DETAILED ACTION
The amendment filed on 01/22/2026 has been entered.
Claims 1 and 35 were amended in the claim set filed on 01/22/2026.
Applicant’s election without traverse of the specie of steps recited in claims 1 in the reply filed on 07/ 21/ 2025 is acknowledged. The claims of 3, 5, 10, 26-28, 32, 34-35, 39, 56, 64, 70 and 84-87 are directed towards claim 1
Claim 53 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected specie of claim steps, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07/21/25.
Claims 1, 3, 5, 10, 11, 26-28, 32, 34, 35, 39, 56, 64, 70, and 84-87 in the claim set filed on 01/22/2026 are currently under examination.
Response to the Arguments
Applicant’s arguments regarding previous rejection(s) of claim(s) 1, 3, 5, 10, 11, 26-28, 32, 34, 35, 39, 56, 64, 70, and 84-87 under 35 U.S.C. 102 and 35 U.S.C. 103 have been fully considered and are not persuasive. Applicant’s argument on Pg. 7, states that “Applicant has amended claim 1 to recite, inter alia, "contacting the biological sample comprising a target nucleic acid with a circular probe and a preformed complex comprising a hairpin molecule bound to a polymerase" (emphasis added). Applicant respectfully submits that at least this recitation is not taught or suggested by Chen.” The rejections documented in the previously mailed non-final have been maintained in light of applicants claim amendments and arguments on Pg. 7. However, upon further consideration and search, revised rejections are made as documented below in the 35 U.S.C. 103 rejection in this office action on Pg. 3-16.
Applicant’s arguments regarding previous provisional rejection of claim 1 under nonstatutory double patenting have been fully considered and are not persuasive. The rejection documented in the previously mailed non-final have been maintained in light of applicants claim amendments and arguments on Pg. 11. However, upon further consideration and search, revised rejections are made as documented below in the nonstatutory double patenting rejection in this office action on Pg. 17-20.
The rejections for claims 1, 3, 5, 10, 11, 26-28, 32, 34, 35, 39, 56, 64, 70, and 84-87 are documented below in this Final Office Action are necessitated by claim amendments filed on 01/22/2026.
Priority
This application claims priority to U.S. Provisional Patent Application No.63/227,825 filed July 30, 2021. The priority date of the claim set filed 07/21/2025 is determined to be July 30, 2021.
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, 3, 5, 10-11, 26-28, 32, 35, 56, 70 and 84 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (“Chen”; Patent App. Pub. No. CN 111534573 A. Pub. Aug. 14, 2020, Filed on May 26, 2020).
Chen discloses a probe composition and application thereof in-situ detection of nucleic acid, wherein the probe composition comprises a circular probe and a hairpin probe; the circular probe comprises a first binding sequence and a non-first binding sequence; the hairpin probe comprises a 5 'fold sequence, a second binding sequence, and a 3' binding sequence; when the hairpin probe is designed by mutually combining a 3 'binding sequence and a 5' folding sequence and is not combined with a target nucleic acid, a stem-loop structure is formed, after the hairpin probe is combined with the target nucleic acid, the stem-loop structure is opened, the 3 'binding sequence is released to be complementarily combined on part or all of non-first binding sequences of the circular probe, the 3' binding sequence of the hairpin probe is used as a primer for rolling-loop amplification, the circular probe is used as a template for rolling-loop amplification, rolling-loop amplification reaction is carried out, an amplification product containing a large number of repeated sequences is obtained at an in-situ nucleic acid, and simple, sensitive and specific in-situ nucleic acid detection effects are realized by detecting and amplifying the repeated sequences.(Abstract)
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Regarding claim 1, Chen teaches a method comprising RCA amplification: Taking circular probe… adding …hairpin probe, target sequence... phi 29 polymerase (NEB), …phi 29 polymerase buffer solution (NEB) and … dNTP… placing at 37 ℃ for reaction... and carrying out… detection” (Pg. 8, (3) RCA Amplification, ln 52-54; Figure 2A, see translated figure below). Chen teaches a method comprising “In the case that the hairpin probe is not bound to the target nucleic acid, the hairpin probe has a stem-loop structure, and the…binding sequence cannot be combined with the circular probe, and no rolling circle amplification reaction occurs; when the hairpin probe binds to the target nucleic acid, the stem-loop structure opens, and … binding … circular probe … to initiate a rolling circle amplification reaction”(Pg. 2 ln 46-50). Chen teaches a method comprising “the circular probe and the hairpin probe are bound to the in-situ nucleic acid by their respective binding sequences, and the design of the binding sequence can have a 70-100% coincidence degree with the sequence of the target nucleic acid. When the loop probe and the hairpin probe bind to the target nucleic acid respectively … and the hairpin probe… binding sequence is used as a primer for rolling circle amplification, and a circular probe is used as a template for rolling circle amplification. Rolling circle amplification reaction is performed to obtain an amplified product… at the nucleic acid in situ” (Pg. 2 ln 36-43). Thus, Chen teaches a method comprising steps (a-d), (a) contacting the biological sample comprising a target nucleic acid with a circular probe and a hairpin molecule bound to a polymerase, wherein: the hairpin molecule comprises a loop region, a stem region, and a primer sequence, and the stem-loop conformation of the hairpin molecule prevents the polymerase from extending the primer sequence; (b) forming a complex comprising the hairpin molecule hybridized to the target nucleic acid and the circular probe, wherein hybridization of the hairpin molecule to the circular probe causes a conformational change of the hairpin molecule that allows the primer sequence to prime rolling circle amplification (RCA) of the circular probe by the polymerase; (c) using the polymerase, the primer sequence, and the circular probe, to generate an RCA product of the circular probe; and (d) detecting the RCA product of the circular probe in the biological sample.
Therefore, the invention as recited in claim 1 is prima facie obvious over the prior art Chen et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to provide a method for analyzing a biological sample according to the limitations of the instant application claim 1 based on Chen et al. (Patent App. Pub. No. CN 111534573 A.).
The teachings of Chen are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claim 3, 5, 10-11, 26-28, 32, 35, 56 and 70 depends on claim 1. Claim 84 depends on claim 3, which depends on claim 1.
Regarding claim 3, Chen teaches a method wherein “stem-loop structure of the probe is opened, the… binding sequence is complementary to the… sequence of the circular probe, the... binding sequence of the hairpin probe is used as a primer” (Pg. 7 ln 51-53). The “stem-loop structure of the probe is opened” reads on opening two regions of the hairpin in which the primer can be comprised. The primer sequence reads on any region of the hairpin that hybridizes to complementary nucleic acids. Thus, Chen teaches a method wherein the primer sequence comprises a first hairpin opening region and a second hairpin opening region.
Regarding claim 5, Chen teaches a method wherein “the circular probe and the hairpin probe are bound to the in-situ nucleic acid by their respective binding sequences, and the design of the binding sequence can have a 70-100% coincidence degree with the sequence of the target nucleic acid. When the loop probe and the hairpin probe bind to the target nucleic acid respectively, the …binding sequence of the hairpin probe is combined with part or all of the non-first binding sequence of the loop probe in the adjacent position” (Pg. 2 ln 36-40). Thus, Chen teaches a method wherein the hairpin molecule and the circular probe are hybridized to adjacent sequences of the target nucleic acid.
Regarding claim 10, Chen teaches a method wherein “In the case that the hairpin probe is not bound to the target nucleic acid, the hairpin probe has a stem-loop structure, and the…binding sequence cannot be combined with the circular probe, and no rolling circle amplification reaction occurs; when the hairpin probe binds to the target nucleic acid, the stem-loop structure opens, and … binding … circular probe … to initiate a rolling circle amplification reaction” (Pg. 2 ln 46-50). “conformational change” as recited in claim 10 reads on any change in conformation of the molecule. “binding … circular probe … to initiate a rolling circle amplification reaction” reads on the limitation of recited in claim 10 wherein “absence of the circular probe bound to the hairpin molecule does not induce the conformational change that allows the primer sequence to prime RCA of the circular probe”. Consequently, absence of circular probe would indicate absence of circular probe being primed by a hairpin primer region for RCA. Thus, Chen teaches a method wherein hybridization of the hairpin molecule to the target nucleic acid in the absence of the circular probe bound to the hairpin molecule does not induce the conformational change that allows the primer sequence to prime RCA of the circular probe.
Regarding claim 11, Chen teaches a method wherein “the circular probe and the hairpin probe can be chemically modified to improve the stability and specificity of binding target nucleic acid, and at the same time, the probe's resistance to nuclease can be enhanced” (Pg. 3 ln 33-34). Chen also teaches a method wherein “Rolling circle amplification reaction is performed to obtain an amplified product” (Pg. 2 ln 42). “chemically modified” reads on a reaction mixture. “Rolling circle amplification reaction is performed to obtain an amplified product” reads on reaction mixture that allows the polymerase to extend the primer sequence. Thus, Chen teaches a method wherein: step (a) is carried out in a first reaction mixture, wherein the first reaction mixture stabilizes the polymerase and/or inhibits its polymerase or exonuclease activity and step (c) is carried out in a second reaction mixture that allows the polymerase to extend the primer sequence.
Regarding claim 26, Chen teaches a method wherein “the hairpin probe…3' binding sequence is used as a primer” (Pg. 2 ln 40-41). Thus, Chen teaches a method wherein the primer sequence or a portion thereof is in a 3' overhang of the hairpin molecule.
Regarding claim 27, Chen teaches a method wherein “the hairpin probe…3' binding sequence is used as a primer” (Pg. 2 ln 40-41). “3’ binding sequence” reads on the stem region of the molecule. Thus, Chen teaches a method wherein the primer sequence or a portion thereof is in the stem region of the hairpin molecule.
Regarding claim 28, Chen teaches a method wherein “the hairpin probe…3' binding sequence is used as a primer” (Pg. 2 ln 40-41). “3’ binding sequence” reads on the loop region of the molecule, since 3’ can be considered any region from the middle point to the furthermost 3’ end of the sequence, and the loop of a stem-loop hairpin resides in the middle. Thus, Chen teaches a method wherein the primer sequence or a portion thereof is in the loop region of the hairpin molecule.
Regarding claim 32, Chen teaches a method wherein “the polymerase is… phi29” (Pg. 6 ln 27-28). “Phi29” reads on a DNA polymerase with inherent 3' → 5' exonuclease activity, which enables it to digest DNA strands from the 3' end. Thus, Chen teaches a method wherein the polymerase digests the hairpin molecule to expose a free 3' end nucleotide of the primer sequence for rolling circle amplification.
Regarding claim 35, Chen teaches a method wherein “Taking circular probe… adding …hairpin probe, target sequence... phi 29 polymerase (NEB), …phi 29 polymerase buffer solution (NEB) and … dNTP… placing at 37 ℃ for reaction... and carrying out… detection” (Pg. 8, (3) RCA Amplification, ln 52-54; Figure 2 see translated figure above). “adding …hairpin probe, target sequence... phi 29 polymerase (NEB)” reads on the hairpin being loaded with the polymerase prior to step (a) as the order of addition or prior mixing was not specified. “Phi 29 polymerase buffer solution …2 µL of BSA (25mg/mL)” (Pg. 10, Para. 4). Chen teaches a method wherein “BSA” reads on a non-catalytic cofactor of the polymerase. Thus, Chen teaches a method wherein the method comprises loading the polymerase onto the hairpin molecule in a binding mixture comprising a non-catalytic co-factor of the polymerase prior to the contacting in step (a).
Regarding claim 56, Chen teaches a method wherein “the nucleic acid includes DNA and/or RNA” (Pg. 5 ln 6) Thus, Chen teaches a method wherein the target nucleic acid is DNA or RNA.
Regarding claim 70, Chen teaches a method wherein “the nucleic acid is located in … tissue section” (Pg. 5 ln 11). Thus, Chen teaches a method wherein the biological sample is a tissue sample.
Regarding claim 84, Chen teaches Figure 2A involving a method wherein the hairpin is a stem-loop hairpin that inherently has an opening in the loop region and upon binding/ conformational change the stem region is able to open. (Figure 2A see translated figure above). Thus, Chen teaches a method wherein the first hairpin-opening region or a portion thereof is in the loop region, and the second hairpin-opening region or a portion thereof is in the 3' strand of the stem region.
Response to Arguments
Applicant' s arguments filed 01/22/2026 (Pg. 7-11) with respect to claim 1 claims 1, 3, 5, 10, 11, 26-28, 32, 34, 35, 39, 56, 64, 70, and 84-87 have been considered but they are not persuasive. The rejections remain rejected over the revised rejections, as necessitated by amendment, documented above. To clarify some instances argued in the response filed 01/22/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Applicant has amended claim 1 to recite, inter alia, "contacting the biological sample comprising a target nucleic acid with a circular probe and a preformed complex comprising a hairpin molecule bound to a polymerase" (emphasis added). Applicant respectfully submits that at least this recitation is not taught or suggested by Chen” (Pg. 7).
Response: Applicant's argument filed 01/22/2026 have been fully considered but they are not persuasive. As stated in the non-final office action mailed on 08/22/2025 “Chen teaches a method wherein “Taking circular probe… adding …hairpin probe, target sequence... phi 29 polymerase (NEB), …phi 29 polymerase buffer solution (NEB) and … dNTP… placing at 37 ℃ for reaction... and carrying out… detection” (Pg. 8, (3) RCA Amplification, ln 52-54; Figure 2 see translated figure above). “adding …hairpin probe, target sequence... phi 29 polymerase (NEB)” reads on the hairpin being loaded with the polymerase prior to step (a) as the order of addition or prior mixing was not specified.” (Pg. 8-9). Furthermore, the MPEP states “Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.)” (MPEP 2144.04 IV). Thus, a method comprising a preformed complex comprising a hairpin molecule bound to a polymerase would be prima facie obvious to the ordinary artisan.
Applicants’ argument: “Importantly, Example 2 of Chen does not describe the rolling circle amplification process being performed in a biological sample but instead uses a short fragment of an hGAPDH mRNA as a target sequence in the bulk reaction mixture.” (Pg. 8)
Response: Applicant's argument filed 01/22/2026 have been fully considered but they are not persuasive. As stated in the non-final office action mailed on 08/22/2025 “Rolling circle amplification reaction is performed to obtain an amplified product… at the nucleic acid in situ” (Pg. 2 ln 36-43) and “an amplification product containing a large number of repeated sequences is obtained at an in-situ nucleic acid, and simple, sensitive and specific in-situ nucleic acid detection effects are realized by detecting and amplifying the repeated sequences” (Abstract). (Pg 4-5). In situ reads on in a biological sample. Thus, a method comprising rolling circle amplification process being performed in a biological sample is taught by Chen.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (“Chen”; Patent App. Pub. No. CN 111534573 A. Pub. Aug. 14, 2020, Filed on May 26, 2020) as applied to claim 1 above, and further in view of Fredriksson et al. (“Fredriksson”; Patent App. No. WO 2012104261 A1, Aug. 09, 2012.
The teachings of Chen are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claim 34 depends on claim 1.
Chen does not explicitly teach the limitations of claim 34.
Fredriksson discloses a proximity probe based detection assay ("proximity assay") for an analyte in a sample, specifically a proximity probe extension assay (PEA), an in particular to an improvement in the method to reduce non-specific "background" signals, wherein the improvement comprises the use in such assays of a component comprising 3' exonuclease activity, said method comprising: (a) contacting said sample with at least one set of at least first and second proximity probes, which probes each comprise an analyte-binding domain and a nucleic acid domain and can simultaneously bind to the analyte; (b) allowing the nucleic acid domains of the proximity probes to interact with each other upon binding of said proximity probes to said analyte, wherein said interaction comprises the formation of a duplex; (c) contacting said sample with a component comprising 3' exonuclease activity; (d) extending the 3' end of at least one nucleic acid domain of said duplex to generate an extension product, wherein the step may occur contemporaneously with or after step (c); and (e) amplifying and detecting the extension product.
Regarding claim 34, Fredriksson teaches a method wherein “the extension… reaction mixture includes 3'-thioate protected hairpin primers” (Pg. 46 ln 31). Thus, Fredriksson teaches a method wherein the hairpin molecule comprises a 3' protective group, wherein the hairpin molecule is 3' thiophosphate-protected, thereby protecting the hairpin molecule from 3' to 5' exonuclease degradation by the polymerase while allowing extension by the polymerase.
Chen and Fredriksson are both considered to be analogous to the claimed invention because they are in the same field of probe-based detection of nucleic acids. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing a biological sample as recited in steps (a-d) of claim 1 as taught by Chen to incorporate the method of a 3' thiophosphate-protected hairpin as taught by Fredriksson and provide a method comprising a hairpin with 3' protective group. Doing so would protect the hairpin molecule from 3' to 5' exonuclease degradation by the polymerase while allowing extension by the polymerase.
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not
persuasive. Arguments against Chen are not persuasive as discussed above.
Claims 39 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (“Chen”; Patent App. Pub. No. CN 111534573 A. Pub. Aug. 14, 2020, Filed on May 26, 2020) as applied to claim 1 above, and further in view of Zhou et al. (“Zhou”; (2019). Programmable DNA ring/hairpin-constrained structure enables ligation-free rolling circle amplification for imaging mRNAs in single cells. Analytical Chemistry, 91(5), 3628-3635.
The teachings of Chen are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 39 and 64 depend on claim 1.
Chen does not explicitly teach the limitations of claims 39 and 64.
Zhou discloses that a rationally designed and programmable DNA ring/hairpin constrained structure can achieve in situ ligation-free rolling circle amplification (RCA), which further leads to highly specific, sensitive, and multicolor imaging of mRNA molecules in single cells. Such a structure aims at addressing current challenges in terms of simplicity, sensitivity, and multiplexing capability related to the detection and imaging of intracellular mRNA sequences. With this new DNA ring/hairpin-RCA approach, we are able to detect the target mRNAs with high sensitivity at the sub picomolar levels in vitro. Besides, the multiplexing capability of the DNA structures can be readily realized by barcoding the DNA rings and hairpins with distinct sequences. Due to the excellent sequence recognition ability of the hairpins, the DNA structures exhibit single-base variation discrimination capability for the target mRNA and can be used to image trace amounts of down-expressed mRNAs in single cells. Moreover, drug-dependent mRNA expression variations can also be clearly differentiated by these DNA structures, highlighting the great potential of such structures for early disease diagnosis and for screening possible therapeutic drugs. (Abstract)
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Regarding claim 39, Zhou teaches a method wherein “the mixture of the DNA ring/hairpin structures… were added and incubated” (Pg. 3630, In Situ Sensitive and Multicolor Imaging of mRNAs in Single Cells, Para. 1; Figure 1 see below). Thus, Zhou teaches a method wherein the contacting step (a) comprises contacting the sample with a complex formed by the circular probe and the hairpin molecule.
Regarding claim 64, Zhou teaches a method wherein “imaging of two types of mRNAs in single cells via mRNA-initiated in situ RCA” (Figure 1 legend, Figure see above). Thus, Zhou teaches a method wherein the method comprises imaging the biological sample to detect the rolling circle amplification product.
Chen and Zhou are both considered to be analogous to the claimed invention because they are in the same field of DNA ring/hairpin-RCA based detection of nucleic acids. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing a biological sample as recited in steps (a-d) of claim 1 as taught by Chen to incorporate the method of contacting the sample with a complex formed by the circular probe and the hairpin molecule and imaging the sample to detect RCA amplification product as taught by Zhou and provide a method comprising complexes formed by the circular probe and the hairpin molecule prior to contacting the sample and imaging of the RCA product. Doing so would allow for specific control of DNA circular probe-hairpin complexes in the initiation of RCA and imaging of distinct nucleic acids in cells through the RCA products.
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not
persuasive. Arguments against Chen are not persuasive as discussed above.
Claims 85-87 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (“Chen”; Patent App. Pub. No. CN 111534573 A. Pub. Aug. 14, 2020, Filed on May 26, 2020) as applied to claims 1, 11 and 84 above, and further in view of Dong-Eun et al. (“Dong-Eun”; Patent App. No. KR20190121000A, Oct. 25, 2019).
The teachings of Chen are documented above in the rejection of claims 1 3, 11 and 84 under 35 U.S.C. 103. Claim 85 depends on claim 84, which depends on claim 3, which depends on claim 1. Claim 86 depends on claim 1. Claim 87 depends on claim 11, which depends on claim 1.
Chen does not explicitly teach the limitations of claims 85-87.
Dong-Eun discloses detecting a target gene based on polymerase chain reaction and rolling circle amplification and to a method for detecting a target gene using the same. (Abstract)
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Regarding claim 85, Dong-Eun teaches Fig. 1 involving the method wherein a portion of the stem opening region and a portion of the loop opening region are complementary to the circular probe. (Fig.1 see below, brown portion). Thus, Dong-Eun teaches a method wherein the first hairpin-opening region and the second hairpin-opening region are complementary to a first primer-binding region and a second primer- binding region, respectively, in the circular probe.
Regarding claim 86, Dong-Eun teaches Fig. 1 involving the method wherein the 5’ overhang sequence binds to the target sequence (Fig. 1 see above, blue portion). Thus, Dong-Eun teaches a method wherein the hairpin molecule comprises a target binding sequence in a 5' overhang.
Regarding claim 87, Dong-Eun teaches a method wherein “phi29 polymerase buffer (50 mM tris-HCl, 10 mM MgCl2,” (Pg. 6 ln 31). “MgCl2” reads on a catalytic cofactor. Thus, Dong-Eun teaches a method wherein the second reaction mixture comprises a catalytic cofactor of the polymerase.
Chen and Dong-Eun are both considered to be analogous to the claimed invention because they are in the same field of DNA ring/hairpin-RCA based detection of nucleic acids. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing a biological sample as recited in steps (a-d) of claim 1 and stem-loop hairpin with a first opening in the loop region and second opening in the stem region as taught by Chen to incorporate the method of the hairpin opening of the loop and hairpin opening of the stem being complementary to a first primer-binding region and a second primer- binding region of the circular probe; a 5’ overhang sequence that binds to the target sequence; and a reaction mixture comprising a polymerase cofactor such as Mg2+ as taught by Dong-Eun and provide a method comprising a hairpin molecule that binds to the circular probe through regions of the hairpin stem and loop to primer binding regions of the circular probe; a hairpin molecule that binds to the target molecule through a 5’ overhang; RCA polymerase cofactors in a reaction mixture. Doing so would increase the specificity of the circular probe priming by the hairpin; increase the stabilization of the hybridization reaction of the hairpin with the target molecule; and promote catalytic activity of the polymerase and extend the primer sequence.
Response to Arguments
Applicant's arguments filed 01/22/2026 have been fully considered but they are not
persuasive. Arguments against Chen are not persuasive as discussed above.
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.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 25 of copending Application No. 17/294364 (Kühnemund et al., filed on May 14, 2021, US 20220010358 A1, Jan. 13, 2022). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made prima facie obvious over the claim 1 of copending Application No. 17/294364.
Claim 1 of copending Application No. 17/294364 is drawn to:
A method for detection of a target nucleic acid in a sample, comprising:(a) contacting the sample with a hairpin probe, the hairpin probe comprising:(i) a first domain capable of hybridizing to a target sequence in the target nucleic acid; and (ii) a second domain capable of hybridizing to a circular or circularizable probe; wherein hybridization of the first domain to the target sequence causes the duplex region to open, thereby exposing the second domain or part thereof; and wherein (1) the first domain is at least partly comprised within a single stranded loop region of the hairpin probe and the second domain is at least partly comprised within a duplex region of the hairpin probe, or (2) the first domain is at least partly comprised within the duplex region and the second domain is at least partly comprised within the single stranded loop region; (b) contacting the sample with the circular or circularizable probe, thereby hybridizing the circular or circularizable probe to the second domain;(c) performing a rolling circle amplification (RCA) reaction using the circular probe or a circularized probe as a template, wherein generation of the circularized probe comprises circularizing the circularizable probe; and(d) detecting a product of the RCA reaction.
Claim 1 of the instantly claimed invention is made prima facie obvious over copending Application No. 17/294364. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to detect and analyze a biological sample using a method comprising: contacting the target nucleic acid of biological sample with a circular probe and a preformed complex comprising a hairpin molecule bound to a polymerase; forming a complex comprising the hairpin molecule hybridized to the target nucleic acid and the circular probe; generating an RCA product of the circular probe using the polymerase, the primer sequence, and the circular probe; and detecting the RCA product of the circular probe in the biological sample. Thus, claim 1 of the instant application is made prima facie obvious over claim 1 of copending Application No. 17/294364.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 01/22/2026 (Pg. 11) with respect to claim 1have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 01/22/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Applicant respectfully traverses this rejection, and requests reconsideration in view of the amendment to claim 1.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because the MPEP states “Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.)” (MPEP 2144.04 IV). Thus, a method comprising a preformed complex comprising a hairpin molecule bound to a polymerase would be prima facie obvious to the ordinary artisan.
Conclusion of Response to Arguments
In view of the amendments, revised rejections and above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
THIS ACTION IS MADE FINAL. 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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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682 /WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682