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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/22/2024 and 02/10/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to an amendment filed on February 10, 2026.
Claims 1, 5, 7-9, 16, 21, 24, 30-33, 37, 43, 50, 62, 89-90, 94-95 were previously pending.
Applicant amended claim 95; cancelled claim 62.
Claims 1, 5, 7-9, 16, 21, 30-33, 37, 43, 50, 89-90 and 94-95 are currently pending, with claims 7, 30-32 and 89-90 withdrawn.
Claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 are under examination. This is the first action on the merits.
Election/Restrictions
The requirement for restriction between group I (claims 1, 5, 7-9, 16, 21, 24, 30-33, 37, 43,50, 89-90 and 94-95) and group II (claim 62) , set forth in the office action mailed on November 10, 2025 has been withdrawn in view Applicant's claim amendment filed on February 10, 2026, which cancelled all claims in Group II.
Applicant’s election without traverse of the following species in the reply filed on February 10, 2026 is acknowledged:
Species of Capturing targets: A) capturing at least an epigenetic target region set of DNA (claim 5) 1;
Species of epigenetic target region set: C) the epigenetic target region set comprises a hypermethylation variable target region set (claim 8);
Species of hypermethylation variable target region set: G) the hypermethylation variable target region set comprises regions having a higher degree of methylation in at least one type of tissue than the degree of methylation in cell-free DNA from a healthy subject (claim 9);
Species of DNA: I) the DNA is obtained from a test subject (claim 16);
Species of partitioning : Q) wherein partitioning the sample into a plurality of subsamples comprises partitioning on the basis of methylation level (claim 24) 2;
Species of nucleobases: S) the first nucleobase is a modified or unmodified cytosine and the second nucleobase is a modified or unmodified cytosine (claim 37);
Species of procedure : Z) the procedure to which the sample is subjected comprises protection of 5hmC (claim 43).
Applicant's election with traverse of the following species in the reply filed February 10, 2026 is acknowledged:
Species of processing DNA molecules: N) the DNA is amplified before sequencing, or wherein the method comprises a capture step and the DNA is amplified before the capture step (claim 21) 3.
Applicant's traversal is on the following ground:
"Applicant respectfully traverses this species election requirement to the extent that claims 32 and 89 are compatible with the elected species of claim 21. Whether the DNA is amplified before sequencing or the method comprises a capture step and the DNA is amplified before the capture step, as in the elected species of claim 21, is independent of whether the method comprises differentially tagging and pooling DNA in the first subsample and second subsample as in claim 32 and whether the DNA of the first subsample and the DNA of the second subsample are differentially tagged; after differential tagging, a portion of DNA from the second subsample is added to the first subsample or at least a portion thereof, thereby forming a pool; and sequence variable target regions and epigenetic target regions are captured from the pool as in claim 89." (Remarks, page 15).
This is not found persuasive because MPEP §818.01 states a traverse must include a written statement of the reasons for traverse, distinctly and specifically pointing out the supposed errors upon which the applicant relies for concluding that the requirement is in error.
MPEP§ 803 sets forth two criteria for a proper requirement for restriction between patentably distinct inventions:
• (A) The inventions must be independent (see MPEP § 802.01, § 806.06, § 808.01) or distinct as claimed (see MPEP § 806.05 - § 806.05(j)); and
• (B) There would be a serious search and/or examination burden on the examiner if restriction is not required (see MPEP § 803.02, § 808, and § 808.02).
MPEP§ 803 further states: "An election of species requirement is a type of restriction requirement."
Here, Applicant argues that the species are "compatible" and independent from each other; however, this argument is unpersuasive. Applicant does not dispute that the species within the species group are independent; instead, Applicant asserts this point. And as noted in the above cited MPEP guidance, compatibility is not one of the two criteria for a proper restriction.
Thus, the traversal by the applicant lacks argument that distinctly and specifically point out the reasons why this requirement for species election is improper. Therefore, the species election requirement for the Species of processing DNA molecules as initially imposed is properly maintained.
In this instant case, the requirement for species election is properly made.
As stated in the restriction requirement (mail date 11/10/2025), and reiterated here:
The species are independent or distinct because the different species recite separate characteristics of such species, and there is no disclosure of relationship between species (see MPEP § 806.04(b)). In addition, these species are not obvious variants of each other based on the current record. The species necessitate separate searches, leading to serious search and/or examination burden (see MPEP § 808.01(a)) because the Species of processing DNA molecules result in search requirements for different combination and order of steps and technical requirements, each require separate search.
Additionally, there is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: The species require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search queries); and/or the prior art applicable to one species would not likely be applicable to another species; and/or the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
To further clarify, the species in claims 21, 32 and 89 are presented as alternatives that do not depend from each other. According to the claims, each method species is intended to be performed independently rather than together. Each species requires a separate search. For example, a search for the method of species N (the DNA is amplified before sequencing, or wherein the method comprises a capture step and the DNA is amplified before the capture step) would not adequately cover the method of species O (differentially tagging and pooling DNA in the first subsample and second subsample).
Therefore, these species are directed to independent and patentably distinct inventions, and there would be a serious search and/or examination burden if species election is not required. The requirement is still deemed proper and is therefore made FINAL.
Claims 7, 30-32 and 89-90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 .
Priority
The priority date of the instant claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 is 11/30/2020, filling date of the US provisional application NO. 63/119,520.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, part b), line 2, "the plurality" should read "the plurality of subsamples."
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claims 1 and 5 both recite a method of analyzing DNA in a sample, comprising the steps of: "a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample" and "b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA."
Under BRI, the claims are construed to encompass any order of these steps, as they do not explicitly require one to be performed before or after the other 4.
Claims 1 and 5 both recite "b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA."
The specification defines the term “partitioning” as follows:
"As used herein, “partitioning” of nucleic acids, such as DNA molecules, means separating, fractionating, sorting, or enriching a sample or population of nucleic acids into a plurality of subsamples or subpopulations of nucleic acids based on one or more modifications or features that is in different proportions in each of the plurality of subsamples or subpopulations. Partitioning may include physically partitioning nucleic acid molecules based on the presence or absence of one or more methylated nucleobases. A sample or population may be partitioned into one or more partitioned subsamples or subpopulations based on a characteristic that is indicative of a genetic or epigenetic change or a disease state." ([000139])
Claim 5 recites "c) capturing at least an epigenetic target region set of DNA or a plurality of sets of target regions of DNA from the first and second subsamples."
The specification defines the term “capturing” as follows:
" “Capturing” one or more target nucleic acids refers to preferentially isolating or separating the one or more target nucleic acids from non-target nucleic acids." ([00146])
Claims 1 and 5 both recite "the first nucleobase and the second nucleobase have the same base pairing specificity."
The specification defines the term “base pairing specificity” as follows:
"As used herein, “base pairing specificity” refers to the standard DNA base (A, C, G, or T) for which a given base most preferentially pairs. For example, unmodified cytosine and 5-methylcytosine have the same base pairing specificity (i.e., specificity for G) whereas uracil and cytosine have different base pairing specificity because uracil has base pairing specificity for A while cytosine has base pairing specificity for G. The ability of uracil to form a wobble pair with G is irrelevant because uracil nonetheless most preferentially pairs with A among the four standard DNA bases." ([000143])
For the purpose of applying prior art, claim 5 recites "epigenetic target region set," which is defined in the specification as follows:
"“Epigenetic target region set” refers to a set of target regions that may show sequence-independent changes in neoplastic cells (e.g., tumor cells and cancer cells) relative to normal cells or that may show sequence-independent changes in cfDNA from subjects having cancer relative to cfDNA from healthy subjects. Examples of sequence-independent changes include, but are not limited to, changes in methylation (increases or decreases), nucleosome distribution, cfDNA fragmentation patterns, CCCTC-binding factor (“CTCF”) binding, transcription start sites, and regulatory protein binding regions. Epigenetic target region sets thus include, but are not limited to, hypermethylation variable target region sets, hypomethylation variable target region sets, and fragmentation variable target region sets, such as CTCF binding sites and transcription start sites. For present purposes, loci susceptible to neoplasia-, tumor-, or cancer-associated focal amplifications and/or gene fusions may also be included in an epigenetic target region set because detection of a change in copy number by sequencing or a fused sequence that maps to more than one locus in a reference genome tends to be more similar to detection of exemplary epigenetic changes discussed above than detection of nucleotide substitutions, insertions, or deletions, e.g., in that the focal amplifications and/or gene fusions can be detected at a relatively shallow depth of sequencing because their detection does not depend on the accuracy of base calls at one or a few individual positions. " ([000152])
Thus, because the term “epigenetic target region set” is defined as a set of target regions that "may show" sequence-independent changes in neoplastic cells (e.g., tumor cells and cancer cells) relative to normal cells or that "may show" sequence-independent changes in cfDNA from subjects having cancer relative to cfDNA from healthy subjects, it is understood that the scope of this term does not require these sequence-independent changes.
Under BRI, “epigenetic target region set” is interpreted to encompass any set of target regions within a genome or target DNA, such as methylated CpG islands.
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.
Claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 are rejected under 35 U.S.C. 112(b), 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.
Regarding claims 1 and 5, they both recite in part b): "contacting the DNA with an agent that recognizes a modified nucleobase in the DNA" and "the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample."
This claim language is indefinite because it is unclear what is encompassed by "a product of the procedure," and what are the required structural and compositional features.
The claims recite in part a):
"subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample,
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase."
However, the claims do not require that the procedure modifies an unmodified nucleobase or further modifies a modified nucleobase. They merely state that the procedure "affects" the nucleobases differently. Accordingly, in part a) both nucleobase can be unmodified, and can remain unmodified after the procedure. The claims do not define any structural change of compositional distinction for the product of the procedure.
The claims further recite that an agent recognizes a modified nucleobase. However, in the scenario that the "product of the procedure" does not comprise any modified nucleobase, it is unclear how the partitioning step employing this agent can be carried out.
Because the claims 1 and 5 do not clearly define any feature for "product of the procedure" that directly relates to the recited partitioning step using an agent that recognizes a modified nucleobase, the scopes of the claims are indefinite.
Claims 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 are rejected for depending from claims 1 and 5 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is 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.
Claim 37 recites: "the first nucleobase is a modified or unmodified cytosine and the second nucleobase is a modified or unmodified cytosine."
Therefore, as written in this claim, both the first and second nucleobase can be the same modified or unmodified cytosine. This dependent claim is improper because it fails to include all the limitations of the base claim 1, which explicitly requires the two nucleobases to be different from each other in the recitation: "wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase."
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Arensdorf (Arensdorf et al., US20200024643A1 - Methods for the epigenetic analysis of dna, particularly cell-free dna; Published 2020-01-23); as evidenced by
Kennedy (Kennedy et al., WO2018119452A2 - Methods and systems for analyzing nucleic acid molecules; 2018-06-28; cited as Foreign patent document #2 in IDS filed on 01/22/2024).
Regarding claims 1 and 5, while they are separate independent method claims, they will be addressed together below as the claims' scopes largely overlap. Claim 5 is narrower in scope than claim 1 and further comprises a capturing step.
Arensdorf teaches methods for epigenetic analysis of cell-free DNA, by partitioning nucleic acids into subsets based on incorporation of epigenetic bases such as 5hmC or 5mC, followed by sequencing (e.g., [0148]-[0149]; claim 45; Fig. 11).
Regarding claims 1 and 5, Arensdorf teaches a method comprising:
subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (Fig. 11, 17-18; [0128] βGT-catalyzed uridine diphosphoglucose 6-azide as described previously, followed by biotinylation of 5hmC),
wherein the first nucleobase is a modified nucleobase (Fig. 11, 17-18, 5hmC), the second nucleobase is a unmodified nucleobase (Fig. 11, unmodified C) different from the first nucleobase, and the first nucleobase and the second nucleobase have the same base pairing specificity; and
partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (Fig. 11; [0128] biotinylated strands and strands containing unmodified (native) 5mC are pulled down simultaneously for further processing), the plurality comprising a first subsample (Fig. 11; [0128] subsample comprising 5mC and biotinylated 5hmC after pull down) and a second subsample (Fig. 11; [0128] pull down supernatant depleted of 5mC and biotinylated 5hmC) , wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and the modified nucleobase recognized by the agent is a modified cytosine (Fig. 11);
capturing at least an epigenetic target region set (Fig. 11; [0128] capture CpG sites in native 5mC-containing strands using methyl-CpG-binding domain (MBD) protein; [0148]; [0150] immunoprecipitation of nucleic acids associate with specific histones or nucleic acid cross-linking (e.g., CTCF) or binding proteins (such as transcription factors ) of DNA,
sequencing the captured DNA in a manner that distinguishes the first nucleobase from the second nucleobase (Fig. 11, 17-18; [0128] lines 24-28 ).
Regarding claim 8, Arensdorf teaches the epigenetic target region set comprises a hypermethylation variable target region set by teaching CpG sites (Fig. 11; [0128] capture CpG sites in native 5mC-containing strands using methyl-CpG-binding domain (MBD) protein).
As evidenced by Kennedy, CpG sites captured by methyl-binding domain (MBD) protein comprises hypermethylation variable target region ([000211] “Identifying DNA molecules that are relatively "hypermethylated" in a DNA sample can be achieved by capturing molecules that bind to a methyl-binding domain (MBD) protein, or a fragment or variant thereof.”).
Regarding claim 9, Arensdorf teaches hypermethylation variable target region set comprises regions having a higher degree of methylation in at least one type of tissue than the degree of methylation in cell-free DNA from a healthy subject, by teaching CpG sites (Fig. 11; [0128] capture CpG sites using methyl-CpG-binding domain (MBD) protein).
As evidenced by Kennedy, capturing CpG sites using methyl-CpG-binding domain (MBD) protein captures regions having a higher degree of methylation in at least one type of tissue than the degree of methylation in cell-free DNA from a healthy subject ([000316]; [000317]-[00319]; see also [000237] “hypermethylation of a normally hypomethylated region, such as transcription start site (TSS) of genes involved in normal growth, DNA repair, cell cycle regulation and cell differentiation, may be indicative of cancer. ”; [00218])
For example, in para. [000316], Kennedy describes using methyl-CpG-binding domain (MBD) protein to capture and analyze regions of hypermethylation with higher methylation enrichment in lung cancer samples compared to healthy samples:
"[000316] MBD-partitioned samples were used to discern nucleosomal occupancy in healthy and cancer samples. In this example, blood samples from six lung cancer patients and three non- malignant healthy adults were obtained. Cell-free Nucleic acids from the samples were extracted and partitioned using MBD- affinity purification into hyper-and hypo-methylated partitions. The nucleic acid samples were sequenced using whole genome sequencing. The percentage hypermethylated fragments for each partition and for all the samples were determined. Fig. 16 shows MBD signal in hyper- and hypomethylated partitions from lung cancer patients (rows 1 and 2 from top) and from healthy adults (rows 3 and 4). As shown in Fig. 16, cell-free DNA fragments from lung cancer patients show enrichment of distal intragenic regions in hypermethylated partition (LungSigHyper) when compared with the hypermethylated partition from healthy individuals. In addition, the distribution of characteristics in top 5% highest percentage hypermethylated peaks (LungSigHyper) and hypomethylated peaks (LungSigHypo) shows significant enrichment of hypomethylated peaks in all exons besides of exon 1 (Fig. 16, rows 1 and 2)."
Regarding claim 16, Arensdorf teaches DNA is obtained from a test subject ([0118]).
Regarding claim 21, Arensdorf teaches DNA is amplified before sequencing (Fig. 12; [0140]).
Regarding claim 24, Arensdorf teaches partitioning on the basis of methylation level (Fig. 11).
Regarding claim 33, Arensdorf teaches wherein the plurality of subsamples comprises a third subsample, which comprises DNA with a cytosine modification in a greater proportion than the second subsample but in a lesser proportion than the first subsample (Fig. 16; [0163] Three groups of fragments comprising, 5mC, 5hmC, and unmethylated DNA. With the 5hmC fraction containing lesser proportion of 5mC than the 5mC fraction by MBD protein pull-down, but greater than the unmethylated DNA fraction; see also Fig. 17 and 18, illustrating 5hmC pulldown fraction by streptavidin also comprise 5mC).
Regarding claim 37, Arensdorf teaches the first nucleobase is a modified or unmodified cytosine and the second nucleobase is a modified or unmodified cytosine (fig. 11).
Regarding claim 43, Arensdorf teaches the procedure to which the sample is subjected comprises protection of 5hmC (Fig. 11. 5hmC is protected by biotin functional group from deamination by borane ; [0128] ; see also [0124]).
Regarding claim 50, Arensdorf teaches protection of hmC followed by deamination of mC (Fig. 11; 5hmC is protected by biotin functional group from deamination by borane ; [0128]).
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 94-95 are rejected under 35 U.S.C. 103 as being unpatentable over Arensdorf (Arensdorf et al., US20200024643A1 - Methods for the epigenetic analysis of dna, particularly cell-free dna; Published 2020-01-23), in view of Quake (WO2017176630A1 - Noninvasive diagnostics by sequencing 5-hydroxymethylated cell-free dna; 2017-10-12).
A) The teachings of Arensdorf are recited above and applied as for base claim 1.
Arensdorf teaches methods for epigenetic analysis of cell-free DNA, by partitioning nucleic acids into subsets based on incorporation of epigenetic bases such as 5hmC or 5mC, followed by sequencing (e.g., [0148]-[0149]; claim 45; Fig. 11).
Regarding claim 94, while Arensdorf does not explicitly teach determining the likelihood of a subject having cancer, it states that its methods have utility in diagnostics ([0002]), and incorporates Quake by reference ([0055]).
Quake, in turn, teaches non-invasive cancer diagnostic methods through sequencing of 5hmC in cfDNA, comprising determining a likelihood that the subject has cancer (Figs. 4A-4C, Cancer type and stage prediction with cell-free 5hmC; page 40-41).
Accordingly, a skilled artisan would readily appreciate and find it obvious that the sequencing methods in Arensdorf for analyzing epigenetics of cfDNA could be applied to determine the likelihood of a subject having cancer. This combination would have been obvious as it represents the KSR principle of predictable use of prior art elements (i.e., hydroxymethylation sequencing in cfDNA) according to a known method (i.e., using hydroxymethylation sequencing in cfDNA for cancer diagnosis) to yield predictable results. (See MPEP §2143).
B) Regarding claim 95, Quake teaches the sequencing generates a plurality of sequencing reads (page 35, lines 31-32) ; and the method further comprises mapping the plurality of sequence reads to one or more reference sequences to generate mapped sequence reads (page 35, lines 33-34 to page 36, lines ), and processing the mapped sequence reads corresponding to the sequence-variable target region set and to the epigenetic target region set to determine the likelihood that the subject has cancer (page 36, lines 7-34 to page 37, lines 1-9; 29-34; page 41, lines 1-2).
Double Patenting- Obvious Type
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, 8, 24, 33, 37, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8-9, 12, 18 of U.S. Patent No. 11891653B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '653 patent.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘653 Patent, claim 1),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity(‘653 Patent, claim 1) ;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘653 Patent, claim 1, 9) ,
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample(‘653 Patent, claim 1), and
the modified nucleobase recognized by the agent is a modified cytosine (‘653 Patent, claim 1, 9) or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample ; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase(‘653 Patent, claim 1).
Therefore, instant claims 1,5, 37 are anticipated by claims 1, 9 of the '653 patent. Instant claims 8; 24; 33; 43 are anticipated by claims 6; 8; 12; 18 of the '653 patent, respectively.
Claims 1, 5, 8, 24, 33, 37, 43, 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21, 26, 28, 32, 38, 40 of copending Application No.18/433,345 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 03/10/2025) of the '345 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘345 Application, claim 21),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA(‘345 Application, claim 21),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase (‘345 Application, claim 21).
Therefore, instant claims 1,5, 37 are anticipated by claim 21 of the '345 application. Instant claims 8; 24; 33; 43; 50 are anticipated by claims 26; 28; 32; 38; 40 of the '345 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 8, 21, 24, 37, 94 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 9-11 of U.S. Patent No. 11946106B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '106 patent.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘106 Patent, claim 1, digestion with methylation sensitive restriction enzyme),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA(‘106 Patent, claim 1, 26),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase (‘106 Patent, claim 1).
Therefore, instant claims 1, 24, 37 are anticipated by claim 1 of the '106 patent. Instant claims 5; 8; 21; 94 are anticipated by claims 3; 9; 11; 10 of the '106 patent, respectively.
Claims 1, 5, 16, 21, 24, 37, 43, 50, 94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 16, 25, 27 of copending Application No. 19/279,313 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 10/13/2025) of the '313 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘313 Application, claim 1),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘313 Application, claim 1, 6),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase (‘313 Application, claim 1).
Therefore, instant claims 1, 21, 24, 37 are anticipated by claims 1, 6 of the '313 application. Instant claims 5; 16, 94; 43, 50 are anticipated by claims 25; 27; 16 of the '313 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 8-9, 16, 21, 24, 33, 37, 94 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11-12, 15-16, 19, 21 of U.S. Patent No. 12234518B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over claims of the '518 patent.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘518 Patent, claim 1) ,
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA(‘518 Patent, claim 1, 16),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase(‘518 Patent, claim 1).
Therefore, instant claims 1, 5, 24, 37 are anticipated by claims 1, 16 of the '518 patent. Instant claims 8-9; 16; 21; 33; 94 are anticipated by claims 11-12; 9; 15; 19; 21 of the '518 patent, respectively.
Claims 1, 5, 8, 9, 16, 21,24, 33, 37, 94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10-11, 15-16, 19, 21-22 of copending Application No. 18/922,116 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 02/27/2025) of the '116 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘116 Application, claim 1),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘116 Application, claim 1, 16),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase(‘116 Application, claim 1).
Therefore, instant claims 1, 5 are anticipated by claims 1, 16 of the '116 application. Instant claims 8-9; 16; 21; 24; 33; 37; 94 are anticipated by claims 10-11; 8; 15; 16; 19; 22; 21 of the '116 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 8, 16, 21, 24, 94-95 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 12, 83, 86, 97, 100, 122 of copending Application No. 18/447,749 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 03/28/2024) of the '749 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘749 Application, claim 97),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘749 Application, claim 97),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase (‘749 Application, claim 1).
Therefore, instant claim 1 is anticipated by claims 1, 97 of the '749 application. Instant claims 5, 21; 8; 16; 21; 24; 94; 95 are anticipated by claims 3; 86; 12; 100; 83; 122 of the '749 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 16, 24, 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 20 of copending Application No. 18/968,047 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 04/11/2025) of the '047 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘047 Application, claim 20),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘047 Application, claim 1),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase (‘047 Application, claim 1).
Therefore, instant claims 1 and 16 are anticipated by claims 1, 20 of the '047 application. Instant claims 24; 37 are anticipated by claims 6; 8 of the '047 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 8, 16, 21, 24, 37, 43, 50, 94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 12-13, 16, 18, 21, 25, 30 of copending Application No. 18/365,744 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by the claims (filed on 02/12/2026) of the '744 application.
Instant claim 1 recites:
A method of analyzing DNA in a sample, the method comprising:
a) subjecting the sample to a procedure that affects a first nucleobase in the DNA differently from a second nucleobase in the DNA of the sample (‘ 744 Application, claim 2),
wherein the first nucleobase is a modified or unmodified nucleobase, the second nucleobase is a modified or unmodified nucleobase different from the first nucleobase, and
the first nucleobase and the second nucleobase have the same base pairing specificity;
b) partitioning the sample into a plurality of subsamples by contacting the DNA with an agent that recognizes a modified nucleobase in the DNA (‘ 744 Application, claim 21),
the plurality comprising a first subsample and a second subsample,
wherein the first subsample comprises DNA with a cytosine modification in a greater proportion than the second subsample, and
the modified nucleobase recognized by the agent is a modified cytosine or a product of the procedure that affects the first nucleobase in the DNA differently from the second nucleobase in the DNA of the sample; and
c) sequencing DNA in at least one of the first and second subsamples in a manner that distinguishes the first nucleobase from the second nucleobase(‘ 744 Application, claim 1).
Therefore, instant claims 1 and 24 are anticipated by claims 1, 2, 21 of the '744 application. Instant claims 5; 8; 16; 21; 37; 43, 50; 94 are anticipated by claims 16; 18; 12; 30; 4; 25; 13 of the '744 application, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claim 1 is objected to; claims 1, 5, 8-9, 16, 21, 24, 33, 37, 43, 50 and 94-95 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at (571) 272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claim 7 is withdrawn as being drawn to non-elected species B.
2 Claims 30-31 are withdrawn as being drawn to non-elected species R.
3 Claims 32 and 89-90 are withdrawn as being drawn to non-elected species O and P.
4 “As a general rule, unless the steps of a method claim actually recite an order, the steps are not ordinarily construed to require one.” Mformation Techs., Inc. v. Rsch. in Motion Ltd., 764 F.3d 1392, 1398 (Fed. Cir. 2014) (cleaned up). “However, a claim requires an ordering of steps when the claim language, as a matter of logic or grammar, requires that the steps be performed in the order written, or the specification directly or implicitly requires an order of steps.” Id. Although not an ironclad rule, when the current step of a method claim refers to a previous step using the definite article “the,” the claim language indicates that the previous step occurs sequentially before the current step. E.g., Wi-Lan, Inc. v. Apple Inc., 811 F.3d 455, 462 (Fed. Cir. 2016).