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 .
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.
Claim 73 is 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 regard(s) as the invention.
(i) Regarding claim 73, the limitation requiring determining “progression” if the number of the biological entity is elevated and “regression” if the number is decreased is indefinite because the claim does not clearly define the baseline for the “a control level,” (second paragraph, line 8) e.g., whether the comparison is to a population reference, healthy control, disease-control value, or prior value from the same subject.
(ii) Regarding claim 73, the limitation requiring determining “progression” if the number of the biological entity is elevated and “regression” if the number is decreased is indefinite because the claim does not clearly define the baseline for the “second control level,” (third paragraph, line 11) e.g., whether the comparison is to a population reference, healthy control, disease-control value, or prior value from the same subject.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 59-67 are rejected under 35 U.S.C. 103 as being unpatented over Morgan et al., (WO 2020/058681 A1, hereinafter as “Morgan”) in view of Jagtiani (WO 2019/236682 A1, hereinafter as “Jagtiani”).
Regarding claim 59, Morgan teaches a microfluidic impedance flow cytometry for measuring frequency-dependent impedance of particles, including cells and bacteria, flowing through a microfluidic channel (Abstract). Morgan discloses a layered substrate having a flow channel, inlet, outlet, signal electrodes, measurement electrodes, voltage/source circuitry, current-to-voltage conversion circuitry, and impedance signal processing (Abstract; p. 2, line 22 thru p. 3 line 2).
Morgan discloses “a microfluidic system for impedance-based detection of a biological entity in a sample, comprising (Fig. 1; p. 5, line 24 thru p. 7, line 12):
a substrate/layered chip structure including glass layers (16a, 16b) and a photoresist layer 14 defining the microfluidic device 10 (Fig. 1, p. 5, lines 30-36);
fabrication in a chip format enables the apparatus to be readily extended to include two or more fluid flow channels and the lab-on-chip format, comprising a series of patterned layers of different materials laid down on a supporting layer or substrate; where the flow channel may be formed with an intermediate layers or layers (p. 24, lines 15-17); and where four microfluidic channels (i.e., four channels 12) on a chip 102 with a layered structure, wherein the four microfluidic channels 12 are configured to conduct passage of the biological entity (i.e., testing of multiple samples simultaneously if desired; (i.e., bacteria samples) (Fig. 13, p. 25 lines 4-7) which meets the recited limitation, two or more microfluidic flow channels positioned on the substrate, wherein the two or more microfluidic flow channels are configured to conduct passage of the biological entity;
wherein the at least one inlet 18 is configured to receive the sample 22 and is in fluid communication with the microfluidic flow channels 12 (Fig. 13; p. 25, lines 47);
an impedance circuit disposed on the substrate (16a, 16b) comprising two or more excitation electrodes (i.e., voltage electrodes 30) and measurement electrodes 32 (Fig. 1; p. 5, line 30 thru p. 7, line 8),
four microfluidic channels 12 where each channel 12 has four associated signal electrodes (excitation electrodes), and a single voltage source 71 provides driving voltages for the signal electrodes 60a, 60b (Fig. 13, lines 4-14) which meets the recited limitation, each of the two or more excitation electrodes is respectively coupled to each of the two or more microfluidic channels and configured to be electrically connected to a signal generator, and
the two or more excitation electrodes are configured to receive and electrically communicate an excitation signal applied by the signal generator to each of the two or more microfluidic channels,
excitation signals generate electric fields between each of the two or more signal electrodes (excitation electrodes) and the measurement (p. 17, line 24 thru p. 18, line 9),
measurement of electrical properties (output signal), specifically a frequency dependent impedance, of individual particles (cells, bacteria) flowing in a microfluidic channel (or channels where the apparatus can be fabricated to have multiple channels; p. 24, lines 15-17) where exposure to antibiotics can alter the impedance characteristics of bacteria and the detection of a change in impedance indicate susceptibility to an antibiotic under test (p. 5, lines 17-23; p. 7, lines 2-9), which meets the recited limitation, the output signal correlates to an impedance variation caused by displacement of the biological entity within each of the two or more microfluidic flow channels.
But Morgan does not explicitly teach:
(I) the “electrode” disposed on substrate and generates an electric field with two or more excitation electrodes is a common electrode;
(II) a common electrode coupled to all of the two or more microfluidic flow channels; and
(III) the common electrode is configured to communicate an output signal to an impedance analyzer.
Jagtiani teaches biological-sample cartridges and impedance sensors for analyzing biological samples, including blood and saliva, and discloses determining cell counts by transporting a biological sample through a channel or pore applying current or voltage, detecting impedance, and determining a cell count based on the detected impedance (Abstract).
Regarding (I) and (II), Jagtiani discloses a common electrode/common ground electrode 1726 arrangement, including a second sensing electrode shows as a common to multiple electrodes and a ground electrode 1726 common to three electrowetting electrodes 1720, 1722, and 1724, where fluid, such as biological sample and/or the one or more reagents (i.e., two or more microfluidic channels) can be transported to the gap 1736 (Fig. 17b; ¶ [0242]).
Regarding (III), Jagtiani further discloses the common electrode 416 to electrodes 410, 412, and 414 configured to electrically communicate an output signal to the impedance analyzer 432, 418 (Fig. 4a; ¶¶ [0177-0178]).
Morgan and Jagtiani are analogous arts because both are directed to microfluidic electrical/impedance analysis of biological samples using electrodes to detect, characterize, or count biological entities. Morgan teaches impedance flow cytometry in which cells, bacteria, or particles pass through microfluidic channels and generate impedance changes. Jagtiani teaches cartridge-based biological-sample impedance sensing in which samples passes through a channel or pore, an electrical signal is applied impedance is detected, and cell counts are determined.
Therefore, before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify Morgan’s multi-channel impedance cytometry system to include Jagtiani’s common-electrode arrangement because a common electrode can cooperate with multiple electrodes in a biological sample cartridge with similar substrate properties helps modulates hydrophobicity of the fluid thereby actuating the fluid to a position above the activated electrode to control the electrochemical environment and improve measurement accuracy (Jagtiani: ¶ [0239]); and wherein common electrode together with two or more excitation electrodes generate electric field provides a robust, uniform, and low impedance reference, improving experimental throughput and consistency (Morgan: p. 20, lines 23-33); it is further obvious to modify Morgan’s multi-channel impedance cytometry system to include Jagtiani’s common-electrode arrangement because coupling a common electrode to the two or more microfluidic flow channels and wherein it is configured to communicate an output signal to an impedance analyzer reduce duplicated electrode structure and enable compact multiplexed electrical operation, where the benefit is reduced complexity and improved suitability of point-of-care biological sample analysis (Morgan: ¶¶ [0117-0119; 0126])
In regard to claim 60, Morgan discloses simultaneous multi-sample testing using multiple channels on a chip (p. 24, lines 24-32).
In regard to claim 61. Morgan discloses four microfluidic channels (p. 25, lines 4-7).
In regard to claim 62, Morgan discloses microfluidic flow channel is defined in a layer of the substrate (p. 35 lines 6-7)
In regard to claim 63, Morgan and Jagtiani both teaches at least inlet and at least one outlet (Morgan: p. 2 lines 24; Jagtiani: ¶ [0164]).
In regard to claim 64, Morgan discloses a substrate/layered chip structure including glass layers (16a, 16b) and a photoresist layer 14 material (an epoxy-based negative photoresist) defining the microfluidic device 10 (Fig. 1, p. 5, lines 30-36). Morgan further discloses that conductive elements (including platinum, gold, indium tin oxide, iridium oxide and titanium nitride) that enable electrical connection of the signal electrodes to one or more voltage or current sources and of the measurement electrodes to the measurement circuitry may also be formed as layers within the structure, or as conductive via passing through the layers (p. 24, lines 15-25).
In regard to claim 65, Morgan discloses fabrication of two or more fluid flow channels (p. 24, lines 26-27) and the channel may have a square cross-section (arising for example from the layered construction and formation with photolithography) with a substantially equal width and height of about 40 μm (p. 14, lines 10-12).
In regard to claim 66, Morgan discloses fabrication of two or more fluid flow channels (p. 24, lines 26-27) and the channel may have a square cross-section (arising for example from the layered construction and formation with photolithography) with a substantially equal width and height of about 40 μm (p. 14, lines 10-12). But Morgan does not disclose the exact claimed dimension range of the microfluidic flow channels’ dimensions.
With respect to the to the width and height of the microfluidic flow channels’ dimensions, design modification of this prior art in order to ascertain optimum operating conditions fail to render applicant’s claims patentable in the absence of unexpected results. In re Aller, 105 USPQ 222. Morgan does not expressly disclose the claimed width and height of the microfluidic flow channel dimensions; however, one of ordinary skill in the art would have been motivated to adjust to optimize the width and height of Morgan’s two or more microfluidic flow channels to having a width of from about 70 to about 90 μm and a height of from about 18 to about 22 μm in order to obtain comparable flow resistance, comparable residence time, and comparable impedance measurement condition across parallel channels as taught by Morgan (p. 14, lines 3-19). A prima facie case of obviousness may be rebutted, however, where the results of the optimizing variable, which is known to be result-effective, are unexpectedly good. In re Boesch and Slaney, 205 USPQ 215.
In regard to claim 67, Jagtiani teaches determining counts of red blood cells (RBCs), white blood cells (WBCs), platelets, and WBC differentials including lymphocytes and neutrophils using impedance-based biological samples analysis (¶ [0049]).
Claims 68-72 are rejected under 35 U.S.C. 103 as being unpatented over Morgan in view of Jagtiani.
Regarding claim 68, as set forth above, Morgan in view of Jagtiani, addresses the microfluidic system recited in claim 59.
Morgan teaches a method of using a microfluidic impedance flow cytometry apparatus by flowing a particle/cell-containing sample through a microfluidic channel (Abstract);
providing microfluidic system recited in claim 59 in light of teachings from Morgan and Jagtiani (please refer to the rejection of claim 59);
applying the sample 22 to the at least one inlet 12 (Fig. 1, p. 6, lines 1-4);
applying electrical signals to electrodes, measuring current/output signals (p. 9, lines 25-30;
receiving an output signal communicated from the measurement electrode (p. 7, lines 4-9);
determining impedance response caused by particles/cells passing through the sensing region (p. 7, lines 4-9);
and determining a type or a number of the biological entity in the sample based on the impedance variation (p. 8, lines 3-9).
But Morgan does not teach the complete biological-sample-cell counting workflow in the exact claimed common-electrode architecture.
However, Jagtiani teaches transporting a biological sample through a sensor comprising a channel or pore, applying electrical current or voltage to the channel or pore, detecting impedance within the channel or pore, and determining a cell count based on the detected impedance (Abstract). Jagtiani further teaches performing full blood count in a microfluidic device, including WBC count, RBC properties/count, platelet count, and hemoglobin measurement (¶ [0049]).
Jagtiani discloses a common electrode/common ground electrode 1726 arrangement, including a second sensing electrode shows as a common to multiple electrodes and a ground electrode 1726 common to three electrowetting electrodes 1720, 1722, and 1724, where fluid, such as biological sample and/or the one or more reagents (i.e., two or more microfluidic channels) can be transported to the gap 1736 (Fig. 17b; ¶ [0242]).
Morgan and Jagtiani because both references concern microfluidic analysis of biological samples to detect, count, or characterize biological entities: Morgan teaches impedance flow cytometry for cells/bacteria in microfluidic channels, Jagtiani teaches cartridge-based impedance cell counting including blood count analysis of WBC, RBC, platelets in biological samples.
Therefore, before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to use Morgan’s impedance cytometry device according to Jagtiani’s common electrode arrangement because a common electrode can cooperate with multiple electrodes in a biological sample cartridge with similar substrate properties helps modulates hydrophobicity of the fluid thereby actuating the fluid to a position above the activated electrode to control the electrochemical environment and improve measurement accuracy as taught by Jagtiani (¶ [0239]).
In regard to claim 69, Morgan discloses electrical signals having one or more frequency in the range of 10 MHZ or less, such as about 1 MHz or about 5 MHz (p. 21, line 7-9). Since the claimed excitation signal of 100 kHz-20 MHz range overlaps the excitation signal of 10 MHZ or less, such as about 1 MHz or about 5 MHz (p. 21, line 7-9) taught by Morgan, the range recited in claim 69 is considered prima facie obvious. See MPEP 2144.05.
In regard to claim 70, Morgan discloses applying by the signal generator a different frequency of the excitation signal to each of the two or more excitation electrodes (p. 20, lines 23-35).
In regard to claim 71, Morgan discloses multiple channels as applied to claim 59 and multiple frequency components as applied to claim 60. Using three channels and three different frequencies would have been obvious multiplexed implementation of Morgan’s teachings.
In regard to claim 72, Morgan discloses electrical signals having frequency, magnitude, and phase (p. 22, lines 7-9). Sinusoidal AC (alternating current) excitation is a conventional waveform for impedance signal measurement, thereby render claim 72 obvious because it is a pure, periodic signal that can be fully described by three parameters: frequency, magnitude (amplitude), and phase.
Claims 73-78 are rejected under 35 U.S.C. 103 as being unpatented over Morgan in view of Jagtiani.
Regarding claim 73, as set forth above, Morgan in view of Jagtiani, addresses the microfluidic system recited in claim 59.
Morgan teaches impedance-based method of detection and characterization of biological entities, including cells and bacteria using a microfluidic impedance flow cytometry system (Abstract).
Morgan discloses a method and apparatus having application for improved diagnosis of bacterial infection (p. 19, lines 10-14) and continuous monitoring of the response of any given sample over an extended period of time ( p. 29, lines 21-24) which meets the recited limitation “method of diagnosing a disease or disorder in a subject, or of monitoring progression of a disease or disorder in a subject, the method of diagnosing the disease or disorder in a subject and the method of monitoring progression of the disease or disorder in a subject comprising providing the microfluidic system, the method comprising:
providing microfluidic system recited in claim 59 in light of teachings from Morgan and Jagtiani (please refer to the rejection of claim 59);
the method of diagnosing the disease or disorder in the subject further comprising
applying the sample 22 to the at least one inlet 12 (Fig. 1, p. 6, lines 1-4);
applying an excitation signal to the two or more excitation electrodes by the signal generator for a period of time (p. 3, lines 16-18);
receiving an output signal communicated from the measurement electrodes (p. 7, lines 4-9);
determining an impedance variation caused by displacement of the biological entity within the two or more microfluidic flow channels (p. 25, lines 5-22);
determining a number of the biological entity in the sample based on the impedance variation (p. 8, lines 3-9); and
comparison of a measurement from an exposed bacteria (biological entity) with that from an unexposed bacteria (control level) may therefore reveal antibiotic susceptibility if the differential signal from the former measurement shows larger amplitude features than the latter sample (p. 20, lines 17-22), having application for diagnosis of bacterial infection (p. 19, lines 3-14) (i.e., subject having a disease), which meets the recited limitation, determining that the subject has the disease or disorder if a difference between the number of the biological entity is elevated or decreased as compared to a second control level ;
continuous monitoring of the response of any given sample to antibiotics over an
extended time period of the apparatus (p. 29, 15-24) indicate that the subject can be monitored for progression or regression of the bacterial infection, which meets the recited limitations, determining that (a) the subject has progression of the disease or disorder if the number of the biological entity is elevated as compared to the second control level ; and (b) the subject has regression of the disease or disorder if the number of the biological entity is decreased as compared to the second control level.
But Morgan does not teach the complete biological-sample-cell counting workflow in the exact claimed common-electrode architecture.
However, Jagtiani teaches transporting a biological sample through a sensor comprising a channel or pore, applying electrical current or voltage to the channel or pore, detecting impedance within the channel or pore, and determining a cell count based on the detected impedance (Abstract). Jagtiani further teaches performing full blood count in a microfluidic device, including WBC count, RBC properties/count, platelet count, and hemoglobin measurement (¶ [0049]).
Jagtiani discloses a common electrode/common ground electrode 1726 arrangement, including a second sensing electrode shows as a common to multiple electrodes and a ground electrode 1726 common to three electrowetting electrodes 1720, 1722, and 1724, where fluid, such as biological sample and/or the one or more reagents (i.e., two or more microfluidic channels) can be transported to the gap 1736 (Fig. 17b; ¶ [0242]).
Morgan and Jagtiani because both references concern microfluidic analysis of biological samples to detect, count, or characterize biological entities: Morgan teaches impedance flow cytometry for cells/bacteria in microfluidic channels, Jagtiani teaches cartridge-based impedance cell counting including blood count analysis of WBC, RBC, platelets in biological samples.
Therefore, before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to use Morgan’s impedance cytometry device according to Jagtiani’s common electrode arrangement because a common electrode can cooperate with multiple electrodes in a biological sample cartridge with similar substrate properties helps modulates hydrophobicity of the fluid thereby actuating the fluid to a position above the activated electrode to control the electrochemical environment and improve measurement accuracy as taught by Jagtiani (¶ [0239]).
In regard to claim 74, it is rejected for the same reasons as claim 69 because Morgan discloses frequency-dependent impedance measurement and one or more frequency ranges.
In regard to claim 75, it rejected for the same reason as claim 70 because Morgan discloses multiple frequency ranges and signal electrodes.
In regard to claim 76, Morgan discloses bacterial infections and antimicrobial susceptibility testing (p. 1, lines 5-28).
In regard to claim 77, Morgan discloses samples which may contain cells or other biological particles including viruses (p. 6, lines 9-12); thereby render claim 77 obvious since disease or disorder comprising influenza or SARS CoV-2 are caused by different viruses.
In regard to claim 78, Morgan discloses diagnostic testing of patients and the method uses fluid as a matrix in impedance flow cytometry apparatus (p. 1, lines 5-17), indicating samples used comprises a bodily fluid.
Conclusion
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, In Suk Bullock can be reached on 571-272-5954. The fax phone number for the organization where this application or processing is assigned is 571-273-8300.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, In Suk Bullock can be reached on 571-272-5954. The fax phone number for the organization where this application or processing is assigned is 571-273-8300.
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/WILSON GALLARDO MENDOZA/Examiner, Art Unit 1772
/YOUNGSUL JEONG/Primary Examiner, Art Unit 1772
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