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 .
The claim amendments dated 11/11/2025 are under consideration.
The amendments and arguments presented in the papers filed 11/11/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 8/11/2025 listed below have been reconsidered as indicated.
a) The amendments to the specification addressing trade names and/or marks usage is acknowledged.
b) Any objections and/or rejections of claim 5 is rendered moot by the cancellation of the claim and are withdrawn as such.
c) The rejections of claims 16, 20 and 30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in view of the amendments to the claims.
d) The rejection of claim(s) 1, 2, 3, 4, 12, 13, 20, 21, 26, 29 and 30 under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (Anal Chem. 2015. 87:5677-5682) are withdrawn in view of the amendments to claim 1 incorporating elements of now cancelled claim 5.
e) The rejection of claim(s) 18 under 35 U.S.C. 103 as being unpatentable over Zhang (Anal Chem. 2015. 87:5677-5682) is withdrawn in view of the amendments to claim 1.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Election/Restrictions
Applicant elected without traverse Group I, claims 1-6, 9, 12-16, 18, 20-21, 26, 29 and 30, in the reply filed on 6/9/2025.
Claims 31 and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/9/2025.
Priority
The present application is a 371 national stage entry of PCT/US20/43382 (filed 7/24/2020), which claims benefit of provisional application 62/879,204 (filed 7/26/2019).
The ‘204 provisional application has: a 3 page specification; 6 claims that are significantly broader than the present claims; and no drawings. The present specification is 40 pages, the original claims included 54 claims and a set of 3 drawings over 15 pages is provided.
The ‘204 provisional application does not adequately support the full scope of the present claims.
The present claims encompass any input strand and output strand. While the ‘204 provisional application specification provides a single example of an input and output strands as depicted in Figure 1 of the ‘204 specification. The ‘204 provisional application specification only describes using outputs with streptavidin attached in a manner such that the output strand does not completely go through the nanopore, while the present claims are not limited as such.
The ‘204 provisional application specification does not describe a nanopore system comprising a nanopore disposed between a first conductive liquid medium and a second conductive liquid medium as presently claimed.
The earlier effective filing date is the filing date of the ‘382 PCT application, which is 7/24/2020.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-4, 6, 9, 12-16, 18, 20, 21, 26, 29-30 and 55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Anal Chem. 2015. 87:5677-5682; previously cited) in view of Davis (WO 2018/069302 A1; previously cited).
Regarding claim 1, Zhang teaches contacting a “double stranded complex” comprising oligonucleotides A and C with an “input strand” comprising oligonucleotide B. Oligonucleotide A is a “partner strand” hybridized along a portion of oligonucleotide C as an “output strand”. See Scheme 1 on p. 5679.
Zhang further teaches permitting hybridization between the “input strand” and the “partner strand”. The sequence of oligonucleotide A is:
5’-TACT CAG GGC ACT GCA AGC AAT TGT GGT CCC AAT GGG CTG AGT A-TTT TTT TTT TTT TTT TTT TTT TTT TTG CTA GGT CTC-3’
The sequence of oligonucleotide B is:
5’-GAG ACC TAG CAA TTT TTT TTT TTT TTT TTT TTT TTT-T ACT CAG GGC ACT GCA AGC AAT TGT GGT CCC AAT GGG CTG AGTA-3’
The sequence of oligonucleotide C is:
5’-C30-GAG ACC TAG CAA −3’
Zhang teaches a “first portion” of the “partner strand” Oligonucleotide A comprising a strand that hybridizes with the “output strand” Oligonucleotide C as depicted below:
Oligonucleotide A 5’ TTG CTA GGT CTC 3’
Oligonucleotide C 3’ AAC GAT CCA GAG 5’
The bold italicized sequence the “first portion”.
Zhang teaches a “second portion” of the “partner strand” Oligonucleotide A comprising a strand that hybridizes with “input strand” Oligonucleotide B as depicted below:
Oligonucleotide A 5’ TTG CTA GGT CTC 3’
Oligonucleotide B 3’ AAC GAT CCA GAG 5’
The bold underlined sequence is the “second portion”. This structure of Oligonucleotide A is broadly encompassed by the “partner strand” as described in the claim.
Zhang teaches translocating the “output strand” Oligonucleotide C through a nanopore from a “cis chamber” to a “trans chamber” and measuring an ionic current as the “output strand” Oligonucleotide C is translocated (p. 5678, Binding-Induced DNA Strand Displacement Reaction and Single-Channel Recording). The nanopore has a “tunnel” through which the “output” strand Oligonucleotide C translocates and is part of a “system” comprising a “first conductive liquid medium” or cis test buffer and a “second conductive liquid medium” or trans test buffer (p. 5678, Binding-Induced DNA Strand Displacement Reaction).
Zhang teaches associating the current pattern of the “input strand” that displaced the output strand as depicted in Scheme 1 (p. 5679) and Figure 1 (p. 5679), which depicts current patterns that differ between different structures “detected” by the nanopore.
Zhang does not specifically teach an “anchor moiety” as part of oligonucleotide C.
Regarding claim 2, the structure of Zhang’s “partner strand” Oligonucleotide A comprises a “toehold” sequence as depicted in the bold sequence below and a “partner sequence” as depicted in italics:
5’-TACT CAG GGC ACT GCA AGC AAT TGT GGT CCC AAT GGG CTG AGT A-TTT TTT TTT TTT TTT TTT TTT TTT TTG CTA GGT CTC-3’
The structure of Zhang’s “output strand” comprises a “first domain” as depicted in bold and a “barcode sequence” that is italicized:
5′-C30-GAG ACC TAG CAA −3′
Regarding claim 3, the structure of Zhang’s “barcode sequence” does not hybridize with any portion of the “partner strand” as depicted in Scheme 1 (p. 5679).
Regarding claim 4, the structure of Zhang’s “input strand” Oligonucleotide B comprises a sequence that hybridizes to a portion the bolded “toehold sequence” and to the italicized portion of the “partner sequence” as depicted below:
Oligonucleotide “A” 5’-TACT CAG GGC ACT GCA AGC AAT TGT GGT CCC AAT GGG CTG AGT A-
Oligonucleotide “B” 3’-ATGA CTG GGG TAA CCC TGG TGT TAA CGA ACG TCA CGG GAC TCA T-
Oligonucleotide “A” TTT TTT TTT TTT TTT TTT TTT TTT TTG CTA GGT CTC-3’
Oligonucleotide “B” TTT TTT TTT TTT TTT TTT TTT TTT AAC TAG CCA GAG-5’
Regarding claim 12, Zhang teaches the above noted contacting and permitting steps are performed in the first conductive liquid medium or cis test buffer of the nanopore system (p. 5678, Binding-Induced DNA Strand Displacement Reaction).
Regarding claim 13, Zhang teaches applying an electrical potential of +40, +50, +60, +70, +75, +80 and +100 mV between the cis test buffer and the trans test buffer (p. 5678, Binding-Induced DNA Strand Displacement Reaction).
Regarding claims 18 and 30,
Zhang teaches the system detects the presence of platelet-derived growth factor as a “biomarker” (p. 5677; Scheme 1; and Figure 1).
Zhang does not specifically teach the elements specifically required by claim 18 or claim 30.
However, the duplication of parts has no significance unless a new and unexpected result is produced as recognized by the courts. MPEP 2144.04.VI.B.
The difference between the method of Zhang and claims 18 and 30 is the inclusion of multiple distinct double stranded complexes, which broadly encompasses a multiplex assay for detecting multiple biomarkers, as opposed to the single biomarker detected by Zhang. It is within the skill of the ordinary artisan to select and include multiple and distinct double stranded complexes that would detect biomarkers other than the platelet-derived growth factor of Zhang.
Regarding claim 20, Zhang teaches providing current patterns to a “machine learning model” within the MATLAB and OriginLab 8.0 softwares to determine the association between the unique digital fingerprint of the current pattern obtained, e.g., differentiate between the structures based on unique current patterns as depicted in Figure 1.
Regarding claim 21, it is noted the claim does not exclude the use of a “current pattern”, but only further limits the alternative use of “one or more signal parameters”. Zhang the teachings of claim 20 are equally relevant to claim 21.
Regarding claim 26, Zhang teaches the use of alpha-HL as a nanopore as encompassed by claim 26.
Regarding claim 29, Zhang teaches the cis and trans test buffers are in contact with Ag/AgCl electrodes (p. 5678, Binding-Induced DNA Strand Displacement Reaction).
Zhang does not teach the additional elements specifically required by amended claims 1 (as noted above), 6, 9, 14-16 and 55.
However, Davis teaches methods of detecting nucleic acids using a nanopore.
Regarding claims 1, 6, 9, 14-16 and 55, Davis teaches bulky structures that stop or “arrest” a single-stranded nucleic acid from passing completely through the nanopore. This allows one to reverse polarity to move the single-stranded nucleic acid in the reverse direction, moving the nucleic acid back to its original location prior to translocation, and allow the process of collecting current to be repeated as desired. See para. 109. In order to “stop” the single-stranded nucleic acid, it must be larger than the diameter of the nanopore.
Davis further teaches bulky structures or “anchor moieties” include hairpin nucleic acid structures (para. 42 and 108).
Davis teaches the bulky structure may be a “pre-bulky structure” that is added prior to translocation.
It would have been prima facie obvious to have modified the method of Zhang by using the above elements of Davis to modify the “output strand” of Zhang in order to repeat the analysis of Zhang for each “output strand” for better and more accurate detection of the output strands. For example, the bulky structures of Davis would be added to the output strands of Zhang. The modification has a reasonable expectation of success as both references relate to the analysis of single-stranded nucleic acids using a nanopore.
Response to the traversal of the 103 rejections
The Remarks summarizes the rejection over Zhang in view of Davis (p. 16-17).
The examiner’s position is detailed in the above 103 rejections.
The Remarks argue there is no prima facie case of obviousness of the presently amended claims because the hypothetical combination of the Zhang and Davis fails to teach or suggest all elements of the claims and that a person of ordinary skill in the art would not have an apparent reason to modify the teachings of the cited references to achieve the present claims (p. 17).
The argument is a summary of applicant’s position and no specific points are presented that need to be addressed.
The Remarks argue neither Zhang nor Davis independently or in combination, teach an output strand comprising a sequence-dependent fingerprint/barcode and an anchor moiety, where the sequence dependent barcode is stalled in the nanopore tunnel via the anchor moiety nor teach or suggest mapping measured patterns of current generated by the stalled fingerprint/barcode to different input-strand identities, as is required by Claim 1 (p. 17).
The arguments have been fully considered but are not persuasive. The combination of Zhang and Davis suggest an “output strand” having a barcode and an anchor moiety. Zhang teaches a structure having: a sequence that hybridizes with a “partner strand”; and a barcode. The Oligonucleotide C of Zhang is identified as being an “output strand” with a barcode in the form of 5′-C30, but lacks the anchor moiety. It is noted that claim does not require multiple “barcodes” that are different from one another and associated with a different input strand. The barcodes as claimed broadly encompass any sequence within an “output strand”. Davis teaches bulky structures or “anchor moieties” that modulate the translocation of nucleic acids through a nanopore, which is the detection format of Zhang. It is the implementation of the bulky structure of Davis into the oligonucleotide C of Zhang that arrives at the claimed “output strand”, which when traveling through the nanopore now is stalled by the bulky structure.
Zhang teaches associating the current pattern of the “input strand” that displaced the output strand as depicted in Scheme 1 (p. 5679) and Figure 1 (p. 5679), which depicts current patterns that differ between different structures “detected” by the nanopore. It is noted that the claim does not require multiple input strands that are different and that are each associated with a different barcode as argued. The claims broadly encompass the use of a single input and the associating of the output strand current with that input.
The Remarks argue Zhang does not teach an output strand comprising a barcode and an anchor moiety, as required by the subject matter encompassed by the claimed method (p. 17, referencing arguments on p. 14-15).
The arguments have been considered but are not persuasive. While Zhang teaches elements of the “output strand”, Zhang does not teach the anchor moiety. However, as discussed in the above rejection and examiner’s response, the combination of Zhang and Davis renders obvious the claimed “output strand”.
The Remarks argue Davis does not cure the defects in Zhang because Davis pertains to nanopore voltage/electrode configurations and feedback to move nucleic acids. The Remarks argue Davis is concerned with resolving challenges associated with sequencing single-stranded DNA that result from rapid translocation of ssDNA through a nanopore. The Remarks further argue Davis does not teach or suggest DNA strand-displacement circuits, barcode design, or anchoring/stalling of a displaced output strand or portion thereof in the nanopore tunnel to extract a multi-level current pattern generated by a unique barcode, and/or associating the pattern to input identity, as required by the subject matter encompassed by the present claims. See p. 17-18.
The arguments have been fully considered but are not persuasive. Some of the elements argued as not being taught by Davis are taught by Zhang, e.g., “DNA strand-displacement circuits”. Furthermore, the arguments rely on elements not required by the present claims, e.g., barcode design, multi-level current pattern, a unique barcode, etc. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
It is the examiner’s position that the combination of Zhang and Davis render obvious the claims when given their broadest reasonable interpretation.
The Remarks argue regarding claim 18, Zhang does not teach all the elements of claim 1 from which claim 18 depends (p. 18-19).
The arguments have been fully considered. The 103 rejection of claim 18 over Zhang alone is withdrawn in view of the amendments to claim 1. However, claim 18 is rejected over the combination of Zhang and Davis as described above.
Conclusion
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682