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 .
Claims 1 and 3-27 are pending. Claims 14-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 2 has been cancelled. Claim 27 is new.
Claims 1, 3-13, and 27 are currently under examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/4/26 has been entered.
Priority
The instant application 17/606,567 filed on 10/26/21 is a 371 US national phase of PCT/US2020/030055 filed on 4/27/20, and claims domestic priority to provisional application 62/840,040 filed on 4/29/19. The priority date is determined to be 4/29/19.
Response to Arguments
Applicant’s arguments, see pages 8-17, filed 2/4/26, with respect to the rejections of claims 1 and 3-13 under 35 USC 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Final mailed 8/29/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by new claim 27 are made in this Non-Final Office Action.
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.
Claims 1, 3-5, and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Cunningham et al. (2010; US 7,768,640 B2; US Patent Document citation A in PTO-892 filed 3/6/25) in view of Zhang et al. (2018; US 2018/0363045 A1; USPGPub citation 1 in IDS filed 10/26/21).
This new 103 rejection is necessitated by new claim 27 filed 2/4/26.
(i) Cunningham et al. teaches limitations relevant to claims 1 and 5.
Cunningham et al. teaches “Photonic crystal sensors are disclosed for use in testing samples in which a fluorophore, e.g., inorganic crystalline semiconductor ("quantum dot) or fluorescent dye is present in the sample. The sample and fluorescent dye are in close proximity, or more typically bound, to the photonic crystal surface, e.g., by depositing the sample with fluorophore on the sensor surface in a dry or aqueous environment” (column 6, lines 29-35).
Cunningham et al. teaches that the photonic crystal sensors are useful in “Gene expression microarrays incorporating the photonic crystal sensor” (column 8, lines 37-38).
Relevant to claim 1, Cunningham et al. teaches that their system “will be easily adaptable for enhanced fluorescence biosensors, for example, where the analytes bound to the fluorophores are typically in an aqueous buffer solution” (column 15, lines 14-16).
Further relevant to claim 1, Cunningham et al. teaches “The fluorophores described herein (e.g., quantum dots) are functionalized by being bound to capture molecules which are in turn deposited onto the surface of the photonic crystal biosensor” (column 25, lines 17-20).
Further relevant to claim 1, Cunningham et al. teaches “While the above examples have used quantum dots as the fluorescent molecule which is excited by incident radiation, other fluorophores can be used in accordance with the inventive biosensor”, including “luminescent compounds… including… transition metal complexes… nanoparticles… or any other light emitting species that can be excited by evanescent fields” (column 24, lines 6-29).
Further relevant to claim 1, Cunningham et al. teaches “Generally speaking the capture molecules used should be capable of affinity reactions. Examples of capture molecules which can be used in the context of this invention include: nucleotides, oligonucleotides…” (column 25, lines 21-25).
These teachings read on claim 1 buffer solution, plurality of nanoparticle probes, and a substrate.
Further relevant to claim 1, Cunningham et al. teaches “As an example, a NH2-activated biosensor surface can have a specific binding substance comprising a single-strand DNA capture probe immobilized on the surface. The capture probe interacts selectively with its complementary target binding partner. The binding partner, in turn, can be designed to include a sequence or tag that will bind a ‘detector’ molecule” (column 26, lines 59-65).
Further relevant to claim 1, Cunningham et al. teaches “One example of a microarray to be used in a method according to the present invention is a nucleic acid microarray, in which each distinct location within the array contains a different nucleic acid molecule. In this embodiment, the spots within the nucleic acid microarray detect complementary chemical binding with an opposing strand of a nucleic acid in a test sample” (column 22, lines 15-21).
Further relevant to claim 1, Cunningham et al. teaches “The sensors described here can be used to sensitively analyze a variety of analytes. Some examples of analytes that can be detected using the sensors and methods herein include, but are not limited to, one or more: … DNA molecules, RNA molecules, oligonucleotides…” (column 22, lines 22-26).
These teachings read on claim 1 probe oligonucleotide that is complementary to a target oligonucleotide and capture oligonucleotides conjugated to the substrate.
Relevant to claim 5, Cunningham et al. teaches “Photonic crystal sensors are disclosed for use in testing samples in which a fluorophore, e.g., inorganic crystalline semiconductor ("quantum dot) or fluorescent dye is present in the sample. The sample and fluorescent dye are in close proximity, or more typically bound, to the photonic crystal surface, e.g., by depositing the sample with fluorophore on the sensor surface in a dry or aqueous environment” (column 6, lines 29-35).
This teaching reads on claim 5 wherein the substrate comprises a photonic crystal.
(ii) Cunningham et al. is silent to specifics regarding protector oligonucleotides (claims 1, 3-4, and 12-13). However, these limitations were known in the prior art and taught by Zhang et al.
Zhang et al. teaches “primers and primer systems having improved specificity and kinetics over existing primers” (Abstract). Zhang et al. teaches that their invented “primers may also be used in nucleic acid detection assays where they function primarily as ‘probes’” (page 1, paragraph 0009).
Relevant to claims 1 and 3(i), Zhang et al. Fig. 1A teaches that their nucleic acid probe system contains a protector strand bound to the complement probe, reading on claim 1 a protector oligonucleotide bound to the probe oligonucleotide and claim 3 the protector oligonucleotide is bound to (i) at least part of the first portion of the probe oligonucleotide.
Further relevant to claim 1, Zhang et al. teaches “methods comprising (1) hybridizing a complement strand of a primer duplex to a target nucleic acid, thereby dissociating the complement strand from its protector strand” (page 20, paragraph 0234). This reads on the target oligonucleotide is able to bind to the probe oligonucleotide and displace the protector oligonucleotide therefrom. Zhang et al. page 3, paragraph 0022 teaches that “The composition may also comprise an excess of single-stranded protector strands”, reading on an excess amount of the protector oligonucleotide in the buffer solution.
Relevant to claim 12, Zhang et al. page 18, paragraph 0195 teaches that “the standard free energy of the strand displacement reaction shown in FIG. 9A between the correct target and the protected complement is roughly ΔG°=0 kcal/mol.” This teaching reads on claim 12 the excess amount of the protector oligonucleotide in the buffer solution is such that binding of the target oligonucleotide to the probe oligonucleotide with displacement of the protector oligonucleotide therefrom has a reaction free energy (ΔG) that is zero.
Relevant to claim 13, Zhang et al. page 18, paragraph 0198 teaches that “The protector strand correspondingly changes the standard free energy of the strand displacement reaction with spurious targets. In the example shown in FIG. 9B, the spurious target differs from the correct target by a single base, which results in the strand displacement reaction with the same two-stranded nucleic acid primer system having a ΔG°= +3.7 kcal/mol”. This teaching reads on the excess amount of the protector oligonucleotide in the buffer solution provides selectivity over a plurality of different single nucleotide variants (SNVs) of the target oligonucleotide in that binding of each SNV to the probe oligonucleotide with displacement of the protector oligonucleotide therefrom has an associated reaction free energy (ΔG) that is positive.
Although Zhang et al. does not explicitly teach or suggest a motivation of combining the protector oligonucleotide with the Cunningham et al. probes, substrate, and capture oligonucleotides, it would have been prima facie obvious to the skilled artisan to combine the teachings of Cunningham et al. and Zhang et al. with reasonable expectation of success because (i) Zhang et al. teaches that “primers and primer systems having improved specificity and kinetics over existing primers, and methods of use thereof” (See abstract), and “For primer duplexes having a hairpin region, the standard free energy of the confinement of the hairpin region may be considered when determining the standard free energy for the reaction in which the protector strand is displaced from the complement strand by the target nucleic acid (see [0105]); and (ii) Cunningham et al. and Zhang et al. are analogous arts in the context of detecting target nucleic acid of interest by hybridization.
Relevant to claims 3 and 4, the skilled artisan would find it obvious to design the Zhang et al. protector oligonucleotide to bind, and thus protect, the second portion of the probe oligonucleotide that interacts with the substrate-bound capture oligonucleotides. As seen in Zhang et al. Fig. 7, the nucleic acid probe system can be designed such that the protector probes have two protector domains and two regions for complementarity binding. Thus, the skilled artisan would find claim 3 obvious in that the protector oligonucleotide would be bound to (i) at least part of the first portion of the probe oligonucleotide and (ii) at least a part of the second portion of the probe oligonucleotide.
As discussed previously within the rejection of claim 1, Zhang et al. renders obvious claim 4 displacement of the protector oligonucleotide from the probe oligonucleotide by the target oligonucleotide. Since it would be obvious to the skilled artisan to design one of the two protector domains in Zhang et al. Fig. 7 to also bind the second portion of the probe oligonucleotide that interacts with the substrate-bound capture oligonucleotides – as in rejection of claim 3 – the skilled artisan would find claim 4 obvious in that the target binding would result in exposure of the second portion of the probe oligonucleotide such that the capture oligonucleotide is able to bind to the probe oligonucleotide.
The skilled artisan would have been motivated to combine the techniques of Cunningham et al. with the protector oligonucleotides of Zhang et al. Zhang et al. teaches that their nucleic acid probes benefit from having “regions complementary to a target sequence that are protected from hybridization to spurious targets by protector regions” (page 7, paragraph 0061). Zhang et al. further teaches that “the protector strand is responsible for altering the standard free energy to allow the complement strand to discriminate between correct and spurious targets” (pages 8-9, paragraph 0073). Thus, the skilled artisan would be motivated to combine the protector with the nanoparticle probe system because Zhang et al. teaches that it would improve discrimination between true target detection and spurious/off-target detection.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Cunningham et al. in view of Zhang et al.
Claims 6-11 are rejected under 35 U.S.C. 103 as being unpatentable over Cunningham et al. (2010; US 7,768,640 B2; US Patent Document citation A in PTO-892 filed 3/6/25) in view of Zhang et al. (2018; US 2018/0363045 A1; USPGPub citation 1 in IDS filed 10/26/21), as applied to the rejection of claims 1, 3-5, and 12-13 above, and further in view of Cytodiagnostics (Gold NanoUrchins (2018 and Gold Nanoparticle Applications (2018); NPL citations U and V, respectively, in PTO-892 filed 4/4/25).
The teachings of Cunningham et al. in view of Zhang et al. are applied to instantly rejected claims 6-11 as they were previously applied to claims 1, 3-5, and 12-13 as rendering obvious a method of nucleic acid detection. Cunningham et al. in view of Zhang et al. is silent to specifics regarding metallic nanoparticles. However, these limitations were known in the prior art and taught by Cytodiagnostics.
Cytodiagnostics manufactures gold nanoparticles with oligonucleotide conjugation applications (Gold Nanoparticle Applications, page 2). Relevant to claims 6-8, Cytodiagnostics teaches that their Gold NanoUrchins have a “spiky uneven surface” (Gold NanoUrchins, page 1, paragraph 1), reading on claim 6 the metallic nanoparticles have a spiked surface. This product’s name and description also reads on claim 7 the metallic nanoparticles are nano-urchins and claim 8 the metallic nanoparticles are gold nanoparticles.
Relevant to claim 9, Cytodiagnostics Figure 1 shows the UV-VIS spectra of their Gold NanoUrchin product across the 400nm – 900nm wavelengths tested (Gold NanoUrchins, page 1). Absent a limiting definition of the photonic crystal resonant wavelength, the large range of tested wavelengths would obviously include – and read on – the metallic nanoparticles have a surface plasmon resonance at a wavelength that matches a resonant wavelength of the photonic crystal.
Relevant to claim 11, the Cytodiagnostics Figure 1 shows that their NanoUrchins range in diameter from 50nm – 100nm (Gold NanoUrchins, page 1), reading on the metallic nanoparticles have a diameter that is between about 50 nanometers and about 100 nanometers.
It would have been prima facie obvious to the skilled artisan to use the Gold NanoUrchins of Cytodiagnostics within the detection method rendered obvious by Cunningham et al. in view of Zhang et al. Cytodiagnostics teaches that their product has oligonucleotide conjugation applications (Gold Nanoparticle Applications, pages 2-3), indicating their ability to be modified via conjugation to the probe and protector oligonucleotides. Additionally, Cytodiagnostics teaches that their product’s “spiky uneven surface causes a red shift in the surface plasmon peak and a larger enhancement of the electromagnetic field at the tips of the Gold NanoUrchin spikes” (Gold NanoUrchins, page 1, paragraph 1). The skilled artisan would be further motivated to include the Cytodiagnostics Gold NanoUrchins because of the teaching that ligands binding to the Gold NanoUrchin surface “causes a larger shift in the surface plasmon resonance peak compared to standard spherical gold nanoparticles. This feature makes them ideal in the development of sensitive SPR-based detection assays” (Gold NanoUrchins, page 1, paragraph 2).
Relevant to claim 10, although Cytodiagnostics does not specify that their Gold NanoUrchins are magnetic, Cunningham et al. column 6 line 62+ teaches that the use of their photonic crystals “gives rise to the formation of high intensity electromagnetic near-fields which serves to efficiently excite the fluorophore present in the sample” and that “While the above examples have used quantum dots as the fluorescent molecule which is excited by incident radiation, other fluorophores can be used in accordance with the inventive biosensor”, including “luminescent compounds… including… transition metal complexes… nanoparticles… or any other light emitting species that can be excited by evanescent fields” (column 24, lines 6-29).
Thus, it would be obvious to the skilled artisan to ensure that the nanoparticles are magnetic, as Cunningham et al. teaches the application of electromagnetic near-fields and metal nanoparticles.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Cunningham et al. in view of Zhang et al., and further in view of Cytodiagnostics.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Cunningham et al. (2010; US 7,768,640 B2; US Patent Document citation A in PTO-892 filed 3/6/25) in view of Zhang et al. (2018; US 2018/0363045 A1; USPGPub citation 1 in IDS filed 10/26/21), as applied to the rejection of claims 1, 3-5, and 12-13 above, and further in view of Wang et al. (2017; “SERS-Activated Platforms for Immunoassay: Probes, Encoding Methods, and Applications”; Chemical Reviews 2017 117 (12), 7910-7963; DOI: 10.1021/acs.chemrev.7b00027).
The teachings of Cunningham et al. in view of Zhang et al. are applied to instantly rejected claim 27 as they were previously applied to claims 1, 3-5, and 12-13 as rendering obvious a method of nucleic acid detection.
Relevant to claim 27, Cunningham et al. teaches single nucleotide polymorphisms as a potential “desired feature[s] under investigation” (column 21, lines 46-51), reading on single-base mismatch sensitivity.
Further relevant to claim 27, Cunningham et al. teaches “This camera 230 has a very large dynamic range to enable high-enhancement measurements, and also has excellent sensitivity for pursuing single-molecule fluorescence detection” (column 29, lines 25-28), reading on single particle resolution for target oligonucleotides.
Cunningham et al. in view of Zhang et al. is silent to specifics regarding a direct 100 aM limit of detection. However, these limitations were known in the prior art and taught by Wang et al.
Wang et al. teaches “One of the most promising routes to improve the sensitivity [of analyte detection] is to fabricate super-hydrophobic SERS substrate to overcome the diffusion limit of analyte molecules. To overcome the limit dictated by diffusion, De Angelis et al. combined super-hydrophobic surfaces with nanoplasmonics for detection (Figure 15). [citations] They achieved an ultrasensitive SERS detection under an attomolar concentration…” (page 7925, Section “3.6. Hydrophobic SERS Substrates”).
Although Cunningham et al. and Zhang et al. are silent to the Wang et al. limits of detection, it would have been prima facie obvious to the skilled artisan. Cunningham et al., Zhang et al., and Wang et al. are analogous disclosures within the instant detection field.
Cunningham et al. section “Photonic Crystal Constructions” (column 20+) provides for customization of layers of the photonic crystal sensor in order to provide enhanced detection applications. The skilled artisan would recognize that the Wang et al. teachings of super-hydrophobic properties would be advantageously applicable to the Cunningham et al. customizable photonic crystal because Wang et al. teaches that these modifications provide improved analyte detection sensitivity.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Cunningham et al. in view of Zhang et al., and further in view of Wang et al.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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