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 the invention of Group I (claims 1-9, directed to methods of library construction) in the reply filed on 01/16/20236 is acknowledged.
Claims 10-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/16/2026.
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.
Claim(s) 1, 2 and 4-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lagace (US PG Pub 2017/0253922 A1) in view of Albitar et al (2017).
Relevant to instantly rejected claim 1, Lagace teaches methods for sequence analysis of low frequency nucleic acids (e.g.: para 0160), such as SNP alleles or mutations, comprising multiplex amplification of a library (e.g.: para 0070) using a plurality of target-specific primers with a cleavable group (e.g.: para 0078) where the cleavable group may be a uracil nucleotide (relevant to claim 5) (e.g.: para 0079). The reference further teaches cleaving the cleavable group of the amplicons, and ligating adapters to the cleaved amplicon (e.g.: claim 1 of Lagace; Figs. 1 and 2).
Relevant to claim 2, Lagace teaches samples including DNA and RNA (e.g.: para 0035).
Relevant to claim 6, Lagace teaches that a primer may be about 15 to about 40 nucleotides in length (e.g.: pare 0037).
Relevant to claim 7, Lagace teaches methods where the steps are performed in a single vessel (e.g.: para 0065).
Relevant to claim 8, Lagace teaches adapters that include barcodes and tags (e.g.: pare 0062).
Lagace does not teach the use of a blocking primer that is specific to a target (relevant to claim 1) or a wild type sequence (relevant to claim 4) that is downstream of a productive target specific primer (relevant to claim 9). However the use of blocking primers to increase sensitivity of the detection of low frequency target nucleic acids in amplification-based methods was known in the art and is taught by Albitar et al.
Albitar et al teaches wild-type blocking PCR (WTB-PCR) to create templates for sequencing reactions. Relevant to the limitations of the rejected claims, Albitar et al teaches including a blocking oligo that preferentially binds to a wild type target nucleic acids, is downstream of a forward primer, and prevents the amplification of the wild type template by the upstream primer (e.g.: Fig 1; p.2 – Wild-type blocking PCR); relevant to claim 1, 4 and 9).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have included blocking oligonucleotides, as taught by Albitar et al, in the adapter ligation-based methods of target detection taught by Lagace. The skilled artisan would have been motivated to use blocking oligonucleotides based on the expressed teachings of Albitar et al that such methods improve the detection of low frequency mutations with fewer occurrences of false positives, greater flexibility and ease of implementation. The skilled artisan wold have a reasonable expectation of success base on the teaching of Lagace, which provides methods in which primers are removed from an amplicon using a cleavable group in the primers, and the teaching of Albitar et al that a blocking oligo increases sensitivity by blocking amplification from the upstream primer.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lagace (US PG Pub 2017/0253922 A1) in view of Albitar et al (2017), as applied to claims 1, 2 and 4-9 above, and further in view of Alam et al (2014).
Lagace in view of Albitar et al renders obvious methods in which a low frequency target nucleic acid such as a SNP allele or mutation is analyzed in a library including the use of primers with cleavable groups, blocking primers directed to wild type sequences, and ligation of adapters. Lagace does not specifically teach target nucleic acids that are bacterial or microbial, but the analysis of rare alleles in microbial populations was known in the art and is taught by Alam et al.
Alam et al teaches the identification and detection of rare mutations in candidate genes associated with Vancomycin-intermediate Staphylococcus aureus (VISA) (e.g.: p.1177 - Identification of Rare Mutations by Comparison to Public S. aureus Genome Project Data).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have applied the methods rendered obvious by Lagace in view of Albitar et al to the detection of rare mutations in Staphylococcus aureus, as taught by Alam et al. The skilled artisan would have been motivated to detect mutations in Staphylococcus aureus based on the expressed teachings of Alam et al that such mutations can be useful for the sensitive and specific classification of vancomycin insensitivity in Staphylococcus aureus which can be related to prolonged bacteremia and in some cases treatment failure.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Parsons et al (2005) teaches the use of competitive blocking oligonucleotides, which overlap with productive primer binding sites, to reduce the amount of background signal generated from the abundant wild-type template (e.g.: Fig. 1).
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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