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 .
Response to Amendment
The Amendment filed 02/25/2026 has been entered. Claims 72-75, 77-80, 83, 90-92 will be examined herein. Claims 72 and 90 have been amended. Claims 53-54, 56-58, 60-65, 68-69, 71-75, 77-80, 83-88, and 90-92 are pending. Claims 1-52, 55, 59, 66-67, 70, 76, 81-82, and 89 were previously canceled. Claims 53-54, 56-58, 60-65, 68-69, 71, and 84-88 are previously withdrawn.
Status of Objections and Rejections
The provisional non-statutory double patenting rejection over co-pending Application No. 18/245131 is maintained.
The rejection of claims 72-75, 77-80, 83, 90-92 under 35 U.S.C. 103 is withdrawn in view of Applicant's amendment.
Response to Arguments
Applicant's arguments, see pages 8-11, filed 02/25/2026, with respect to the rejections of claims 72-75, 77, 79-80, 83, and 90-92 under 35 U.S.C. 103, have been fully considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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.
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.
Claims 72-75,77, 79-80, 83, and 90-92 are rejected under 35 U.S.C. 103 as being unpatentable over Gopinath et al. (US 20190323002 A1) and (Kershner, “Placement and orientation of individual DNA shapes on lithographically patterned surfaces”; 2009) incorporated by reference, in view of Dagher et al. (US 20210285937 A1, entitled to the EFD 20201001 by provisional application US 63/086,536,) and Chiou (US 20110306039 A1).
Regarding claim 72, Gopinath teaches a substrate for detecting one or more analyte molecules in a sample (The present invention relates to structures for…the multiplexed detection and quantification of a set of analytes, where an analyte is a type of molecule or particle in a fluid sample”; [0003], [0136]; Fig. 9C), the substrate comprising:
a base layer (“substrate,” such as “silicon dioxide” or “ultra-flat template-stripped gold”; [0243]; Fig. 9C);
a binding layer on the base layer (“monolayer,” like “carboxylated thiols such as 11-mercaptoundecanoic acid,” which are used “to create negatively-charged binding sites,”; [0243]; See dotted compounds atop each type of base layer or substrate in Fig. 9C)
a supramolecular structure (Bistable molecular sensor; [104]; Figs. 1B below, 9C) associated with each binding site of the plurality of binding sites (each of the plurality of the bistable molecular sensors are positioned using one or more lithographically patterned binding sites; [0041]), the supramolecular structure comprising:
a core structure (a polynucleotide platform forming a first shape and a second shape; [0104]) (Fig. 1B below) comprising:
a polynucleotide structure (a scaffolded deoxyribonucleic acid (DNA) origami; [0105])
a capture molecule (“a first binding molecule and a second binding molecule,” wherein a first interpretation designates the first binding molecule as the capture molecule and a second interpretation designates the second binding molecule as the capture molecule; [0108]; Fig. 1B below) linked to the core structure at a first location (a first interpretation designates the first location to be where the first binding molecule meets the first polynucleotide platform shape and a second interpretation designates the first location to be where the second binding molecule meets the second polynucleotide platform shape as shown in Fig. 1B below), wherein said capture molecule comprises a protein (the first molecule and the second molecule are selected from a first protein and a second protein; [0068]), a peptide, an antibody, an aptamer, or combinations thereof,
wherein said capture molecule binds an analyte molecule (a first binding molecule and a second binding molecule both capable of binding the target molecule; [0108]), and wherein said analyte molecule comprises a protein (See “target protein,” in Fig. 2A which employs “a sandwich actuation mechanism using antibodies for the detection of proteins”; [0189]), a peptide, a peptide fragment, or any combination thereof, and
a detector molecule linked to the core structure at a second location when the supramolecular structure is in a stable state, wherein said detector molecule comprises a protein, a peptide, an antibody, an aptamer, or combinations thereof, and
wherein said detector molecule binds the analyte molecule (one or more of the first antibody are bound to the first shape inside surface, one or more of the second antibody are bound to the second shape inside surface, and the binding of the target molecule to the first antibody and the second antibody actuates the bistable molecular sensor from the opened state to the closed state; [0117]; See unstable state 02 and stable state 03 in Fig. 2B),
wherein: each supramolecular structure is configured to shift from an unstable state to the stable state through interaction between the detector molecule, the capture molecule, and a respective analyte molecule of the one or more analyte molecules (“the binding of the target molecule to the first and second binding molecules capable of actuating the bistable molecular sensor from the open state to the closed state,” wherein “each of the plurality of bistable molecular sensors when not bound to a target molecule are in the opened state and…the closed state bistable molecular sensors remain in solution”; [0108]-[0109]; See unstable state 02 and stable state 03 in Fig. 2B),
when the supramolecular structure of the substrate is in the stable state, the detector molecule and the capture molecule are configured to link together through binding to the analyte molecule, thereby forming a link between the detector molecule and capture molecule (See target molecule between the first and second binding molecules as shown in sandwich method in stable state 03 of Fig. 2B).
Gopinath fails to teach:
the detector molecule is linked to the core structure at a second location through a cleavable linkage when the supramolecular structure of the substrate is in the unstable state and upon cleavage of the cleavable linkage at the second location of the core structure, the detector molecule is unbound from the core structure at the second location and remains indirectly bound to the core structure as the detector molecule and the capture molecule are both bound to the analyte molecule, and
a patterned top layer exposing portions of the binding layer, the exposed portions corresponding to a plurality of binding sites on the binding layer (Emphasis added).
Gopinath instead teaches two different embodiments of actuations of the bistable sensor based on the event that triggers the sensor to change from an open to closed state (stable to unstable) or vice versa. During sandwich actuation (Figs. 1B below and 2A), a target molecule within a sample binds to both the first and second binding molecules which are positioned on different locations of the polynucleotide structure (first and second shapes), creating a bridge that transitions the sensor to a closed state. In cleavage actuation (Fig. 5D), when a sample contains a specific enzyme, this enzyme acts on a cleavable substrate already incorporated into the sensor, causing the sensor to transition from a closed to open state (stable to unstable). This is different than the claimed invention which would require that while the target molecule is bound to both the first and second binding molecules in the sandwich actuation, cleavage is intentionally triggered to separate the second binding molecule from the second shape of the polynucleotide structure.
Dagher teaches that when the supramolecular structure is in the unstable state and upon cleavage of the cleavable linkage at the second location of the core structure, the detector molecule is unbound from the core structure at the second location and remains indirectly bound to the core structure as the detector molecule and the capture molecule are both bound to the analyte molecule. (“capture binders (CB) and detection binders (DB) are provided pre-assembled to the support before contacting with the sample. The binders can bind simultaneously to the analyte of interest…Detection of the analyte presence proceeds using the "release-dependent transduction" (RDT) principle, which relies on simultaneously labeling the detection binder and displacing it from the support. This step can be performed using DNA oligonucleotide displacement, among other strategies. Importantly, DB only become detectably labeled upon correct displacement, and remains on the support if it is bound to the analyte which itself is bound to the support via the CB,” wherein the DB is “releasably attached to the support via a first anchor oligonucleotide” and satisfies the cleavable linkage limitations; [0126])(See para. [0135] and Fig. 1 of Dagher below showing first and second locations where the first and second oligos are attached to the support which correspond to the linkages of the DB and CB or first and second binders respectively).
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Dagher, Fig. 1
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Fig. 1B, Gopinath
Dagher is considered to be analogous to the claimed invention because it is in the same field of endeavor for the use of molecular sensors in detecting analytes through specific binding interactions. Both Dagher and Gopinath teach analyte detection using a sandwich binding mechanism in which two different binding molecules interact with the same target analyte at different binding regions to provide selective detection (Dagher, [0126])(Gopinath, [0161],[0202]-[0203]). However, Gopinath teaches the conventional sandwich ELISA based detection approach ([0202]), while Dagher builds upon this established sandwich assay principle by providing a releasable linkage and release dependent mechanism ([0126]). Dagher identifies shortcomings associated with conventional ELISA such as “non-specific adsorption of molecules containing such common epitopes…often result[ing] in high background signals” ([0137]). As a solution, Dagher uses its release dependent transduction (RDT) mechanism so that the detectable event is associated with the specifically captured analyte rather than simply detecting every molecule possessing the common epitope. For example, Dagher explains that when the analyte of interest includes an epitope that is common to a class of analytes (e.g., Fc portion of IgG antibody proteins), then the capture reagent first binds to the more specific epitope (paratope) of the analyte of interest (e.g. IgG1) and washes away all other analytes in the sample that do not contain this specific epitope ([0136]). The detector reagent then binds to the common epitope associated with the same analyte of interest and the detector reagent is displaced from the support structure using a displacer reagent ([0126], [0146]). In this way, if the detector reagent is not bound to the analyte which itself is bound to the support via the capture reagent (in other words, if the analyte is not present in the sample), then the displaced detector reagent is washed from the support (Dagher, [0126]). Subsequently, the capture reagent-analyte-detection reagent complex can be removed from the support, and the analyte of interest can be detected (Dagher, [0205](c), [0207]). Dagher’s new method, the colocalization-by-linkage (CLA) sandwich assay, thereby eliminates background signals created from detector molecules that can bind to non-target analytes that would interfere with true analysis of the targets of interest. A person of ordinary skill in the art would have had a reasonable expectation of success in incorporating the releasable detector molecule linkage (first oligo; Dagher, [0146]) into the supramolecular structure of Gopinath because the modification would not alter Gopinath’s underlying analyte recognition mechanism. Gopinath’s sandwich mechanism allows the sensor to transition from an open to closed state when the two binding molecules recognize different regions of the same target analyte. Dagher’s first oligo is only released when a displacer reagent is intentionally introduced and therefore would not interfere with analyte binding. Accordingly, providing the detector molecule through a releasable linkage would predictably allow detector molecules not associated with the analyte of interest to be removed, thereby reducing background signal, while detector molecules bound to captured analyte would remain associated with the analyte and available for detection. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the supramolecular structure taught by Gopinath to incorporate the teachings of Dagher by including a cleavable linkage at the second location of the core structure for release of the detector molecule because this configuration would reduce non-specific background noise and improve detection sensitivity, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Modified Gopinath fails to teach:
a patterned top layer exposing portions of the binding layer, the exposed portions corresponding to a plurality of binding sites on the binding layer (Emphasis added).
Modified Gopinath does, however, teach that each of the binding sites are patterned (Gopinath, [0041]), by providing a protective photoresist layer atop the binding layer (template layer) to act as a stencil (Kershner, Fig. 1; incorporated by reference [0181]). Sections of the photoresist layer are removed, exposing portions of the binding layer where O2 plasma is then used to etch the stenciled pattern onto the portions. The photoresist layer, however, is removed before the supramolecular structures (DNA origami) are deposited within each site (Kerner, p. 557, col. 2, para. 2, ll. 10-20; See Fig. 1).
Chiou teaches a patterned top layer exposing portions of the binding layer (a portion of the upper cladding layer 114 may be removed to expose the core layer 112; [0075])(See nanowells 120 created from top layer or upper cladding layer 114 atop binding layer or core layer 112; [0051]; Fig. 4) (Paragraph [0136] of the instant specification US 20220170918 A1 defines patterned as “patterned, e.g., by removing portions of the top layer”), the exposed portions corresponding to a plurality of binding sites on the binding layer (“at least one nucleic acid molecule individually within the at least one nanowell,” wherein “nucleic acid molecule comprising an insert with a known sequence, which can be used as a binding site for a primer”; [0116][0100]; Fig. 4, 120)(Since there are multiple wells on the binding layer as shown in Fig. (nanowells 121-124), then there will be also a plurality of binding sites because each contains a nucleic acid with a binding site).
Chiou is considered to be analogous to the claimed invention because it is in the same field of endeavor for substrate for single molecule organization. Gopinath teaches that “the bistable molecular sensor in the closed state is detected optically,” and that “microfabricated cavities,” such as waveguides used “to enhance optical detection by scattering or fluorescence may achieve high performance” ([0039],[0237]). Chiou creates a waveguide by forming a nanowell from the walls of a cladding layer that exposes a core or binding layer; light is then detected by light emitted from a single molecule object contained in the at least one nanowell (Abstract). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the substrate taught by Gopinath in view of Dagher to incorporate the teachings of Chiou with the addition of a top layer on the binding layer exposing portions of the binding layer because enhancing the sensor detection would improve the validity of the sample test results, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Regarding claim 73, Modified Gopinath teaches the substrate of claim 72, comprising a passivating layer disposed on the top layer (“the surface of the upper protection layer…is formed over the upper cladding layer; Chiou, [0060]) and not on the binding layer (“making the bottom surface of the nanowell 120 hydrophobic but keeping the sidewall surface of the nanowell 120 hydrophilic,” and since these are different materials, then the passivating layer is not disposed on the binding layer; [0061])(This layer constitutes a passivating layer in that “the object being detected may be kept in the effective excitation zone near the bottom of the nanowell 120 but may not adhere to the sidewall surface of the nanowell 120” (Chiou, [0061]) as described in paragraph [000125] of the instant specification).
Regarding claim 74, Modified Gopinath teaches the substrate of claim 73, wherein the passivating layer is a polymer layer reactive with reactive group on the top layer (Paragraph [0061] of Chiou teaches the passivating layer can be either hydrophobic or hydrophilic, whichever is opposite the bottom surface of the nanowell, and polymers are mentioned as an example of a material for either surface)(Since the passivating layer is “formed over the upper cladding layer,” there is a natural reaction between the layers when a reactive group is contacted on either layer).
Regarding claim 75, Modified Gopinath teaches the substrate of claim 72, wherein the top layer has a prescribed thickness and forms a plurality of wells in which the respective plurality of binding sites are disposed (The nanowells extend through the full thickness of the upper cladding layer; Chiou, [0173])(Under broadest reasonable interpretation, the Examiner understands any thickness to be prescribed since prescription can be determined at any time depending on any factor such as the mere capability of the instrumentation or human hand to coat the layer, wherein walls of the wells are formed by material of the top layer (See Fig. 4 of Chiou, item 114).
Regarding claim 77, Modified Gopinath teaches the substrate of claim 72, wherein the binding layer comprises silicon, silicon dioxide, silicon nitride (silicon nitride; Chiou, [0051]), graphene, quarts, gold, silver, metal, platinum, palladium, PDMS, or a polymer film.
Regarding claim 78, Modified Gopinath teaches the substrate of claim 72, wherein the top layer comprises a metal oxide (upper cladding layer 114…may comprise… aluminum oxide; Chiou, [0051]), graphene, HfO2, or CO2.
Regarding claim 79, Modified Gopinath teaches the substrate of claim 72, wherein the base layer comprises a silicon wafer (a silicon dioxide wafer; Gopinath, [0243]; Fig. 9C).
Regarding claim 80, Modified Gopinath teaches the substrate of claim 72, wherein the substrate is coupled to a detection system (the detection system for detecting a selected stimulus as disclosed above, wherein DNA origami placement is used to position a bistable device at a binding site between electrodes; Gopinath, [0139]) that detects a shift of the supramolecular structure from the unstable state to the stable state (electrochemical measurements distinguishing open and closed states; Gopinath, [0139]) at each binding site of the plurality of binding sites “position a bistable device at a binding site between electrodes,” wherein “each one of said binding sites is filled by exactly one bistable molecular sensor”; Gopinath, [0138];[0137]).
Regarding claim 83, Modified Gopinath teaches the substrate of claim 72, wherein each core structure independently comprises a scaffolded deoxyribonucleic acid (DNA) origami (the polynucleotide platform is selected from scaffolded deoxyribonucleic acid (DNA) origami; Gopinath, [0012]), a scaffolded ribonucleic acid (RNA) origami, a scaffolded hybrid DNA:RNA origami, a single-stranded DNA tile structure, a multi-stranded DNA tile structure, a single-stranded RNA origami, a multi-stranded RNA tile structure, hierarchically composed DNA or RNA origami with multiple scaffolds, or combinations thereof.
Regarding claim 90, Modified Gopinath teaches the substrate of claim 72, wherein each well of the plurality of wells is between 3 angstroms and 300 nm in depth (the depth of the nanowell extending in the core layer was set to be 50 nm; Chiou, [0158]).
Regarding claim 91, Modified Gopinath teaches the substrate of claim 80, wherein the base layer comprises a plurality of light pipes (ring resonators coupled to a waveguide of paragraph [0221]; Gopinath, Fig. 7D) coupled to each respective binding site of the plurality of binding sites (4000 distinct bistable sensors…spotted onto substrate; Gopinath, [0138]), and wherein the detection system comprises a photodiode (“an electrochemical sensor built using CMOS,” where a CMOS by design comprises a photodiode; Gopinath, [0138]) coupled to each light pipe of the plurality of light pipes (Paragraph [0221] of Gopinath explains that the substrate or bistable sensor is immobilized on a microfabricated ring resonator, and the ring resonator is strongly coupled to an optical waveguide that transmits a signal at the output. Since each spot of the microarray is positioned over a distinct electronic sensor that is the CMOS (Gopinath, [0138]), then the photodiode is coupled to each light pipe of the plurality of light pipes).
Regarding claim 92, Modified Gopinath teaches the substrate of claim 80, wherein each binding site of the plurality of binding sites is coupled to one or more electrical leads (See source and drain leads that connect to the semiconductor in Fig. 6A of Gopinath), and wherein the detection system comprises a field effect transistor (the bistable molecular sensor is immobilized on the channel region of field effect transistor (FET); Gopinath, [0219]; Fig. 6B).
Double Patenting
Claims 72-75,77, 79-80, 83, and 90-92 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 223-224, 227, 229, 210-211 of co-pending Application No. 18/245131 in view of Chiou (US 20110306039 A1).
Regarding claim 72, ‘131 teaches
A substrate for detecting one or more analyte molecules in a sample (A substrate for detecting one or more analyte molecules in a sample; claim 223), the substrate comprising:
a base layer (a solid support; claim 224);
a supramolecular structure ( supramolecular structure; claim 223) comprising:
a core structure comprising a polynucleotide structure (each core structure independently comprises a scaffolded deoxyribonucleic acid (DNA) origami; claim 227)
a capture molecule linked to the supramolecular core structure at a first location (a capture molecule linked to the core structure at a first location; claim 223),
wherein said capture molecule comprises a protein, a peptide, an antibody, an aptamer, or combinations thereof (the capture molecule and detector molecule for each supramolecular structure independently comprise a protein, a peptide, an antibody, an aptamer…or a combination thereof; claim 229).
wherein said capture molecule binds an analyte molecule (“capture molecule are linked together through binding to the analyte molecule,” wherein the method requires the use of the claimed substrate; claim 210), and wherein said analyte molecule comprises a protein, a peptide, a peptide fragment, or any combination thereof (the analyte molecule comprises a protein, a peptide, a peptide fragment…or any combinations thereof; claim 211), and
a detector molecule linked to the supramolecular core at a second location (a detector molecule linked to the core structure at a second location; claim 223) through a cleavable linkage (wherein the supramolecular structure is in an unstable state, such that the detector molecule is configured to be unbound from the core through cleavage of a link therebetween at the second location; claim 223), when the supramolecular structure is in a stable state (if the supramolecular structure is in an unstable state upon cleavage of a link then it is naturally in a stable state before cleavage), wherein said detector molecule comprises a protein, a peptide, an antibody, an aptamer, or combinations thereof ((the capture molecule and detector molecule for each supramolecular structure independently comprise a protein, a peptide, an antibody, an aptamer…or a combination thereof; claim 229), and wherein said detector molecule binds the analyte molecule (“the detector molecule and the capture molecule are linked together through binding to the analyte molecule,” wherein the method requires the use of the claimed substrate; claim 210),
wherein the supramolecular structure is in an unstable state, such that the detector molecule is configured to be unbound from the core structure through cleavage of a link therebetween at the second location (wherein the supramolecular structure is in an unstable state, such that the detector molecule is configured to be unbound from the core structure through cleavage of a link therebetween at the second location; claim 223) and
wherein each supramolecular structure is configured to shift from an unstable state to the stable state through interaction between the detector molecule, the capture molecule, and a respective analyte molecule of the one or more analyte molecules when the supramolecular structure of the substrate is in the stable state (contacting the sample with the supramolecular structure, such that the supramolecular structure shifts from the unstable state to a stable state wherein the detector molecule and the capture molecule are linked together through binding to the analyte molecule; claim 223),
the detector molecule and the capture molecule are configured to link together through binding to the analyte molecule, thereby forming a link between the detector molecule and capture molecule, and when the supramolecular structure of the substrate is in the unstable state and upon cleavage of the cleavable linkage at the second location of the core structure, the detector molecule is unbound from the core structure at the second location and remains indirectly bound to the core structure as the detector molecule and the capture molecule are both bound to the analyte molecule (“the detector molecule and the capture molecule are linked together through binding to the analyte molecule, thereby forming a link between the detector molecule and capture molecule; (c) providing a trigger to cleave the link between the detector molecule and the core structure at the second location, wherein the detector molecule remains linked to the core structure through the link with the capture molecule,” wherein step ii. explains that the supramolecular structure is in an unstable state upon cleavage of a link therebetween at the second location; claim 210)
‘131 fails to teach
a binding layer on the base layer;
a patterned top layer exposing portions of the binding layer, the exposed portions corresponding to a plurality of binding sites on the binding layer;
Chiou teaches a patterned top layer exposing portions of the binding layer (a portion of the upper cladding layer 114 may be removed to expose the core layer 112; [0075])(See nanowells 120 created from top layer or upper cladding layer 114 atop binding layer or core layer 112; [0051]; Fig. 4) (Paragraph [0136] of the instant specification US 20220170918 A1 defines patterned as “patterned, e.g., by removing portions of the top layer”), the exposed portions corresponding to a plurality of binding sites on the binding layer (“at least one nucleic acid molecule individually within the at least one nanowell,” wherein “nucleic acid molecule comprising an insert with a known sequence, which can be used as a binding site for a primer”; [0116][0100]; Fig. 4, 120)(Since there are multiple wells on the binding layer as shown in Fig. (nanowells 121-124), then there will be also a plurality of binding sites because each contains a nucleic acid with a binding site).
Chiou is considered to be analogous to the claimed invention because it is in the same field of endeavor for substrate for single molecule organization. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified ‘131 to incorporate the teachings of Chiou with the addition of a top layer on the binding layer exposing portions of the binding layer. Claim 223 of ‘131 explains the substrate comprises “a plurality of supramolecular structures for the detection of one or more analytes in a sample”. Claim ‘219 also states the need to create spacing between the capture and detector molecules of each supramolecular structure so as to prevent cross-reactions with other supramolecular structures. By adding a top layer that encamps a binding layer, a well or cavity is creating which can separate each supramolecular structure in order to avoid cross-reactions by partitioning each within a wall. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have created these wells for the benefit listed above.
Regarding claim 73, Modified ‘131 teaches the substrate of claim 72.
Modified ‘131 fails to teach a passivating layer disposed on the top layer and not on the binding layer.
Chiou teaches a passivating layer disposed on the top layer (“the surface of the upper protection layer…is formed over the upper cladding layer; [0060]) and not on the binding layer (“making the bottom surface of the nanowell 120 hydrophobic but keeping the sidewall surface of the nanowell 120 hydrophilic,” and since these are different materials then the passivating layer is not disposed on the binding layer)(This layer constitutes a passivating layer in that “the object being detected may be kept in the effective excitation zone near the bottom of the nanowell 120 but may not adhere to the sidewall surface of the nanowell 120” (Chiou, [0061]) as described in paragraph [000125] of the instant specification).
Chiou is considered to be analogous to the claimed invention because it is in the same field of endeavor for substrate for single molecule organization. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified ‘131 in view of Chiou to further incorporate the teachings of Chiou with the addition of a passivating layer disposed on the top layer and not on the binding layer. Doing so will keep the captured analytes near the bottom of the wells to prevent loss the analyte from adhering to the walls of the well causing friction and possible unbinding. This in turn will lead to a more stable analyte detection which is the goal of ‘131 (Chiou, [0061]).
Regarding claim 74, Modified ‘131 teaches the substrate of claim 73, wherein the passivating layer is a polymer layer reactive with reactive group on the top layer (Paragraph [0061] of Chiou teaches the passivating layer can be either hydrophobic or hydrophilic, whichever is opposite the bottom surface of the nanowell, and polymers are mentioned as an example of a material for either surface)(Since the passivating layer is “formed over the upper cladding layer,” there is a natural reaction between the layers when a reactive group is contacted on either layer).
Regarding claim 75, Modified ‘131 teaches the substrate of claim 72, wherein the top layer has a prescribed thickness and forms a plurality of wells in which the respective plurality of binding sites are disposed (The nanowells extend through the full thickness of the upper cladding layer; Chiou, [0173])(Under broadest reasonable interpretation, the Examiner understands any thickness to be prescribed since prescription can be determined at any time depending on any factors as the capability of the instrumentation used to coat the layer, wherein walls of the wells are formed by material of the top layer (See Fig. 4 of Chiou, item 114).
Regarding claim 77, Modified ‘131 teaches the substrate of claim 72, wherein the binding layer comprises silicon, silicon dioxide, silicon nitride (silicon nitride; Chiou, [0051]), graphene, quarts, gold, silver, metal, platinum, palladium, PDMS, or a polymer film.
Regarding claim 78, Modified ‘131 teaches the substrate of claim 72, wherein the top layer comprises a metal oxide (upper cladding layer 114…may comprise… aluminum oxide; Chiou, [0051]), graphene, HfO2, or CO2.
Regarding claim 79, Modified ‘131 teaches the substrate of claim 72. Modified ‘131 is silent to teaching the base layer comprises a silicon wafer, however, claim 224 of ‘131 does teach the substrate to be a solid support.
Chiou teaches a base layer, lower cladding layer 116, may comprise silicon oxide ([0051]). Chiou also states that the material of the base layer may have a specific refractive index ([0051]). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified ‘131 to combine the two structures to specify the solid support to be a silicon wafer. Doing so would help to guide light for a better detection.
Regarding claim 80, Modified ‘131 teaches the substrate of claim 72, wherein the substrate is coupled to a detection system that detects a shift of the supramolecular structure from the unstable state to the stable state at each binding site of the plurality of binding sites (each supramolecular structure is configured to shift from the unstable state to a stable state through interaction between the detector molecule; claim 223).
Regarding claim 83, Modified ‘131 teaches the substrate of claim 72, wherein each core structure independently comprises a scaffolded deoxyribonucleic acid (DNA) origami, a scaffolded ribonucleic acid (RNA) origami, a scaffolded hybrid DNA:RNA origami, a single-stranded DNA tile structure, a multi-stranded DNA tile structure, a single-stranded RNA origami, a multi-stranded RNA tile structure, hierarchically composed DNA or RNA origami with multiple scaffolds, a peptide structure, or combinations thereof (each core structure independently comprises a scaffolded deoxyribonucleic acid (DNA) origami, a scaffolded ribonucleic acid (RNA) origami, a scaffolded hybrid DNA:RNA origami, a single-stranded DNA tile structure, a multistranded DNA tile structure, a single-stranded RNA origami, a multi-stranded RNA tile structure, hierarchically composed DNA or RNA origami with multiple scaffolds, or a combination thereof; claim 227).
Regarding claim 90, Modified ‘131 teaches the substrate of claim 72, wherein each well of the plurality of wells is between 3 angstroms and 300 nm in depth (the depth of the nanowell extending in the core layer was set to be 50 nm; Chiou, [0158]).
Regarding claim 91, Modified ‘131 teaches the substrate of claim 80. Modified ‘131 fails to teach the base layer comprises a plurality of light pipes coupled to each respective binding site of the plurality of binding sites, and wherein the detection system comprises a photodiode coupled to each light pipe of the plurality of light pipes.
Gopinath teaches the base layer comprises a plurality of light pipes (ring resonators coupled to a waveguide of paragraph [0221]; Gopinath, Fig. 7D) coupled to each respective binding site of the plurality of binding sites (4000 distinct bistable sensors…spotted onto substrate; Gopinath, [0138]), and wherein the detection system comprises a photodiode (“an electrochemical sensor built using CMOS,” where a CMOS by design comprises a photodiode; Gopinath, [0138]) coupled to each light pipe of the plurality of light pipes (Paragraph [0221] of Gopinath explains that the substrate or bistable sensor is immobilized on a microfabricated ring resonator, and the ring resonator is strongly coupled to an optical waveguide that transmits a signal at the output. Since each spot of the microarray is positioned over a distinct electronic sensor that is the CMOS (Gopinath, [0138]), then the photodiode is coupled to each light pipe of the plurality of light pipes).
Gopinath is considered to be analogous to the claimed invention because it is in the same field of endeavor for substrate for single molecule organization. Since ‘131 claims that the capture molecule can be a fluorophore (claim 229), it would be beneficial to amplify the transmission of this light to an actual detection device. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the substrate taught by ‘131 in view of Chiou to further incorporate the teachings of Chiou with the addition of the base layer comprising a plurality of light pipes coupled to each respective binding site of the plurality of binding sites, and a detection system comprising a photodiode because it would help to process the signals from the sample and further aide in the functionality of the device for “detecting one or more analyte molecules in a sample” (claim 223, ‘131), and this includes combining prior art elements according to
known methods to yield predictable results (See MPEP 2143(I)(A)).
Regarding claim 92, Modified ‘131 teaches the substrate of claim 80. Modified ‘131 fails to teach each binding site of the plurality of binding sites is coupled to one or more electrical leads and the detection system comprises a field effect transistor.
Gopinath teaches each binding site of the plurality of binding sites is coupled to one or more electrical leads (See source and drain leads that connect to the semiconductor in Fig. 6A of Gopinath), and wherein the detection system comprises a field effect transistor (the bistable molecular sensor is immobilized on the channel region of field effect transistor (FET); Gopinath, [0219]; Fig. 6B).
Gopinath is considered to be analogous to the claimed invention because it is in the same field of endeavor for substrate for single molecule organization. Claims 223 and 232 of ‘131 state the use of a barcode signal to detect the shift of stability. The signal would need to transmit energy that would need to be interpreted. Applying electrical leads and a transistor helps to convert this current into readable data to complete the detection process. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the substrate taught by ‘131 in view of Chiou and Gopinath to further incorporate the teachings of Gopinath with the addition of electrical leads and a field effect transistor coupled to the binding sites because these components would increase the accuracy and precision of detection results, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Dagher et al., 2019 (instant PTO-892) is fully incorporated by reference into Dagher (US 63/086,536, EFD 20201001) and teaches a supramolecular structure with a detector and capture molecule attached to a support at different locations that both bind the same analyte and is cleavable between the detector molecule and a first location on the support such that the capture and detector molecule are still bound to the same analyte and coupled to a second location of the support (See Fig. 7).
No claims are allowed.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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