the target DNA molecules (claim 7g, claim 17f; Methods - Optimized ACE-seq protocol for whole-genome sequencing).
Schutsky teaches that the adapters are added post-deaminase treatment and does not teach that the oligonucleotide adapters comprise deaminase-resistant CTP analogs or a first member of a specific binding pair wherein the binding pair comprises streptavidin-biotin. Additionally, Schutsky does not teach contacting the oligonucleotide adapter to a solid support which comprises the second member of the specific binding pair (relevant to claim 7). However, appending adapters to DNA molecules pre-deamination treatment which contain deamination-resistant CTP analogs and a first member of a specific binding pair followed by contacting with a solid support is known in the art, as taught by Kennedy.
Kennedy teaches a method of determining methylation in which adapters are attached to the methylated DNA prior to deamination of said DNA (in this case, bisulfite treatment; Abstract, paragraph [00012, 00015, 000156-000157]). Kennedy teaches that the adapters are modified to protect against the action of deamination (such as 5mC in the case of bisulfite; paragraph [000157]). Kennedy teaches that the adapters comprise a capture moiety (reads on a first member of a specific binding pair; relevant to claim 7 and 17; paragraph [000156-000157]). Kennedy teaches that one such capture moiety is biotin, which “can be a member of a binding pair, such as biotin/streptavidin” and allows for “binding to streptavidin linked or linkable to a solid phase” (relevant to claim 7 and 17; paragraph [000156]). Kennedy teaches that binding between the specific binding pair also allows for binding to magnetically attractable particles (paragraph [000156]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Schutsky to append adaptors to the DNA before deamination, to include modified cytosine analogs that make said adaptors resistant to deamination, and to include a first member of a specific binding pair that allows for binding to a second member for immobilization or optional linkage to a magnetic particle. One would be motivated to include a specific binding pair member in the adapter given the assertion by Kennedy that this enables selective recovery of the labeled molecule from solution following amplification, allowing for parallel library generation (paragraph [000160]). One would be motivated to append adaptors to the DNA prior to deamination given the teaching by Ariazi that “combining dsDNA adaptor ligation before enzymatic conversion preserves fragment endpoint information while providing the highest possible library complexity for target enrichment…thereby providing greater sensitivity to detect rare events, such as methylated ctDNA” (paragraph [0114]). One would be motivated to incorporate modified cytosine residues in the adaptor to “protect against” the action of deamination, as taught by Kennedy (paragraph [000157]). One would have a reasonable expectation of success given that Schutsky, Kennedy, and Ariazi are performing methods which involve determination of DNA methylation through deamination of cytosines and subsequent sequencing.
Schutsky in view of Kennedy and Ariazi do not teach that the cytosine analog resistant to deamination included in the adaptor is 5pyC. However, 5pyC is a cytidine analog known to be resistant to bisulfite treatment and DNA deaminases, as taught by Zatopek.
Zatopek teaches that 5-propynylcytosine is resistant to deamination by DNA deaminases and bisulfite treatment (paragraph [0096]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Schutsky in view of Kennedy and Ariazi, to use 5pyC in the adapters as taught by Zatopek. One would be motivated to do so given the teaching Zatopek that this particular base analog is resistant to both DNA deaminases and bisulfite, which would be compatible with the methodology of Schutsky in view of Kennedy. One would have a reasonable expectation of success given that Zatopek teaches that this analog is compatible with any suitable sequencing method (paragraph [0096]).
Claim 8: Schutsky teaches treating the DNA with bisulfite prior to contacting the DNA with a deaminase (Supplementary Figure 11b, 5mC-ACE-Seq).
Claims 14, 24, and 33: Kennedy teaches that following linking of capture moiety to the nucleic acids, such as through an adaptor, the target nucleic acids serve as templates for amplification (paragraph [000156-000157]; claim 40). Kennedy does not explicitly teach that the dCTP analogs used as unmodified, however one of skill in the art would recognize, given Kennedy’s disclosure in Figure 4 that it is a “standard library amplification”, that the analogs used would be standard, or “unmodified”.
Claim 27: The teachings of Schutsky in view of Kennedy, Ariazi, and Zatopek as they pertain claim 7, which is incorporated in its entirety in claim 27, are detailed above. Relevant to claim 27, Kennedy teaches that the adapters that are joined to the DNA molecules comprise barcodes (paragraph [000178]) and that these barcodes can be unique (paragraph [000180]). As noted in the rejection of claim 8, Schutsky teaches treating the duplex DNA with bisulfite (which converts C to U and 5hmC to a CMS adduct; Schutsky, Supplementary Figure 11) and generating a library of constructs, which when modified by the methodology of Kennedy, would comprise a first set of barcodes. Schutsky also teaches treating the bisulfite converted library with A3A and generating a second library of constructs, which would constitute a second set of barcodes when modified by the teachings of Kennedy. Schutsky does not explicitly teach comparing the two sets of barcodes to distinguish between 5mC and 5hmC, but Schutsky does teach that merging base-resolution profiles from BS-seq and ACE-Seq allows for distinguishing between 5mC and 5hmC modifications (Discussion, paragraph 2).
Claim 36: Schutsky teaches obtaining the DNA from tissue (ACE-seq detects true-positive 5hmC bases).
Claim 37: Kennedy teaches that DNA is cfDNA which is of fetal origin (paragraphs [000169, 000171].
Claims 7, 14, 17, 24, 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Kohli (Kohli et al., US 2023/0183793 A1) in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026).
The applied reference has a common inventor and assignee 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.
Claim 7 and 17: Kohli teaches a method of determining the methylation state of a DNA containing CpG regions of interest (paragraph [0004]). Kohli teaches a method of providing a nucleic acid sample comprising methylated duplex DNA which is optionally sheared (claim 7 and 17, step a), conjugating oligonucleotide adaptors to said DNA, wherein the adapters comprise 5pyC (claim 7 and 17, step b), denaturing the duplex DNA (claim 7d, claim 17c), contacting the ssDNA with at least one deaminase (claim 7e, claim 17d), PCR amplifying the deaminase-treated DNA (claim 7f, claim 17e), and sequencing the amplicons to generate methylation profiles (claim 7g, claim 17f; paragraphs [0011, 0080-0084]).
Kohli does not teach that the adapters ligated to the duplex DNA comprise a first member of a specific binding pair wherein the binding pair comprises streptavidin-biotin. Kohli additionally does not teach contacting the oligonucleotide adapter to a solid support which comprises the second member of the specific binding pair (relevant to claim 7). However, appending adapters to DNA molecules pre-deamination treatment which contain a first member of a specific binding pair followed by contacting with a solid support is known in the art, as taught by Kennedy.
Kennedy teaches a method of determining methylation in which adapters are attached to the methylated DNA prior to deamination of said DNA (in this case, bisulfite treatment; Abstract, paragraph [00012, 00015, 000156-000157]). Kennedy teaches that the adapters are modified to protect against the action of deamination (such as 5mC in the case of bisulfite; paragraph [000157]). Kennedy teaches that the adapters comprise a capture moiety (reads on a first member of a specific binding pair; relevant to claim 7 and 17; paragraph [000156-000157]). Kennedy teaches that one such capture moiety is biotin, which “can be a member of a binding pair, such as biotin/streptavidin” and allows for “binding to streptavidin linked or linkable to a solid phase” (relevant to claim 7 and 17; paragraph [000156]). Kennedy teaches that binding between the specific binding pair also allows for binding to magnetically attractable particles (paragraph [000156]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kohli to append adaptors to the DNA before deamination which include a first member of a specific binding pair that allows for binding to a second member for immobilization or optional linkage to a magnetic particle. One would be motivated to include a specific binding pair member in the adapter given the assertion by Kennedy that this enables selective recovery of the labeled molecule from solution following amplification, allowing for parallel library generation (paragraph [000160]). One would have a reasonable expectation of success given that Kohli and Kennedy are performing methods which involve determination of DNA methylation through deamination of cytosines and subsequent sequencing.
Claims 14 and 24: Kohli teaches that the DNA in step b (following attachment of the adaptors) is contact with a polymerase and a deamination-resistant dCTP analog (5mdCTP; paragraph [0031] and Figure 17).
Claim 36: Kohli teaches that the sample is tissue (paragraph [0037]).
Claim 37: Kennedy teaches that DNA is cfDNA which is of fetal origin (paragraphs [000169, 000171].
Claims 8, 27, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kohli (Kohli et al., US 2023/0183793 A1) in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026) as applied to claims 7, 14, 17, 24, 36 and 37 above, and further in view of Schutsky (Schutsky et al., Nature Biotechnology 2018; cited on IDS of 7/6/2026).
The teachings of Kohli in view of Kennedy, as they apply to claims 7 and 17, are detailed above. Relevant to the instantly rejected claims, Kohli in view of Kennedy do not teach performing both bisulfite treatment and deaminase treatment on the same sample. Kohli teaches comparing the results of bisulfite sequencing to ACE-seq in an effort to distinguish between 5mC and 5hmC, but does not teach combination of the two (paragraph [0011]). However, performing both bisulfite treatment and deaminase treatment combined is known in the art, as taught by Schutsky.
Claim 8: Schutsky teaches treating the DNA with bisulfite prior to contacting the DNA with a deaminase (Supplementary Figure 11b, 5mC-ACE-Seq).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Kohli in view of Kennedy to contact the DNA with bisulfite before contacting the DNA with a deaminase. While Schutsky teaches that this carries over the “limitations of bisulfite”, one would be motivated to make this modification to the methodology to successfully differentiate between 5hmC and 5mC without having to perform two different adapter applications, reducing the number of steps of the protocol which is art recognized as a beneficial change. One would have a reasonable expectation of success given that the resistant adaptors employed by Kohli are resistant to both bisulfite treatment and deamination by A3A (paragraph [0148]).
Claim 27: The teachings of Kohli in view of Kennedy, as they pertain claim 7, which is incorporated in its entirety in claim 27, are detailed above. Relevant to claim 27, Kennedy teaches that the adapters that are joined to the DNA molecules comprise barcodes (paragraph [000178]) and that these barcodes can be unique (paragraph [000180]). As noted in the rejection of claim 8, Schutsky teaches treating the duplex DNA with bisulfite (which converts C to U and 5hmC to a CMS adduct; Schutsky, Supplementary Figure 11) and generating a library of constructs, which when modified by the methodology of Kennedy, would comprise a first set of barcodes. Schutsky also teaches treating the bisulfite converted library with A3A and generating a second library of constructs, which would constitute a second set of barcodes when modified by the teachings of Kennedy. Schutsky does not explicitly teach comparing the two sets of barcodes to distinguish between 5mC and 5hmC, but Schutsky does teach that merging base-resolution profiles from BS-seq and ACE-Seq allows for distinguishing between 5mC and 5hmC modifications (Discussion, paragraph 2).
Claim 33: Kohli teaches that the DNA in step b (following attachment of the adaptors) is contact with a polymerase and a deamination-resistant dCTP analog (5mdCTP; paragraph [0031] and Figure 17).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 7, 14, 17, 24, 36, and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7 and 10-13 of U.S. Patent No. US 12680128 B2 in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026) according to citations and rationales provided above.
Claims 8, 27, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7 and 10-13 of U.S. Patent No. US 12680128 B2 in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026), as applied to claims 7, 14, 17, 24, 36, and 37 above, and further in view of Schutsky (Schutsky et al., Nature Biotechnology 2018; cited on IDS of 7/6/2026) according to citations and rationales provided above.
Claims 7, 14, 17, 24, 36, and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-8, 13, and 14 of copending Application No. 19/741,388 in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Claims 8, 27, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5-8, 13, and 14 of copending Application No. 19/741,388 in view of Kennedy (Kennedy et al., WO 2018/119452 A2; cited on IDS of 7/6/2026), as applied to claims 7, 14, 17, 24, 36, and 37 above, and further in view of Schutsky (Schutsky et al., Nature Biotechnology 2018; cited on IDS of 7/6/2026) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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