DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
2. Claim 2 is objected to because of the following informalities: Claim 2, line 1 recites the phrase “more than one bases…” it is believed that this is a typographical error, and the claim should read “more than one base…”
Claim 5 is objected to because of the following informalities: Claim 5, line 27 recites the phrase “…wherein the target nucleic is reduced acid…” It is believed that this is a typographical error and the claim should read “…wherein the target nucleic acid is reduced…” Appropriate correction is required.
Claim Rejections - 35 USC § 112
3. 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.
4. Claims 1-12 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.
A. Claim 1 recites the limitation "the terminal guanine" in lines 8-9, 11, 16-17, 19 and 23-24. The antecedent basis for this phrase is “at least one terminal of the probe-binding region is a guanine,” and it is unclear how the metes and bounds of the claim are to be interpreted in embodiments wherein both terminals are guanine bases (an embodiment that is currently encompassed by the claim language). In such an embodiment do the limitations related to “the terminal guanine” apply to both terminal guanines? Only a particular one of the terminal guanines? The scope of these limitations lack clarity and there is insufficient antecedent basis for this limitation in the claim, therefore this claim is indefinite.
Claim 1 recites the limitation "the cytosine that is present within 1 to 7 bases from the terminal guanine" in line 16 of the claim. There is insufficient antecedent basis for this limitation in the claim with respect to the phrase “…and one or more cytosines are present within 1 to 7 bases from the terminal guanine…” It is unclear, as written, if the oligonucleotide is complementary to the nucleic acid in the probe-binding region: except for [each of] the one or more cytosines present within 1 to 7 bases of the terminal guanine, or except for [only] the cytosine that is closest to the terminal guanine.
Claim 1 recites the limitation "the base" in line 18. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the phrase “…at a position complementary to the cytosine closest to the terminal guanine…” and then provides limitations that the base at this position “is selected from the group consisting of adenine, thymine, cytosine and nebularine.” It is unclear how these bases would be considered “complementary to” or how a position could be considered “complementary to” a cytosine, when applicant’s specification describes “complementary” as a term indicating that certain bases make pairs and form hydrogen bonds ([0026]). For the reasons outlined about, this claim lacks clarity and is therefore indefinite.
B. Claim 2 recites the phrase “wherein more than one bases in the oligonucleotide at a position complementary to the one or more cytosines…” It is unclear how more than one base can be present at a position complementary to one cytosine, which is an embodiment encompassed by the claim as written. It is unclear how these limitations affect the metes and bounds of the claim and therefore the claim is indefinite.
C. Claim 5 recites the limitation "the terminal guanine" in lines 13-14, 16, 21, 22, 24 and 28-29. The antecedent basis for this phrase is “at least one terminal of the probe-binding region is a guanine,” and it is unclear how the metes and bounds of the claim are to be interpreted in embodiments wherein both terminals are guanine bases (an embodiment that is currently encompassed by the claim language). In such an embodiment do the limitations related to “the terminal guanine” apply to both terminal guanines? Only a particular one of the terminal guanines? The scope of these limitations lack clarity and there is insufficient antecedent basis for this limitation in the claim, therefore this claim is indefinite.
Claim 5 recites the limitation "the cytosine that is present within 1 to 7 bases from the terminal guanine" in line 21 of the claim. There is insufficient antecedent basis for this limitation in the claim with respect to the phrase “…and one or more cytosines are present within 1 to 7 bases from the terminal guanine…” It is unclear, as written, if the oligonucleotide is complementary to the nucleic acid in the probe-binding region: except for [each of] the one or more cytosines present within 1 to 7 bases of the terminal guanine, or except for [only] the cytosine that is closest to the terminal guanine.
Claim 5 recites the limitation "the base" in line 23. There is insufficient antecedent basis for this limitation in the claim.
Claim 5 recites the phrase “…at a position complementary to the cytosine closest to the terminal guanine…” and then provides limitations that the base at this position “is selected from the group consisting of adenine, thymine, cytosine and nebularine.” It is unclear how these bases would be considered “complementary to” or how a position could be considered “complementary to” a cytosine, when applicant’s specification describes “complementary” as a term indicating that certain bases make pairs and form hydrogen bonds ([0026]). For the reasons outlined about, this claim lacks clarity and is therefore indefinite.
D. Claim 6 recites the limitation "the terminal guanine" in lines 8, 10, 16, 21 and 27. The antecedent basis for this phrase is “at least one terminal of the probe-binding region is a guanine,” and it is unclear how the metes and bounds of the claim are to be interpreted in embodiments wherein both terminals are guanine bases (an embodiment that is currently encompassed by the claim language). In such an embodiment do the limitations related to “the terminal guanine” apply to both terminal guanines? Only a particular one of the terminal guanines? The scope of these limitations lack clarity and there is insufficient antecedent basis for this limitation in the claim, therefore this claim is indefinite.
Claim 6 recites the limitation "the base" in line 20. There is insufficient antecedent basis for this limitation in the claim.
E. Claims 1, 5 and 6 each recite the phrase “…a fluorescent dye that is quenched by fluorescence resonance energy transfer between the fluorescent dye and a guanine…” However, based on the prior art at the time the instant application was filed, it seems that the interaction between fluorescent dyes and guanine residues is based on photoinduced electron transfer (PET), not fluorescence resonance energy transfer as currently claimed (see Qu et al, Fluorescence quenching of TMR by guanosine in oligonucleotides, abstract and pg. 1653 column 1 ¶ 2; Torimura et al, Fluorescence-quenching phenomenon by photoinduced electron transfer between a fluorescent dye and a nucleobase, abstract and pg. 155 column 2 ¶ 2; and Xiang et al, Multiplexed DNA detection with a composite molecular beacon based on guanine-quenching, pg. 5318 column 2 ¶ 2). It is unclear, based on the language of the claim and the applicant’s specification, if the claim limitations are related to a specific, different fluorescence resonance energy transfer phenomenon or if the claims are drawn to the standard PET-based energy transfer discussed in the prior art. For the purpose of prosecution, this term is being interpreted broadly as “energy transfer” between a fluorophore and one or more guanine residues.
F. Claims 3, 4 and 7-12 are further rejected for being dependent on a previously rejected claim.
Double Patenting
5. 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
6. Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11434533 in view of Qu et al (Fluorescence quenching of TMR by guanosine in oligonucleotides, Science in China Series B: Chemistry, 52, 1653-1659, published 18 October 2009).
The limitations of instant claims 1, 5 and 6 are taught in claims 3, 5 and 6 of the issued patent, respectively, except the limitations wherein the base having no fluorescence quenching effect is selected from the group consisting of adenine, thymine, cytosine and nebularine and the limitation wherein a decrease in fluorescence intensity of the nucleic acid probe which is not hybridized with the target nucleic acid is reduced compared to the case where the base in the oligonucleotide at a position complementary to they cytosine closest to the terminal guanine would be guanine.
However, Qu teaches two single-stranded DNA probes having the same sequence except for the nucleotides at positions 4 and 5 counting from the 5' end of each probe (Table 1, ss-G having 5'-TMR-ATCGG… and ss-NG having 5'-TMR-ATCCC…). Qu teaches that the nucleic acid probe having cytosines at positions 4 and 5 (ss-NG) has increased fluorescence compared to the probe having guanine at positions 4 and 5 (ss-G; FIG 2(a)) in the absence of a target.
It would have been obvious to one having ordinary skill in the art to have replaced the guanine nucleotides present in positions 1-7, as taught by the issued patent, with cytosine residues as taught by Qu to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification because the claims of issued patent teach the substitution of guanine residues with a non-complementary base (hypoxanthine) and Qu specifically teaches that fluorescent probes without guanine near the 5' end have improved starting fluorescence (Table 1 and FIG 2a). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the design and study of fluorescently labeled nucleic acid probes based on fluorophore-guanine interactions.
The limitations of instant claims 2-4, and 7-9 are taught in claims 3, 4, 6 and 8 of the issued patent.
The limitations of instant claims 10-12 are taught by Qu for the embodiment wherein the fluorescent dye is tetramethylrhodamine (abstract).
Allowable Subject Matter
7. The following is a statement of reasons for the indication of allowable subject matter:
The claims in the current application stand rejected under U.S.C. § 112(b) and nonstatutory double-patenting, however the claims are free of the prior art and would be allowable if these rejections are overcome by amendment and/or the filing of appropriate terminal disclaimers.
The claims of the instant application are drawn to a method for detecting a target nucleic acid comprising the steps of mixing a nucleic acid probe and a sample to prepare a mixture and detecting the target nucleic acid based on the fluorescence of the mixture. The nucleic acid probe is complementary to a probe-binding region in the target nucleic acid, except for one or more cytosines present within 1 to 7 bases from a terminal guanine. The nucleic acid probe is modified to comprise bases that have no fluorescence-quenching activity at positions opposite to the one or more cytosines in the probe-binding region of the target nucleic acid (i.e., the bases in the probe would be guanine but are modified/substituted by a base selected from the group consisting of adenine, thymine, cytosine and nebularine).
The closest prior art is the combination of Kurata et al (Fluorescent quenching-based quantitative detection specific DNA/RNA using a BODIPY FL-labeled probe or primer), Qu et al (Fluorescence quenching of TMR by guanosine in oligonucleotides) and Hall et al (Sequence context and thermodynamic stability of a single base pair mismatch in short deoxyoligonucleotide duplexes). Kurata teaches a method of detecting a target nucleic acid comprising the steps of mixing a nucleic acid probe and a sample to prepare a mixture, measuring the fluorescence intensity from the mixture and detecting a target nucleic acid based on the fluorescence intensity (FIG 1 and pg. 3 column 1 ¶ 3). Kurata additionally teaches that guanine bases at the 5' end near the fluorophore significantly quench fluorescence of the probe not bound to the target (Table 1 and pg. 2 column 2 ¶ 4). Qu teaches single stranded DNAs with guanine residues within 5 nucleotides from a 5' fluorophore significantly quench fluorescence of a TMR dye compared to a single stranded DNA of the same sequence except that the guanine residues are replaced by cytosine (FIG 2a and pg. 1655 column 2 ¶ 2). Qu specifically does not teach a situation where the nucleotides in the probe are substituted with respect to the nucleotides in the target strand. Hall teaches that single-base mismatches are tolerated in the hybridization of a probe nucleic acid to a target nucleic acid (FIGs 1 and 2). None of these references, alone or in combination, anticipate or make obvious a nucleic acid probe that is complementary to a target sequence except for one or more positions opposite one or more cytosines in a probe-binding region of a target nucleic acid, wherein the one or more bases at the one or more positions are substituted with a base having no fluorescence-quenching effect selected from the group consisting of adenine, thymine, cytosine and nebularine.
Response to Arguments
8. Upon further consideration, the rejections under U.S.C. § 112(a), 112(b) and 103 established in the Office Action filed 13 March 2024 are withdrawn. However, new rejections under U.S.C. § 112(b) and nonstatutory double-patenting have been established.
9. Applicant’s arguments with respect to claims 1-12 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
10. No claims are allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-T 0800 - 1630.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
Prosecution Insights