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 .
Claim Objections
Claim 27 is objected to because of the following informalities: In line 5, it is suggested to recite “a first layer” as “the first layer” since “first layer” is established in line 3. Appropriate correction is required.
Claim 30 is objected to because of the following informalities: It is suggested to recite “an electric field” as “the electric field” since “electric field” is established in claim 27. Appropriate correction is required.
Claim 31 is objected to because of the following informalities: It is suggested to recite “an electric field” as “the electric field” since “electric field” is established in claim 27. Appropriate correction is required.
Claim 32 is objected to because of the following informalities: It is suggested to recite “current” as “the current” since “current” is established in claim 27. Appropriate correction is required.
Claim 48 is objected to because of the following informalities: It is suggested to recite “current” as “the current” since “current” is established in claim 27. Appropriate correction is required.
Claim 49 is objected to because of the following informalities: It is suggested to recite “an electric field” as “the electric field” since “electric field” is established in claim 27. Appropriate correction is required.
Claim 54 is objected to because of the following informalities: It is suggested to recite “a beam” in line 2 as “the beam” since “beam” is established in claim 27. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 27-55 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 27, claim 27 recites the limitation "the first layer" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claims 28-55 are rejected by virtue of their dependency on claim 27. Note that claim 5 also recites “a first layer” in line 5. It is unclear if the “first layer” being referred to in lines 9-14 and 14 are the same or different from the first layer of line 3 or line 5. It is suggested to recite “the first layer” of line 3 as “a first layer”, and “a first layer” of line 5 as “the first layer” to correct the antecedent issue.
Regarding claim 31, claim 31 recites “translocation events” in line 2. It is unclear if the “translocation events” of claim 31 is the same or different from “one or more translocation events” established in claim 27.
Regarding claim 46, claim 46 recites “an optical trapping event” in line 1. It is unclear if the “optical trapping event” of claim 46 is the same or different from “one or more optical trapping events” established in claim 45.
Regarding claim 46, claim 46 recites the limitation "the optical trapping of a single non-complexed or complexed biomolecule" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 47, claim 47 recites the limitation "the exit" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 48 is rejected by virtue of its dependency on claim 47.
Regarding claim 52, claim 52 recites the limitation "the translocation time" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 53 is rejected by virtue of its dependency on claim 52.
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 27-28, 30-33, 45-48, and 52-54 are rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh et al. (Ghorbanzadeh et al., “Improvement of Sensing and Trapping Efficiency of Double Nanohole Apertures via Enhancing the Wedge Plasmon Polariton Modes with Tapered Cusps”, ACS Photonics, 2017, 4, 1108-1113; cited in the IDS filed 03/14/2024) in view of Gershow et al. (US 20090136958 A1; cited in the IDS filed 03/14/2024).
Regarding claim 27, Ghorbanzadeh teaches a method of sensing (abstract teaches sensing nanoparticles) comprising:
providing a test sample comprising particles (Fig. 5 teaches a DNH sample with nanoparticles are suspended in a liquid);
contacting the test sample with the first layer of a sensor (Fig. 5 teaches the sample with nanoparticles in the liquid filling the DNH, therefore the sample is contacted with the first layer of the DNH, i.e. sensor; Fig. 1 shows the sensor, i.e. DNH), wherein the sensor (Fig. 1, DNH) comprises:
a first layer (Fig. 1, gold layer) having at least one dual nanohole structure (Fig. 1), and
a second layer (Fig. 1, glass layer) having at least one nanopore (Fig. 1, interpreted as the opening/pore in the glass),
wherein the dual nanohole structure comprises a first nanohole and a second nanohole connected by a gap (Fig. 1a and 1b teaches two nanoholes connected by a gap); and
wherein the gap of the first layer is aligned with the nanopore of the second layer in a direction corresponding to a translocation direction across the first and second layers (Fig. 1);
irradiating the dual nanohole structure of the first layer of the sensor with a beam of electromagnetic radiation (Fig. 5a teaches irradiating the DNH, which includes the dual nanohole structure of the first layer, with light from a laser diode and LED);
optically trapping the particles in the dual nanohole structure and/or the gap of the first layer of the sensor (Figs. 4-5 and page 1111, right column teaches a PS nanoparticle is trapped in the DNH) and measuring a surface plasmon resonance of the dual nanohole structure (abstract and Fig. 4 teaches transmission variations due to trapping of nanoparticles of the DNH are measured at wavelengths near the corresponding wedge mode resonance, therefore the surface plasmon resonance of the DNH is measured via measuring transmission variations).
Ghorbanzadeh fails to teach: the test sample comprising complexed and/or non-complexed biomolecules; optically trapping the biomolecules in the dual nanohole structure; applying an electric field across the nanopore of the second layer of the sensor; and measuring change in current across the nanopore during one or more translocation events of the biomolecules.
Ghorbanzadeh teaches double nanohole apertures have been used to trap and sense biological nanoparticles; and the designed DNH open up new routes toward the design and optimization of efficient aperture structures for trapping and sensing applications (abstract). Ghorbanzadeh teaches applying an E-field to the DNH (page 1109, left column, last paragraph).
Gershow teaches a molecular analysis system including a nanopore and a detector to detect molecular species translocation of the nanopore (abstract). Gershow teaches with this system, a molecular species, such as a molecule or component of a molecule, can be captured, recaptured, and analyzed with regard to the conditions of the nanopore (paragraph [0007]). Gershow teaches nanopore capture and recapture processes can be employed with biomolecules (paragraph [0040]). Gershow teaches applying an electric field in the vicinity of the nanopore (paragraph [0026]). Gershow teaches molecules translocate through the nanopore due to the electrophoretic force caused by the applied voltage and electric field (paragraph [0028]). Gershow teaches the capture and recapture of a molecule at the nanopore is detected and controlled based on the needs of a given application or experiment; wherein detection of ionic current flowing between reservoirs of the nanopore are measured to provided indication of the translocation of the molecule (paragraph [0031]). Gershow teaches nanopore translocation detection by ionic current measurement (paragraph [0051]), and nanopore translocation by a molecule can also be detected by, e.g., transverse current measurements, such as measurement of electron flow across the nanopore, or measurement of current tunneling through a molecule at a nanopore, both monitored by electrodes sited at the nanopore (paragraph [0051]). Gershow teaches repeated capture and recapture cycles thereby enable improvements in measurements of ionic current signals, increases in signal to noise ratios, and enable measurement and signal error correction, e.g., in application in which one or more devices are integrated with the nanopore (paragraph [0063]). Gershow teaches detection of ionic current blockage corresponding to nanopore translocation by the molecule, reveals the position of the molecule within the trap, and with triggered voltage or other driving force polarity reversals, provides a feedback mechanism to maintain the molecular trap conditions, which enables detection and characterization of a trapped molecule without the need for chemical modification (paragraph [0067]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ghorbanzadeh to incorporate Ghorbanzadeh’s teachings of trapping and sensing biological particles and applying an E-field to the sensor (abstract; page 1109, left column, last paragraph) and Gershow’s teachings of a nanopore for capturing and analyzing biomolecules (abstract; paragraphs [0007],[0040]) and applying an electric field and measuring ionic current signals during translocation events (paragraphs [0026],[0028],[0031],[ 0051], [0063], [0067]) to provide: the test sample comprising complexed and/or non-complexed biomolecules; optically trapping the biomolecules in the dual nanohole structure; applying an electric field across the nanopore of the second layer of the sensor; and measuring change in current across the nanopore during one or more translocation events of the biomolecules. Doing so would have a reasonable expectation of successfully improving trapping, translocation, analysis of translocation, and characterization of biomolecules as discussed by Gershow.
It is suggested to recite “wherein the at least one nanopore entirely passes through the second layer in the translocation direction” to differentiate the sensor from the prior art.
Regarding claim 28, Ghorbanzadeh further teaches wherein optically trapping the biomolecules results in the surface plasmon resonance (abstract and Fig. 4 teaches transmission variations due to trapping of nanoparticles of the DNH are measured at wavelengths near the corresponding wedge mode resonance, therefore transmission variations of the surface plasmon resonance of the DNH is a result of optically trapping of the nanoparticles).
Regarding claim 30, modified Ghorbanzadeh fails to teach wherein applying an electric field includes temporarily reversing the electric field.
Gershow teaches with this system, a molecular species, such as a molecule or component of a molecule, can be captured, recaptured, and analyzed with regard to the conditions of the nanopore (paragraph [0007]). Gershow teaches to recapture the molecule, the driving force across the nanopore is reversed before the molecule can escape into the bulk solution of the trans reservoir (paragraph [0029]). Gershow teaches to voltage is reversed to recapture the molecule and to drive the molecule back to the nanopore (paragraphs [0032]-[0033]). Gershow teaches whatever translocation force is employed, such preferably enables reversal in directionality between the reservoirs to enable multiple molecular recapture and trapping events (paragraph [0043]). Gershow teaches detection of ionic current blockage corresponding to nanopore translocation by the molecule, reveals the position of the molecule within the trap, and with triggered voltage or other driving force polarity reversals, provides a feedback mechanism to maintain the molecular trap conditions, which enables detection and characterization of a trapped molecule without the need for chemical modification (paragraph [0067]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of recapturing molecules in the nanopores by reversing a driving force and voltage of Gershow to provide: wherein applying an electric field includes temporarily reversing the electric field. Doing so would have a reasonable expectation of successfully improving recapturing of molecules for improved detection and characterization of the trapped molecule.
Regarding claim 31, modified Ghorbanzadeh further teaches wherein applying an electric field across the nanopore results in translocation events (see above claim 27; Ghorbanzadeh in view of Gershow teaches applying an electric field across the nanopore of the second layer of the sensor, which allows for improved translocation of the biomolecules; Gershow, paragraph [0028], teaches molecules translocate through the nanopore due to the electrophoretic force caused by the applied voltage and electric field).
Regarding claim 32, modified Ghorbanzadeh fails to teach wherein measuring change in current further comprises determining the charge of a translocating biomolecule.
Gershow teaches ionic current measurements of molecules at the nanopore (paragraph [0051]), wherein additionally transport properties that can be measured as a molecule traverses a nanopore includes charge (paragraph [0051]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified measuring change in current of modified Ghorbanzadeh to incorporate the teachings of ionic current measurements and measuring charge of a molecule of Gershow (paragraph [0051]) to provide: wherein measuring change in current further comprises determining the charge of a translocating biomolecule. Doing so would have a reasonable expectation of successfully improving additional characterization of properties of the biomolecule.
Regarding claim 33, Ghorbanzadeh further teaches wherein the first layer (Fig. 1, gold layer) and the second layer of the sensor (Fig. 1, glass layer) are immediately adjacent layers (Fig. 1).
Regarding claim 45, modified Ghorbanzadeh further teaches wherein optically trapping the biomolecules in the dual nanohole structure and/or the gap of the first layer of the sensor comprises one or more optical trapping events (see above claim 27; modified Ghorbanzadeh teaches optical trapping of the biomolecule, wherein Ghorbanzadeh, Figs. 4-5 and page 1111, right column, teaches one or more optical trapping events).
Regarding claim 46, modified Ghorbanzadeh fails to teach: wherein an optical trapping event comprises the optical trapping of a single non-complexed or complexed biomolecule.
Ghorbanzadeh teaches optical manipulation methods are of high interest for sensing on a single particle level (page 1108, left column), wherein one nanoparticle is trapped (page 1111, right column).
Gershow teaches with this system, a molecular species, such as a molecule or component of a molecule, can be captured, recaptured, and analyzed with regard to the conditions of the nanopore (paragraph [0007]). Gershow teaches nanopore capture and recapture processes can be employed with biomolecules (paragraph [0040]). Gershow teaches nanopore device configurations and techniques for employing such configurations to enable single molecule manipulation and characterization with a nanopore (paragraph [0006]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ghorbanzadeh to provide: wherein an optical trapping event comprises the optical trapping of a single non-complexed or complexed biomolecule. Doing so would have a reasonable expectation of successfully improving single particle sensing, manipulation, and characterization as discussed by Ghorbanzadeh and Gershow.
Regarding claim 47, modified Ghorbanzadeh fails to teach: wherein the one or more translocation events comprises the exit of biomolecules through the nanopore.
Gershow teaches with this system, a molecular species, such as a molecule or component of a molecule, can be captured, recaptured, and analyzed with regard to the conditions of the nanopore (paragraph [0007]). Gershow teaches nanopore capture and recapture processes can be employed with biomolecules (paragraph [0040]). Gershow teaches applying an electric field in the vicinity of the nanopore (paragraph [0026]). Gershow teaches molecules translocate through the nanopore due to the electrophoretic force caused by the applied voltage and electric field (paragraph [0028]). Gershow teaches the capture and recapture of a molecule at the nanopore is detected and controlled based on the needs of a given application or experiment; wherein detection of ionic current flowing between reservoirs of the nanopore are measured to provided indication of the translocation of the molecule (paragraph [0031]). Gershow teaches nanopore translocation detection by ionic current measurement (paragraph [0051]), and nanopore translocation by a molecule can also be detected by, e.g., transverse current measurements, such as measurement of electron flow across the nanopore, or measurement of current tunneling through a molecule at a nanopore, both monitored by electrodes sited at the nanopore (paragraph [0051]). Gershow teaches repeated capture and recapture cycles thereby enable improvements in measurements of ionic current signals, increases in signal to noise ratios, and enable measurement and signal error correction, e.g., in application in which one or more devices are integrated with the nanopore (paragraph [0063]). Gershow teaches detection of ionic current blockage corresponding to nanopore translocation by the molecule, reveals the position of the molecule within the trap, and with triggered voltage or other driving force polarity reversals, provides a feedback mechanism to maintain the molecular trap conditions, which enables detection and characterization of a trapped molecule without the need for chemical modification (paragraph [0067]). Gershow teaches exiting of the molecule from the nanopore (paragraphs [0079],[0080]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate Gershow’s teachings of a nanopore for capturing, recapturing, and analyzing biomolecules (abstract; paragraphs [0007],[0040]) and applying an electric field and measuring ionic current signals during translocation events (paragraphs [0026],[0028],[0031],[ 0051], [0063], [0067]) and molecules exiting the nanopores (paragraphs [0079]-[0080]) to provide: wherein the one or more translocation events comprises the exit of biomolecules through the nanopore. Doing so would have a reasonable expectation of successfully improving manipulation and translocation of biomolecules with respect to the nanopore and to allow for further analysis of other biomolecules as discussed by Gershow.
Regarding claim 48, modified Ghorbanzadeh fails to teach: wherein measuring the change in current across the nanopore during one or more translocation events of the biomolecules comprises measuring a drop in ionic current as the biomolecules exit through the nanopore.
Gershow teaches nanopore translocation detection by ionic current measurement (paragraph [0051]), and nanopore translocation by a molecule can also be detected by, e.g., transverse current measurements, such as measurement of electron flow across the nanopore, or measurement of current tunneling through a molecule at a nanopore, both monitored by electrodes sited at the nanopore (paragraph [0051]). Gershow teaches repeated capture and recapture cycles thereby enable improvements in measurements of ionic current signals, increases in signal to noise ratios, and enable measurement and signal error correction, e.g., in application in which one or more devices are integrated with the nanopore (paragraph [0063]). Gershow teaches detection of ionic current blockage corresponding to nanopore translocation by the molecule, reveals the position of the molecule within the trap, and with triggered voltage or other driving force polarity reversals, provides a feedback mechanism to maintain the molecular trap conditions, which enables detection and characterization of a trapped molecule without the need for chemical modification (paragraph [0067]). Gershow teaches measuring a drop in ionic current as the biomolecules exit through the nanopore (Figs. 1B and 2 and paragraph [0032] teaches a reduction in current is measured corresponding to the molecule exiting through the nanopore).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ghorbanzadeh to incorporate Gershow’s teachings of a nanopore for capturing and analyzing biomolecules (abstract; paragraphs [0007],[0040]), applying an electric field and measuring ionic current signals during translocation events (paragraphs [0026],[0028],[0031],[ 0051], [0063], [0067]), and measuring a drop in ionic current as a biomolecule exits a nanopore (Figs. 1B, 2, paragraph [0032]) to provide: wherein measuring the change in current across the nanopore during one or more translocation events of the biomolecules comprises measuring a drop in ionic current as the biomolecules exit through the nanopore. Doing so would have a reasonable expectation of successfully improving analysis of translocation and characterization of biomolecules as discussed by Gershow.
Regarding claim 52, modified Ghorbanzadeh fails to teach wherein the method further comprises measuring the translocation time of the biomolecules.
Gershow teaches measuring time of ionic blockage current during translocation of a molecule through a nanopore (paragraph [0019]). Gershow teaches through measurement of changes in duration in molecular translocation of the nanopore as a function of, e.g., the duration of delay before molecular recapture, or the direction of passage, there can be determined the time period in which molecular condensing events, e.g., nucleic acid or protein folding, begin or are completed (paragraph [0037]). Gershow teaches because the translocation duration is directly impacted by the configuration of a molecule, a non-equilibrium configuration of a molecule produced by a difference between the cis and trans reservoir conditions can be distinctly identified by a deviation in translocation duration, a difference in ionic current blockage, a modulation of another detection mechanism, such as tunneling measurement or optical detection, or all of these (paragraph [0053]). Gershow teaches detecting changes in translocation duration or other characteristic that can indicate a change in the molecule caused by exposure to the species in the trans reservoir (paragraph [0060]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of detecting changes in translocation duration of Gershow (paragraphs [0037],[0053],[0060]) to provide: wherein the method further comprises measuring the translocation time of the biomolecules. Doing so would have a reasonable expectation of successfully improving characterization and analysis of the biomolecules, such as condensing events, configuration, and changes in the molecule as discussed by Gershow.
Regarding claim 53, modified Ghorbanzadeh fails to teach wherein the average translocation time is 50 microseconds-100 milliseconds.
Gershow teaches most molecules arrived at the nanopore and translocated the nanopore in less than 10 ms (paragraph [0111]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of molecules translocating in less than 10 ms of Gershow (paragraph [0111]) to provide: wherein the average translocation time is 50 microseconds-100 milliseconds. Doing so would have a reasonable expectation of successfully improving trapping, translocation, analysis of translocation, and characterization of biomolecules as discussed by Gershow.
Additionally, since Gershow teaches most molecules translocating in less than 10 ms (paragraph [0111]), wherein the range of less than 10 ms overlaps with the claimed range of 50 microseconds-100 milliseconds, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to provide wherein the average translocation time is 50 microseconds-100 milliseconds. I.e., it would have been prima facia obvious to have selected the overlapping portion of the range from the taught range of less than 10 ms (Gershow, paragraph [0111]) (In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); see MPEP 2144.05 (I)).
Regarding claim 54, Ghorbanzadeh further teaches wherein irradiating the dual nanohole structure of the first layer of the sensor with a beam of electromagnetic radiation comprises irradiating the dual nanohole structure with a laser beam (Fig. 5a shows irradiation of the DNH with a laser beam from a laser diode), and the laser beam is polarized (Fig. 5a teaches the laser beam pass through a half wave plate, therefore the laser beam is polarized since a half wave plate is used; wherein half wave plates function to rotate the plane of linear polarized light; Ghorbanzadeh, supplementary information, page 2, last paragraph teaches applying a p-polarized plane-wave as an incident optical beam).
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Wang et al. (Wang et al., “Label-free imaging, detection, and mass measurement of single viruses by surface plasmon resonance”, PNAS, Sept 14, 2014, vol. 107, no. 37, 16028-16032).
Regarding claim 29, modified Ghorbanzadeh fails to teach wherein measuring the surface plasmon resonance further comprises determining the mass of an optically trapped biomolecule.
Wang teaches a label-free imaging, detection, and mass/size measurement of a single particle by surface plasmon resonance microscopy (abstract). Wang teaches intensity of particle images are related to the mass of the particle, which allows for determination of mass of particles (abstract). Wang teaches mass is a fundamental parameter of substances and precise measurement of mass is one of the most important analytical methods; wherein SPR measures optical mass of particles which is directly related to the inertial mass of the particle (page 16029, section “Quantitative Analysis of…”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of quantitative analysis of mass particles by measuring SPR of Wang (abstract; page 16029, section “Quantitative Analysis of…”) to provide: wherein measuring the surface plasmon resonance further comprises determining the mass of an optically trapped biomolecule. Doing so would have a reasonable expectation of successfully improving characterization of an important parameter of the biomolecule as discussed by Wang.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Heron et al. (US 20200024654 A1; effectively filed 09/29/2016).
Regarding claim 43, modified Ghorbanzadeh fails to teach wherein the method further comprises determining whether the biomolecules are complexed.
Heron teaches a method of detecting a target polynucleotide in a sample comprising contacting the sample with a membrane comprising a transmembrane pore, applying a potential to the membrane, and monitoring for the presence or absence of an effect from interaction of the complex with the pore to determine presence or absence of the complex, thereby detecting the target polynucleotide in the sample (abstract; paragraphs [0008]-[0017]). Heron teaches the guide polynucleotide/polynucleotide-guided effector protein complex tags or labels the target polynucleotide such that the effect of the guide polynucleotide/polynucleotide-guided effector protein complex on the current passing through the pore can be used to determine the presence or absence of, quantify or identify the target polynucleotide (paragraph [0097]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of determining the presence or absence of a complex via interaction with a pore of Heron (abstract; paragraphs [0008]-[0017],[0097]) to provide: wherein the method further comprises determining whether the biomolecules are complexed. Doing so would have a reasonable expectation of successfully improving identification of target biomolecules, such as desired biomolecules that form a complex.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Gordon et al. (US 20140045277 A1; cited in the IDS filed 03/14/2024).
Regarding claim 44, modified Ghorbanzadeh fails to teach: wherein optically trapping the biomolecules in the dual nanohole structure and/or the gap of the first layer of the sensor lasts for 1 microsecond to 100 seconds.
Gordon teaches molecules or particles being optically trapped using a double-nanohole structure defined in a film or layer (abstract), wherein the molecules are biological particles (paragraph [0002]). Gordon teaches trapping and releasing of trapped proteins after observation (Fig. 3 and paragraphs [0047]-[0048]), wherein Fig. 3 shows trapping molecules lasts for 1 microsecond to 100 seconds (Fig. 3 shows regions where optical transmissions are at trapped states T1 or T2 for about 10 seconds).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Ghorbanzadeh to incorporate the teachings of trapping and releasing of trapped particles in a double-nanohole structure for 1 microsecond to 100 seconds (paragraphs [0047]-[0048]; Fig. 3) to provide: wherein optically trapping the biomolecules in the dual nanohole structure and/or the gap of the first layer of the sensor lasts for 1 microsecond to 100 seconds. Doing so would have a reasonable expectation of successfully allowing for trapping and sensing the biomolecules before releasing the trapped proteins after observation as taught by Gordon.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Yamakawa et al. (US 20050148064 A1).
Regarding claim 49, modified Ghorbanzadeh fails to teach wherein applying an electric field across the nanopore of the second layer of the sensor comprises induces molecular bobbing or oscillation of the biomolecules.
Yamakawa teaches a microfluidic device for trapping molecules including a diffusion barrier or porous membrane (abstract). Yamakawa teaches an electric field is used to create electrophoretic and dielectricphoretic trapping and/or control and particularly can jiggle/vibrate a molecule to let them go through the nanopores of the porous membrane faster and thermodynamically more favorable (paragraph [0035]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate the teachings of an electric field to vibrate a molecule to let them go through nanopores faster and more thermodynamically favorable of Yamakawa (paragraph [0035]) to provide: wherein applying an electric field across the nanopore of the second layer of the sensor comprises induces molecular bobbing or oscillation of the biomolecules. Doing so would have a reasonable expectation of successfully improving favorable manipulation and translocation of the biomolecules in relation to the nanopore as taught by Yamakawa.
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Schmidt et al. (US 20200284783 A1; effectively filed 10/02/2017).
Regarding claim 50, modified Ghorbanzadeh fails to teach: wherein the test sample comprising complexed and/or non-complexed biomolecules has femto- (10^15) to atto- (10^18) molar concentration of the biomolecules.
Schmidt teaches a system that uses modulations of ionic current across a nanopore to detect target molecules passing through the nanopore (abstract). Schmidt teaches biomarkers occur in samples at femto- to atto-molar concentrations and are unlikely to be detectable without a more efficient delivery of target molecules to a nanopore (paragraph [0004]). Schmidt teaches the approach can enable molecular diagnostics using nanopore detection with high throughput using an integrated platform that combines advanced sample preparation with individual molecule electrical detection (paragraph [0055]) and high throughput molecular detection at attomolar concentrations (paragraph [0055]). Schmidt teaches a low limit of detection (LoD) down to attomolar concentrations can be reached using nanopore detection (paragraph [0057]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the test sample of modified Ghorbanzadeh to incorporate the teachings of biomarkers occurring in samples at femto- to atto-molar and detection at attomolar concentrations of molecules (paragraphs [0004],[0055],[0057]) to provide: wherein the test sample comprising complexed and/or non-complexed biomolecules has femto- (10^15) to atto- (10^18) molar concentration of the biomolecules. Doing so would have a reasonable expectation of successfully improving analysis of biomolecules at low concentrations as discussed by Schmidt.
Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 27 above, and further in view of Davis (US 20150111779 A1).
Regarding claim 51, modified Ghorbanzadeh fails to teach: wherein 1 to 10 biomolecules per second are optically trapped from the test sample.
Gershow teaches molecules arrive at the nanopore at a rate of under 0.4 Hz (paragraph [0117]).
Davis teaches methods and devices for capturing and determining the identify of molecules using nanopores (abstract). Davis teaches capturing and identifying the markers with the array of nanopores at a rate of at least about 1 marker per second per nanopore (paragraph [0004]); and in some embodiments, the markers are captured and identified at a rate of at least about four markers per second per nanopore (paragraph [0009]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of modified Ghorbanzadeh to incorporate Gershow’s teachings of molecules arriving at the nanopore at a rate of under 0.4 Hz (paragraph [0117]) and Davis’ teachings of capturing markers at a rate of at least 1 or 4 markers per second per nanopore (paragraphs [0004],[0009]) to provide: wherein 1 to 10 biomolecules per second are optically trapped from the test sample. Doing so would have a reasonable expectation of successfully optimizing the desired biomolecular capture and analysis rate based on the characteristics of the biomolecules.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Ghorbanzadeh in view of Gershow as applied to claim 54 above, and further in view of Kaneko et al. (US 20210356386 A1; effectively fled 07/24/2016).
Regarding claim 55, modified Ghorbanzadeh fails to explicitly teach: wherein the laser beam is polarized circularly or linearly.
Kaneko teaches a detection system including a light source and detection unit, wherein surface plasmon resonance is generated (abstract). Kaneko teaches a laser diode (paragraph [0059]) that is converted into a linearly polarized light (paragraph [0059]). Kaneko teaches a beam shaping optical system includes a linear polarization filter and a half wave plate (paragraph [0060]). Kaneko teaches a detection chip includes a nanohole array (paragraphs [0153],[0156]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the laser beam of modified Ghorbanzadeh to incorporate the teachings of linearly polarized light for a detection system of Kaneko (paragraphs [0059],[0060]) to provide: wherein the laser beam is polarized linearly. Doing so would have a reasonable expectation of successfully improving shaping of the laser beam.
Furthermore, the claimed limitations are obvious because all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements (i.e. a linearly polarized laser beam) by known methods with no change in their respective functions (i.e. irradiating a surface), and the combinations yielded nothing more than predictable results (i.e. providing the laser beam as linearly polarized would yield nothing more than the obvious and predictable result of enabling irradiating of a surface with a desired shaped light beam). See MPEP 2143(A).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 27-33 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13-19 of U.S. Patent No. 11,971,405 (herein, “Patent ‘405”). Although the claims at issue are not identical, they are not patentably distinct from each other because the entire scope of the reference claim falls within the scope of the examined claim.
Regarding claim 27, Patent ‘405 recites a method of sensing (claim 13) comprising:
providing a test sample comprising complexed and/or non-complexed biomolecules (claim 13);
contacting the test sample with the first layer of a sensor (claim 13, “sensor of claim 1”), wherein the sensor (claims 1 and 13) comprises:
a first layer having at least one dual nanohole structure (claim 1), and
a second layer having at least one nanopore (claim 1),
wherein the dual nanohole structure comprises a first nanohole and a second nanohole connected by a gap (claim 1); and
wherein the gap of the first layer is aligned with the nanopore of the second layer in a direction corresponding to a translocation direction across the first and second layers (claim 1);
irradiating the dual nanohole structure of the first layer of the sensor with a beam of electromagnetic radiation (claim 13);
optically trapping the biomolecules in the dual nanohole structure and/or the gap of the first layer of the sensor and measuring a surface plasmon resonance of the dual nanohole structure (claim 13);
applying an electric field across the nanopore of the second layer of the sensor (claim 13); and
measuring change in current across the nanopore during one or more translocation events of the biomolecules (claim 13).
Regarding claim 28, Patent ‘405 recites wherein optically trapping the biomolecules results in the surface plasmon resonance (claim 14).
Regarding claim 29, Patent ‘405 recites wherein measuring the surface plasmon resonance further comprises determining the mass of an optically trapped biomolecule (claim 15).
Regarding claim 30, Patent ‘405 recites wherein applying an electric field includes temporarily reversing the electric field (claim 16).
Regarding claim 31, Patent ‘405 recites wherein applying an electric field across the nanopore results in translocation events (claim 17).
Regarding claim 32, Patent ‘405 recites wherein measuring change in current further comprises determining the charge of a translocating biomolecule (claim 18).
Regarding claim 33, Patent ‘405 recites wherein the first layer and the second layer of the sensor are immediately adjacent layers (claim 19).
Claims 27-29 and 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 6-8 of copending Application No. 18/730,176 (reference application) (herein, “App ‘176”). Although the claims at issue are not identical, they are not patentably distinct from each other because the entire scope of the reference claim falls within the scope of the examined claim.
Regarding claim 27, App ‘176 recites a method of sensing (claim 1) comprising:
providing a test sample comprising complexed and/or non-complexed biomolecules (claims 1 and 8);
contacting the test sample with the first layer of a sensor (claim 1), wherein the sensor comprises:
a first layer having at least one dual nanohole structure (claim 1), and
a second layer having at least one nanopore (claim 1),
wherein the dual nanohole structure comprises a first nanohole and a second nanohole connected by a gap (claim 1); and
wherein the gap of the first layer is aligned with the nanopore of the second layer in a direction corresponding to a translocation direction across the first and second layers (claim 1);
irradiating the dual nanohole structure of the first layer of the sensor with a beam of electromagnetic radiation (claim 1);
optically trapping the biomolecules in the dual nanohole structure and/or the gap of the first layer of the sensor and measuring a surface plasmon resonance of the dual nanohole structure (claim 1);
applying an electric field across the nanopore of the second layer of the sensor (claim 1); and
measuring change in current across the nanopore during one or more translocation events of the biomolecules (claim 1).
Regarding claim 28, App ‘176 recites wherein optically trapping the biomolecules results in the surface plasmon resonance (claim 6).
Regarding claim 29, App ‘176 recites wherein measuring the surface plasmon resonance further comprises determining the mass of an optically trapped biomolecule (claim 7).
Regarding claim 31, App ‘176 recites wherein applying an electric field across the nanopore results in translocation events (claim 1).
Regarding claim 32, App ‘176 recites wherein measuring change in current further comprises determining the charge of a translocating biomolecule (claim 4).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached at (571) 270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HENRY H NGUYEN/ Primary Examiner, Art Unit 1758