DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 16, 2026 has been entered.
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 .
Preliminary Remark
Claims 6 and 13-27 are canceled.
Claims 7-12 and 28-34 remain withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention without traverse.
Claim Rejections - 35 USC § 112
The new matter rejection of claims 1-6 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, made in the Office Action mailed on January 20, 2026, is withdrawn in view of the Amendment received on April 16, 2026.
Claim Rejections - 35 USC § 112 - Rejection – New Grounds
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 1-5 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 1 is indefinite because the claim preamble recites a method of detecting a mutant nucleic acid in a sample, but the claim only contains a single active step of contacting a riboregulatory to a sample. The subsequent “wherein” clauses recite the characteristics of what would happen, but the method itself does not actively require any active step of detection.
Claims 2-5 are indefinite by way of their dependency on claim 1.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Green et al. (Cell, 2014, vol. 159, pages 925-939, herein “Green-1”) in view of Green et al. (WO 2014/074648 A2, published May 2014, herein, “Green-2”), and Byrom et al. (Nucleic Acids Research, 2014, vol. 42, no. 15, e120, pages 1-13).
With regard to claim 1, Green-1 teaches a riboregulatory sensor comprising the below reproduced structure (from Fig. 1(B)):
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As seen, Green-1 teaches a riboregulatory sensor comprising a synthetic nucleic acid molecule comprising a docking site1, a toehold domain, and a hairpin domain, the hairpin domain comprising a fully double-stranded stem domain and a loop domain, wherein the stem domain is complementary to a target nucleic acid, wherein if the target nucleic acid is present, the target nucleic acid will bind to and form a complex with the riboregulatory sensor, leaving the 3’ region of the riboregulatory in a position to produce a reporter protein (see “Repressed gene” resulting in active GFP).
The “toehold” region disclosed by Green-1 is 12 nucleotides long and therefore, any number of its region can be deemed 2-6 nucleotides in length and the rest of the remaining region be considered “docking site”.
Green-1 explicitly suggests that their sensor can be used to detect antibiotic resistance conferring mRNA (i.e., nucleic acids containing a target sequence):
“we validated two sensors for detecting antibiotic resistance conferring mRNAs: chloramphenicol acetyltransferase (cat) and aadA (spectinomycin resistance)” (page 931, 2nd column, 2nd paragraph)
With regard to the complex being in an energy state sufficient to produce a reporter protein when target-specifically bound, this wherein clause does not further distinguish the riboregulator as claimed. As well, a specifically-bound riboregulatory to its target nucleic acid would necessarily possess a stable energy state (i.e., stably bound) resulting in the translation in producing a reporter protein.
The structure of the riboregulator disclosed by Green-1, however, does not comprise an AUG (or start codon) within the fully-double stranded stem domain (it contains a bulge).
Green-1 does not explicitly teach that their sensor can be used in a method of targeting nucleic acids comprising an SNP therein, wherein the stem region of their sensor comprises a sequence complementary to said SNP.
Consequently, Green-1 does not explicitly teach that the SNP-containing nucleic acid molecule is associated with disease (claim 5).
Green-1 does not explicitly teach that the sample is a biological sample (claim 3), which is a liquid sample (claim 4).
Green-2 teaches a riboregulator having a similar structure as that of Green-1, with an AUG start codon in the fully double-stranded stem domain (see FIG. 1):
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Byrom et al. teach a method of detecting an SNP nucleotide on a target utilizing a stem-loop structure comprising a “toehold” region (see Figure 1), wherein the complementarity between the nucleotides in the toehold region and the target sequence favors the displacement of the stem loop structure and polymerase mediated extension to occur (see Figure 1):
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Green-1 with the teachings of Green-2 and Byrom et al., and conventional knowledge available in the art of molecular diagnostics, thereby arriving at the invention as claimed for the following reasons.
As discussed above Green-1 teaches a nucleic acid sensor which is designed to produce a reporter protein (GFP) in the presence of a target nucleic acid. As shown, the sensor comprises a region comprising 12 nucleotides (i.e., identified as “toehold”) which complements the target nucleic acid, as well as a portion stem region which form complementarity to the same target nucleic acid (regions a and b that complements to regions a’ and b’ of the target nucleic acid), resulting in the opening of the stem-loop region containing a ribosome binding region, which further results in the generation of GFPs.
While Green-1 did not explicitly teach that their sensor can be utilized to detect other forms of target nucleic acids, such as SNPs from biological samples, such as liquid samples, because Green-1 explicitly taught that their sensor can be used to detect specific target nucleic acids from samples to indicate the presence of antibiotic resistant sequences, one of ordinary skill in the art in the field of molecular diagnostics/sensors would have readily recognized that the sensors could also be utilized in the detection of other types of target nucleic acids, such as SNP containing target nucleic acids from samples (such as blood) which correlate with disease phenotypes, thus being motivated to extend the sensor of Green-1 for detecting SNP target sequences from human samples that are commonly used (i.e., blood).
As well, Byrom et al. also teach that a stem-loop comprising structure with a “toehold” region specifically tailored for complementarity with a target nucleic acid sequence and is very sensitive to mismatches (“[w]e have now applied … to design of hairpin primers that have an initiating toehold sequence that is exquisitely sensitive to mismatches” (page 2, 1st column) and teach that this feature can be utilized to detect SNPs.
Based on the obvious motivation to apply the teachings of Green-1 for detecting routinely assayed target nucleic acid sequences, such as those containing SNPs associated diseases, one of ordinary skill in the art would have been motivated to combine the teachings of Byron et al. into the toehold region of Green-1’s sensor, allowing for better discrimination capability when detecting a single-base pair mutation from a target, avoiding signal generation from mis-matched hybridization which could occur, a common issue in detection of SNPs:
“However, certain mismatches are efficiently extended, leading to inaccurate genotyping …” (page 1, 2nd column, Byrom et al.)
Lastly, with regard to the structure of riboregulator comprising a start codon within the fully double-stranded stem domain instead of a “bubble” structure (of Green-1), the same artisan (i.e., Green-2) in a different publication teaches that the start codon can be within a fully double-stranded stem as well, providing a reasonable expectation of success of yielding a predictable outcome (i.e., produce a reporter protein when bound to target) to the ordinarily skilled artisan.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
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.
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.
Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,125,743 (herein, “the ‘743 patent”) in view of Green et al. (WO 2014/074648, published May 2014, herein, “Green-2”), and Byrom et al. (Nucleic Acids Research, 2014, vol. 42, no. 15, e120, pages 1-13).
With regard to instant claim 1, claims of the ‘743 patent also claims a method for detecting a target nucleic acid comprising a riboregulator comprising a synthetic nucleic acid molecule comprising: a docking site, a toe-hold domain, and a hairpin domain, the hairpin domain comprising a fully or partially double-stranded stem domain and a loop domain, wherein the stem domain is complementary to a target sequence containing nucleic acid molecule, whereby if present in the sample, the target nucleic acid molecule will bind to and form a complex with the riboregulator, leaving a 3’ region of the riboregulator in position to produce a reporter protein (“norovirus-specific toehold switch comprising, in order 5’ to 3’, a toehold domain, a first stem domain, a loop domain … and at least a portion of a coding sequence, wherein the first stem domain, the loop domain, and seconds stem domain anneal to form a fully or partially double-stranded stem-loop structure”, see claim 1; also Fig. 2A which depicts the riboregulator structure; see claim 7, which is utilized in a method of detecting the target nucleic acid).
The “toehold”, any number nucleotides within the “toehold” region can be deemed 2-6 nucleotides in length and the rest of the remaining region be considered “docking site”.
With regard to the complex being in an energy state sufficient to produce a reporter protein when target-specifically bound, this wherein clause does not further distinguish the riboregulator as claimed. As well, a specifically-bound riboregulatory to its target nucleic acid would necessarily possess a stable energy state (i.e., stably bound) resulting in the translation in producing a reporter protein.
The structure of the riboregulator disclosed by the p743 patent, however, does not comprise an AUG (or start codon) within the fully-double stranded stem domain (it contains a bulge).
While the ‘743 patent explicitly claims the usage of the sensor to detect a target nucleic acid of norovirus (see claim 7), the ‘743 patent does not explicitly claim that sensor is used in a method of targeting nucleic acids comprising an SNP therein, wherein the stem region of their sensor comprises a sequence complementary to said SNP.
Claims of the ‘743 patent do not claim that the SNP detection is from a biological sample (claim 3), which is a liquid sample (claim 4).
Green-2 teaches a riboregulator having a similar structure as that of the ‘743 patent, with an AUG start codon in the fully double-stranded stem domain (see FIG. 1):
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Byrom et al. teach a method of detecting an SNP nucleotide on a target utilizing a stem-loop structure comprising a “toehold” region (see Figure 1), wherein the complementarity between the nucleotides in the toehold region and the target sequence favors the displacement of the stem loop structure and polymerase mediated extension to occur (see Figure 1):
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the claims of the ‘743 patent with the teachings of Green-2, Byrom et al., and conventional knowledge available in the art of molecular diagnostics, thereby arriving at the invention as claimed for the following reasons.
As discussed above claims of the ‘743 patent claim a nucleic acid sensor which is designed to produce a reporter protein (GFP) in the presence of a target nucleic acid. As shown, the sensor comprises a region which complements the target nucleic acid, as well as a portion stem region which form complementarity to the same target nucleic acid resulting in the opening of the stem-loop region containing a ribosome binding region, which further results in the generation of GFPs.
While the claims of the ‘743 patent did not explicitly claim a method to detect other forms of target nucleic acids, such as SNPs from biological samples, such as liquid samples, because the claims of the ‘743 patent claim method of using the sensor to detect specific target nucleic acids from samples to indicate its presence, one of ordinary skill in the art in the field of molecular diagnostics/sensors would have readily recognized that the sensors could also be utilized in the detection of other types of target nucleic acids, such as SNP containing target nucleic acids from samples (such as blood) which correlate with disease phenotypes, thus being motivated to extend the method of the ‘743 patent for detecting SNP target sequences from human samples that are commonly used (i.e., blood).
As well, Byrom et al. also teach that a stem-loop comprising structure with a “toehold” region specifically tailored for complementarity with a target nucleic acid sequence and is very sensitive to mismatches (“[w]e have now applied … to design of hairpin primers that have an initiating toehold sequence that is exquisitely sensitive to mismatches” (page 2, 1st column) and teach that this feature can be utilized to detect SNPs.
Based on the obvious motivation to apply the claims of the ‘743 patent for detecting routinely assayed target nucleic acid sequences, such as those containing SNPs associated diseases, one of ordinary skill in the art would have been motivated to combine the teachings of Byron et al. into the toehold region of the ‘743 patent sensor, allowing for better discrimination capability when detecting a single-base pair mutation from a target, avoiding signal generation from mis-matched hybridization which could occur, a common issue in detection of SNPs:
“However, certain mismatches are efficiently extended, leading to inaccurate genotyping …” (page 1, 2nd column, Byrom et al.)
Lastly, with regard to the structure of riboregulator comprising a start codon within the fully double-stranded stem domain instead of a “bubble” structure (of the ‘743 patent), the same artisan (i.e., Green-2) in a different publication teaches that the start codon can be within a fully double-stranded stem as well, providing a reasonable expectation of success of yielding a predictable outcome (i.e., produce a reporter protein when bound to target) to the ordinarily skilled artisan.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 August 22, 2026
/YJK/
1 An arbitrary number of the 12 nt sequences in the toehold region can be considered a “docking site” because the region can “dock” to the target nucleic acid via complementarity.
Prosecution Insights