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 .
Status of the Claims
The Amendment filed 06/17/2025 has been entered. Claims 1-2, 5, 7, 9-10, 14, 18, 20-21, 23, 27-28, 30-31, and 34 have been amended. Claims 36-37 have been withdrawn. Claim 13 is canceled. Claims 1-2, 5, 7, 9-10, 14, 17-18, 20-21, 23, 27-28, 30-31, 34, and 36-37 are currently pending. Claims 1-2, 5, 7, 9-10, 14, 17-18, 20-21, 23, 27-28, 30-31, and 34 are examined herein.
Status of the Rejection
The drawing objections have been overcome by the applicant's amendments.
The claim objections have been overcome by the applicant's amendments except for the objection of claim 31 which is essentially maintained and modified in response to the amendment. New grounds of objection are necessitated by the amendments as outlined below.
All 35 U.S.C. § 112(b) rejections from the previous office action are withdrawn in view of the Applicant’s amendments, except for the 112(b) rejections of claim 14 which are essentially maintained and modified only in response to the amendments.
New grounds of rejection under 35 U.S.C. § 112(b) are necessitated by the amendments as outlined below.
The 35 U.S.C. § 103 rejections for independent claim 1 from the previous office action are essentially maintained and modified only in response to the amendments to the claims. New grounds of rejection under 35 U.S.C. § 103 for the dependent claims are necessitated by the amendments as outlined below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/20/2024 has been considered by the examiner.
Claim Objections
Claims 1 and 31 are objected to because of the following informalities:
Claim 1, line 13: please amend the limitation (f) to start on a new line after the limitation (e) as previously presented in the claim set of 06/03/2022.
Claim 31, line 15 and line 16: please amend “the DNA nanostructure” to – the
Claim Rejections - 35 USC § 112
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.
Claim 1, 2, 5, 7, 9-10, 14, 17-18, 20-21, 23, 27-28, 30-31, and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claim 1, claim 1 recites “the nucleic acid” in line 9. There is insufficient antecedent basis for this limitation in the claim. Furthermore, it is unclear if the nucleic acid refers to the previously recited deoxyribonucleic acid, the previously recited ribonucleic acid, both, or a newly recited, different feature. It is unclear if “a base of the nucleic acid is an unnatural nucleic acid base or the nucleic acid comprises a mixture of unnatural and natural nucleic acid bases“ is limiting the deoxyribonucleic acid, the ribonucleic acid, both, or a newly recited, different feature. Applicant should clarify the relationship between the nucleic acid and the deoxyribonucleic acid and ribonucleic acid that were previously recited in claim 1. Therefore, the scope of claim 1 is indefinite. Claims 2, 5, 7, 9-10, 14, 17-18, 20-21, 23, 27-28, 30-31, and 34 are further rejected by virtue of its dependence upon and because it fails to cure the deficiencies of claim 1.
Regarding claim 14, claim 14 recites the term “substantially” in line 10 which is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Substantially is not defined in the instant specification and it is unclear how close a substantially one-dimensional geometry needs to be to the claimed structure to be “substantially” that structure. Therefore, the scope of claim 14 is indefinite.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 2, 5, 7, 9, 14, 17, 31, and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman et al. (US 20170044605 A1) in view of Kelley et al. (US20020172963A1) and Winnacker et al. (Artificial Genetic Sets Composed of Size-Expanded Base Pairs, 2013, Angew. Chem. Int. Ed., 52, 12498 – 12508), which is cited in the Information Disclosure Statement filed on 04/06/2023. Pellestor et al. (The peptide nucleic acids (PNAs), powerful tools for molecular genetics and cytogenetics, 2004, European Journal of Human Genetics, 12, Pages 694 – 700) used as evidence for claim 17.
Regarding claim 1, a system for identification, characterization, or sequencing of a biopolymer (Merriman teaches a system for identification, sequencing and/or characterization of a biopolymer such as DNA, [Abstract, Para. 0040, 0041, and 0047; Figures 1 – 3]) comprising:
(a) a non-conductive substrate (Merriman teaches the substrate 320/263 and that the support/substrate may be a silicon chip, Para. 0049, Figure 2 and 3. The examiner takes the position that silicon is a non-conductive substrate as evidenced by the instant claim 2 which lists silicon as a non-conductive substrate);
(b) a nanogap formed by a first electrode and a second electrode placed next to each other on the non-conductive substrate (Merriman teaches an electrode gap 330 formed by placing the first electrode [302 and 306] and a second electrode [303 and 307] next to each other on the non-conductive substrate 320, [Fig. 3 and Para. 0050]. The gap 330 is a nanogap because it is in the range of 3 nm to about 30 nm, [Para. 0082]. The first electrode is interpreted to be the electrode base 302 and metal contact 306. The second electrode is interpreted to be the electrode base 303 and metal contact 307. Merriman further teaches contacts are not strictly required, and a sensor in accordance with their disclosure need not comprise a first and second contact, [Para. 0050]);
(c) a nanostructure that bridges the nanogap by attaching one end to the first electrode and another end to the second electrode through a chemical bond, wherein the nanostructure comprises either deoxyribonucleic acid (DNA nanostructure) or ribonucleic acid (RNA nanostructure) or a combination thereof (Merriman teaches a nanostructure 333/337 that bridges the nanogap 330 by attaching one end 334 of the nanostructure 333/337 to the first electrode 302/306 and another end 335 to the second electrode 303/307 through a chemical bond [the termini/each end of the bridge molecule comprise thiol for binding to the (gold) electrodes, which would form a Au-thiol chemical bond], wherein a nanostructure 333/337 comprising a double stranded DNA nanostructure, [Para. 0076, 0053, 0059, 0061, 0064, 0065, 0093, Fig. 3]),
(d) an enzyme attached to the nanostructure (Merriman teaches an enzyme probe 336 attached to the nanostructure 333/337 that performs biochemical reactions [such as catalyzing nucleotide bases into a growing oligonucleotide strand] with the biopolymer [such as DNA], [Para. 0064 and 0065]) the limitation “that performs a biochemical reaction” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Merriman teaches the above enzyme that is specifically configured to perform the functional limitations above (Merriman teaches an enzyme probe 336 attached to the nanostructure 333/337 that performs biochemical reactions [such as catalyzing nucleotide bases into a growing oligonucleotide strand] with the biopolymer [such as DNA], [Para. 0064 and 0065]);
(e) a bias voltage that is applied between the first electrode and the second electrode (Merriman teaches a bias voltage [such as less than 10 V] that is applied between the first electrode and the second electrode, [Para. 0047 and 0069; Figures 1 – 3]);
(f) a device that records a current fluctuation through the nanostructure resulting from a distortion within the nanostructure caused by a conformation change initiated by the enzyme attached to the nanostructure (Merriman teaches an integrated circuit 120 [corresponding to a device] for recording a current fluctuation [flow of current as a function of time] resulting from a distortion in the electrical conductance within the nanostructure/bridge molecule caused by a conformational change initiated by the enzyme attached to the nanostructure in response to sequentially encountering template strand nucleic acid bases and/or incorporating template-specified natural or analog bases, [Fig. 1 - 3, Para. 0065 and 0069]); and
(g) a software for data analysis that identifies or characterizes the biopolymer or a subunit of the biopolymer (Merriman teaches providing a signal processing system 121 comprising a computer system with a processor and a data analysis software for receiving and processing the signal patterns that is used to determines the identity of the biopolymer, [Para. 0046, 0047 and 0069, Figures 1 – 3]),
Merriman is silent to wherein a base of the nucleic acid is an unnatural nucleic acid base or the nucleic acid comprises a mixture of unnatural and natural nucleic acid bases;
Kelley teaches a biological sensing device for identification or characterization of a biopolymer (Abstract). Kelley further teaches a DNA nanostructure that bridges a nanogap (Figure 11, Para. 0075, 0084, 0015) wherein a base of the nucleic acid is an unnatural nucleic acid base and the unnatural bases are incorporated into bridging DNA sequences [corresponding to DNA nanostructures] which can alter the voltage-current profiles obtained (Para. 0084).
Merriman and Kelley are considered analogous art to the claimed invention because they are in the same field of biological sensing device for identification or characterization of a biopolymer (Abstract of Kelley and Abstract, Fig. 1-3 of Merriman). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the nucleic acid nanostructure of Merriman to incorporate unnatural nucleic acid bases as taught by Kelley, since Kelly teaches this would be beneficial for altering the voltage-current profiles obtained and would enable engineering of variations in bridging sequences that would provide molecular resistors, diodes and transistors (Para. 0084 of Kelley). Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
Modified Merriman is silent to wherein the unnatural nucleic acid base is selected from the group consisting of (a) a Hachimoji nucleic acid base; (b) a size expanded nucleobase; (c) a non-hydrogen bonding nucleobase; (d) an universal base; and (e) a combination thereof.
Winnacker teaches biochemical tools and methods for nanostructures [Abstract]. Winnacker further teaches size-expanded nucleobases incorporated into DNA sets which is beneficial because longer expanded DNA could use its stability, rigidity and charge conductivity in self-assembling nanostructures [Page 12498, Col. 1, Para. 2 continued to next column; Page 12507, Col. 1, Para. 1]. Size expanded nucleobases confer useful properties such as high binding affinity and high helix stability and these properties are also potentially useful for the development of new biotechnological tools [Page 12498, Col. 2, Para. 1].
Modified Merriman and Winnacker are considered analogous art to the claimed invention because they are in the same field of DNA technologies including self-assembled nanostructures [Abstract and Page 12498, Col. 2, Para. 1 of Winnacker and Abstract and Figs. 1-3 of Merriman]. It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructure and unnatural nucleic acid base of Modified Merriman to provide (b) a size expanded nucleobase, as taught by Winnacker, since Winnacker teaches it would be beneficial because longer expanded DNA could use its stability, rigidity and charge conductivity in self-assembling nanostructures [Page 12498, Col. 1, Para. 2 continued to next column; Page 12507, Col. 1, Para. 1 of Winnacker] and size expanded nucleobases confer useful properties such as high binding affinity and high helix stability and these properties are also potentially useful for the development of new biotechnological tools [Page 12498, Col. 2, Para. 1 of Winnacker]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A]. Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
Regarding claim 2, the system of claim 1, wherein the non-conductive substrate is selected from the group consisting of a silicon (Merriman teaches the non-conductive substrate 320/263 comprises silicon, Para. 0049, Figure 2 and 3),
wherein the biopolymer is selected from the group consisting of a DNA, a RNA, an oligonucleotide (Merriman teaches the biopolymer that is sequenced is selected from the group consisting of DNA, RNA or other oligonucleotides, Para. 0010),
wherein the enzyme is selected from the group consisting of a DNA polymerase, a RNA polymerase, a reverse transcriptase (Merriman teaches the enzyme is selected from the group consisting of DNA polymerase, RNA polymerase [a polymerase suitable for interacting with individual DNA or RNA target molecules] and reverse transcriptase, [Para. 0065]).
Regarding claim 5, the system of claim 2, wherein the enzyme is selected from the group consisting of ϕ29 DNA polymerase, T7 DNA polymerase, Taq polymerase, DNA polymerase Y, DNA Polymerase Pol I, Pol II, Pol III, Pol IV and Pol V, Pol a (alpha), Polb (beta), Pol s (sigma), Pol1 (lambda), Pol d (delta), Pol e (epsilon), Poln (mu), PolI (iota), Pol k (kappa), pol h (eta) (Merriman teaches the enzyme is DNA Polymerase [Pol] I enzyme, [Para. 0091]).
Regarding claim 7, the system of claim 1, wherein the first electrode and the second electrode are separated by a distance of 3 nm to 1000 nm (Merriman teaches the electrode gap is defined by the first electrode and the second electrode and the electrode gap dimension [corresponding to separated by a distance] may be about 10 nm, falling within the claimed range [Para. 0082 of Merriman and Fig. 1-3]), and wherein an end of the first electrode and the second electrode have a rectangular face with a width of 3 nm to 1000 nm (Merriman teaches the first and second electrode comprises a generally rectangular cross-section [corresponding to the ends of the electrodes having a rectangular face] as seen in Figs. 2-3 which shows an end of the first and second electrodes having a rectangular face, with a width of about 10 nm to about 40 nm, falling within the claimed range, [Figs. 1-3 and Para. 0077, 0082], and
Modified Merriman is silent to a depth of 2 nm to 1000 nm.
Kelley teaches using thick electrodes introduces problems such as difficulty in obtaining and maintaining electrode gaps of the right magnitude (~10 nm) as the metal electrode thickness increases [the electrode thickness corresponds to a depth] [Para. 0015]. Thus, the thickness or depth of the metal electrode affects the obtaining and maintaining of electrode gaps when making electrode gaps of ~10 nm.
As the obtaining/production and maintaining of electrode gaps of ~10 nm are variables that can be modified (Para. 0015 of Kelley), among others, by adjusting the electrode depth/thickness, including the ends of the electrodes [Para. 0015 of Kelley] the precise depth/thickness would have been considered a result effective variable by one having ordinary skill in the art before the effective filing date of the invention. As such, without showing unexpected results, the claimed depth of 2 nm to 1000 nm cannot be considered critical. Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have optimized and would have optimized, by routine experimentation, the ends of the first and second electrodes depth in Modified Merriman to be 2 nm to 1000 nm in order to obtain the desired balance between the obtaining/production and maintaining of electrode gaps of ~10 nm, as taught by Kelley. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). The discovery of an optimum value of a known result effective variable, without producing any new or unexpected results, is within the ambit of a person of ordinary skill in the art. See In re Boesch, 205 USPQ 215 (CCPA 1980) (see MPEP § 2144.05, II.).
Regarding claim 9, the system of claim 1, wherein the first electrode and/or the second electrode comprises: a) a metal electrode (Merriman teaches the first and second electrodes are comprised of conductive metal electrodes that can react with thiol [Para. 0076 and 0053 of Merriman]) the limitation “that can react with a thiol, a amine, a selenol, and another organic functional group” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Merriman teaches the above first and second electrodes as shown in Fig. 3 that is specifically configured to perform the functional limitations above (Merriman teaches the electrodes (including the contacts) are comprised of a metal such as gold, and the nanostructure comprises thiol or amine groups that are configured to bind to electrode or contact materials, and thus the first and second electrodes can react with thiol and amine, [Para. 0076 and 0053 of Merriman]. The examiner takes the position the electrodes can also react with selenol and other organic functions since it is made of the same material (gold) as the instant application which describes the metal electrodes made of gold nanowires (see e.g., Para. 0036 of the instant specification). Accordingly, products of identical chemical composition (i.e., gold electrodes) cannot have mutually exclusive properties, and thus, the claimed property (i.e., react with selenol and other organic functions), is necessarily present in the prior art material. [See MPEP 2112.01 (II)].).
Regarding claim 14, the system of claim 1,
(b) wherein the nanostructure is self-assembled from either linear or circular DNAs, or linear or circular RNAs, or a combination thereof (Modified Merriman teaches the nanostructure is self-assembled from a linear double-stranded DNA [Para. 0056, 0058, 0093 – 0095 and Fig. 3 of Merriman]).
Regarding claim 17, the system of claim 1, wherein the nanostructure comprises: a. a non-phosphate backbone comprising an amide, a guanidinium, or a triazole linkage (Modified Merriman teaches the nanostructure [the bridge molecule that comprises a biopolymer] can comprise peptide nucleic acids (PNAs) [Para. 0054 of Merriman], and PNA contains a non-phosphate backbone comprising an amide linkage as evidenced by Pellestor, [Figure 1 showing PNA structure having an aminoethyl glycine backbone comprising an amide linkage which is boxed in]).
Regarding claim 31, the system of claim 1, the limitation “wherein the biochemical reaction comprises: (a) a reaction catalyzed by a DNA polymerase using DNA as a template and DNA nucleotides as substrates; wherein the DNA nucleotides comprises: (i) a polyphosphate of DNA/RNA nucleosides; (ii) polyphosphate of DNA/RNA nucleosides tagged with an organic molecule; (iii) a polyphosphate of DNA/RNA nucleosides tagged with an intercalator: (iv) a polyphosphate of DNA/RNA nucleosides tagged with a minor groove binder, and/or (v) a polyphosphate of DNA/RNA nucleosides tagged with a drug molecule, wherein the polyphosphate comprises two or more phosphate units, wherein the polyphosphate is a hexaphosphate of DNA nucleosides tagged with 1,8-naphthalimide that binds to the DNA nanostructure, a hexaphosphate of DNA nucleoside tagged with a derivative of 1,8-naphthalirmide that binds to the nanostructure or a combination thereof” is a functional recitation as outlined in the rejection of claim 1 above, because it further limits the biochemical reaction. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Merriman teaches the above enzyme, a polymerase [a DNA polymerase when DNA is the target] using a DNA template molecule (i.e., the target) and a DNA nucleotide base as the substrate incorporated into a growing oligonucleotide strand, [Para. 0065 and 0069 of Merriman]. The DNA polymerase enzyme is specifically configured to perform the functional limitations above. Since the prior art does disclose a DNA polymerase comprising substantially the same elements or components as that of the applicant [see e.g., claim 13, Para. 0055] it is contended that the DNA polymerase enzyme of the prior art is capable of catalyzing a reaction using DNA as a template and DNA nucleotides as substrate wherein the DNA nucleotide comprises the claimed limitations above. Accordingly, products of identical chemical composition cannot have mutually exclusive properties, and thus, the claimed property (i.e., a reaction catalyzed using DNA as a template and DNA nucleotides as substrates, ; wherein the DNA nucleotide comprises: (i) a polyphosphate of DNA/RNA nucleosides; (ii) polyphosphate of DNA/RNA nucleosides tagged with an organic molecule; (iii) a polyphosphate of DNA/RNA nucleosides tagged with an intercalator: (iv) a polyphosphate of DNA/RNA nucleosides tagged with a minor groove binder, and/or (v) a polyphosphate of DNA/RNA nucleosides tagged with a drug molecule, wherein the polyphosphate comprises two or more phosphate units, wherein the polyphosphate is a hexaphosphate of DNA nucleosides tagged with 1,8-naphthalimide that binds to the DNA nanostructure, a hexaphosphate of DNA nucleoside tagged with a derivative of 1,8-naphthalirmide that binds to the DNA nanostructure or a combination thereof), is necessarily present in the prior art material. [See MPEP 2112.01 (II)]).
Regarding claim 34, the system of claim 1 comprises a plurality of nanogaps (Modified Merriman teaches a plurality of nanogaps [see e.g., Fig. 2B, Para. 0049, 0045, 0048-0052, 0059-0065, and Fig. 1-3 in Merriman]),
Modified Merriman is silent to wherein the plurality of nanogaps comprises an array of 100 to 100 million nanogaps.
However, as outlined above Modified Merriman teaches a plurality of nanogaps [Fig. 2B, Para. 0049 and Fig. 2 in Merriman].
It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to duplicate the plurality of nanogaps of Modified Merriman to provide an array of 100 to 100 million nanogaps. Furthermore, to incorporate an array of 100 to 100 million nanogaps instead of only a single nanogap or a plurality of nanogaps would constitute a mere duplication of parts that would yield the predictable result of a plurality of sensors and nanogaps [Para. 0048 and Fig. 2B of Merriman]. It has been held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced. See MPEP § 2144.04(VI)(B).
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 1 above, and further in view of Parviz et al. (Investigation of the Antifouling Properties of Phenyl Phosphorylcholine-Based Modified Gold Surfaces, 2014, Electroanalysis, Vol. 27, 7, Pages 1471-1480) and Chandradoss et al. (Surface Passivation for Single-molecule Protein Studies, 2014, J Vis Exp, 86, 50549). Diessel et al. (US 20050112617 A1) and BroadPharm et al. (m-PEG-NHS ester, MW 5,000, 2025, Pages 1-5, https://broadpharm.com/product/bp-24177) used as evidence for claim 10.
Regarding claim 10, the system of claim 1, wherein the substrate and one or more of the first electrode and the second electrode are passivated with an insulating layer except for an end surface of the substrate, the first electrode and/or the second electrode that faces the nanogap (Merriman teaches a surface passivation may be applied to the substrate surface and portions of the exposed electrodes to reduce electrical noise that can occur from contact with liquid samples [Para. 0091 of Merriman]. Merriman further teaches the passivation treatment [corresponding to an insulating layer because it insulates portions of the electrodes and substrate from electrical noise] can be applied to leave the electrodes and/or contacts in the area of the sensor gap [nanogap] untreated and thus corresponding to wherein the electrode and the substrate are passivated except for the end surface that faces the nanogap [Para. 0091 of Merriman]),
Modified Merriman is silent to wherein the insulation layer comprises a monolayer or multi-layers of an inert chemical.
However, Merriman teaches in an another embodiment using an aminosilane APTES [a layer of an inert chemical] for surface derivatization of the electrodes surfaces [Para. 0088]. APTES is aminopropyltriethoxysilane as evidenced by Diessel et al. (Para. 0096).
It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the insulating/passivation layer of Modified Merriman to provide a layer including an inert chemical aminopropyltriethoxysilane, APTES, as taught by Merriman, since Merriman teaches it would be beneficial for surface derivatization of the electrodes/substrate surfaces [Para. 0088 of Merriman]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A]. Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
Furthermore, in the insulation layer, there are only two finite solutions: a monolayer or multi-layers. Therefore, there is a finite number of identified, predictable solutions with a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try by choosing from the above finite number of identified solutions, which would lead to an insulating layer that is a monolayer or multi-layers of the inert chemical. Choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, is likely to be obvious to a person if ordinary skill in the art (see MPEP§ 2143[I][E]).
Modified Merriman is silent to wherein the inert chemical comprises an 11 -mercaptoundecvl-hexaethyleneglycol (CR-1) for a metal surface, and
Parviz teaches antifouling coatings on gold electrodes and their ability to limit nonspecific adsorption of proteins to electrode surfaces [Abstract]. Parviz specifically teaches coating 11 -mercaptoundecvl-hexaethyleneglycol on a gold/metal surface electrode as a monolayer [Scheme 1; Page 1473, Col. 1, Para. 2) for applications in biosensing, and would be beneficial for antifouling of the metal/gold surface and for resisting non-specific adsorption on an electrode which may lead to a decrease in sensor selectivity by interfering with the interaction of target species with the sensing surface [Abstract, Conclusion, Page 1471, Col. 1, Paras. 1-2 and Scheme 1; Page 1473, Col. 1, Para. 2).
Modified Merriman and Parviz are considered analogous art to the claimed invention because they are in the same field of biosensing applications (Figs. 1 – 3 of Merriman and Page 1471, Col. 1, Paras. 1-2 of Parviz). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the inert chemical of Modified Merriman to comprise 11 -mercaptoundecvl-hexaethyleneglycol for a metal surface, as taught by Parviz, since Parviz teaches it would be beneficial for antifouling of the metal/gold surface and for resisting non-specific adsorption on an electrode which may lead to a decrease in sensor selectivity by interfering with the interaction of target species with the sensing surface [Abstract, Conclusion, Page 1471, Col. 1, Paras. 1-2 and Scheme 1; Page 1473, Col. 1, Para. 2 of Parviz). Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A]. Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
Modified Merriman is silent to an N-hydroxysuccinimidyl 2-(co-0-methoxy-hexaethylene glycol)acetate (CR-3) for a substrate surface.
Chandradoss teaches a protocol for surface passivation for single-molecule studies [Title and Abstract]. Chandradoss teaches using APTES and NHS-ester mPEG (5,000 Da) for substrate surface passivation (see e.g., Fig. 1 and Page 2, Section 3, Step 2 and Page 3, Section 4, Step 3), which is beneficial for achieving high quality surface passivation, preventing proteins from non-specifically interacting with a substrate surface, and removing one of the major bottle necks of single-molecule studies (Abstract, Introduction, and Perspectives). NHS-ester mPEG (5,000 Da) has the same structure as N-hydroxysuccinimidyl 2-(co-0-methoxy-hexaethylene glycol)acetate (CR-3) shown in Fig. 10 of the instant specification, as evidenced by BroadPharm et al. (Page 1, Fig. 1 showing the chemical structure of m-PEG-NHS ester, MW 5,000), except that the integer n= 6 is not explicitly disclosed, rather only n is shown indicating a number or integer in the structure of NHS-ester mPEG (5,000 Da).
Modified Merriman and Chandradoss are considered analogous art to the claimed invention because they are in the same field of single-molecule studies (Abstract of Merriman and Title and Abstract of Chandradoss). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the inert chemical of Modified Merriman to comprise m-PEG-NHS ester for a substrate surface, as taught by Chandradoss, since Chandradoss teaches it would be beneficial in combination with APTES for achieving high quality surface passivation, preventing proteins from non-specifically interacting with a substrate surface, and removing one of the major bottle necks of single-molecule studies (Abstract, Introduction, and Perspectives of Chandradoss). Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A]. Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
Furthermore, in the chemical composition and structure of m-PEG-NHS ester, there are only a finite number of solutions because there is a finite number of integers for n (such as n=6). Therefore, there is a finite number of identified, predictable solutions with a reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try by choosing from the above finite number of integers of n and identified solutions, which would lead to choosing m-PEG-NHS ester, n=6, which is the same as N-hydroxysuccinimidyl 2-(co-0-methoxy-hexaethylene glycol)acetate (CR-3) shown in Fig. 10 of the instant specification. Choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, is likely to be obvious to a person if ordinary skill in the art (see MPEP§ 2143[I][E]).
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 1 above, and further in view of Hatano et al. (Synthesis and redox-active base-pairing properties of DNA incorporating mercapto C-nucleosides, 2005, Tetrahedron, 61, Pages 1723-1730). Holze et al. (The adsorption of thiophenol on gold – a spectroelectrochemical study, 2015, Phys. Chem. Chem. Phys., 17, Pages 21364-21372) used as evidence for claim 18.
Regarding claim 18, the system of claim 1, wherein the nanostructure comprises: a. a functional group configured for attachment to the first electrode or the second electrode (Modified Merriman teaches a nanostructure DNA biopolymer bridge with a functional group (5′-thiol modification) configured to bind to the first or second electrodes or their contact materials [Para. 0053, 0095 and Fig. 3 of Merriman]); and/or
Modified Merriman is silent to wherein the functional group configured for electrode attachment comprises (i) a thiol on a sugar ring of a nucleoside; (ii) a thiol and a selenol on a nucleobase of a nucleoside: (iii) an aliphatic amine on a nucleoside; and/or (iv) a catechol on a nucleoside:(v) a RXH or a RXXR, where R is an aliphatic or an aromatic group, and X is a chalcogen, wherein the chalcogen is S and Se: and/or (vi) [AltContent: textbox (Annotated Chart 1 (left image) of Hatano and Scheme 1 (right image) of Holze)]a base chalcogenated nucleoside.
Hatano teaches the incorporation of nucleoside bases into DNA (Abstract). Hatano further teaches a thiol (as circled above in Annotated Chart 1) on a sugar ring of a nucleoside and incorporation of these synthetic mercapto C-nucleosides into DNA (Chart 1 and Page 1723, Col. 2, last paragraph). Hatano teaches this strategy would be beneficial for increasing the functionality of DNA in order to generate new functional materials, a new genetic code or novel antisense nucleotides (Page 1727, Col. 2, Para. 1). The thiol functional group present on a sugar ring of a nuceloside of Hatano is specifically configured for attachment to electrodes such as gold electrodes as evidenced by Holze above (see e.g., Scheme 1 and 2 of Holze).
Modified Merriman and Hatano are considered analogous art to the claimed invention because they are in the same field of DNA technologies (Figs. 1 – 3 of Merriman and Chart 1 of Hatano). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to modify the nanostructure of Modified Merriman with (i) a thiol on a sugar ring of a nucleoside as taught by Hatano, since Hatano teaches this strategy would be beneficial for increasing the functionality of DNA in order to generate new functional materials, a new genetic code or novel antisense nucleotides (Page 1727, Col. 2, Para. 1). Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A].
Thus, Modified Merriman as outlined in the rejection above yields a thiol on a sugar ring of a nucleoside, which is a sugar modified nucleoside [the sugar is modified with thiol], meeting the claimed limitations above.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 9 above, and further in view of Staderini et al. (A tripod anchor offers improved robustness of peptide-based electrochemical biosensors, 2018, 274, Pages 662 - 667).
Regarding claim 20, the system of claim 9, modified Merriman is silent to wherein the anchoring molecule comprises one of the following or a combination thereof: (a) a molecule configured to interact with a metal surface through multivalent bonds; (b) a tripod structure configured to react with a metal surface through trivalent bonds and (c) a molecule comprised of a tetraphenylmethane core wherein three of its phenyl rings are functionalized with L-H2SH or -CH2SeH and a fourth phenyl ring is functionalized with an azide, a carboxylicacid,aboronicacid, and/or an organic group configured to react with a functional group incorporated into the nanostructure.
However, Merriman teaches an anchoring molecule comprising a 5’ thiol modification for interacting with the metal surface of the electrodes (Para. 0099 and 0122 of Merriman).
Staderini teaches an electrochemical biosensor with an anchoring molecule including a tripod structure (Abstract). As seen in Fig. 1(a) the tripod anchor is configured to interact with a metal surface through trivalent (three) bonds (Fig. 1). Staderini further teaches this tripod structure is beneficial because it improved stability and is robust in comparison to a monoanchor structure (Abstract).
Modified Merriman and Staderini are considered analogous art to the claimed invention because they are in the same field of biosensors for analyte detection (Abstracts of Merriman and Staderini). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the anchoring molecule of Modified Merriman with an anchoring molecule with a tripod structure configured to interact with a metal surface through trivalent bonds, as taught by Staderini, since Staderini teaches this would be beneficial for improving stability and robustness in comparison to a monoanchor structure (Abstract of Staderini). Furthermore, the simple substitution of one known element for another (i.e., an anchoring molecule with a thiol monoanchor structure with an anchoring molecule with a thiol tripod structure) is likely to be obvious when predictable results are achieved (i.e., binding to a gold electrode) [MPEP 2143[I][B]].
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 9 above, and further in view of Sarap et al. (Optical Properties of Single- and Double-Functionalized Small Diamondoids, 2018, The Journal of Physical Chemistry A, 122, Pages 3583–3593).
Regarding claim 21, the system of claim 9, modified Merriman is silent to wherein the anchoring molecule comprises one of the following or a combination thereof: (a) an N-heterocyclic carbene (NHC); (b) an N-heterocyclic carbene (NHC) in a metal complex configured to be selectively deposited on the first electrode or the second electrode by an electrochemical method in solution, wherein the metal complex comprises Au, Pd, Pt, Cu, Ag, Ti, and/or another transition metal; (c) an N-heterocyclic carbene (NHC) configured to be deposited on the first electrode and the second electrode in organic and/or aqueous solutions; and (d) an N-heterocyclic carbene (NHC) containing functional groups comprising an amine, a carboxylic acid, a thiol, a boronic acid, and/or any organic group configured for attachment.
However, Merriman teaches an anchoring molecule comprising a 5’ thiol modification for interacting with the metal surface of the electrodes (Para. 0099 and 0122).
Sarap teaches functionalized gold electrodes that can be excellent sensors for distinguishing DNA nucleotides in their natural and mutated form (Page 3583, Col. 2, last paragraph). Sarap further teaches N-heterocyclic carbene (NHC)-mediated binding to be an excellent alternative to the thiol functional group and that NHC mediation is beneficial for 1) improving the stability and work function against a thiol-mediated binding and 2) for demonstrating a much greater resistance to heat and chemical reagents than the thiol-based counterparts (Page 3584, Col. 1, first paragraph).
Merriman and Sarap are considered analogous art to the claimed invention because they are in the same field of sensors for analyte detection (such as DNA) with functionalized electrodes (Figs. 1 - 3 of Merriman and Page 3583, Col. 2, last paragraph of Sarap). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to substitute the anchoring molecule of Modified Merriman with an anchoring molecule comprising a N-heterocylic carbenes (NHC), as taught by Sarap, since Sarap teaches (NHC)-mediated binding to be an excellent alternative to the thiol functional group and that NHC mediation would be beneficial for 1) improving the stability and work function against a thiol-mediated binding and 2) for demonstrating a much greater resistance to heat and chemical reagents than the thiol-based counterparts (Page 3584, Col. 1, first paragraph of Sarap). Furthermore, the claimed limitations are obvious because the substitution of one known element for another yields predictable results to one of ordinary skill in the arts (MPEP 2143[I][B]).
Claim(s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 1 above, and further in view of McGovern et al. (US6159695A).
Regarding claim 23, the system of claim 1, further comprising a protein (Modified Merriman teaches a protein such as avidin-like proteins which includes streptavidin or the protein can be an antibody, [Para. 0066 of Merriman], the limitation “configured to be immobilized at the bottom of the nanogap to support and stabilize the nanostructure” is a functional recitation. Apparatus claims cover what a device is, not what a device does [MPEP 2114(II)]. A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. See MPEP 2114. In the instant case, Modified Merriman teaches the above protein that is specifically configured to perform the functional limitations above (Merriman teaches a protein such as avidin-like proteins which includes streptavidin or the protein can be an antibody, [Para. 0066 of Merriman]. For example, the protein streptavidin is specifically configured to perform the function of immobilized at the bottom of the nanogap to support and stabilize the nanostructure, since it is the same protein molecule [streptavidin] used as the instant application [see e.g., Fig. 15 of the instant application and instant claim 23]. Since the prior art does disclose a streptavidin protein comprising substantially the same elements or components as that of the applicant, it is contended that the streptavidin protein is capable of being immobilized at the bottom of the nanogap to support and stabilize the nucleic acid nanostructure. Accordingly, products of identical chemical composition cannot have mutually exclusive properties, and thus, the claimed property (i.e., immobilized at the bottom of the nanogap to support and stabilize the nanostructure), is necessarily present in the prior art material. [See MPEP 2112.01 (II)].)
wherein the protein is a streptavidin or an avidin (Modified Merriman teaches the protein is streptavidin [Para. 0066 of Merriman]), and the nanostructure is functionalized bv a biotin (Modified Merriman teaches the nanostructure is functionalized with biotin [Para. 0066 and 0060 of Merriman]),
Modified Merriman is silent to wherein the bottom of the nanogap is functionalized with a chemical reagent to immobilize protein, wherein the chemical reagent comprises: (a) a silane configured to react with an oxide surface; (b) a silatrane configured to react with an oxide surface; (c) a multi-arm linker that comprises a silatrane and a functional group,(d) a four-arm linker that comprises an adamantane core; (e) a four-arm linker that comprises two silatranes and two biotin moieties; and/or (f) a four-arm linker that comprises an adamantane core and silatranes and organic functional groups.
McGovern teaches biochemical sensor element structures of the type in which covalently immobilized biomolecules such as nucleic acids are bound and is in the field of sequencing of nucleic acids [see e.g., Col. 1, lines 14-25 and Col. 2, lines 38-40]. McGovern further teaches a chemical reagent (alkyl silanes in column 5, lines 10-15, 46-51) configured to immobilize proteins that is immobilized on a substrate/bottom surface (see e.g., Col. 3, lines 55-58, which recites “many of the techniques used to immobilize proteins can also be adapted for nucleic acids” and Fig. 3), wherein the chemical reagent comprises at least one of the following or a combination thereof: (a) a silane configured to react with an oxide surface (see Col. 5, lines 10-15, which recites “Alkylsilanes have been extensively used to immobilize a wide variety of biomolecules to surfaces. The alkoxy or chloro leaving groups are particularly reactive towards hydroxyl groups found on glass, quartz, Silicon and metal oxide Surfaces”) (see also Col. 22, lines 48-53 which recites “BMBS can be used as a homo bifunctional reagent for the attachment of many types of biomolecules in general to other biomolecules such as proteins’).
Merriman and McGovern are considered analogous art to the claimed invention because they are in the same field of biochemical sensor element structures and sequencing of nucleic acids (Abstract and Figs. 1 - 3 of Merriman and see e.g., Col. 1, lines 14-25 and Col. 2, lines 38-40 of McGovern). It would have been obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the substrate including the bottom of the nanogap of Modified Merriman to be functionalized with a silane chemical reagent which immobilizes protein and reacts with an oxide surface as taught by McGovern, since McGovern teaches it would be beneficial for enabling attachment of biomolecules to surfaces such as proteins [see e.g., Col. 5, lines 10-15 and Col. 22, lines 48-53 of McGovern]. Furthermore, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results, MPEP 2143[I][A]. Additionally, the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art [MPEP § 2144.07].
or wherein the protein is selected from the group consisting of an antibody, a receptor, an aptamer, and a combination thereof (This limitation is optional and therefore, does not necessarily limit the claim, and is not given patentable weight. Thus, Modified Merriman meets all the required limitations of this claim).
Claim(s) 27-28, and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Merriman in view of Kelley and Winnacker as applied to claim 1 above, and further in view of Bergmann et al. (US20190002968A1).
Regarding claim 27-28 and 30, the system of claim 1, Modified Merriman is silent to the following limitations: (I) wherein the enzyme is a recombinant DNA polymerase or a recombinant reverse transcriptase and the enzyme comprises an orthogonal functional group configured to be attached to the nanostructure [of the instant claim 27], (II) wherein the recombinant DNA polymerase comprises: (a) an organic group at