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 .
Claim Status/Action Summary
This action is in response to the papers filed on March 22, 2026.
Claims 1-20 are pending. Claims 10-14 are withdrawn as directed to a non-elected invention. Claims 1-9 and 15-20 are under examination.
Any objections and rejections not reiterated herein are hereby withdrawn.
The objection to the drawings is withdrawn in view of the replacement drawings filed with the response on March 22, 2026.
The objections to the specification have been withdrawn in view of the substitute specification filed with the response on March 22, 2026.
The claim objections of record have been withdrawn in view of the amendments to the claims.
The 112(d) rejection of record of claim 15 has been withdrawn in view of the amendments to the claims now presenting claim 15 as an independent claim.
The 102 rejections of record have been withdrawn in view of the amendments to the independent claims requiring “the specific detection site is a single nucleotide”, interpreted as requiring (see claim interpretation section below) that:
The 3’ end of the upstream primer (i.e. the single nucleotide at the 3’ terminus) hybridizes to the single nucleotide at the specific detection site on a negative strand; and
The 3’ end of the downstream primer (i.e. the single nucleotide at the 3’ terminus) hybridizes to the single nucleotide at the specific detection site on a positive strand
(i.e. the term “single nucleotide” is used interchangeably with “single base pair”).
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-9 and 15-20 in the reply filed on October 21, 2025 is acknowledged. The traversal is on the grounds that the response asserts that the cited prior art does not disclose: “the 3’-end of [the upstream AND downstream primers are] capable of being complementary to the same specific detection site”. The response further asserts that “the same specific detection site” requires the following configuration of claimed primers and “reduces the requirement for the length of the target sequences to the theoretical minimum”. Note, this figure is not present in the disclosure as filed.
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This argument has been thoroughly reviewed and is not found persuasive because the claims do not clearly limit the primers to the particular embodiment argued above. The response appears to assert that “the same specific detection site” requires that the 3’ end nucleotide of the “upstream” primer hybridizes to a first particular single nucleotide and the “downstream” primer hybridizes to a particular single nucleotide that is complementary to the first nucleotide (i.e. the specific embodiment illustrated by the new drawing introduced in the response). However, the claims require that the 3’ ends of the upstream and downstream primers are “capable of being complementary to the same specific detection site”. The specification provides, “a specific detection site refers to a base site that can distinguish a target nucleic acid from other nucleic acids” (page 14, line 2-3). Related target nucleic acids may differ from each other by more than one consecutive nucleic acid, for example, in the case of an insertion/deletion or inversion mutation.
Furthermore, claim 9, dependent upon claim 1, further requires that the “specific detection site is a mutation site”. The specification further provides “mutation may be selected from the following items: base substitution mutation, insertion mutation and deletion mutation” (Specification, page 13, line 28-29).
Therefore, a “specific detection site” or “a base site that can distinguish a target…” encompasses embodiments wherein the two primers anneal to opposite strands of a target nucleic acid that are separated by one or more intervening base pairs and the claim as presently written is not limited to the specific embodiment asserted by the response.
Furthermore, the preferred narrower embodiment asserted by the response likewise does not make a contribution over the prior art, as described in the 103 rejection(s) below.
The requirement is still deemed proper and is therefore made FINAL.
Claims 10-14 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. Applicant timely traversed the restriction requirement in the reply filed on October 21, 2025.
The response filed March 22, 2026 reasserts that the inventions listed as Group I and Group II belong to a single overall invention because none of the cited references alone teach all of the claimed features as amended (i.e. the claims are not anticipated by any of the cited references). The response further asserts that Kelly et al. does not teach “the same specific detection site, wherein the specific detection site is a single nucleotide.”
These arguments have been reviewed and are not persuasive. While the amendments to the claims have overcome the 102 (anticipation) rejections of record, the 103 rejections which follow have been updated as necessitated by the amendments to the claims demonstrate that the claimed invention, as currently recited, would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention (i.e. Unity of invention is lacking a posteriori due to the lack of a common technical feature among the claims which makes a contribution over the prior art because the cited references demonstrate that the claimed invention, while apparently novel over the references of record, lacks an inventive step in view of the references of record).
It is reiterated that applicant elected product claims and timely traversed the restriction requirement in the reply filed on October 21, 2025. As detailed below, none of the elected product claims have been found to be allowable. As detailed below, if the product claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product claims should be considered for rejoinder at that time. The relevant “notice of potential rejoinder of process claims in Ochai/Brouwer situation” is reproduced below for convenience.
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Priority/Effective Filing date
The present application, filed March 23, 2023, is a 371 of PCT/CN2020/117163, filed on September 23, 2020.
Drawings
The drawings filed with the response on March 22, 2026 are acceptable.
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.
Claims 7 and 19 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
This rejection has been updated as necessitated by the claim amendments.
Regarding claims 7 and 19, the term “all or part of the sequence of the second primer are the same as that of the of the signal detection region; wherein the region on the signal detection region that is the same as the signal oligonucleotide is located downstream of the region thereon that is the same as the second primer…” renders the claim indefinite because it contradicts the limitation of claim 1, “the signal oligonucleotide is designed to be independent of the upstream primer and/or the downstream primer and contain the same sequence as the signal detection region” (i.e. the signal oligonucleotide sequence comprises the entirety of the signal detection region). Claims 7 and 19 appear to require that the signal detection region comprises an additional 3’ sequence comprising a binding site for a second primer (i.e. the signal oligonucleotide does not contain (i.e. comprise) the same sequence as the signal detection region).
Response to arguments
The response asserts that the “the signal oligonucleotide contains the sequence identical to the signal detection region, and may also contain sequence[s] [that are] different from the signal detection region”, the intended claim language corresponding to non-English language claims in the published PCT application “is an open-ended expression meaning “contain” or “comprise” or “include” or “have” and has been amended as “contain”.
The amended open-ended claim language is addressed in the updated 112(b) rejection of claims 7 and 19 above.
To summarize the updated rejection, the open-ended claim language requires that the signal oligonucleotide comprises the same (i.e. an identical) sequence as the signal detection region (i.e. the entire region). Claims 7 and 19 contain limitations that contradict this limitation. Claims 7 and 19 require that the signal detection region further comprises a region that is not the same as the sequence of the signal oligonucleotide (i.e. a sequence that is not comprised within the sequence of the signal oligonucleotide): “the region on the signal detection region that is the same as the signal oligonucleotide is located downstream of (i.e. closer to the 3’ end relative to) the region that is the same as the second primer”.
Claim Interpretation
In the interest of compact prosecution and for the purposes of the prior art rejections which follow, the independent claims have been interpreted in view of the preferred embodiments asserted by the response and supported by the examples in the specification.
It is noted that the specification contains the following definitions:
“according to customary terms in the art, the length of the nucleic acid can be represented by base pair, nucleotide, or kilobase” (page 13, lines 8-11) (i.e. the terms “nucleotide” and “base pair” have distinct meanings in the art).
“The term “specific detection site” refers to a base site that can distinguish a target nucleic acid from other nucleic acids… for example, for a point mutation… the “specific detection site” is the mutant base” (page 13, line 30 – page 14, line 2).
“The term “upstream primer”… also known as a forward primer, is an oligonucleotide that continuously elongates along a negative strand” and “The term “downstream primer”… also known as a reverse primer… is an oligonucleotide that continuously elongates along a positive strand” (page 14 line 32-page 15, line 2).
The claim term “the specific detection site is a single nucleotide” has been interpreted in view of the definitions of “upstream primer” and “downstream primer” in the specification requiring that these two oligonucleotides hybridize to opposite strands of a particular target sequence. It is not non-standard in the art to represent a double-stranded nucleic acid sequence with a single sequence of nucleotides having a specified polarity, with the sequence of the complementary strand being implicit therein. Because the claimed “combination for detection of nucleic acids” comprises oligonucleotide primers that are capable of hybridizing to a particular nucleotide sequence, this claim term has been given the broad interpretation wherein “a single nucleotide” is interpreted as “a single base pair”. One skilled in the art would recognize that an upstream primer and downstream primer, as defined in the specification, cannot have 3’ ends that are both complementary to one nucleotide member of a single base pair.
Therefore, the particular alternative embodiments recited by independent claims 1 and 15 have been interpreted as follows.
IN the recited embodiment “the upstream primer and/or the downstream primer further comprises a signal detection region upstream of the target sequence binding region, and the signal oligonucleotide is designed to be independent of the upstream primer and/or the downstream primer and contain the same sequence as the signal detection region” (claim 1, line 13-17):
One example in the specification supporting this embodiment is found in table 1:
The exemplary oligonucleotides of SEQ ID Nos: 1-3 (see below) wherein the 3’ end of the upstream primer is complementary to a specific detection site that is a single nucleotide on a first strand of a target sequence and the 3’ end of the downstream primer is complementary to a specific detection site that is a single nucleotide on a second strand of a target sequence that is complementary to the single nucleotide specific detection site on the first strand of the target sequence.
The oligonucleotides of table 1 target a known G>C single nucleotide polymorphism (SNP) in exon 18 of the human EGFR gene (sequence as follows, retrieved from the annotated GRCh37/hg19 genome at UCSC Genome browser)
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(Sequence from 5’ > 3’, first uppercase and highlighted sequence beginning “AAAA” is identical to the second (i.e. more 3’) highlighted sequence in SEQ ID NO: 1 (see below).
(Sequence from 5’ > 3’, second uppercase and highlighted sequence beginning “CTCC” is identical to the highlighted sequence in SEQ ID NO: 2 (see below)
(Sequence from 5’ > 3’, the Bold, uppercase, and underlined “G” is the single polymorphic nucleotide that is detected by the exemplary oligonucleotides of Table 1.
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The first uppercase and highlighted sequence beginning “CCGA” in SEQ ID NO: 1 is a “signal detection region” upstream of (i.e. closer to the 5’ end relative to) the target sequence binding region wherein the signal detection oligo (e.g. SEQ ID No: 3, see below) contains the same sequence as (i.e. comprises) the signal detection region.
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Sequence from 5’ > 3’, “FAM” = 5’ FAM (fluorophore) modification, “GBHQ” = Black Hole Quencher modified nucleotide, c9= C9 spacer moiety separating the two underlined “stem” regions which are complementary to each other such that they can form a hairpin wherein the FAM and BHQ molecules are in close proximity (i.e. the FAM is quenched).
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In practice, the exemplary oligos are interpreted as being capable of binding to and amplifying the exemplary target molecule as follows:
IN the alternative embodiment recited by the independent claims “the signal oligonucleotide is designed as a part of the upstream primer and/or the downstream primer, and to be located upstream of the target sequence binding region”
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An exemplary “upstream primer” wherein “the signal oligonucleotide is designed as a part of the upstream primer…” corresponding to the example in Table 1 (“SEQ1” in the figure above) is:
Therefore, as best understood, the independent claims have been interpreted as requiring: embodiment 2: a) an upstream primer (exemplified by SEQ ID 1)… wherein the 3’ end… is… complementary to a [single nucleotide]” comprising a signal detection region upstream of the target sequence binding region, b) a downstream primer (exemplified by SEQ ID 2)… wherein the 3’ end… is… complementary to a [single nucleotide that is complementary to the single nucleotide to which the 3’ end of the upstream primer is complementary]” (i.e. requiring the “single nucleotide” to which each 3’ end is complementary are different, are complementary in a target sequence, and are on opposite strands of the target sequence), and c) a signal oligonucleotide that is independent of the upstream primer and/or the downstream primer… contain[ing] the same sequence as the signal detection region”
Or
Embodiment 1: a) an upstream primer comprising from the 5’ end to the 3’ end: a signal oligonucleotide…a target sequence binding region…a 3’ end that is complementary to a specific detection site that is a single nucleotide in a target sequence, and b) a downstream primer (and/or wherein the downstream primer comprises the signal oligonucleotide)
Claim 1 recites the limitation to the embodiment wherein one or both of the upstream or downstream primers comprise a signal detection region wherein “the signal oligonucleotide is designed to be independent of the upstream primer and/or downstream primer and contain the same sequence as the signal detection region”. This limitation has been interpreted as requiring that the signal oligonucleotide contains (i.e. comprises) the entirety of the signal detection region.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 9, and 15-18 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Jatayev et al., “Advantages of Amplifluor-like SNP markers over KASP in plant genotyping”, BMC Plant Biology 2017, 17(Suppl 2):254, pp. 83-93 (previously cited on form PTO-892 dated August 25, 2025) in view of Kelley et al., WO 2013/093432 A1 (Published 27 June, 2013).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claims 1 and 15, Jatayev et al. teach: a) an upstream and downstream primer pair that comprise target-specific binding sequences at their 3’ ends, b) “Universal probes” (i.e. signal oligonucleotides) having a first and second detection group (a fluorophore and quencher) that generate a change in signal by means of a change in distance (probe unfolding). Jatayev et al. teach that the Universal probes are independent of the primers, and the forward primers comprise a signal detection region at the 5’ end (i.e. upstream of the target binding region) that is the same sequence as the signal oligonucleotide, which does not anneal to the target sequence (Jatayev et al., Figure 1 (see below), Table 1 (see below), page 84-85, and additional file 3).
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Jatayev et al. do not teach that the upstream and downstream primers are capable of being complementary to the same “specific detection site” (using the preferred embodiment wherein the “downstream” (i.e. 3’) ends of the primers comprise the entirety of the detection site).
However, Kelly et al. teach combinations/kits comprising primers for enriching and detecting nucleic acids wherein the 3’ ends of the upstream and downstream primers fully encompass the locus to be enriched/detected/amplified (Kelly et al., Abstract and figure 1, see below). Kelly et al. teach that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Kelly et al. further teach that overlapping primers that bind with their 3’ terminus at a variant nucleotide were known in the art (i.e. overlapping by one nucleotide) with particular reference to WO2008/104794 (Kelly et al., page 5, line 22-23).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the upstream and downstream primers taught by Jatayev et al. that anneal to either strand of a nucleic acid template flanking a SNP of interest to comprise the SNP at the 3’ ends of the respective primers, as taught by Kelly. The ordinary artisan would have been motivated to modify the primers of Jatayev et al. with the teachings of Kelly because Kelly teaches that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Regarding claims 2 and 16, Jatayev et al. teach the signal oligonucleotide is designed to be independent (a distinct oligonucleotide) from the upstream and downstream primers (see figure 1), the signal oligonucleotide comprises a first stem, a loop, a second stem, and an anchor region from 5’ to 3’. Jatayev et al. further teach the signal oligonucleotide is complementary to the signal detection region of the primers, and the first detection group modifies the first stem region, and the second detection group modifies the second stem region (Jatayev et al., figure 1).
Regarding claims 3 and 17, Jatayev et al. teach the second stem region and anchor region are separated by one base (Jatayev et al., figure 1).
Regarding claim 4, Jatayev et al. teach the first detection group is in the first stem region and the second detection group is between the second stem region and the anchor region (at the 3’ end of the second stem region) (Jatayev et al., figure 1)
Regarding claims 5 and 18, Jatayev et al. teach the signal oligonucleotide is independent of the primers, is a flexible oligonucleotide (that is “curled on itself” when not bound to the signal detection region) (i.e. is a hairpin probe), and the two detection groups are not located at the 3’ end of the signal oligonucleotide (Jatayev et al., Figure 1).
Regarding claim 6, Jatayev et al. teach the two detection groups are 21 (i.e. 5-25) nucleotides away from each other in the signal oligonucleotide.
Regarding claim 9, Jatayev et al. teach the specific detection site is a mutation site (Jatayev et al., Table 1 and page 85, column 1, paragraph 3).
Claims 1, 8, 15, and 20 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Nazarenko et al., “A closed tube format for amplification and detection of DNA based on energy transfer” Nucleic Acids Research, 1997, Vol. 25, No. 12, page 2516-2521 in view of Kelley et al., WO 2013/093432 A1 (Published 27 June, 2013).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claims 1 and 15, Nazarenko et al. teach a set of primers comprising a forward and reverse primer wherein a hairpin structure comprising a pair of detection groups that generate a change in signal by means of a change in distance (i.e. a FRET pair) is present on the 5’ end of one or both of the primers (Nazarenko et al., Figure 1, see below and page 2518, column 1, paragraph 5) (i.e. the signal oligonucleotide is designed as a part of the upstream primer and/or the downstream primer upstream (5’) of the target sequence binding region).
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Nazarenko et al. do not teach that the upstream and downstream primers are capable of being complementary to the same “specific detection site” (using the preferred embodiment wherein the “downstream” (i.e. 3’) ends of the primers comprise the entirety of the detection site).
However, Kelly et al. teach combinations/kits comprising primers for enriching and detecting nucleic acids wherein the 3’ ends of the upstream and downstream primers fully encompass the locus to be enriched/detected/amplified (Kelly et al., Abstract and figure 1, see below). Kelly et al. teach that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Kelly et al. further teach that overlapping primers that bind with their 3’ terminus at a variant nucleotide were known in the art (i.e. overlapping by one nucleotide) with particular reference to WO2008/104794 (Kelly et al., page 5, line 22-23).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the upstream and downstream primers taught by Nazarenko et al. that anneal to either strand of a nucleic acid template flanking a SNP of interest to comprise the SNP at the 3’ ends of the respective primers, as taught by Kelly. The ordinary artisan would have been motivated to modify the primers of Nazarenko et al. with the teachings of Kelly because Kelly teaches that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Regarding claim 8, Nazarenko et al. teach the signal oligonucleotide is designed as part of the upstream and/or downstream primer and is/are located upstream of the respective target sequence binding region(s). Nazarenko et al. further teach the signal oligonucleotide comprises, from 5’ to 3’, a first stem, a loop region, and a second stem region wherein the first detection group (i.e. a donor fluorophore) is located in the first stem region and the second detection group (i.e. a quencher) is located in the second stem region (Nazarenko, figure 1).
Regarding claim 20, Nazarenko et al. further teach the first stem is complementary to the second stem region and the first detection group (i.e. a donor fluorophore) is located in the first stem region and the second detection group (i.e. a quencher) is located in the second stem region (Nazarenko, figure 1).
Claims 1, 7, 15, and 19 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Rajagopal et al., WO 2020/051521 A1 (published 12 March 2020, international filing date 6 September, 2019) in view of Kelley et al., WO 2013/093432 A1 (Published 27 June, 2013).
This rejection has been updated as necessitated by the amendments to the claims.
Regarding claims 1 and 15, Rajagopal et al. teach combinations/kits for nucleic acid detection comprising allele-specific upstream and downstream primers having 5’ “universal tails” comprising a signal detection region, and a signal oligonucleotide that is independent from the primers (Rajagopal et al., Figure 1).
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Rajagopal et al. do not teach that the upstream and downstream primers are capable of being complementary to the same “specific detection site” (using the preferred embodiment wherein the “downstream” (i.e. 3’) ends of the primers comprise the entirety of the detection site).
However, Kelly et al. teach combinations/kits comprising primers for enriching and detecting nucleic acids wherein the 3’ ends of the upstream and downstream primers fully encompass the locus to be enriched/detected/amplified (Kelly et al., Abstract and figure 1, see below). Kelly et al. teach that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Kelly et al. further teach that overlapping primers that bind with their 3’ terminus at a variant nucleotide were known in the art (i.e. overlapping by one nucleotide) with particular reference to WO2008/104794 (Kelly et al., page 5, line 22-23).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the upstream and downstream primers taught by Rajagopal et al. that anneal to either strand of a nucleic acid template flanking a SNP of interest to comprise the SNP at the 3’ ends of the respective primers, as taught by Kelly. The ordinary artisan would have been motivated to modify the primers of Rajagopal et al. with the teachings of Kelly because Kelly teaches that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Regarding claims 7 and 19, Rajagopal et al. teach that the signal probe is hydrolyzed by the extension of a second primer (Rajagopal et al., Figure 5b).
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Response to arguments
The response summarizes embodiments of Kelly et al. wherein “enriching primers” hybridize to the reference sequence (i.e. non-mutated) comprising the locus wherein variant alleles comprise SNPs relative to the reference sequence and upstream and downstream “amplification primers” hybridize to loci that are not the same as those bound by the enriching primers.
The response asserts that the claimed invention is distinct from the combination of cited references because Kelly et al. do not teach that the 3’ end of the amplification primer is complementary to the mutation site.
The response further asserts that Kelly et al. “do not teach the design of amplification primers with only one overlapped base”
Finally, the response asserts that the overlapping enrichment primers of Kelly et al. initiate amplification from the reference sequence rather than from the mutant sequences… “which is fundamentally different from the… present application” and that “the technical solution of the present application… differs from the technical problem to be solved by Kelly et al…”
These arguments have been thoroughly reviewed and are not persuasive for the following reasons.
Each of the primary references Jatayev et al., Nazarenko et al., and Rajagopal et al. (i.e. not Kelly) are cited in their respective rejections for their teachings that the 3’ end of an amplification primer is advantageously complementary to a mutation site to achieve allele-specific amplification.
Kelly et al. is cited as a secondary reference for the teaching that overlapping primers selectively amplify complementary target sequences relative to mismatched sequences.
It is noted that the only difference between the cited primary references and the claimed invention appears to be that the 3’ end of the “reverse” primer hybridizes to the same base pair (on the other strand) as the 3’ end of the “forward” primer.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As described in the 103 rejections above, the claims are prima facie obvious in view of the combination of the teachings of any one of the primary references (teaching the structural features of the claimed primers and probe(s)) with the teaching of Kelly et al. that primers with overlapping 3’ ends successfully amplify complementary target nucleic acids, motivated by the teachings of Kelly et al. that combinations of primers comprising said overlapping 3’ ends “allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample”.
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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Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 15 of copending Application No. 18/027,971 (herein referred to as ‘971) in view of Kelley et al., WO 2013/093432 A1 (Published 27 June, 2013).
This is a new grounds of rejection necessitated by the amendments to the claims.
Claim 15 of ‘971 recites a composition (i.e. a combination/kit) comprising an upstream primer and downstream primer both of which are specific to a first target, a first probe, all or part of the sequence thereof is the same as those of a first signal detection region, the first probe comprises a first detection group and a second detection group and the first and second detection groups can generate signal change.
The claims of ‘971 do not require that the upstream and downstream primer are specific to a first target, wherein the first target (i.e. specific detection site) is a single nucleotide.
However, Kelly et al. teach combinations/kits comprising primers for enriching and detecting nucleic acids wherein the 3’ ends of the upstream and downstream primers fully encompass the locus to be enriched/detected/amplified (Kelly et al., Abstract and figure 1, see below). Kelly et al. teach that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
Kelly et al. further teach that overlapping primers that bind with their 3’ terminus at a variant nucleotide were known in the art (i.e. overlapping by one nucleotide) with particular reference to WO2008/104794 (Kelly et al., page 5, line 22-23).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the upstream and downstream primers recited by the claims of ‘971 that anneal to either strand of a nucleic acid template flanking a SNP of interest to comprise the SNP at the 3’ ends of the respective primers, as taught by Kelly. The ordinary artisan would have been motivated to modify the primers claimed by ‘971 with the teachings of Kelly because Kelly teaches that such overlapping primers allow for rapid and sensitive detection of genetic variations for use in assays to detect rare mutations in a sample (Kelly, page 17, line 20-25).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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