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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/9/2026 has been considered by the examiner.
Election/Restrictions
Applicant's election of Group I without traverse and election of species A with traverse in the reply filed on 6/8/2026 is acknowledged.
The traversal on the species is on the ground(s) that Figs. 2B and 2C are example embodiments of the system 200 of Fig.2A. Applicant’s arguments regarding the traversal on the species are convincing, thus Examiner withdraw the restriction of species between Figs. 2A, 2B, and 2C.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-4, 22-26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Manickam et al. (A CMOS electrochemical impedance spectroscopy (EIS) biosensor array, IEEE Transactions on Biomedical Circuits and Systems, 2010, 4(6), 379-390), and in view of Götz (Expanding the scope of impedance spectroscopy for the analysis of adherent cells: electrode material, electrode design and data analysis, dissertation of Der Universität Regensburg, 2017). Manickam was provided in IDS filed on 6/9/2026.
Regarding claim 1, Manickam teaches a method for polar mode impedance biosensing (a CMOS EIS biosensor array to detect various biological analytes [title, abstract, Figs.5 and 10]), comprising:
applying an electrical excitation signal at a stimulation frequency across an electrode-electrolyte interface of an electrochemical sensor of a biosensor device (Fig.5 shows applying Vx([Symbol font/0x77]) at a stimulation frequency [Symbol font/0x77] across an electrode-electrolyte interface [Au sensing electrode with capturing probes] of an electrochemical sensor of a biosensor device);
measuring an electrical signal at the electrochemical sensor using a transimpedance amplifier in communication with the biosensor device (Fig.5 shows the On-chip sensing electrode is connected to a TIA, and Figs.5-6 show measuring an electrical signal at the electrochemical sensor using a transimpedance amplifier in communication with the biosensor device; Ii([Symbol font/0x77]) is the measured current at the ith pixel [the first paragraph in Col. 1 on pg. 381]);
determining a relative phase shift caused by a change of electrode impedance associated with caused by a molecular binding event of a target molecule with a molecular binding site of a functionalization layer of an electrode of the electrochemical sensor (Figs. 3 and 5 show the Au sensing electrode has a functionalization layer with capture probes; Fig.16 shows the changes in impedance of the diffusion layer that occurs with probe-analyte binding, which permits the detection of the analyte [caption of Fig.16]; To find Yi([Symbol font/0x77]), we only need to calculate the relative amplitude and phase shift of Ii([Symbol font/0x77]) compared to Vx([Symbol font/0x77]), and the phase of Yi([Symbol font/0x77]) is determined by Eq. 3 [section B. Impedance Detection]).
Manickam is silent to quantizing and averaging phase data points in time to remove uncorrelated noise from the detected electrical signal.
Götz teaches impedance spectroscopy for analysis of adherent cells (title), and section 1.2.1 details the experimental setup for impedance spectroscopy. A weak sinusoidal AC voltage was used to record the magnitude and phase shift of the impedance at 61 distinct frequencies between 100 and 106 Hz, equally distributed on a logarithmic scale. For each data point the impedance was averaged over five periods at that frequency or at least 10 ms in order to minimize the noise (the first paragraph in section 1.2.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method by providing the step of quantizing and averaging phase data points in time to remove uncorrelated noise from the detected electrical signal, as taught by Götz, since it would minimize the noise (the first paragraph in section 1.2.1 of Götz).
Regarding claim 2, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the measured electrical signal includes a corresponding induced current with respect to the applied electrical excitation signal (Ii([Symbol font/0x77]) is the measured current at the ith pixel [the first paragraph in Col. 1 on pg. 381]).
Regarding claim 3, modified Manickam teaches the method of claim 1, and Manickam is silent to wherein the stimulation frequency is in a range between 1 mHz and 10 MHz.
But Manickam teaches the frequency is in a range between 10 Hz and 50 MHz (Table 1), which overlaps with the claimed frequency range between 1 mHz and 10 MHz.
It would have been obvious to have selected and utilized a stimulation frequency within the disclosed range, as taught by Manickam, including those amounts that overlap within the claimed range, since one of ordinary skill in the art would reasonably expect any value within the taught range to be suitable given that Manickam specifically teaches the frequency range to be suitable for the electrical excitation signal for EIS measurement of the probe-analyte binding to detect the analyte (Fig.6 and Table 1). It has been held that obviousness exists where the claimed ranges overlap or lie inside ranges disclosed by the prior art. See MPEP 2144.05 (I).
Regarding claim 4, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the excitation signal includes a sinusoidal signal (sinusoidal excitation voltage signal Vx([Symbol font/0x77]) [the first paragraph in Col. 1 on page 381]).
Regarding claim 22, modified Manickam teaches the method of claim 1, wherein the quantizing and averaging phase data points is based on a number of cycles in a readout time that correspond to the stimulation frequency of the applied electrical excitation signal (as outlined in the rejection of claim 1 above, the quantizing and averaging phase data points is based on a number of cycles in a readout time that correspond to the stimulation frequency of the applied electrical excitation signal [For each data point the impedance was averaged over five periods at that frequency [the first paragraph in section 1.2.1 of Götz]).
Regarding claim 23, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the electrochemical sensor comprises a first electrode (Au sensing electrode with capturing probes as shown in Figs. 3 and 5) and a second electrode (reference electrode in Fig.5), wherein the first electrode includes the functionalization layer on an outer surface of the first electrode (see Figs. 3 and 5 wherein the Au sensing electrode includes the functionalized layer with capturing probes on an outer surface of the Au sensing electrode), and the second electrode does not include the functionalization layer (Fig.5 shows the reference electrode does not include the functionalization layer).
Regarding claim 24, modified Manickam teaches the method of claim 23, and Manickam teaches wherein the second electrode is operable as a reference electrode to account for global variations in an electrochemical cell and provide a phase reference (Fig.5 shows the second electrode is the reference electrode, and calculate the relative amplitude and phase shift of Ii([Symbol font/0x77]) compared to Vx([Symbol font/0x77]) [the first paragraph in Col. 1 on pg. 381]; thus, the second electrode is operable as a reference electrode to account for global variations in an electrochemical cell and provide a phase reference).
Regarding claim 25, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the molecular binding site of the functionalization layer includes one or more molecules comprising one or more of a nucleic acid having a single- stranded region (we immobilized thiolated ssDNA molecules directly onto the Au electrode surface as the capturing probe [section C. Biological Measurements on pg.387]).
Regarding claim 26, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the electrochemical sensor includes an array of electrodes (10x10 pixels [section C. system Architecture on pg. 381]; EIS Biosensor Array in Fig.10), wherein each respective electrode of the array corresponds to an electrochemical sensor pixel (10x10 pixels [section C. system Architecture on pg. 381]) to detect an impedance change in a detected electrical signal at an outer surface of the respective electrode (Figs. 5 and 16 show each electrochemical sensor pixel is configured to detect an impedance change in a detected electrical signal at an outer surface of the respective electrode).
Regarding claim 28, modified Manickam teaches the method of claim 1, and Manickam teaches wherein the biosensor device includes a circuitry layer (see Fig.5) comprising the transimpedance amplifier (see TIA in Fig.5), a phase detector (see Fig.4 to obtain VI(i) and VQ(i) and phase is calculated using Eq. 3 [section B. Impedance Detection]), and a time-to-digital converter (digitized using NI PCI 6289 DAQ in Fig.11 [Section IV. Results and Discussion on pg. 384]), and a sensing layer in electrical communication with the circuitry layer comprising an array of sensor pixels (Figs. 3 and 5 show on-chip sensing layer with capturing probes is in electrical communication with the circuitry layer comprising an array of sensor pixels).
Regarding claim 29, modified Manickam teaches the method of claim 28, and Manickam teaches wherein the circuitry layer is configured under the array of sensor pixels (Fig.5 shows the circuitry layer is configured under the array of sensor pixels) on an electrically insulating substrate (the EIS biosensor chip is fabricated with the standard CMOS process, and Fig.1 shows passivation openings in standard CMOS structure used as sensing electrodes on an electrically insulating substate [see Dielectric in Fig.1]).
Claims 5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Manickam and Götz, as applied to claim 1 above, and further in view of Huang et al. (A TDC-based front-end for rapid impedance spectroscopy, 2013 IEEE 56th Int. Midwest Symp. on Circuits and Systems, page 169-172). Huang was provided in IDS filed on 6/9/2026.
Regarding claim 5, modified Manickam teaches the method of claim 1, and is silent to further comprising: converting a rail-to-rail signal by a zero-crossing detector of a electronic circuit unit.
Huang teaches an EIS in Fig.1 wherein the electronic circuit (the circuit within the IS Front-end box in Fig.1) comprising converting a rail-to-rail signal by a zero-crossing detector of an electronic circuit unit (converting VTIA and stimulus signal by a zero-crossing detector prior to the phase detector is shown in Fig.1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of determining the relative phase shift by providing the step of converting a rail-to-rail signal by a zero-crossing detector of an electronic circuit unit, as taught by Huang, since Huang teaches a suitable alternative circuit to determine the relative phase shift as shown in Fig.1.
Regarding claim 16, modified Manickam teaches the method of claim 1, and is silent to wherein the determining the relative phase shift comprises using a phase detector in communication with the transimpedance amplifier.
Huang teaches an EIS in Fig.1 wherein determining the relative phase shift comprises using a phase detector in communication with the transimpedance amplifier (the circuit within the IS Front-end box in Fig.1 comprises a “Phase Detector” in communication with “TIA”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of determining the relative phase shift by providing a phase detector in communication with the transimpedance amplifier, as taught by Huang, since Huang teaches a suitable alternative circuit to determine the relative phase shift as shown in Fig.1.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Manickam, Götz and Huang, as applied to claim 16 above, and further in view of Chen et al. (Dual-mode urinalysis chip by using electrochemical impedance spectroscopy, 2011 Int. Conf. Intelligent Computation and Bio-Medical Instrumentation, 2011, DOI 10.1109/ICBMI.2011.55). Chen was provided in IDS filed on 6/9/2026.
Regarding claim 17, modified Manickam teaches the method of claim 16, and Huang teaches wherein the phase detector produces a pulse with a duty cycle linearly proportional to the relative phase shift (Fig.2c; the duty cycle of the phase detector output is directly proportional to the impedance phase shift [the first paragraph in Col. 1 on pg. 170]).
modified Manickam is silent to wherein the phase detector includes an XOR logic gate operable to produce the pulse with a duty cycle linearly proportional to the relative phase shift.
Chen teaches wherein the phase detector includes an XOR logic gate (XOR logical cell in Fig.6 and section II.D) operable to produce a pulse with a duty cycle linearly proportional to the relative phase shift (a nearly dc signal, whose value is proportional to the phase difference between two input signals is generated [section II.D]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the phase detector to include an XOR logic gate operable to produce a pulse with a duty cycle linearly proportional to the relative phase shift, as taught by combined Huang and Chen, since Chen teaches a suitable phase detector design including XOR logic gate to produce the pulse (Fig.6).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Manickam and Götz, as applied to claim 1 above, and further in view of Huang et al. (A TDC-based front-end for rapid impedance spectroscopy, 2013 IEEE 56th Int. Midwest Symp. on Circuits and Systems, page 169-172) and Straayer et al. (A multi-path gated ring oscillator TDC with first-order noise shape, IEEE J. Solid-state circuits, 2009, 44(4) 1089-1098). Straayer was provided in IDS filed on 6/9/2026.
Regarding claim 18, modified Manickam teaches the method of claim 1, and is silent to wherein the quantizing and averaging phase data points in time comprises using a time-to-digital converter including a first-order noise-shaped gated ring oscillator configured to convert pulses to a digital output.
Huang teaches an EIS in Fig.1 wherein the electronic circuit (the circuit within the IS Front-end box in Fig.1) comprising a time-to-digital converter (TDC) configured to convert pulses to a digital output.
Straayer teaches a TDC includes a first-order noise-shaped gated ring oscillator configured to convert pulses to a digital output (title, abstract, Fig.5, section II.B and conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the quantizing and averaging phase data points in time by using a time-to-digital converter including a first-order noise-shaped gated ring oscillator configured to convert pulses to a digital output, as taught by combined Huang and Straayer, since it would convert pulses to a digital output for further calculating the phase shift.
Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Manickam and Götz, as applied to claim 1 above, and further in view of Sun et al. (A multi-technique reconfigurable electrochemical biosensor: enabling personal health monitoring in mobile devices, IEEE transactions on biomedical circuits and systems, 2016, 10(5), 945-954). Sun was provided in IDS filed on 6/9/2026.
Regarding claim 19, modified Manickam teaches the method of claim 1, and is silent to wherein the transimpedance amplifier includes a resistive feedback transimpedance amplifier (R-TIA).
Sun teaches a reconfigurable electrochemical biosensor (abstract), wherein in the EIS mode as shown in Fig.6 each of working electrodes WE1 and WE2 electrically couples to a corresponding TIA, wherein the gain and bandwidth of the WE TIA is adjusted depending on the impedance and frequency being measured (section III.C on page 948). To further increase the flexibility and compatibility of the platform with POC type of tests, the potentiostat includes dual WEs each with its own resistive feedback transimpedance amplifier (TIA), which is based on circuit topology commonly used in potentiostats (the 2nd paragraph in Col. 2 on 947).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the TIA in modified Manickam with the resistive feedback TIA, as taught by Sun, since it would increase the flexibility and compatibility of the system for POC use (the 2nd paragraph in Col. 2 on 947 in Sun). The simple substitution of one known element (i.e., a TIA) for another TIA is likely to be obvious when predictable results are achieved (i.e., amplifying the measured signal). See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143(I)(B)).
Regarding claim 20, modified Manickam teaches the method of claim 19, further comprising: bandpass filtering an output of the R-TIA using impedance of a signal sensor pixel and bandwidth of a signal from the R-TIA to limit noise (As outlined in the rejection of claim 19 above, the TIA is a resistive feedback transimpedance amplifier that is coupled to a bandpass filter [dual WEs each with its own resistive feedback transimpedance amplifier (TIA). Each TIA has a bandwidth 1 Hz-100 kHz [the 2nd paragraph in Col. 2 on page 947 in Sun]; “to limit noise” is an intended result of a positively recited step. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Allowable Subject Matter
Claims 21, 27 and 30 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter.
Regarding claim 21, the prior art of the record does not teach and/or suggest
wherein the quantizing and averaging phase data points in time provides an increased signal-to-noise ratio (SNR) of at least 10 dB for each 10x increase in readout time.
Regarding claim 27, Manickam teaches wherein the array of electrodes includes one or more signal sensor pixels including the functionalization layer (Fig.3 shows capturing probes immobilized on Au sensing electrode; each pixel comprising one sensing electrode and the capturing probe of each pixel can be different [section C. System Architecture]). Manickam further teaches a large and shared reference electrode in solution, and Fig.5 shows the reference electrode is an unfunctionalized electrode (the first paragraph in Col. 1 on pg. 381). Since the reference electrode is large and shared by all Au sensing electrodes and Fig.5 also shows the large and shared reference electrode is positioned above the sensing electrodes, one of ordinary skill in the art would not be motivated to have the unfunctionalized reference electrode placed in one or more reference sensor pixels since it would place the reference electrode and the sensing electrodes on the same plane instead of having the reference electrode positioned above the sensing electrodes.
Regarding claim 30, Manickam teaches wherein the method detects both the phase and magnitude of an impedance change at the electrode-electrolyte interface (see Eq. 2 and 3). The prior art of the record does not teach and/or suggest detecting only the phase of an impedance change at the electrode-electrolyte interface without detecting magnitude of the impedance change.
As allowable subject matter has been indicated, applicant's reply must either comply with all formal requirements or specifically traverse each requirement not complied with. See 37 CFR 1.111(b) and MPEP § 707.07(a).
Conclusion
The prior arts made of record and not relied upon are considered pertinent to applicant's disclosure: Carminati et al. (Attofarad resolution potentiostat for electrochemical measurements on nanoscale biomolecular interfacial systems, Review of Scientific Instruments, 2009, 80, 124701) teaches EIS measurement on nanoscale biomolecular interfacial systems (section VI.A). Crescentini et al. (Recent trends for (bio)chemical impedance sensor electronic interface, electroanalysis, 2012, 24, 563-572) teaches EIS system for measuring impedance change at an electrode/electrolyte interface (Fig.10). Merriman et al. (US20200242482A1) teaches a CMOS chip comprising an array of biosensors and each single pixel circuit comprises a TIA.
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/SHIZHI QIAN/Primary Examiner, Art Unit 1795
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