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, 3-4, 6, and 8-12 are pending and under examination. Claims 2, 5, 7, and 13-20 are cancelled.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/2/26 has been entered.
Priority
The instant application 17/927,491 filed on 11/23/22 is a 371 US national phase of PCT/EP2021/064271 filed on 5/27/21, and claims foreign priority to GB2007911.7 filed on 5/27/20. Receipt is acknowledged of GB2007911.7 certified copies of papers required by 37 CFR 1.55. Priority Documents were electronically retrieved by USPTO from participating IP office on 11/23/22. The priority date is determined to be 5/27/20.
Response to Arguments
Applicant's arguments, see pages 4-9, filed 2/2/26, with respect to the rejections of claims 1, 3-4, 6, and 8-12 under 35 USC 103 have been fully considered and are found unpersuasive, and the 103 rejections documented in the Final mailed on 12/1/25 have been revised to address arguments filed 2/2/26 in this Non-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, 6, and 8-9 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Morin et al. (2017; WO 2017/091724 A1; FOR citation 1 in IDS filed on 11/23/22).
This rejection is revised/updated in response to arguments filed 2/2/26.
Morin et al. Abstract teaches “The present invention is directed to a target molecule modified to facilitate detection in a nanopore deice. The present invention further relates to a method of detecting such a modified target molecule using a nanopore device.”
Relevant to claim 1, Morin et al. teaches "In some embodiments, the present invention provides a complex designed for nanopore detection, comprising: a target molecule comprising a first attachment site; and a linker molecule comprising a first attachment site and a second attachment site, wherein the first attachment site of the linker molecule makes a covalent bond to the first attachment site of the target molecule, and the second attachment site of the linker molecule is a binding site for a driver molecule. In some embodiments, the complex further comprises a driver molecule, wherein the driver molecule is bound to the second attachment site of the linker molecule via … an electrostatic bond …" (paragraph 0009).
Further relevant to claim 1, Morin et al. teaches “In some embodiments, the target molecule further comprises a second attachment site, wherein said second attachment site is bound to a first payload molecule” (paragraph 0017).
Further relevant to claim 1, Morin et al. teaches “In some embodiments, the driver molecule further comprises a second attachment site, wherein said second attachment site is bound to a second payload molecule. In some embodiments, the second payload molecule is bound to the driver molecule via… an electrostatic bond” (paragraph 0018).
Further relevant to claim 1, Morin et al. teaches “In some embodiments, the first or the second payload molecule is… a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), a ribonucleic acid (RNA), a nanoparticle… or any combination thereof” (paragraph 0019).
Further relevant to claim 1, Morin et al. teaches “In some embodiments, the driver molecule is a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), or a ribonucleic acid (RNA)” (paragraph 0015).
Further relevant to claim 1, Morin et al. teaches "In some embodiments, the linker molecule comprises a peptide, a protein, a carbohydrate, a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), a ribonucleic acid (RNA), a nanoparticle, …, or any combination thereof " (paragraph 0010).
These teachings read on claim 1 A method of detecting one or more analytes in a target sample, the method comprising: a. providing a nanoparticle dimer adapted to bind the analyte, wherein the Morin et al. “target molecule” (analyte), and “complex” with the “linker molecule”, “driver molecule”, and “payload molecule” (nanoparticle dimer) read on the instant limitations. Additionally, the target molecule binding to the payload molecule via nucleic acid reads on claim 1 wherein at least one of the nucleic acids includes an aptamer specific for the analyte.
Further relevant to claim 1, Morin et al. teaches "Also provided herein are methods of analyzing data to detect the presence or absence of a target molecule in a, comprising obtaining an electrical signal from a nanopore device comprising a sample suspected of containing the modified target molecule described herein; and analyzing the electrical signal to detect the presence or absence of a signature correlated to the translocation of the target molecule through the nanopore, wherein the presence of the signature indicates the presence of the target molecule in said sample, and wherein the absence of the signature indicates the absence of the target molecule from said sample" (paragraph 0041).
Further relevant to claim 1, Morin et al. teaches "In several of the embodiments, the electrical or optical signal provided may be compared against a database that correlates a target molecule with an electrical or optical signal" (paragraph 00162).
These teachings read on claim 1 b. causing the dimer to pass through a nanopore by voltage-driven translocation; c. observing changes in the translocation current; and d. comparing the translocation current profile of the target sample to the translocation current profile of a control sample; wherein a change in the translocation current profile of the target sample versus the control sample indicates the presence of the analyte in the target sample.
For clarity, the Morin et al. structure can be depicted as:
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Further relevant to claim 1, and relevant to claim 3, Morin et al. teaches “In some embodiments, the driver molecule further comprises a second attachment site, wherein said second attachment site is bound to a second payload molecule. In some embodiments, the second payload molecule is bound to the driver molecule via a covalent bond, an intermediate linker, a Van der Waals bond, an electrostatic bond, a hydrophobic interaction, a pi-stacking interaction, an ionic bond, or another non-covalent electrostatic interaction” (paragraph 0018).
Further relevant to claims 1 and 3, Morin et al. teaches “In some embodiments, the first or the second payload molecule is … a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), a ribonucleic acid (RNA), a nanoparticle, …, or any combination thereof” (paragraph 0019).
As discussed above, Morin et al. teaches that the “driver molecule” (comprising a nucleic acid) can bind the “payload molecule” (also comprising a nucleic acid) via “a covalent bond, an intermediate linker, a Van der Waals bond, an electrostatic bond, a hydrophobic interaction, a pi-stacking interaction, an ionic bond, or another non-covalent electrostatic interaction” (paragraph 0018). Thus, relevant to claims 1 and 3, Morin et al. teaches wherein the dimer comprises two nanoparticles linked by one or more nucleic acids, wherein at least one of the nucleic acids includes an aptamer specific for the analyte; and claim 3 wherein the nanoparticles are linked by partially complementary nucleic acids. Morin et al. hydrophobic interactions of the nucleic acids read on the hydrogen bonds formed between the complementary nucleic acids.
Further relevant to claim 1, Morin et al. teaches "In some embodiments, the target molecule comprises a biological therapeutic. In some embodiments, the biological therapeutic is a monoclonal antibody, a protein, a protease, a peptide, a sugar, a nucleic acid, or any combination thereof” (paragraph 0011).
This teaching reads on claim 1 wherein the analyte is a protein.
Relevant to claim 4, Morin et al. teaches “In some embodiments, the target molecule further comprises a second attachment site, wherein said second attachment site is bound to a first payload molecule. In some embodiments, the first payload molecule is bound to the target molecule via a covalent bond, an intermediate linker, a Van der Waals bond, an electrostatic bond, a hydrophobic interaction, a pi-stacking interaction, an ionic bond, or another non-covalent electrostatic interaction” (paragraph 0017). As discussed above, the payload molecule can comprise nucleic acid (paragraph 0019).
Further relevant to claim 4, Morin et al. teaches "In some embodiments, the first attachment site comprises a reactive group on: an amino acid, a deoxyribose nucleic acid (DNA), or a ribonucleic acid (RNA), an amine group, a thiol, an aldehyde, a ketone, an azide, an alkyne, a sulfur, a phosphorous or other reactive atom, a ketone, a carboxylic acid, an ether, an amide, alkyl halide, an ester, an alkyne, an hydroxyl, or an alcohol. In some embodiments, the first attachment site can bind to the driver molecule or the linker molecule via a covalent bond, an intermediate linker, a Van der Waals bond, an electrostatic bond, a hydrophobic interaction, a pi-stacking interaction, an ionic bond, or another non-covalent electrostatic interaction" (paragraph 0029).
This teaching, in addition to those relevant to claim 1, reads on claim 4 wherein the dimer comprises two nanoparticles, each of which is attached to a nucleic acid, and each of the nucleic acids includes part of an aptamer specific for the analyte, such that in the presence of the analyte an aptamer is formed and thereby a dimer is formed.
Relevant to claim 6, Morin et al. teaches "In some embodiments, the driver molecule is a single stranded deoxyribonucleic acid (ssDNA)" (paragraph 0035) and “In some embodiments, the first or the second payload molecule is … a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), a ribonucleic acid (RNA), a nanoparticle, …, or any combination thereof” (paragraph 0019).
These teachings, in addition to those relevant to claims 1, and 3-4, read on claim 6 wherein the dimer comprises two nanoparticles, each of which is modified with a single stranded DNA (ssDNA), wherein one ssDNA includes a sequence which is complementary to the sequence of one end of the analyte, and the other ssDNA includes a sequence which is complementary to the sequence of the other end of the analyte, such that in the presence of the analyte a dimer is formed.
Relevant to claim 8, Morin et al. teaches "In some embodiments, the driver molecule further comprises a second attachment site, wherein said second attachment site is bound to a second payload molecule. In some embodiments, the second payload molecule is bound to the driver molecule via a covalent bond, an intermediate linker, a Van der Waals bond, an electrostatic bond, a hydrophobic interaction, a pi-stacking interaction, an ionic bond, or another non-covalent electrostatic interaction" (paragraph 0018).
Further relevant to claim 8, Morin et al. teaches "In some embodiments, the first or the second payload molecule is a peptide, a protein, a carbohydrate, a single stranded deoxyribonucleic acid (ssDNA), a double stranded deoxyribonucleic acid (dsDNA), a ribonucleic acid (RNA), a nanoparticle, a peptide nucleic acid, a polyethylene glycol (PEG), a dendrimer, or any combination thereof" (paragraph 0019).
These teachings read on claim 8 wherein the dimer comprises two nanoparticles, each of which is conjugated to an antibody specific to a different epitope on the analyte, such that in the presence of the analyte a dimer is formed.
Relevant to claim 9, Morin et al. teaches "In some embodiments, the target molecule comprises a biological therapeutic. In some embodiments, the biological therapeutic is a monoclonal antibody, a protein, a protease, a peptide, a sugar, a nucleic acid, or any combination thereof” (paragraph 0011).
This reads on claim 9 wherein the analyte is an antigen.
Morin et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements — including nanoparticles, nucleic acids, ssDNA, and analytes— for a method of detecting one or more analytes in a target sample, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Applicant’s Arguments and Responses to Applicant’s Arguments
Applicant argues “that Morin does not teach the use of nanoparticle dimers and aptamers for the detection of target molecules” (Remarks 2/2/26, page 4) and that “the present application is distinct from Morin in that an unmodified target is detected” (Remarks 2/2/26, page 5).
The Examiner respectfully disagrees. As reiterated above and reproduced below, Morin et al. provides embodiments wherein nanoparticle dimers (payload molecule and linker+driver molecule) comprise nucleic acids that contain regions for heterodimer formation via nucleic acid complementarity, and analyte detection. The Morin et al. embodiment can be visualized below, with the relevant Morin et al. paragraphs cited with the corresponding structure/function.
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The Morin et al. “target” is defined as “a molecule of interest that may be modified for detection by a nanopore” (paragraph 0065). Morin et al. further teaches that “the target molecule is modified by one or more payload molecules that provide a unique electrical signal as it translocates into or through the nanopore” (paragraph 0091). Morin et al. detects target molecules via payload molecule-binding, similar to instant claim 1 detection of analytes via nanoparticle dimer-binding of the analyte. In the instant invention, the analyte is modified in a way to allow the nanoparticle dimer to recognize and bind the analyte, similar to how the Morin et al. target is modified to enable payload molecule-binding. Additionally, it is noted that the claims, as written, do not require the argued “unmodified target” to be detected, but rather, “one or more analytes in a target sample”.
Applicant further argues that “the claimed combination was not taught nor suggested by Morin. Applicant respectfully submits that the claimed combination was not taught or suggested by the cited prior art, and it was only with the benefit of improper hindsight reasoning after reading Applicant’s own disclosure that a rejection was formulated” (Remarks 2/2/26, page 5).
The Examiner respectfully disagrees with this assertion. Per MPEP 2145(X)(A):
Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). (emphasis added)
As reiterated above within the motivation provided to reject claim 1, Morin et al. does not disclose a single embodiment having all the claimed elements. However, Morin et al. does disclose “knowledge which was within the level of ordinary skill in the art” throughout the disclosure.
Furthermore, as set forth in MPEP 2141.02:
Ascertaining the differences between the prior art and the claims at issue requires
interpreting the claim language, and considering both the invention and the prior art references
as a whole… A prior art reference must be considered in its entirety, i.e., as a whole,
including portions that would lead away from the claimed invention… However, ‘the prior art’s
mere disclosure of more than one alternative does not constitute a teaching away from any
of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage
the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir.
2004) (emphasis added)
Thus, since the skilled artisan is capable of ordinary creativity – and not an automaton – the skilled artisan would have found it prima facie obvious to have selected various combinations of the various Morin et al. disclosed elements to arrive at the instant invention.
The Applicant further argues that “Paragraph [0010] of Morin also does not disclose nucleic acid complementarity, partial complementarity, or hybridization between nucleic acids on separate nanoparticles” (Remarks 2/2/26, page 5).
The Examiner respectfully disagrees. As reiterated above and summarized within the diagram, the two components of the Morin et al. heterodimer include nanoparticles and nucleic acids through the payload molecule. Morin et al. paragraph 0018 teaches that the payload molecule (which comprises a nanoparticle and nucleic acid) can be bound to the driver molecule (which is a nucleic acid linked to the linker molecule’s nanoparticle) via hydrophobic interactions or the broader genus of “another non-covalent electrostatic interaction”. The skilled artisan would find it obvious that two nucleic acids would have to share partial complementarity in order to participate in the Morin et al. payload molecule-driver molecule nucleic acid binding via hydrophobic interactions (hydrogen bonds).
The Applicant argues that “paragraph [0010] does not disclose nor suggest aptamers. Aptamers are not disclosed nor suggested in all of Morin. While Morin generically lists ssDNA, dsDNA, and RNA as possible linker materials, generic disclosure of nucleic acids does not constitute a disclosure of aptamers” (Remarks 2/2/26, page 6).
The Examiner respectfully disagrees. It is noted that page 3 of the instant Specification recites “Aptamers are ssDNA or RNA oligonucleotides that are capable of binding target molecules with high specificity and affinity”. This broad definition of “aptamers” is embraced by the Morin et al. teaching of paragraphs 0017 and 0019 payload molecule ssDNA and RNA designed to specifically bind the target.
The Applicant further argues that Morin et al. does not teach “nanoparticle dimerization”, “linkage between two nanoparticles”, “nanoparticle-nanoparticle linkage, nor of a nanoparticle dimer formed via one or more nucleic acids that itself constitutes the translocating entity in accordance with the present claims”, motivation to combine the Morin et al. teachings, and “analyte-mediated nanoparticle dimer formation” (Remarks 2/2/26, pages 6-8).
The Examiner respectfully disagrees, and directs Applicant to the above responses regarding the Morin et al. heterodimer structure, motivation to combine, and dimerization process.
The Applicant further argues that Morin et al. does not disclose antibody-mediated detection (Remarks 2/2/26, page 8).
The Examiner respectfully disagrees, and directs Applicant to Morin et al. paragraphs 0052-0053 and Figs. 10-11 teachings of antibody-mediated detection.
Claims 10-12 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Morin et al. (2017; WO 2017/091724 A1; FOR citation 1 in IDS filed on 11/23/22), as applied to claims 1, 3-4, 6, and 8-9 above, and further in view of Wang et al. (2013; NPL citation 13 in IDS filed on 6/6/24; “Resistive-pulse measurements with nanopipettes: detection of Au nanoparticles and nanoparticle-bound anti-peanut IgY”; Chem Sci. 2013 February 1; 4(2): 655–663. doi:10.1039/C2SC21502K).
The teachings of Morin et al. are applied to instantly rejected claims 10-12 as they were previously applied to claims 1, 3-4, 6, and 8-9 as rendering obvious a method of detecting one or more analytes in a target sample.
Morin et al. is silent to specifics regarding nanoparticle diameters (claims 10-11) and nanopipette tips (claim 12). However, these limitations were known in the prior art and taught by Wang et al.
Wang et al. teaches “Resistive-pulse measurements with nanopipettes: detection of Au nanoparticles and nanoparticle-bound anti-peanut IgY” (Title).
Relevant to claims 10-11, Wang et al. page 2, Section "Size distribution and zeta (ζ)-potentials of particles" teaches that "…size distribution (Fig. 3A) show an average diameter of 9.5 ± 0.3 nm in a good agreement with the 10 nm nominal particle size given by the manufacturer." As seen in Wang et al. Fig. 3A, the nanoparticle diameters are of the same diameter (claim 10) and of different diameters (claim 11).
Relevant to claim 12, Wang et al. Fig. 1 depicts the tip of their nanopore nanopipette, reading on claim 12 wherein the nanopore is the tip of a nanopipette.
Although Morin et al. does not explicitly teach nanoparticle diameters and nanopipette tips, these limitations would have been prima facie obvious to the skilled artisan. It is noted that Morin et al. and Wang et al. are analogous disclosures to the instant nanopore detection method.
The skilled artisan would have been motivated to combine the analogous art. Wang et al. teaches “Here, particles with no aggregation and a larger diameter than the AuNP–peptide were specifically sought out for imaging so that we could characterize the sizes of particles assumed to be AuNP–peptide–IgY. Significant aggregation on the TEM grids did not allow counting of different particle types. The somewhat larger diameter of AuNP–peptide particles (13.9 ± 0.8 nm; Fig. 2C and 3C) corresponds to the thickness of a peptide monolayer (~4.5 nm). The peptide film appears as a white halo around each particle in Fig. 2C. The halos around AuNP–peptide–IgY in Fig. 2D are thicker and less uniform in agreement with the larger average diameter (15.1 ± 1.4 nm) and higher polydispersity (Fig. 2D and 3D) of these particles” (page 3, paragraph 1).
This Wang et al. teaching indicates that nanoparticle diameter corresponds with the nature of the functionalized molecules, and that the skilled artisan would find it obvious that nanoparticle diameter would be substantially similar or different based on the application. The skilled artisan would be motivated to include Wang et al. nanoparticle diameter measurements within the method rendered obvious by Morin et al. because Wang et al. teaches that diameter differences can enable flexibility in nanoparticle coating.
Additionally, the skilled artisan would be motivated to include the Wang et al. nanopipette tip nanopore within the methodology rendered obvious by Morin et al. because Wang et al. Abstract teaches that "Solid-state nanopores have been widely employed in sensing applications from Coulter counters to DNA sequencing devices. The analytical signal in such experiments is the change in ionic current flowing through the orifice caused by the large molecule or nanoparticle translocation through the pore. Conceptually similar nanopipette-based sensors can offer several advantages including the ease of fabrication and small physical size essential for local measurements and experiments in small spaces." Thus, the skilled artisan would be motivated by the Wang et al. teachings of “several advantages… including ease of fabrication and small physical size”.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Morin et al. and further in view of Wang et al. as discussed in the preceding paragraphs.
Applicant’s Arguments and Responses to Applicant’s Arguments
The Applicant argues that Wang et al. does not teach the above-argued limitations relevant to the rejection of claims 1, 3-4, 6, and 8-9. The Examiner directs Applicant to the responses above.
The Applicant further argues that “Wang only discloses the use of nanoparticles of the same size” (Remarks 2/2/26, page 9).
The Examiner respectfully disagrees. There is no limiting definition for how “different” the nanoparticle diameters must be to fulfill the limitations of claim 11. Therefore, the Wang et al. disclosure of “average diameter of 9.5 ± 0.3 nm” indicates that there are nanoparticles of “different diameters” in order to contribute to the ± 0.3 nm average variation.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
Prosecution Insights