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 8-15 are pending, claims 16-20 have been canceled and claims 21-22 are newly added.
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 8–15 and 21–22 are rejected under 35 U.S.C. § 103 as being unpatentable over US 11,029,306 B2 (“Chen et al.”) in view of Hsu et al., US 10,962,523 (Fish et al.), GB 2 580 988, and Ono et al (WO2006/041085).
Chen et al. (USP 11029306) discloses a nanopore-based sequencing cell comprising a membrane, a nanopore, a working electrode, a counter electrode, an electrolyte, and analog measurement circuitry, see claims 1–3, Figures 1 and 5, and the description corresponding to the cell and nanopore architecture. Chen et al. further discloses nanopore sequencing using tagged nucleotides. A polymerase incorporates tagged nucleotides, and the tag produces a nucleotide-dependent ionic-current or conductance signal as the tag is held in or passes through the nanopore. See claims 1–3, Figure 2, and the description corresponding to the Nano-SBS and preloaded-tag embodiments. Chen et al. also discloses a circuit having an integrating capacitor connected to the nanopore measurement path and an ADC configured to read the capacitor voltage. See claims 1–3, Figure 6, and the description of circuitry 600. The reference explains that current through the nanopore is integrated at capacitor ncap and read by ADC 610.
Chen et al. further discloses a circuit in which a precharging voltage source is connected to the integrating capacitor and working electrode during a reset or precharging period and disconnected during an integrating period. See Figure 7A, Figure 7B, and claims 1, 8, and 13. After the voltage source is disconnected, the capacitor voltage changes as current flows through the nanopore. The rate of voltage decay or increase is used to determine the state of the nanopore and identify a tag or molecule in the nanopore. See Figures 8–10 and the corresponding description. Chen et al. further discloses varying the liquid voltage between a tag-reading voltage and an open-channel voltage. The tag-reading voltage tends to capture a tag into the nanopore, and the open-channel voltage tends to repel the tag. See claim 1, Figures 11–14, and the corresponding description.
Hsu et al. (IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS, VOL. 9, NO. 5, OCTOBER 2015) disclose a nanopore-based DNA-sequencing readout circuit comprising a capacitive-feedback integrator, a differentiator, and a semi-digital feedback loop. The feedback loop includes an ADC, digital low-pass filter, DAC, and DC-compensation circuitry for discharging baseline and low-frequency current components, improving settling time, preventing saturation, and increasing dynamic range. See Hsu et al., pp. 653–658 and Figures 3–5.
Fish et al. (10,962,523) disclose a current-sensing circuit comprising a charge amplifier configured to integrate sensor current during successive sensing frames, sample-and-hold circuitry, ADC processing, and output processing. See Fish et al., (see paragraphs 014 – 023, 044 – 047, 058 – 078, and claims 1, 11, 12, and 16–23. Fish et al. further disclose charge-amplifier operation using an integrating capacitor and charge-balancing soft reset in which charge stored on one capacitive element is transferred to cancel charge stored on another capacitive element. See paragraphs 019 – 020 and 075– 081, Figures 19–30, and claims 13, 14, 24, and 25.
Fish et al. (10,962,523) further discloses molecular entity sensing using sensor arrays, ion channels, membrane proteins, and amphiphilic membranes. See claims 16–19 and paragraphs 044 – 047, and 058 – 066. Fish et al. (10,962,523) also discloses a charge amplifier having an integrating capacitor and a reset switch. See paragraphs 075 – 078. The charge-balancing soft-reset embodiment integrates current across first and second capacitive elements and transfers charge from the second capacitive element to cancel charge stored on the first capacitive element. See paragraphs 019 – 020 and 075 – 081, Figures 19–30, and claims 13, 14, 24, and 25.
GB2580988 discloses a first charge amplifier, a processing circuit that filters an output of the first charge amplifier, and a second charge amplifier that integrates current derived from the filtered output. See, pp. 8–10 and claims 1, 14, 17, and 23–25. GB2580988 further discloses first and second capacitive elements that are charged during integration and charge transfer between the elements to cancel at least part of the stored charge. See pp. 19–21, Figures 19–24, and claims 13, 14, 23, and 24.
Ono et al. (WO2006/041085) discloses a switched-capacitor sample-and-hold circuit having an operational amplifier, a feedback capacitor, input/sample capacitors, and switches that control sampling and amplification phases. See paragraphs 0002 – 0004. During the sampling or reset phase, the feedback capacitor is initialized or precharged relative to a reference operating point. During the amplification phase, the sampled input is amplified according to the ratio of the sampling capacitance to the feedback capacitance. See paragraphs 0002 – 0004 and 0012 – 0019. Ono et al. further discloses feedforward and feedback correction circuits that precharge the feedback capacitor with a correction value to reduce operating-point variation. See paragraphs 0032 – 0039 and 0042 – 0049.
Rationale and Motivation to combine
It would have been obvious to modify the capacitor-based nanopore readout of Chen et al. (US 11,029,306) using the capacitive-feedback and baseline-compensation teachings of Hsu et al., the frame-based charge-amplifier and ADC teachings of Fish et al. (US 10,962,523), the charge-balancing teachings of GB 2 580 988 A, and the precharged-feedback-capacitor correction teachings of Ono et al. (WO 2006/041085) because the references address the same technical field and related problems, including measurement of small nanopore currents in the presence of larger baseline currents, reduction of reset-related noise, compensation for operating-point variation, prevention of amplifier saturation, and improved dynamic range and ADC resolution. The proposed combination would have been a predictable use of known capacitor-based signal-conditioning techniques according to their established functions, with a reasonable expectation of improving nanopore signal-to-noise ratio and readout accuracy. A person of ordinary skill in the art would have been motivated to make the combination to remove a relatively large nanopore baseline component, center or condition the signal within the operating range of an ADC, reduce amplifier saturation and reset-related noise, and improve dynamic range and measurement accuracy. The proposed combination would have been a predictable use of known switched-capacitor correction and nanopore readout techniques according to their established functions.
Regarding the disclose the signal relationship recited in amended claim 8: “such that the signal obtained by the electronic circuit is shifted from the electrical response by a value associated with the charged feedback capacitor.” Ono et al. (WO 2006/041085) disclose a capacitor-associated correction value that affects the amplifier output, Chen et al. (11029306) supplies the nanopore and capacitor-measurement context, and Hsu et al., Fish et al. (10962523), and GB2580988 combined teach that capacitive-feedback, charge-amplifier, and charge-balancing teachings were well known in the art.
Regarding claims 9-12, which depend from claim 8, claim 9 requires charging the feedback capacitor by connecting it to a current source via a gate. The cited references disclose capacitor precharge, compensation current, and switched-capacitor correction.
Regarding claim 10, which requires connecting the electronic circuit to the sequencing cell by switching the gate. The cited references disclose separate capacitor-conditioning and nanopore-measurement phases.
Regarding claim 11, which requires that the feedback capacitor be disconnected from the current source while the electronic circuit is connected to the sequencing cell. The references do not clearly disclose this specific switching state.
Regarding claim 12, which requires setting a switch in parallel with the feedback capacitor to a disconnected state before charging the feedback capacitor Ono et al (WO 2006/041085), and (GB 2 580 988), disclose switches associated with feedback or reset capacitors and phase-controlled capacitor operation.
Regarding claim 13, which depends from claim 8 and further recites that the electrical response is an ionic current through the nanopore or an equivalent thereof. Chen et al. discloses ionic current through a nanopore and measurement of the current as a function of the nucleotide or molecule in the nanopore. See paragraphs 0038 – 0041. Hsu et al. disclose sensing ionic current through a nanopore using a capacitive feedback transimpedance amplifier. See pp. 653–658. Fish et al. (10962523) disclose sensor elements including ion channels and membrane proteins and current measurement using a charge amplifier and ADC. See paragraphs 044–047 and 058–078. Accordingly, the additional limitation of claim 13 is therefore taught or suggested
Regarding claim 14, which depends from claim 8 and further recites that the electrical response is modulated by nucleotides or labels on nucleotides near a sensing zone of the nanopore, nucleotides or labels being incorporated into the polynucleotide, or a combination thereof, Hsu et al. disclose nanopore DNA sequencing and current signatures caused by single-stranded DNA translocation. See pp. 652–658. The additional limitation of claim 14 is therefore taught or suggested.
Regarding claim 15, which depends from claim 8 and further recites providing an electrolyte to the sequencing cell before providing the polynucleotide, Chen et al. (110293062) discloses electrolyte-containing nanopore chambers and application of a potential across the nanopore. Hsu et al. disclose nanopore sequencing in ionic buffer between cis and trans chambers. See pp. 652–653 and 659. The additional limitation of claim 15 is therefore taught or suggested.
Regarding claim 21 which depends from claim 8 and recites that the electronic circuit comprises an analog-to-digital converter. US 11,029,306 discloses ADC 710 for reading the integrating-capacitor voltage. See Figure 7A, Figure 7B, and claims 1 and 8. Fish et al. (US 10,962,523) discloses ADC processing of analog samples from a charge amplifier. See paragraphs 014 – 021 and 078 – 079.The additional limitation of claim 21 is therefore taught or suggested
Regarding claim, which 22 depends from claim 21 and further requires: “the signal, which is shifted from the electrical response by the value associated with the charged feedback capacitor, is fed to the analog-to-digital converter.”
Ono et al. (WO 2006/041085) discloses a switched-capacitor sample-and-hold and pipeline-ADC architecture in which a capacitor-associated correction or reference value affects the amplifier output that is subsequently supplied for analog-to-digital conversion. See paragraphs 0012 – 0019, 0032 –0039, and 0050–0054. Similarly Hsu et al. and Fish et al. (10,962,523) supply nanopore readout and ADC-processing teachings. It would have been prima facie obvious to apply the switched-capacitor correction technique of Ono et al. (WO 2006/041085) to the nanopore readout of Chen et al. so that the baseline-shifted nanopore signal is presented to the ADC, thereby teaching the claimed invention.
Conclusion
No claim is allowed.
Applicants’ amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicants are 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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GARY BENZION, Ph.D.
Supervisory Patent Examiner
Art Unit 1681
/GARY BENZION/ Supervisory Patent Examiner, Art Unit 1681
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