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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/19/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on April 06, 2026. No claims amendment are made in the response filed on 04/06/2026.
Claims 1-20 are currently pending, with claims 4-5, 7 and 9-20 withdrawn.
Claims 1-3, 6 and 8 are under consideration. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on April 06, 2026 is acknowledged:
Species of DNA manipulation methods: A) a method for manipulating DNA conformation and/or orientation (claim 1) 1;
Species of adjusting strength of external force: D) adjusting the strength of electric field (claim 3) 2;
Species of charged molecule : G) polycationic tag (claim 6) 3;
Species of DNA modification: H) single end of DNA is modified by coupling a charged molecule (claim 1) 4;
Species of DNA structure: K) DNA is double stranded (Fig. 1D).
Claims 4-5, 7 and 9-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1-3, 6 and 8.
Priority
The priority date of the instant claims 1-3, 6 and 8 is November 1, 2023, filling date of the present application. No domestic or foreign priority claim has been made by the Applicant according to the latest filling receipt (11/16/2023).
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claim 6 recites the term "polycationic tag," which is not expressly defined with any structural feature in the application's disclosure.
The specification provides relevant description as follows:
"Polycationic tags may include phenols, poly-allylamine, poly(4-vinylbenzylthrimethyl-ammonium) salts, poly-diallyldimethyl-ammonium sales, poly-ethylenimine, poly-vinylamine, poly-vinylpyridine, poly-vinylammonium salts, spermines, or spermidines, peptide sequences (e.g., poly-lysine), aminoplasts (e.g., melamine resins), or polyamidoamines (dendrimers)." ([0036] lines 6-10)
Therefore, under BRI and in light of the specification, the term "polycationic tag" is interpreted to encompass any polymer (.e.g., polypeptide) having a net positive charge or comprising a positively charged portion (.e.g., phenol is neutral in net charge. As phenol's oxygen atom in the hydroxyl group is more electronegative than the carbon atom it is bonded to, resulting in a partial negative charge on the oxygen and a partial positive charge on the carbon. 5)
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gu (Gu et al. ; US20130220809A1 - Nanopore-facilitated single molecule detection of nucleic acid; Published on 2013-08-29).
Regarding claim 1, Gu teaches a method comprising:
obtaining a DNA molecule ([0040] paired oligonucleotides; [0058] “A variety or target nucleic acids or oligonucleotides that can be detected and distinguished from non-target nucleic acids by the probes, nanopores, kits comprising the probes and nanopores, and associated methods of use probes, provided herein… the target can be a PCR products or a synthetic oligonucleotide. In certain embodiments, a target can comprise a genomic DNA”);
modifying an end of the DNA molecule by coupling a charged molecule to the end of the DNA molecule ([0042] “The inventive probe is a multi-domain single strand molecule, which comprises a central domain fully complementary to the target oligonucleotide and at least one terminal extension,”; [0054] “Probe terminal extensions can also comprise a polypeptide… it is believed that the probe/target complex can be selectively trapped using a probe comprising a positively charged polypeptide terminal extension under an appropriate voltage while all other negatively charged non-target oligonucleotides in the mixture are prevented from entering into the pore, resulting in ultra-selective detection”);
applying an external force to the DNA molecule ([0044] “providing the system with a pre-determined voltage”); and
adjusting a strength of the external force to induce the DNA molecule to change the conformation and/or the orientation of the DNA molecule ([0044]; Fig. 4; The duplex, driven by voltage undergoes conformation change and unzip, the voltage is adjustable for unzipping different duplex length with different unzipping time, see also [0061] ).
Regarding claim 2, Gu teaches subjecting the DNA molecule to an electric field ([0044]; Fig. 4).
Regarding claim 3, Gu teaches adjusting the strength of the electric field ([0044]; Fig. 4; The duplex, driven by voltage undergoes conformation change and unzip, the voltage is adjustable for unzipping different duplex length with different unzipping time, see also [0061] ).
Regarding claim 6, Gu teaches the charged molecule is a polycationic tag ([0054] “Probe terminal extensions can also comprise a polypeptide… it is believed that the probe/target complex can be selectively trapped using a probe comprising a positively charged polypeptide terminal extension under an appropriate voltage while all other negatively charged non-target oligonucleotides in the mixture are prevented from entering into the pore, resulting in ultra-selective detection”).
Regarding claim 8, Gu teaches coupling the charged molecule to the end of the DNA molecule indirectly via hybridization ([0044]; Fig. 1).
Claims 1-3, 6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ferree (Ferree et al. ; US20100261026A1 - Compositions comprising oriented, immobilized macromolecules and methods for their preparation; Published 2010-10-14), as evidenced by Goldman (Goldman et al.; Avidin: a natural bridge for quantum dot-antibody conjugates. J Am Chem Soc. 2002 Jun 5;124(22):6378-82. doi: 10.1021/ja0125570. PMID: 12033868).
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Regarding claim 1, Ferree teaches a method for manipulating a conformation and/or an orientation of a DNA molecule, the method comprising:
obtaining a DNA molecule (Fig. 4);
modifying an end of the DNA molecule by coupling a charged molecule to the end of the DNA molecule (Fig. 4; [0129]; [0063]” the first portion of the macromolecule can be immobilized to the substrate via an avidin-biotin binding pair.” Avidin is highly positively charged, see Abstract in Goldman );
applying an external force to the DNA molecule (Fig. 4B;) toward the positive electrode); and
adjusting a strength of the external force to induce the DNA molecule to change the conformation and/or the orientation of the DNA molecule (Fig. 4B; [0130] An electric field of 200 V/cm is applied to extend the long negatively charged DNA (see FIG. 4B); ; [0131] “The flow also acts to further stretch the DNA in addition to the electric field.”; [0072] “the macromolecule can be extended in an electric or magnetic field. The field should be strong enough to extend the macromolecule according to the judgment of one of skill in the art”; [0077]; [0082]; [0108]).
Regarding claim 2, Ferree teaches subjecting the DNA molecule to an electric field (Fig. 4B).
Regarding claim 3, Ferree teaches adjusting the strength of the electric field (Fig. 4B; [0130]; [0072] “the macromolecule can be extended in an electric or magnetic field. The field should be strong enough to extend the macromolecule according to the judgment of one of skill in the art”).
Regarding claim 6, Ferree teaches wherein the charged molecule is a polycationic tag (Fig. 4; [0063]” the first portion of the macromolecule can be immobilized to the substrate via an Avidin -biotin binding pair.”)). Avidin is highly positively charged, as evidenced by Goldman (Abstract).
Regarding claim 8, Ferree teaches coupling the charged molecule to the end of the DNA molecule indirectly via hybridization ([0131]-[0132]).
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
The principle that DNA’s conformation is subject to change with the application of external force is well known and have been extensively disclosed in the art:
For example, Yang 6 summarizes the knowledge in the field as follows:
“DNA is a randomly coiled flexible molecule that can be stretched into a linear form under the influence of external forces such as electric field and hydrodynamic flow.6 Recently, several techniques have been developed for stretching and immobilization of DNA, including electrostretching,7 optical trapping,8 and molecular combing.9 In electrostretching, the motion of an ac field, a phenomenon known as dielectrophoresis.” (page 2352, left-hand col, lines 8-17).
Specifically, applying electric field to change DNA’s conformation (e.g. stretching) and/ or orientation (e.g., position of DNA’s termini) is well-known in the art.
Ferree2 7specifically teaches stretching DNA tethered to a surface by applying electric fields.
Rant8 teaches the conformation and orientation of surface-tethered probe nucleic acids is modulated by alternating electric fields.
Matsumoto9 teaches stretching DNA in an aqueous solution by electric field, thereby changing the orientation of DNA's termini.
Kokoris 10 teaches that terminal affinity labels can be used to selectively modify one end of polynucleotide (e.g. to allow for electrophoretic elongation as it travels through a nanopore (Fig. 4; [0427]). Attachment of a modifier to either the 3′ or 5′ end (not both) produces an electrophoretic drag on the polynucleotide that causes the non-modified end to elongate as it travels to the detector (e.g. nanopore). End modifiers can be used to influence the structure (elongation), position, and rate at which the polynucleotide is presented to the detector by imparting unique, differentiating properties to its termini such as charge (+/−/neutral), buoyancy (+/−/neutral), hydrophobicity, and paramagnetism, to name a few.
Keyser 11 teaches DNA being stretched as it travels through a nanopore (Figure 1).
Dorfman 12 teaches stretching DNA based on Dielectrophoresis (Fig. 67).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 9-20 are withdrawn as being drawn to non-elected species B-C.
2 Claim 4 is withdrawn as being drawn to non-elected species E.
3 Claim 5 is withdrawn as being drawn to non-elected species F.
4 Claim 7 is withdrawn as being drawn to non-elected species I.
5 see Phenol - Wikipedia; Archived Dec 17, 2021 on WaybackMachine
6 Yang (Yang, B., et al. "Stretching and selective immobilization of DNA in SU-8 micro-and nanochannels." Journal of Vacuum Science & Technology B: Microelectronics and Nanometer Structures Processing, Measurement, and Phenomena 25.6 (2007): 2352-2356)
7 Ferree2 (Ferree et al. Electrokinetic stretching of tethered DNA. Biophys J. 2003 Oct;85(4):2539-46. doi: 10.1016/S0006-3495(03)74676-1. PMID: 14507716; PMCID: PMC1303477.)
8 Rant (Rant et al. Switchable DNA interfaces for the highly sensitive detection of label-free DNA targets. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17364-9. doi: 10.1073/pnas.0703974104. Epub 2007 Oct 19. PMID: 17951434; PMCID: PMC2077262)
9 Matsumoto (US20070184446A1- Method of stretching single-stranded nucleic acid, single-stranded nucleic acid stretching system and dna chip)
10 Kokoris (US20090035777A1- High throughput nucleic acid sequencing by expansion; Published on 2009-02-05)
11 Keyser (Keyser et al. "Direct force measurements on DNA in a solid-state nanopore." Nature Physics 2.7 (2006): 473-477.)
12 Dorfman (Dorfman et al. Beyond gel electrophoresis: microfluidic separations, fluorescence burst analysis, and DNA stretching. Chem Rev. 2013 Apr 10;113(4):2584-667. doi: 10.1021/cr3002142. Epub 2012 Nov 12. PMID: 23140825; PMCID: PMC3595390.)
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