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 .
DETAILED ACTION
Application status
In response to the previous Office action, a non-final rejection (mailed on
08/22/2025), Applicants filed a response received on 02/18/2026.
Thus, Claims 64-65, 67-75, 77-80 and 83-84 are at issue and present for examination.
It is noted by the Examiner that Claims 53-54, 57 and 61-62 are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention in the previous Office actions, a non-Final rejection (mailed on 03/12/2024).
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 previous rejection of Claims 64-65, 67-75, 77-80 and 83-84 under 35 U.S.C. 103 as being unpatentable over MAGER et al. (US Patent No. 10317392) in view of Metrohm (“EIS Data fitting – How to obtain good starting values of equivalent circuit elements” Metrohm Autolab, published May, 2019) is withdrawn in favor of a new rejection of record shown below.
Applicants’ Arguments:
Metrohm does not cure the above-mentioned deficiency of Mager. Metrohm discloses measuring impedance directly with an electrochemical impedance spectroscopy (EIS) and fitting the measured impedance data to derive parameters of an adequate equivalent circuit including "resistance for the electrolyte (Rel), one resistance for the charge transfer (Rct), a constant phase element (CPEdL) or a capacitor (Cdl) for the double layer, and a Warburg (WD) for the semi-infinite diffusion of the ionic species through the diffusion layer (i.e., from the bulk electrolyte to the double layer)." See Metrohm at Figure 4 (plotting imaginary part of measured impedance vs. real part of measured impedance), Figure 5 (plotting measured impedance and phase vs. frequency), and the right column of page 2.
Therefore, Metrohm is onnosite to the claimed invention. It teaches directly measuring impedance values and using the measured impedance values to derive other electrical elements of the circuit. It does not disclose or even hint at "using the voltage signal or change thereof measured by the sensor to derive a bulk impedance or change thereof associated with a nucleotide incorporation" as instantly claimed in claim 64. The combination of Mager and Metrohm does not meet each and every element of claim 64.
Examiner’s Explanations:
In view of the new rejection of record (see below) which do not depend on the teachings of Metrohm, Applicants’ arguments regarding Metroehm, and why it would not have been obvious to combine the teachings with Mager et al. are moot.
Claims 64-65, 67-75, 77-80 and 83-84 are rejected under 35 U.S.C. 103 as being unpatentable over MAGER et al. (US Patent No. 10317392) in view of Tektronix (“TDR Impedance Measurements: A Foundation for Signal Integrity”, published on September 2008).
The instant claims are drawn to a system for nucleic acid sequence identification, comprising:
a sensor comprising:
(i) a membrane comprising a nanopore;
(ii) a polymerizing enzyme configured to perform an extension reaction on a nucleic acid molecule when said nucleic acid molecule is disposed in a solution in proximity to said nanopore, wherein said extension reaction comprises incorporating a nucleotide into a growing strand that is complementary to at least a portion of said nucleic acid molecule; and
(iii) an electrode in proximity to said nanopore; and
a processor operatively coupled to said sensor, wherein said processor is configured to (1) direct said sensor to measure a voltage signal or change thereof associated with said nucleic acid molecule and said solution during incorporation of said nucleotide into said growing strand, (2) use said voltage signal or change thereof measured by said sensor to derive a bulk impedance or change thereof, and (3) analyze said bulk impedance or change thereof that is derived from said voltage signal or change thereof to identify said nucleotide, thereby identifying at least a portion of a sequence of said nucleic acid molecule.
Mager et al. teach a system for nucleic acid sequencing, comprising: a sensor comprising: (i) a membrane comprising a nanopore, which is either a lipid bilayer or a polymeric membrane (see column 4, lines 47-51); (ii) a polymerizing enzyme (i.e., DNA polymerase covalently attached to nanopore (see column 9, lines 37-41) configured to perform an extension reaction on a nucleic acid molecule when said nucleic acid molecule is disposed in a solution in proximity to said nanopore, wherein said extension reaction comprises incorporating a nucleotide into a growing strand that is complementary to at least a portion of said nucleic acid molecule; and (iii) an electrode in proximity to said nanopore; and a processor operatively coupled to said sensor, wherein said processor is configured to (1) direct said electrode to measure at least one sensor signal associated with said nucleic acid molecule or said solution during incorporation of said nucleotide into said growing strand, wherein said at least one sensor signal comprises a voltage signal, and (2) analyze said at least one sensor signal that is measured in (1) to identify said nucleotide, thereby identifying at least a portion of a sequence of said nucleic acid molecule (see Figs. 1-4 and their descriptions, starting from column 6, line 15 to column 14, line 23). Mager et al. further teach that “[a] signal value may represent any measurable quantity that correlates with the resistivity of a nanopore and from which the resistivity and/or conductance of the nanopore (threaded and/or unthreaded) may be derived” (see column 5, lines 28-32).
Claim 68 is included in this rejection because Mager et al. teach that one or more processors is configured to identify said nucleotide based at least in part on a plurality of measurements of said at least one sensor signal during said incorporation of said nucleotide into said growing strand (see column 18, lines 29-34).
Claims 69, 70 and 78 are included in this rejection even though Mager et al. do not disclose how their processor is configured to [i] take measurements within about 100 microseconds to about 10 milliseconds, [ii] identify in part on a residence time at which said nucleotide is disposed in proximity to said polymerizing enzyme, or [iii] direct the voltage source to generate an impedance spectrum of the sensor. The reason is that these would be inherent characteristics of the processor taught by Mager et al. to be configured to carry out these functions. Furthermore, the claimed invention is drawn to a product, and therefore, the patentability of the claimed product rests on the novelty or unobviousness of the product, and not how the product (processor) is configured.
Since the Office does not have the facilities for examining and comparing applicants’ processor with that of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Claim 71 is included in this rejection because Mager et al. teach the use of reference electrode, i.e., counter electrode or common electrode, which is disposed on the opposite side of a working electrode (see column 8, last paragraph continued to column 9, 1st paragraph, especially lines 12-13).
Claim 72 is included in this rejection because Mager et al. teach a protein nanopore (see column 6, line 5).
Claims 73 and 74 are included in this rejection because Mager et al. teach the nucleotide comprises a tag, wherein, during said incorporation of said nucleotide into said growing strand, said tag is configured to interact with said nanopore to yield said at least one sensor signal, and wherein subsequent to said incorporation of said nucleotide into said growing strand, said tag is configured to move through at least a portion of said nanopore (see column 14, lines 25-33).
Claim 75 is included in this rejection because Mager et al. teach that measured signals are indicative of electrical characteristics, such as changes in electrical resistance, electrical capacitance or electrical ionic current flow (see column 9, lines 10-11).
Claim 77 is included in this rejection because Mager et al. teach said system further comprising a voltage source, wherein said processor is further configured to direct said voltage source to apply a voltage to said electrode and a reference electrode prior to directing said electrode to measure said at least one sensor signal (see Fig. 4, and column 11, lines 20-40, especially line 30).
Claim 79 is included in this rejection because Mager et al. teach the use of AC voltage which has an alternating current (AC) waveform (i.e., sine wave voltage) (see column 10, lines 43-45).
Claim 80 is included in this rejection even though Mager et al. do not disclose the cross-sectional dimension of the electrode to be no more than about 10 micrometers because this would be an inherent characteristics of the electrode taught by Mager et al. which is used with a nanopore.
Since the Office does not have the facilities for measure the thickness of the electrode taught by Mager et al. and compare it to the applicants’ electrode, the burden is on the applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Claims 83 and 84 are included in this rejection because Figures 2 and 3 of Mager et al. teach that at least a portion of said bulk impedance or change thereof is outside of a Debye layer of said electrode, and that said electrode is not in direct contact with said nanopore.
Mager et al. do not teach deriving bulk impedance from voltage signal.
Tektronix specifically teaches the fundamental principle of deriving bulk impedance from a voltage signal alone. Tektronix teaches a method of performing Time Domain Reflectometry (TDR) and a formula which can be used to calculate the impedance ρ = V reflected / V incident = (ZL + Z0) / (ZL + Z0), solving for Z (the impedance) without needing a direct current measurements (see pages 2-3).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to make and use a system for nucleic acid sequencing taught by Mager et al. and derive bulk impedance from voltage signal as taught by Tektronix. One of ordinary skill in the art would be motivated to make and use such system because measuring voltage signals and deriving bulk impedance was a routine for a person of ordinary skill in the art (POSITA) as taught by Tektronix.
Furthermore, MPEP 2141(III) states that the combination these prior art references must lead to predictable results. Regarding this, the prior art references of Tektronix demonstrates that deriving bulk impedance from detection of voltage signal is feasible, and it would have led a POSITA to predict that such bulk impedance can be derived from the voltage signal measured using the nanopore DNA sequencing system. Such derivation using a known mathematical relationship, i.e., ρ = V reflected / V incident = (ZL + Z0) / (ZL + Z0), solving for Z (the impedance), would have led to predictable results as taught by Tektronix. Furthermore, it would have been "obvious to try" for a POSITA because there were only a finite number of identified, predictable solutions, with a reasonable expectation of success, i.e., measuring voltage signal to derive bulk impedance.
While the reference of Mager et al. might not teach a specific embodiment with the claimed nucleic acid sequencing system, i.e., deriving bulk impedance, the reference of Tektronix does teach that mathematical conversion of voltage signal to impedance/bulk impedance as being routine and appropriate. As discussed in KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007), it is considered obvious to combine prior art elements known to be used in equivalent fields of endeavor together into a single combination when it leads to predictable results. These references clearly show that measuring voltage signal to derive bulk impedance were known to be used in equivalent fields of endeavor, i.e., in a nucleic acid sequencing system using voltage signal sensing electrodes; thus, it is considered obvious to combine them together.
One would have had a reasonable expectation of success to make and use such
system for nucleic acid sequencing because all of the required techniques, biochemical reagents and materials were rampantly used as evidenced by Mager et al. and Tektronix prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Conclusion
Claims 64-65, 67-75, 77-80 and 83-84 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
The instant Office action is non-final.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (5712720939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656(nr)