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 1-11, drawn to methods of gene analysis) in the reply filed on 05/29/2026 is acknowledged.
Claim 12 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/29/2026
Claim Rejections - 35 USC § 112 - 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 2 and 7-11 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 2 is unclear over recitation of the recitation of the limitation “a fluorescent dye of a substrate incorporated by a single-base extension reaction of a wild type and a mutant of the first target nucleotide sequence and a fluorescent dye of a substrate incorporated by a single-base extension reaction of a wild type and a mutant of the second target nucleotide sequence are different.” The intended requirements for the fluorescent dyes of the claims are unclear because it is not clear if the claim requires that every dye for every product is different. For example, where the claim addresses four products that are WT#1, MUT#1, WT#2 and MUT#2, it is unclear if there is a requirement for four different dyes (i.e.: a different dye for each product), or if the claim encompasses three dyes where, for example, MUT#1 and MUT#2 are different from each other and each are different than the same dye used for WT#1 and WT#2.
Claim 7 is unlcear over recitation of the limitation “the mutant of the target nucleotide sequence comprises a plurality of mutants”. The limitation is unclear over the combination of the singular “the mutant” with the recitation of “a plurality of mutants”. It is further unclear if the claim intends to require that “a plurality of mutants” are in fact present in the targets of the claimed method, or it the limitation is intended to require that the target is a target in which different non-wildtype alleles may be present at the particular target locus.
Claims 8, 9, 10 and 11 are unclear over recitation of the limitation “to adjust a difference in the mobility of the electrophoresis according to the content ratio of the mutant to the wild type of the target nucleotide sequence”, as recited in claim 8 from which claim 9 depends, and recited in claim 10 from which claim 11 depends. It is unclear what is required for any adjustment to be “according to” any content ratio. The limitation is further unclear where no particular content ratio is recited or required by the claims.
Claim 9 is unclear over recitation of the limitation “the first target nucleotide sequence in which the content ratio of the mutant to the wild type is in a range of 0.01% to 10%” because there is no antecedent basis for any “target nucleotide sequence in which the content ratio of the mutant to the wild type is in a range of 0.01% to 10%”.
Claim 9 is unclear over recitation “at least 4.46 to 3.16 bases”, because the phrase “at least” denotes a minimum point, but the recitation of the range in “4.46 to 3.16 base” makes it unclear what the minimum point is intended to be.
Claim Rejections - 35 USC § 102
It is noted that several aspects of the claims are addressed as unclear under 35 USC 112 as set forth above in this Office Action. In so far as the prior art appears to meet the required limitations of the claims, those claims are addressed here.
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.
Claim(s) 1, 2, 8,10 and 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Di Cristofaro et al (2010).
Relevant to the limitations of claims 1 and 10, Di Cristofaro et al teaches the SNaPshot assay to detect alleles at a plurality of target nucleotide sequences, including single base extension of target specific primers using four fluorescent dideoxy nucleotides (A dR6G, green;C dTAMRA, black;G dR110, blue; T dROX, red), and mobility analysis of dye-labeled products using capillary electrophoresis (e.g.: p.454 – Materials and Methods). Here it is noted that the nomenclature of “wild type” and “mutant” as set forth in the claims requires only that different alleles at target loci are detectable. Relevant to the limitations of claim 1 and 11 as they requires that the dye of a wild type product is different than the dye of a mutant product with adjacent electrophoretic mobility, and the limitations of claim 2 where the dyes of adjacent wild type and mutant products are different, Di Cristofaro et al exemplifies detection of alleles of adjacent mobility products with distinct dyes (e.g.: see the loci FY (C-wt/FY*X; C>T detection) and DO (DO*1/DO*2; A>G detection) in Fig 2E and Fig 2F).
Relevant to the limitations of claim 8 and 11, Di Cristofaro et al teaches primers the electrophoretic mobility of which are adjusted by the addition of 5 poly-thymidine tails of different lengths (e.g.: Table 2).
Claim(s) 1, 2, 5, 7, 8-11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mangin et al (2011).
Relevant to the limitations of claims 1 and 10, Mangin et al teaches the SNaPshot assay to detect alleles at a plurality of target nucleotide sequences, including single base extension of target specific primers using four different colors (A green; C black; G blue; T red) (Figure 1), and mobility analysis of dye-labeled products using capillary electrophoresis (e.g.: p.486 – Materials and Methods). Mangin et al teaches multiplex analysis of a several KRAS mutation positions which have multiple mutant alleles (e.g. Table 1; relevant to claim 7), and teaches (e.g.: Figure 1; Figures S1-S7) the detection of products where the dye of a wild type product is different than the dye of a mutant product with adjacent electrophoretic mobility (relevant to claims 1 and 11), where the dyes of adjacent and mutant products are different than the wild type products (relevant to claim 2).
Relevant to the limitations of claim 5, Mangin et al exemplifies the analysis of samples in which the mutant target nucleic acid is present in the sample at 1%, 5% and 10% (e.g.: Figures S1-S7).
Relevant to the limitations of claim 8, 9 and 10, Mangin et al teaches primers the electrophoretic mobility of which are adjusted by the addition of 5 poly-d(C) tails of different lengths (e.g.: Table 1); and teaches primers that create products that have at least a 3.16 base difference in mobility (relevant to claim 9) (e.g.: Table 1) in the detection of mutants that are present at 1%, 5% and 10% (e.g.: Figures S1-S7).
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) 1-5, 7, 8-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mangin et al (2011) in view of Nygren et al (WO 2017/172571; cited on the IDS of 01/30/2024).
The teachings of Mangin et al are addressed above in this Office Action with regard to claims 1, 2, 5, 7 and 8-11, where instantly rejected claims 3 and 4 depend from claim 1.
Further relevant to the instant rejection of claim 4, Mangin et al teaches the detection of mutant target nucleotide sequences using a primer that is shorter than other primers used for single-base extension reactions (e.g.: Fig. 1)
Mangin et al does not exemplify quantifying a content ratio between the wild type and the mutant of the target nucleotide sequence based on magnitude of the fluorescence intensity, as recited in claim 3 from which claim 4 depends. However, the quantifying of nucleic acid content using a ratio of fluorescent intensity was known in the prior art and is taught by Nygren et al.
Nygren et al teaches methods for quantifying alleles and polymorphisms in target nucleic acids including the use of single base extension (e.g.: p.65) and detection of fluorescent products using electrophoretic methods (e.g.: p.35). Relevant to the limitations of claim 3, Nygren et al teaches quantifying target nucleic acid amounts using ratios of intensities (e.g.: p.67) related to minor (e.g.: a mutant) to a major (e.g.: a wild type) species (e.g.: p.5).
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 the quantifying of a content ratio of target nucleic acids, as taught by Nygren et al, in the detection of mutant nucleic acids in a sample as taught by Mangin et al. The skilled artisan would have been motivated to quantify mutant content based on the expressed teaching of Mangin et al that the predictive value of the detected mutations have been confirmed clinically, and that clinical samples may be highly heterogeneous with respect to the quantity and distribution of tumor cells within samples. The skilled artisan would thus recognize that quantifying the mutations in the sample would allow for a measure of the resistance to treatment by monoclonal antibodies of a tumor. The skilled artisan would have a reasonable expectation of success based on the exemplificaiton of target nucleic acid quantification provided by Nygren et al.
Claim(s) 1, 2, 6, 8,10 and 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Di Cristofaro et al (2010).
The teachings of Di Cristofaro et al are addressed above in this Office Action with regard to claims 11, 2, 8,10 and 11, where instantly rejected claim 6 depends from claim 1.
Di Cristofaro et al exemplifies the detection of 11 different nucleic acid target loci (Figure 2) defining 18 blood group alleles (p.456 – Results).
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 modified the particular assay of Di Cristofaro et al to the detection of more loci, including 20 or more loci. Where the prior art teaches that a plurality of different SNPs can determine the genetic variability of blood groups in different populations, the prior art thus teaches the selection of different SNPs as a results effective variable in the analysis of blood alleles. It would thus be obvious to the skilled artisan to select different targets, and different numbers of targets, to provide the information necessary to effectively genotyping any different population of subjects to provide an accurate identification of the blood allele of any subject in a population.
Claim(s) 1, 2, 5, 7, and 8-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mangin et al (2011) in view of Reid (US PG Pub 20090104612 A1).
The teachings of Mangin et al are addressed above in this Office Action with regard to claims 1, 2, 5, 7 and 8-11.
Here it is noted that claims 8, 9, 10 and 11 include limitations related to adjusting a difference in the mobility of the electrophoresis according to the content ratio of the mutant to the wild type of the target nucleotide sequence (as recited in claim 8 and 10). This aspect of the claims has been addressed previously in this Office Action as unclear (under 35 USC 112), and in so far as Mangin et al teaches primers with different lengths that are modified with 5’ poly-d(C) tails the claims were addressed as anticipated under 35 USC 102.
Here it is noted that with regard to the lengths of primers used in the detection of target nucleic acids (e.g.: Reid at page 9) using fluorescent nucleotides in single base extension reaction followed by electrophoresis and fluorescence detection. Reid et al teaches that tails of differing length cause the corresponding product sequences to form bands at different locations in the gel or capillary, permit the corresponding nucleotide differences in the DNA being analyzed to be identified, and that such primers are also useful to avoid overlap between the final products (e.g.: para 0066).
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 performed the detection methods of Mangin et al and to have adjusted the length of the primers to prevent overlap of signals from peaks of adjacent products. The skilled artisan would be motivated to use tail length to adjust mobility based on the expressed teachings of Reid et al that each primer included in a multiplex reaction can be varied by increments through the addition of poly-A tails to the 5' end in order to avoid overlap between the final products (e.g.: para 0077), and the teachings of Mangin et al which provide that that peaks may overlap.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Johnsen (2015) teaches that a combination of 24 SNPs can be identified to call 38 blood group antigens).
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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