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 .
Election/Restrictions
Applicant’s election without traverse of Group I, a method for identifying, in a sample, one or more parent nucleic acid molecules, in the reply filed on 1/7/26 is acknowledged.
Claims 1-9, 12, 14, 32-33, 35, 37-41, and 45 are pending. Claims 1-2, 4, 32-33, 35, 37-41, and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/7/26.
Applicant’s election without traverse of species election (c), detection using only primary and secondary oligonucleotide primers with two rounds of PCR in the reply filed on 1/7/26 is acknowledged.
Claims 10-11, 13, 15-31, 34, 36, and 42-44 are cancelled.
Claims 3, 5-9, 12, and 14 are currently under examination.
Priority
The instant application 17/922,589 filed on 10/31/22 is a 371 US national phase of PCT/US2021/029998 filed on 4/29/21, and claims domestic priority to provisional application 63/019,142 filed on 5/1/20. The priority date is determined to be 5/1/20.
Claim Rejections - 35 USC § 103
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 3, 5-9, 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Barany et al. (2018; US 2018/0265917 A1; USPGPub citation 1 in IDS filed 10/31/22) in view of Vaisvila et al. (2013; US 2013/0244237 A1; USPGPub citation 2 in IDS filed 10/31/22).
(i) Barany et al. teaches limitations relevant to claims 3, 5-9, 12, and 14.
Relevant to claim 3, Barany et al. paragraph 0026 teaches a method for identifying differentially methylated nucleotides. Relevant excerpts include: “A first aspect of the present invention is directed to a method for identifying, in a sample, one or more nucleic acid molecules containing a target nucleotide sequence differing from nucleotide sequences in other nucleic acid molecules in the sample, or other samples, by… one or more methylated residues. This method involves providing a sample potentially containing one or more nucleic acid molecules containing the target nucleotide sequence differing from the nucleotide sequences in other nucleic acid molecules by… one or more methylated residues…”
Further relevant to claim 3, Barany et al. paragraphs 0026-0027 teach enzymatic digestion of dU. Relevant excerpts include: “contacting the sample with one or more enzymes capable of digesting deoxyuracil (dU) containing nucleic acid molecules present in the sample.”
Further relevant to claim 3, Barany et al. paragraphs 0027-0029 teach primary/secondary oligonucleotide primer sets, reaction mixture blending, and polymerase extension reaction cycle limitations. Relevant excerpts include: “providing one or more primary oligonucleotide primer sets, each primary oligonucleotide primer set comprising (a) a first primary oligonucleotide primer that comprises a nucleotide sequence that is complementary to a sequence adjacent to the target nucleotide sequence and (b) a second primary oligonucleotide primer that comprises a nucleotide sequence that is complementary to a portion of an extension product formed from the first primary oligonucleotide primer… The sample is blended with the one or more primary oligonucleotide primer sets, the one or more enzymes capable of digesting deoxyuracil (dU) containing nucleic acid molecules in the sample, a deoxynucleotide mix including dUTP, and a DNA polymerase to form a polymerase chain reaction mixture. The polymerase chain reaction mixture is subjected to conditions suitable for digesting deoxyuracil (dU) containing nucleic acid molecules present in the polymerase chain reaction mixture… The method further involves blending the primary extension products with a ligase and one or more oligonucleotide probe sets to form a ligation reaction mixture, wherein each oligonucleotide probe set comprises (a) a first oligonucleotide probe having a 5' primer-specific portion and a 3' target nucleotide sequence-specific portion”.
Further relevant to claim 3, Barany et al. paragraph 0027 teaches enzymatic digestion of dU and PCR. See above relevant excerpts.
Further relevant to claim 3, Barany et al. paragraph 0027 teaches identification of differential methylation. See above relevant excerpts.
Relevant to claim 5, Barany et al. paragraph 0282 teaches repair of abasic sites. Relevant excerpts include: “Other possible modifications included abasic sites, e.g., internal abasic furan or oxo-G. These abnormal ‘bases’ are removed by specific enzymes to generate ligation-competent 3'-OH or 5'P sites.”
Relevant to claim 6, Barany et al. paragraphs 0285-0287 teach contacting the sample with methylation sensitive enzymes and detection. Relevant excerpts include: “In accordance with this aspect of the present invention, the method further comprises contacting the sample with at least a first methylation sensitive enzyme to form a restriction enzyme reaction mixture prior to forming a polymerase chain reaction mixture.”
Relevant to claim 7, Barany et al. paragraph 0293 teaches enrichment via methylation specific antibodies. Relevant excerpts include: “Optionally, methylated DNA can be enriched using methylation specific antibodies.”
Relevant to claim 8, Barany et al. paragraphs 0288 and 0306 teach oligonucleotide primer design limitations. Relevant excerpts include: “In this embodiment the first primary oligonucleotide primer of the primary oligonucleotide primer set comprises a nucleotide sequence that is complementary to the bi sulfite-treated target nucleotide sequence containing the one or more methylated, uncleaved restriction sites and the second primary oligonucleotide primer of the provided primary oligonucleotide primer set comprises a nucleotide sequence that is complementary to a portion of the extension product formed from the first oligonucleotide primer” and “The region of interest is selectively amplified using locus-specific upstream primers, locus-specific downstream primers, a blocking LNA or PNA probe comprising the bisulfite converted unmethylated sequence or its complement, and a deoxynucleotide mix that includes dUTP. In this embodiment, another layer of selectivity can be incorporated into the method by including a 3' cleavable blocking group”.
Relevant to claim 9, Barany et al. paragraph 0290 teaches oligonucleotide primers with 3' cleavable portions. Relevant excerpts include: “one or both primary oligonucleotide primers of the primary oligonucleotide primer set have a 3' portion having a cleavable nucleotide or nucleotide analogue and a blocking group, such that the 3' end of said primer or primers is unsuitable for polymerase extension… cleaving the cleavable nucleotide or nucleotide analog of one or both oligonucleotide primers during the hybridization treatment thereby liberating free 3'OH ends on one or both oligonucleotide primers prior to said extension treatment.”
Relevant to claim 12, Barany et al. paragraph 0306 teaches blocking oligonucleotide primer limitations. Relevant excerpts include; “The region of interest is selectively amplified using locus-specific upstream primers, locus-specific downstream primers, a blocking LNA or PNA probe comprising the bisulfite converted unmethylated sequence or its complement, and a deoxynucleotide mix that includes dUTP. In this embodiment, another layer of selectivity can be incorporated into the method by including a 3' cleavable blocking group… A blocking LNA or PNA probe comprising the bisulfite converted unmethylated sequence (or its complement) that partially overlaps with the upstream PCR primer will preferentially compete for binding to the bisulfite converted unmethylated sequence over the upstream primer and over the bisulfite converted methylated sequence DNA, thus suppressing amplification of bisulfite converted unmethylated sequence DNA during each round of PCR.”
Relevant to claim 14, Barany et al. paragraph 0037 teaches third primary oligonucleotide primer limitations. Relevant excerpts include: “The method further involves providing one or more oligonucleotide primer sets, each primer set comprising… (c) a third oligonucleotide primer comprising a nucleotide sequence that is the same as the 5' primer-specific portion of the first oligonucleotide primer.”
(ii) Barany et al. is silent to conversion of residues and DNA deamination enzymes relevant to claims 3, 8, and 12. However, these limitations were known in the prior art and taught by Vaisvila et al.
Relevant to claims 3, 8, and 12, Vaisvila et al. paragraphs 0006-0007, 0011, 0018, 0057, and 0064 teach limitations relevant to conversion of residues and DNA deamination enzymes.
Relevant excerpts include: “In general, in another aspect, an in vitro mixture is provided that includes a cytidine deaminase and a purified oxygenase”; “Embodiments of the mixture may include one or more of the following features: the cytidine deaminase … and/or the oxygenase may be a… DNA polymerase; and/or at least one primer and dNTPs”; “a method for differentiating an unmethylated cytosine (C) or a 5-methylcytosine (5-mC) from a 5-hydroxymethylcytosine (5-hmC), … 5-carboxycytosine (5-CaC) … that includes reacting a polynucleotide optionally containing C, 5-mC, 5-hmC, 5-fC, 5-CaC and/or 5-ghmC, with a cytidine deaminase wherein the 5-mC is converted to a T and only the C is converted to a U; and (b) amplifying or cleaving the polynucleotide to identify the location of at least one converted nucleotide in the polynucleotide”.
(iii) Although Barany et al. does not teach the Vaisvila et al. conversion of residues and DNA deamination enzymes, it would have been prima facie obvious to the skilled artisan. It is noted that Barany et al. and Vaisvila et al. are analogous to the instant methylation characterizations.
The skilled artisan would have been motivated to combine the analogous disclosures. The skilled artisan would have been motivated to include the Vaisvila et al. limitations within the Barany et al. methodology because Vaisvila et al. teaches “Hence, methylome sequencing continues to be performed by sodium bisulfite sequencing despite problems associated with this method that include the use of multiple biochemical steps, an inability to distinguish methyl from hydroxymethylcytosine, the requirement for heat to denature the DNA, additional shearing of DNA into small fragments by the chemical treatment, and a limitation on the length of a DNA that can be sequenced” (paragraph 0003). Vaisvila et al. further teaches “Another problem associated with sodium bisulfite sequencing is that the method damages the target DNA causing extensive fragmentation… Another problem of sodium bisulfite sequencing is that it involves multiple chemical steps and therefore is intrinsically inefficient and costly to perform” (paragraph 0093).
Thus, the skilled artisan would have been motivated to include the Vaisvila et al. conversion of residues and DNA deamination enzymes within the Barany et al. method in order to be minimize DNA damage and improve residue resolution and efficiency. The skilled artisan would have a reasonable expectation of success based on the disclosures of Barany et al. in view of Vaisvila et al., as discussed in the preceding paragraphs.
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.
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 3, 5-9, 12, and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 9, 11, 14, 17, and 29 of U.S. Patent No. 10,344,321 B2 (hereafter patent ‘321). Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims are broad and generic so as to encompass the claims of the ‘321 patent.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682