DETAILED ACTION
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 3-26 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 Claims 14-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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. Claims 1, 3, and 5 have been amended.
Claims 1 and 3-13 are currently under examination.
Response to Amendment
The Amendment filed 7/7/25 has been entered. Claims 1 and 3-26 are currently pending.
Response to Arguments
Applicant’s arguments, see pages 7-9, filed 7/7/25, with respect to the rejections of claims 1 and 3-13 under 35 USC 103 have been fully considered and are found unpersuasive, and the 103 rejections documented in the Non-Final mailed on 4/4/25 have been revised to address claim amendments filed 7/7/25 in this Final Office Action. More detailed responses to Applicant’s arguments are provided at the end of each maintained rejection.
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, 3-4, and 12-13 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al. (2002; US 6,361,944 B1; US Patent citation 1 in IDS filed 10/26/21) in view of Zhang et al. (2018; US 2018/0363045 A1; USPGPub citation 1 in IDS filed 10/26/21).
(i) Mirkin et al. teaches "methods of detecting a nucleic acid" through “contacting the nucleic acid with one or more types of particles having oligonucleotides attached thereto” (Abstract). Mirkin et al. teaches limitations relevant to claim 1.
Relevant to claim 1, Mirkin et al. teaches that “All [of their invention’s] hybridization experiments were performed in a 0.3 M NaCl, 10 mM phosphate, pH 7.0, buffer solution” (column 58, lines 31-32). This teaching reads on An assay medium, comprising: a buffer solution. Mirkin et al. teaches that “the method comprises providing a first type of metallic or semiconductor nanoparticles having oligonucleotides attached thereto” (column 6, lines 57-59). This teaching, in combination with all the hybridization experiments being performed within a buffer solution, reads on a plurality of nanoparticle probes in the buffer solution, wherein the nanoparticle probes comprise metallic nanoparticles in which each metallic nanoparticle is conjugated to a probe oligonucleotide. Mirkin et al. teaches that “The oligonucleotides have a sequence complementary to a first portion of the sequence of the nucleic acid” (column 6, lines 59-61). This teaching reads on a first portion of the probe oligonucleotide is complementary to a target oligonucleotide such that the target oligonucleotide is able to bind to the probe oligonucleotide.
Further relevant to claim 1, Mirkin et al. column 23, lines 5-21 teach that “In another embodiment, nanoparticles are attached to the substrate. Nanoparticles can be attached to substrates as described in, e.g., [citations]… After the nanoparticles are attached to the substrate, oligonucleotides are attached to the nanoparticles. This may be accomplished in the same manner described above for the attachment of oligonucleotides to nanoparticles in solution. The oligonucleotides attached to the nanoparticles have a sequence complementary to a first portion of the sequence of a nucleic acid. The substrate is contacted with the nucleic acid under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with the nucleic acid. In this manner the nucleic acid becomes bound to the substrate.”
This teaching reads on claim 1 a substrate; and a plurality of capture oligonucleotides conjugated to the substrate, wherein at least a portion of each capture oligonucleotide is complementary to a second portion of the probe oligonucleotide.
(ii) Mirkin 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 Mirkin et al. nanoparticle probes, substrate, and capture oligonucleotides, it would have been prima facie obvious to the skilled artisan to combine the teachings of Mirkin 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) Mirkin 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 Mirkin 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 Mirkin et al. in view of Zhang et al.
Applicant’s Arguments
Applicant has amended claim 1 to include the limitations of now-canceled claim 2. Applicant remarks that the prior art does not teach or suggest that the nanoparticle probe binds to the oligonucleotide on the substrate.
Response to Applicant’s Arguments
The rejection of claims 1, 3-4, and 12-13 under 35 USC 103 as being unpatentable over Mirkin et al. in view of Zhang et al. has been revised as stated above in this Final Office Action that specifically address the amended limitation “--- a substrate; and a plurality of capture oligonucleotides conjugated to the substrate, wherein at least a portion of each capture oligonucleotide is complementary to a second portion of the probe oligonucleotide” recited in claim 1 filed on 7/7/25.
Mirkin et al. column 23, lines 5-21 teach that “In another embodiment, nanoparticles are attached to the substrate. Nanoparticles can be attached to substrates as described in, e.g., [citations]… After the nanoparticles are attached to the substrate, oligonucleotides are attached to the nanoparticles. This may be accomplished in the same manner described above for the attachment of oligonucleotides to nanoparticles in solution. The oligonucleotides attached to the nanoparticles have a sequence complementary to a first portion of the sequence of a nucleic acid. The substrate is contacted with the nucleic acid under conditions effective to allow hybridization of the oligonucleotides on the nanoparticles with the nucleic acid. In this manner the nucleic acid becomes bound to the substrate.”
Thus, Mirkin et al. obviates conjugation of nanoparticles to substrate surfaces. Mirkin et al. further describes attachment of oligonucleotides to nanoparticles. The skilled artisan would recognize that Mirkin et al. teaches an embodiment wherein the nanoparticle probe does bind to the substrate, and that oligonucleotides and complementarity allow for nanoparticle conjugations. The skilled artisan would find the amendments obvious given Mirkin et al. in view of Zhang et al. When the Mirkin et al. methodologies are combined with Zhang et al., the skilled artisan would recognize that the combination would fulfill the intended “nanoparticle probe oligonucleotide… binds to the capture oligonucleotide on the substrate and the target oligonucleotide” (Applicant response page 8, paragraph 2).
Claim 5 remains/is rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al. (2002; US 6,362,944 B1; US Patent citation 1 in IDS filed 10/26/21) 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, 3-4, and 12-13 above, and further in view of Cunningham et al. (2010; US 7,768,640 B2; US Patent Document citation A in PTO-892 filed 3/6/25).
The teachings of Mirkin et al. in view of Zhang et al. are applied to instantly rejected claim 5 as they were previously applied to claims 1 and 2 as rendering obvious a method of nucleic acid detection. Mirkin et al. in view of Zhang et al. is silent to substrates comprising photonic crystals.
However, this limitation was known in the prior art and taught by Cunningham et al. Cunningham et al. teaches “Enhancement of fluorescence emission from fluorophores bound to a sample and present on the surface of two-dimensional photonic crystals” (Abstract).
Relevant to claim 5, Cunningham et al. teaches that “the photonic crystal structures of this disclosure may be produced uniformly over large surface areas”, including within “microarray formats” (column 21, lines 57-58 and 62). Cunningham et al. further teaches that “one example of a microarray to be used in a method according to the present invention is a nucleic acid microarray” and the “detect[ion of] complementary chemical binding with an opposing strand of a nucleic acid in a test sample” (column 22, lines 15-17 and 19-21). This teaching reads on claim 5 substrate comprises a photonic crystal, wherein the substrate is conjugated to a plurality of capture oligonucleotides.
It would have been prima facie obvious to the skilled artisan to combine the Cunningham et al. photonic crystal substrate with the methods rendered obvious by Mirkin et al. in view of Zhang et al. Cunningham et al. teaches that “The ability of photonic crystals to provide high quality factor (Q) resonant light coupling, high electromagnetic energy density, and tight optical confinement can also be exploited to produce highly sensitive biochemical sensors” (column 1, lines 55-58). Thus, the skilled artisan would be motivated to use the Cunningham et al. photonic crystal substrate within the nucleic acid detection rendered obvious by Mirkin et al. and Zhang et al. in order to result in “highly sensitive biochemical sensors”.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Mirkin et al. in view of Zhang et al., and further in view of Cunningham et al.
Applicant’s Arguments
Applicant has amended claim 1 to include the limitations of now-canceled claim 2. Applicant remarks that the prior art does not teach or suggest that the nanoparticle probe binds to the oligonucleotide on the substrate. Applicant further remarks that Cunningham et al. fails to cure the deficiencies of Mirkin et al. and Zhang et al.
Response to Applicant’s Arguments
The rejection of claim 5 under 35 USC 103 as being unpatentable over Mirkin et al. in view of Zhang et al., and further in view of Cunningham et al. has been revised as stated above in this Final Office Action that specifically address the amended limitation “--- a substrate; and a plurality of capture oligonucleotides conjugated to the substrate, wherein at least a portion of each capture oligonucleotide is complementary to a second portion of the probe oligonucleotide” recited in claim 1 filed on 7/7/25.
As discussed in the above Response to Applicant’s Arguments relevant to claims 1, 3-4, and 12-13, Mirkin et al. in view of Zhang et al. render obvious a nanoparticle probe bound to the substrate oligonucleotide.
The skilled artisan would find the amendments obvious given Mirkin et al. in view of Zhang et al., and further in view of Cunningham et al. Taken together, the prior art teaches the intended “nanoparticle probe oligonucleotide… binds to the capture oligonucleotide on the substrate and the target oligonucleotide” (Applicant response page 8, paragraph 2). Thus, the only independent claim is obvious, and as such, all of the claims are obvious.
Claims 6-11 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin et al. (2002; US 6,362,944 B1; US Patent citation 1 in IDS filed 10/26/21) in view of Zhang et al. (2018; US 2018/0363045 A1; USPGPub citation 1 in IDS filed 10/26/21) and Cunningham et al. (2010; US 7,768,640 B2; US Patent Document citation A in PTO-892 filed 3/6/25), as applied to the rejection of claim 5 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 Mirkin et al. in view of Zhang et al., and further in view of Cunningham et al. are applied to instantly rejected claims 6-11 as they were previously applied to claim 5 as rendering obvious a method of nucleic acid detection. Mirkin et al. in view of Zhang et al., and further in view of Cunningham 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 Mirkin et al., Zhang et al., and Cunningham 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, Mirkin et al. teaches that “Methods of making metal, semiconductor and magnetic nanoparticles are well-known in the art” (column 16, lines 41-42). Thus, it would be obvious to the skilled artisan to follow well-known methods to ensure that the nanoparticles are magnetic, as Mirkin et al. teaches the motivating advantage that “Detection [of oligonucleotide hybridization] is accomplished by applying a magnetic field and removing the particles from solution” (column 33, lines 45-46). The skilled artisan would be motivated to use a magnetic method to separate the complex mixtures of probes, particles, and oligonucleotides in order to facilitate detection, as taught by Mirkin et al.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Mirkin et al. in view of Zhang et al. and Cunningham et al., and further in view of Cytodiagnostics.
Applicant’s Arguments
Applicant has amended claim 1 to include the limitations of now-canceled claim 2. Applicant remarks that the prior art does not teach or suggest that the nanoparticle probe binds to the oligonucleotide on the substrate. Applicant further remarks that Cytodiagnostics fails to cure the deficiencies of Mirkin et al. in view of Zhang et al., and further in view of Cunningham et al.
Response to Applicant’s Arguments
The rejection of claims 6-11 under 35 USC 103 as being unpatentable over Mirkin et al. in view of Zhang et al. and Cunningham et al., and further in view of Cytodiagnostics has been revised as stated above in this Final Office Action that specifically address the amended limitation “--- a substrate; and a plurality of capture oligonucleotides conjugated to the substrate, wherein at least a portion of each capture oligonucleotide is complementary to a second portion of the probe oligonucleotide” recited in claim 1 filed on 7/7/25.
As discussed in the above Response to Applicant’s Arguments relevant to claims 1, 3-4, and 12-13, Mirkin et al. in view of Zhang et al. render obvious a nanoparticle probe bound to the substrate oligonucleotide.
The skilled artisan would find the amendments obvious given Mirkin et al. in view of Zhang et al. and Cunningham et al., and further in view of Cytodiagnostics. Taken together, the prior art teaches the intended “nanoparticle probe oligonucleotide… binds to the capture oligonucleotide on the substrate and the target oligonucleotide” (Applicant response page 8, paragraph 2). Thus, the only independent claim is obvious, and as such, all of the claims are obvious.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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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