DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1-20 filed on 06/27/2023 are pending and under examination.
Claim Rejections - 35 USC § 112
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 1-20 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.
Regarding claim 1, the recitation of “thereby detecting at least one (SNP) in the first allelic variant” in line 22 of the claim is unclear if the element inside the parenthesis are required for detection of the first allelic variant.
Regarding claim 2, the recitation of “an A to G SNP, a C to T SNP,” in lines 1-2 followed by the recitation of “a C to G SNP or an A to T SNP” in line 2 of the claim is unclear whether the at least one SNP reads on at least one or a particular combination of SNP’s or if the result of a grammatical error and should read “an A to G SNP, a C to T SNP, a C to G SNP, or an A to T SNP”.
Regarding claim 5, the recitation of “thereby detecting at least one (SNP) in the second allelic variant” in line 18 of the claim is unclear if the element inside the parenthesis are required for detection of the second allelic variant.
Regarding claim 6, the recitation of “an A to G SNP, a C to T SNP,” in lines 1-2 followed by the recitation of “a C to G SNP or an A to T SNP” in line 2 of the claim is unclear whether the at least one SNP reads on at least one or a particular combination of SNP’s or if the result of a grammatical error and should read “an A to G SNP, a C to T SNP, a C to G SNP, or an A to T SNP”.
Regarding claim 11, the recitation of “at least one of the first allele-specific primer, the second-allele-specific primer,” in lines 1-2 of the claim followed by the recitation of “the first allele-specific blocker or the second allele-specific blocker probe” in lines 2-3 of the claim is unclear whether at least one or a particular combination of the first allele-specific blocker probe and the second allele-specific blocker probe or if this is the result of a grammatical error and should read “at least one of the first allele-specific primer, the second-allele-specific primer, the first allele-specific blocker, or the second allele-specific blocker probe”.
Regarding claim 13, the recitation of “(a) the 3’-end, (b) the 5’-end,” in lines 1-2 of the claim followed by the recitation of “(c) at an internal position or at any combination of (a), (b) or (c)” in line 2 of the claim is unclear whether at least one of (a), (b), or (c) is required or a particular combination is required or if this is the result of a grammatical error and should read “(a) the 3’-end, (b) the 5’-end, (c) at an internal position, or at any combination of (a), (b), or (c)”. In addition, the recitation of “at least one of the first allele-specific primer, the second-allele-specific primer,” in lines 2-3 of the claim followed by the recitation of “the first allele-specific blocker or the second allele-specific blocker probe” in lines 3-4 of the claim is unclear whether at least one or a particular combination of the first allele-specific blocker probe and the second allele-specific blocker probe or if this is the result of a grammatical error and should read “at least one of the first allele-specific primer, the second-allele-specific primer, the first allele-specific blocker, or the second allele-specific blocker probe”.
Regarding claim 16, the claim recites the limitation “the first cycling stage” in line 2 and “the second stage” in line 3 and there is insufficient antecedent basis for these limitations in the claim. In addition, the recitation of “the second stage” in line 3 of the claim is unclear if this limitation is referring to a second cycling stage? A second amplification stage?
Claims 3, 4, 9 are rejected due to their dependence on claim 1, claims 7, 8, 10, 14, 15, & 17-20 are rejected due to their dependence on claim 5, and claim 12 is rejected due to its dependence on claim 11.
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.
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Claims 1, 5, 9-14, & 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 17, & 18 of U.S. Patent No. 9,512,473 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because each provides a method for detecting a first allelic variant and a second allelic variant of a target sequence in a nucleic acid sample through forming a first and a second reaction mixture.
Regarding claim 1, the instant application claims a method for detecting at least one single nucleotide polymorphism (SNP) in a first allelic variant and a second allelic variant of a target sequence in a nucleic acid sample comprising forming a first reaction mixture comprising the nucleic acid sample that contains the first allelic variant of the target sequence, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out and amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the at least one SNP in the first allelic variant of the target sequence. U.S. Patent No. 9,512,473 B2 claims a method for detecting a first allelic variant of a target sequence in a nucleic acid sample suspected of comprising at least a second allelic variant of the target sequence comprising forming a first reaction mixture comprising the nucleic acid sample, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out an amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the first allelic variant of the target sequence (see claim 1).
Regarding claim 5, the instant application claims a method further comprising forming a second reaction mixture comprising the nucleic acid sample, a second allele-specific primer, a second allele-specific blocker probe comprising a minor groove binder, a second locus-specific primer, and a second detector probe and carrying out an amplification reaction to form a second amplicon and detecting the second amplicon thereby detecting at least one SNP the second allelic variant of the target sequence. U.S. Patent No. 9,512,473 B2 claims a method further comprising forming a second reaction mixture comprising the nucleic acid sample, a second allele-specific primer, a second allele-specific blocker probe comprising a minor groove binder, a second locus-specific primer, and a second detector probe and carrying out an amplification reaction to form a second amplicon and detecting the second amplicon thereby detecting the second allelic variant of the target sequence (see claim 3).
Regarding claim 9, the instant application claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant possessing the at least one SNP. U.S. Patent No. 9,512,473 B2 claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant (see claim 2).
Regarding claim 10, the instant application claims a method further comprising comparing the change in the detectable property of the first detector probe in the first reaction mixture to the change in the detectable property of the second detector probe in the second reaction mixture. U.S. Patent No. 9,512,473 B2 claims a method further comprising comparing the change in the detectable property of the first detector probe in the first reaction mixture to the change in the detectable property of the second detector probe in the second reaction mixture (see claim 4).
Regarding claim 11, the instant application claims a method wherein at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe comprises at least one modified base. U.S. Patent No. 9,512,473 B2 claims a method wherein at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe comprises at least one modified base (see claim 5).
Regarding claim 12, the instant application claims a method wherein the modified based is an 8-aza-deaza-dN (ppN) base analog, where N is adenine (A), cytosine (C), guanine (G), or thymine (T). U.S. Patent No. 9,512,473 B2 claims a method wherein the modified based is an 8-aza-deaza-dN (ppN) base analog, where N is adenine (A), cytosine (C), guanine (G), or thymine (T) (see claim 6).
Regarding claim 13, the instant application claims a method wherein the modified base is located at (a) the 3’-end, (b) the 5’-end, (c) at an internal position, or at any combination of (a), (b), or (c) within at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe. U.S. Patent No. 9,512,473 B2 claims a method wherein the modified base is located at (a) the 3’-end, (b) the 5’-end, (c) at an internal position, or at any combination of (a), (b), or (c) within at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe (see claim 8).
Regarding claim 14, the instant application claims a method wherein step (b) and/or (e) comprise a 2-stage cycling protocol. U.S. Patent No. 9,512,473 B2 claims a method wherein carrying out amplification reaction comprises a 2-stage cycling protocol (see claim 17).
Regarding claim 16, the instant application claims a method wherein the first annealing/extension temperature used during the first cycling stage is between 1-3°C lower than a second annealing/extension temperature used during the second stage. U.S. Patent No. 9,512,473 B2 claims a method wherein the first annealing/extension temperature used during the first cycling stage is between 1-3°C lower than a second annealing/extension temperature used during the second stage (see claim 18).
Claims 1, 5, & 9-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 11, 12, 15, 17, 18, & 20 of U.S. Patent No. 10,081,833 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because each provides a method for detecting a first allelic variant and a second allelic variant of a target sequence in a nucleic acid sample through forming a first and a second reaction mixture.
Regarding claim 1, the instant application claims a method for detecting at least one single nucleotide polymorphism (SNP) in a first allelic variant and a second allelic variant of a target sequence in a nucleic acid sample comprising forming a first reaction mixture comprising the nucleic acid sample that contains the first allelic variant of the target sequence, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out and amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the at least one SNP in the first allelic variant of the target sequence. U.S. Patent No. 10,081,833 B2 claims a method for detecting a first allelic variant of a target sequence in a nucleic acid sample suspected of comprising at least a second allelic variant of the target sequence comprising forming a first reaction mixture comprising the nucleic acid sample, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out an amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the first allelic variant of the target sequence (see claim 1).
Regarding claim 5, the instant application claims a method further comprising forming a second reaction mixture comprising the nucleic acid sample, a second allele-specific primer, a second allele-specific blocker probe comprising a minor groove binder, a second locus-specific primer, and a second detector probe and carrying out an amplification reaction to form a second amplicon and detecting the second amplicon thereby detecting at least one SNP the second allelic variant of the target sequence. U.S. Patent No. 10,081,833 B2 claims a method further comprising forming a second reaction mixture comprising the nucleic acid sample, a second allele-specific primer, a second allele-specific blocker probe comprising a minor groove binder, a second locus-specific primer, and a second detector probe and carrying out an amplification reaction to form a second amplicon and detecting the second amplicon thereby detecting the second allelic variant of the target sequence (see claim 3).
Regarding claim 9, the instant application claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant possessing the at least one SNP. U.S. Patent No. 10,081,833 B2 claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant (see claim 2).
Regarding claim 10, the instant application claims a method further comprising comparing the change in the detectable property of the first detector probe in the first reaction mixture to the change in the detectable property of the second detector probe in the second reaction mixture. U.S. Patent No. 10,081,833 B2 claims a method further comprising comparing the change in the detectable property of the first detector probe in the first reaction mixture to the change in the detectable property of the second detector probe in the second reaction mixture (see claim 4).
Regarding claim 11, the instant application claims a method wherein at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe comprises at least one modified base. U.S. Patent No. 10,081,833 B2 claims a method wherein at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe comprises at least one modified base (see claim 5).
Regarding claim 12, the instant application claims a method wherein the modified based is an 8-aza-deaza-dN (ppN) base analog, where N is adenine (A), cytosine (C), guanine (G), or thymine (T). U.S. Patent No. 10,081,833 B2 claims a method wherein the modified based is an 8-aza-deaza-dN (ppN) base analog, where N is adenine (A), cytosine (C), guanine (G), or thymine (T) (see claim 6).
Regarding claim 13, the instant application claims a method wherein the modified base is located at (a) the 3’-end, (b) the 5’-end, (c) at an internal position, or at any combination of (a), (b), or (c) within at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe. U.S. Patent No. 10,081,833 B2 claims a method wherein the modified base is located at (a) the 3’-end, (b) the 5’-end, (c) at an internal position, or at any combination of (a), (b), or (c) within at least one of the first allele-specific primer, the second allele-specific primer, the first allele-specific blocker probe, or the second allele-specific blocker probe (see claim 9).
Regarding claim 14, the instant application claims a method wherein step (b) and/or (e) comprise a 2-stage cycling protocol. U.S. Patent No. 10,081,833 B2 claims a method wherein carrying out amplification reaction comprises a 2-stage cycling protocol (see claim 11).
Regarding claim 15, the instant application claims a method wherein the number of cycles in a first stage of the 2-stage cycling protocol comprises fewer cycles than the number of cycles used in a second stage. U.S. Patent No. 10,081,833 B2 claims a method wherein the number of cycles in a first stage of the 2-stage cycling protocol comprises fewer cycles than the number of cycles used in a second stage (see claim 12).
Regarding claim 16, the instant application claims a method wherein the first annealing/extension temperature used during the first cycling stage is between 1-3°C lower than a second annealing/extension temperature used during the second stage. U.S. Patent No. 10,081,833 B2 claims a method wherein the first annealing/extension temperature used during the first cycling stage is between 1-3°C lower than a second annealing/extension temperature used during the second stage (see claim 15).
Regarding claim 17, the instant application claims a method wherein step (a) is preceded by a pre-amplification step. U.S. Patent No. 10,081,833 B2 claims a method wherein step (a) is preceded by a pre-amplification step (see claim 17).
Regarding claim 18, the instant application claims a method wherein the pre-amplification step comprises a multiplex amplification reaction that uses at least two sets of allele-specific primers and locus-specific primers, wherein each set is suitable or operative for amplifying a specific polynucleotide of interest. U.S. Patent No. 10,081,833 B2 claims a method wherein the pre-amplification step comprises a multiplex amplification reaction that uses at least two sets of allele-specific primers and locus-specific primers, wherein each set is suitable or operative for amplifying a specific polynucleotide of interest (see claim 18).
Regarding claim 19, the instant application claims a method wherein the multiplex amplification reaction further comprises a plurality of allele-specific blocker probes. U.S. Patent No. 10,081,833 B2 claims a method wherein the multiplex amplification reaction further comprises a plurality of allele-specific blocker probes (see claim 20).
Claims 1 & 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 & 2 of U.S. Patent No. 11,530,450 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because each provides a method for detecting a first allelic variant of a target sequence in a nucleic acid sample through forming a first reaction mixture.
Regarding claim 1, the instant application claims a method for detecting at least one single nucleotide polymorphism (SNP) in a first allelic variant and a second allelic variant of a target sequence in a nucleic acid sample comprising forming a first reaction mixture comprising the nucleic acid sample that contains the first allelic variant of the target sequence, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out and amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the at least one SNP in the first allelic variant of the target sequence. U.S. Patent No. 11,530,450 B2 claims a method for detecting a first allelic variant of a target sequence in a nucleic acid sample suspected of comprising at least a second allelic variant of the target sequence comprising forming a reaction mixture comprising the nucleic acid sample, a first allele-specific primer, a first allele-specific blocker probe comprising a minor groove binder, a first locus-specific primer, and a first detector probe and carrying out an amplification reaction to form a first amplicon and detecting the first amplicon thereby detecting the first allelic variant of the target sequence (see claim 1).
Regarding claim 9, the instant application claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant possessing the at least one SNP. U.S. Patent No. 11,530,450 B2 claims a method further comprising using the change in the detectable property of the first detector probe to quantitate the first allelic variant (see claim 2).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure.
No prior art was found that teaches or suggests a method for detecting a first allelic variant of a target sequence in a nucleic acid sample suspected of comprising at least a second allelic variant of the target sequence as currently claimed. The closest prior art of Kolodney et al. (U.S. Patent Pub. No. 2010/0009355), as cited on the IDS dated 03/03/2023, teaches the use of high affinity nucleic acid blocker analogs for preferential amplification of a rare mutant target nucleic acid in a population of excess wild-type nucleic acids where the method may be used to identify one or more assays or more than one mutation in a sample, wherein one or more detection probes, primers, and high affinity blockers may be provided, paragraph 41, lines 1-6 and paragraph 58, lines 1-20), comprising: a) hybridizing an allele-specific primer to a first a nucleic acid molecule comprising a target allele (paragraph 7, lines 1-8 and nucleic acid templates shown in Figure 1); b) hybridizing an allele-specific blocker probe to a second nucleic acid molecule comprising an alternative allele (paragraph 7, lines 10-18 and Figure 1); c) hybridizing a locus-specific detector probe to the first nucleic acid molecule (paragraph 8, lines 12-16, paragraph 29, lines 9-14 and paragraph 30, lines 1-3); d) hybridizing a locus-specific primer to the extension product of the allele-specific primer (paragraph 7, lines 5-10 and paragraph 71); and e) PCR amplifying the target allele (paragraph 8, lines 1-12 and paragraph 30, lines 1-9), but does not teach the use of blocker analogs comprising a minor groove binder (MGB), and does not reach the level of discrimination using LNA blocker probes as that obtained with the instant invention using MGB-modified blocker probes. While the reference of Afonina et al. (Proc. Natl. Acad. Sci. U.S.A. (1996), Vol. 93, pp. 3199-3204), as cited on the IDS dated 03/03/2023, teaches methods for blocking primer extension by a polymerase using probes comprising a MGB, the reference does not teach methods wherein MGB moieties are placed in blocker analogs that block the binding of an allele-specific primer to the wild-type target at the same loci as the rare allele.
Also of particular interest to the instant application are the references of Boyd, V. L. (U.S. Patent Pub. No. 2007/0087360), as cited on the IDS dated 03/03/2023, and Kutyavin et al. (Nucleic Acids Research (2000) Vol. 28, No. 2, pp. 655-661), as cited in the IDS dated 03/03/2023. Boyd and Kutyavin each teach different types of probes comprising a MGB, but do not teach blocking probes that function to block primer extension during PCR to detect one allele preferentially over another.
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682