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 .
DETAILED ACTION
Status of the Claims
Claims 16-32 are pending and the subject of this NON-FINAL Office Action.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/16/2026 has been entered.
New Grounds of 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.
Claim(s) 16-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over TANG (US20210010069), in view of BUIS (US20170298427).
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to apply familiar MIPs with multiple barcodes/IDs and CpG sites in the gaps to achieve greater multiplexing with a reasonable expectation of success.
As to claims 16-19, 21 and 24-26, TAN teaches to digest methylated DNA with one or more methylation-sensitive RE (AKA methylation-specific RE) such as HPAII (paras. 0088, 0184), then use smMIP that have two ends that hybridize “next to” methylation sites (para. 0088- “MIP designed to target CpG islands,” which encompasses MIP that hybridize “next to” methylated CpG site and extend through methylated CpG for downstream detection, the only other option is MIP ends that hybridize directly to methylated CpG; thus, with only two options, a PHOSITA would immediately envisage the former option), and central portion/backbone that includes primer binding sites and barcode/tag region (paras. 0053, 0070, 0072), the ends being extended, ligated and the reaction subject to exonuclease treatment before amplification using the primers (paras. 0002-05, 0097, 0102).
As to multiple tags/barcodes, TAN states there can be one or more (e.g. two) tags/barcodes in the linker region (para. 0072, for example).
As to claims 22-23, the amplified reaction is subject to sequencing, which uses adaptor sequence in the MIP (paras. 0017, 0072, 0103, 0108, 0130).
As to claim 27, a control MIP can be used (paras. 0062).
As to claims 28-31, any sample type such as blood from any subject such as human can be used (paras. 0042, 0079).
TAN does not specifically teach (i) a specific extension probe that specifically hybridizes to a first region upstream of the at least one target methylation site, (iii) a specific ligation probe that specifically hybridizes to a second region downstream of the at least one target methylation site, or 4nt+ tags/barcodes at both ends of the backbone region.
However, this specific configuration was a well-known option in the MIP art. For example, BUIS teaches MIPs with tags/barcodes/UMIs at both ends of the backbone used to generate flanking MIP arms around CpG sites in the gap (Figs. 5-6):
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“[T]he length of the first and/or second unique molecular tag is between 4 and 15 bases” (paras. 0157-58, 0361-62, 0407-08, 0642). “The use of unique molecular identifiers allows for each capture event to be characterized. More specifically, these identifiers are used to bin reads resulting from the same capture event, remove duplicates and report a single consensus read” (para. 0739). “The ligation and extension arms of the MIP (i.e., the first and second targeting polynucleotide arms) are then matched to the sequence reads, allowing a maximum of one base pair mismatch in each arm. Reads that fail to meet this criterion are treated as invalid and discarded. At the same time, the molecular tags from both the ligation and the extension ends are kept separately for counting of the capture events in a later step—although in some embodiments the tags are kept together” (para. 0749). The gap contains the target of interest such as CpG sites (para. 0473, 0478ff; Fig. 6). The gap can be 1-200 bases (para. 0463).
In sum, the claims amount to the obvious combination of familiar MIPs with arms that flank CpG sites and multiple backbone-end barcodes to achieve familiar detection results.
Prior Art
The following prior art is pertinent to dual-barcoded MIPs and MSRE: US 20170183731; US 20190024149; US11761037; US 2006/292585; WO 2012/112970; WO 2004/051224; WO 2015/014962; QUAN PENG ET AL: "Reducing amplification artifacts in high multiplex amplicon sequencing by using molecular barcodes", BMC GENOMICS, vol. 16, no. 1, 7 August 2015, page 589, XP021224943; US 20160055293.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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