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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on March 5, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1-23 are currently pending. Claims 1 and 3 have been amended by Applicants’ amendment filed 02-02-2026. No claims have been added or canceled by Applicants’ amendment filed 02-02-2026.
Applicant's election without traverse of Group I, claims 1-8, directed to a cell preparation system, in the reply filed November 6, 2024 was previously acknowledged.
Claims 9-23 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
Therefore, claims 1-8 are under consideration to which the following grounds of rejection are applicable.
Priority
The instant application filed June 6, 2022 is a 371 of PCT/US2020/025044, filed March 26, 2020.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed February 2, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Claim Rejections - 35 USC § 112(a) – New Matter
The rejection of claims 1-8 is withdrawn 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement due to Applicant’s amendment of the claims, in the reply filed 02-02-2026.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Interpretation: The cell preparation system of claim 1 is interpreted to comprise: (a) a waste receptacle; (b) a well plate; (c) a fluidic channel; (d) an ejector; (e) a plurality of detection devices each of the plurality of detection devices comprising a constriction, a pair of electrodes, a sensor, a signal generator, and a filter device; and (f) a controller coupled with the plurality of detection devices. The system of claim 1 is interpreted not to comprise cells.
The constriction as recited in claim 1 is interpreted to refer to any constriction that deforms a cell traveling through the fluidic channel including a fluidic channel having a diameter/width that is smaller than the diameter/width of a cell.
The term “configured to measure a state within the constriction” as recited in claim 1 is interpreted to refer to a sensor capable of measuring any type of state within the constriction, such as: the number of cells, flow rate, fluorescence, channel pressure, temperature, etc.
The terms “a fluidic channel configured to” such as recited in claim 1, lines 4 and 6 is interpreted to mean that the fluidic channel is configured to both receive a plurality of cells and to transport a plurality of cells.
Double Patenting
The provisional rejection of claims 1-8 is maintained on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 10, 12, 14, 16, 17, 19-22, 25, 28-31 and 34 of copending US Patent Application No. 18/564,484 in view of Koltay (US8834793), where it is known that microfluidic devices used for measuring or detecting a property of a cell or particle including the impedance or conductivity of a cell can comprise waste outlets, well plates, and that cells can be ejected via a pressure wave from an ejection orifice (col 1, lines 33-34; col 2, lines 40-47 and 50-57; col 4, lines 6-8; col 6, lines 6-11; and col 11, lines 43-45)
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed February 2, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant requests that the provisional rejection be held in abeyance (Applicant Remarks, pg. 8, Double Patenting).
Regarding (a), Applicant did not specifically indicate how the claims of the copending applications recited supra are patentably distinct from the instant claims as required by 37 CFR 1.111(b). Thus, the claims remain rejected for the reasons already of record.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-8 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1-8 are indefinite because the claims appear to recite both a product and process in the same claim. The examiner cautions that according to the MPEP 2173.05(p)(II) states that a single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b). PXL Holdings v. Amazon.com, Inc., 430 F.2d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112(b). For example, claim 1 recites; “a cell preparation system” in line 1; “a waste receptacle; a well plate; a fluidic channel” in lines 2-4; and “a pair of electrodes” in line 12; while claim 1 also recites “to an ejector to eject cells from the fluidic channel” in lines 5-6; “cells traveling through the fluidic channel” in lines 10-11; and “when the cell is within the constriction” in line 13. Such claims may also be rejected under 35 U.S.C. 101 based on the theory that the claim is directed to neither a “process” nor a “machine,” but rather embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. Id. at 1551.
Claim 1 is indefinite for the recitation of the term “the electric field” such as recited in claim 1, lines 18-20. There is insufficient antecedent basis for the term “the electric field” in the claim because claim 1, line 18 recites the term “an electrical field.” The Examiner suggests that Applicant amend the claim to recite, for example, “such that the electrical field of the pair of electrodes.”
Claim 7 is indefinite for the recitation of the term “constriction shape of each of the plurality of detection devices” such as recited in claim 7, line 2 because it is unclear what ‘shapes’ are encompassed by the term “constriction shapes” (e.g., linear, circular, triangular, pin-point, etc.). Moreover, claim 7 depends from instant claim 1, wherein claim 7 recites components not recited in claim 1. For example, claim 1 does not recite a plurality of channels and/or a plurality of constrictions (e.g., the plurality of devices may share a single constriction), thus, the metes and bounds of the claim cannot be determined.
The rejection of claim 8 is maintained as being indefinite for the recitation of the term “quantity and types of cells indexed based on properties of each detection device” such as recited in claim 8, lines 3-4 because claim 8 depends from claim 1, wherein claim 1 does not recite a quantity of cells, different types of cells, cells that are indexed, and/or that each detection device has ‘properties’ and, thus, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 8 is maintained, and claim 7 is newly rejected, under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 recites (in part): “wherein each constriction has a constriction shape and wherein…of each of the plurality of detection devices varies between the plurality of detection devices” in lines 1-3 because claim 7 depends from instant claim 1, where claim 7 recites components that are not recited in claim 1, such that the cell preparation system of claim 1 recites a fluidic channel, a plurality of constrictions, and/or any constriction shapes. Thus, claim 7 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites (in part): “further comprising a database, wherein the controller is further configured to reference the database comprising: for each of the plurality of detection devices, mappings between sensor outputs and quantity and types of cells indexed based on properties of each detection device” in claim 8, lines 1-4 because claim 8 depends from instant claim 1. Claim 1 does not recite sensor outputs, the presence of a quantity of cells, different types of cells, cells that are indexed, and/or that each detection device has ‘properties.’ Thus, claim 8 is an improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Response to Arguments
Applicant’s arguments filed February 2, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) the dependent claim properly further limits a parent claim by adding new limitations, not by merely restating parent claim limitations. Claim 8 adds both a structural element (the database) and narrows the controller's functionality (referencing the database with specific mappings); and the as-filed Specification supports this limitation at Figs. 1 and 2 and paragraph [00100] (Applicant Remarks, pg. 11 through pg. 12, first partial paragraph).
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). It is noted that the claims are directed to a product, and not to a method of using the product. Although the system of claim 1 further comprises a database, and the controller is further configured to reference the database, instant claim 1 does not recite that the detection devices have properties, the presence of cells, quantities of cells, and/or indexed cells. Therefore, a database cannot quantitate, map, store, manage, and/or organize information on indexed cells of different types if no cells are present and/or indexed. The rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of claims 1-8 is maintained under 35 U.S.C. 103 as being unpatentable over Koltay et. al. (hereinafter “Koltay”) (US Patent No. 8834793, issued September 16, 2014; of record) in view of Sharei et al. (hereinafter “Sharei”) (US Patent No. 1069644, issued June 30, 2020; WO2013059343, filed October 17, 2012; of record) as evidenced by Renaud et al. (hereinafter “Renaud”) (US Patent Application Publication 20080286751, published November 20, 2008).
Regarding claim 1, Koltay teaches a device for detecting information on cells or particles located in an observation volume of the suspension within the branch-less one-way channel is provided, wherein an ejected droplet is directed to a first position or a second position depending on the detected information, wherein the first position can be a target position and the second position can be a waste position or vice versa, such that the droplet generating device is controlled to eject out of the orifice free flying droplets repeatedly, wherein the free flying droplet is directed to a first position in case the detected information indicates that the suspension within the observation volumes fulfills a predetermined condition, and directed to a second position if this is not the case (interpreted as a characteristic; ejector; ejecting cells at the end of a channel; controller; and controlling the ejector to eject into waste or well, claim 1) (Abstract; and col 4, lines 6-8 and 16-22). Koltay teaches a preparation measuring channel area to influence and separate the particle by dielectrophoresis, a having at least two sensing areas arranged in series, and a sorting area having electrode devices for sorting particles identified in the measuring channel area (interpreted as a filter per detection device configured to generate an electrical field specific to a detection device, claim 1) (col 2, lines 1-7). Koltay teaches a piezoelectric actuating device (interpreted as a filter per detection device configured to generate an electrical field specific to a detection device, claim 1) (col 13, claim 1, line 64). Koltay teaches that the component comprises a preparation area to specifically influence and separate the particles by means of dielectrophoresis, a measuring channel area having at least two sensing areas arranged in series with respect to the fluid flow direction, and a sorting area having electrode devices for sorting particles identified in the measuring channel area (interpreted as a dielectrophoretic cell ejector; fluidic channel; detectors, electrodes, and sensors are arranged in series, claim 1) (col 2, lines 1-7). Koltay teaches impedance measurements and/or optical analysis are used to measure properties of cells in the microchannel (interpreted as detection devices in sequence, claim 1) (col 2, lines 47-49). Koltay teaches a program product comprising program code executable on a computing device, wherein the program code is effective to derive the information on the cells or particles from an output of a sensor device and to control an apparatus as mentioned above to direct an ejected droplet to the first position or the second position depending on the detected information (interpreted as a controller configured to receive outputs, determine the characteristics of the cells, generate signals, to direct the ejector, a filter device per detection device to generate an electric field, etc.; a sensor; and computer database, claim 1) (col 3, lines 57-63). Koltay teaches that the device is a piezo-driven on-demand droplet generating device configured to eject out of an orifice a free flying droplet of a suspension of cells or particles, the droplet generating device comprising a branch-less one-way channel having the orifice at one end thereof; a device for detecting information on cells or particles located in an observation volume of the suspension within the branch-less one-way channel (interpreted as a piezo-electric cell ejector, claim 1) (col 4, lines 35-42). Koltay teaches a controller 30 is provided to control the operation of the apparatus, and to this end, is connected to the droplet generating device 10, the device 16, 18 for detecting information, and the means 20 for directing, wherein the first position can be a target position and the second position can be a waste position or vice versa (interpreted as a controller, claims 1-3 and 8) (col 6, lines 6-11). Koltay teaches that Figure 1 shows that the measuring device can be implemented by an impedance sensor, such as disclosed in US 2008/0286751, wherein the device for detecting can be implemented by making use of an optical camera (interpreting an impedance sensor and optical camera as a plurality of detection devices; and as a controller coupled to a plurality of detection devices; and configured to receive outputs from sensors including single file transport, impedance, whether a cell is present, elasticity, cell size, conductivity, etc., claims 1-4) (col 6, lines 42-46; and Figure 1), where the device for dispensing droplets comprises channels including a series of electrodes for measuring a physical property of particles or cells in the first channel, matching electrodes being arranged on either side of a channel branch; and where the device for dispensing droplets comprises channels including wherein the electrodes are suitable for measuring optical properties of a fluid flow and/or the impedance of the medium and/or electric parameters of a fluid flow, and/or differential variation of impedance as evidenced by Renaud (interpreted as a plurality of detection devices in sequence; and interpreted as electrodes configured to provided different electric fields, claim 1) (pg. 9, claims 40 and 41). Koltay teaches that any device for detecting or measuring means is applicable that can determine information on cells/particles within the observation volume, such as the status of the cell suspension inside the droplet generator in terms of at least one of number, size, position, type, color, or any other property of the cells/particles inside the observation volume of the droplet generator (interpreted as a controller coupled to a plurality of detection devices; and configured to receive outputs from sensors including single file transport, impedance, whether a cell is present, elasticity, cell size, type of cell, conductivity, etc., claims 1-4) (col 6, lines 47-53). Koltay teaches that Figure 2 shows the fluidic channel 42 comprises a fluid flow focusing section 54 and a single-cell detection section 56 including a device for detecting (not shown in FIG. 2) is configured to detect information on cells, such as the presence of cells, within the single-cell detection section, and to be more specific, within the region of interest 50 (interpreted as single file cell transport; detecting characteristics of the cell; fluidic channel; detectors and sensors, claim 1) (col 7, lines 18-23; and Figure 2). Koltay teaches that dielectrophoresis techniques can be used to make cells or particles flow in a single file, wherein conventional actuators (not shown in Figures 2 and 3) can be arranged at an appropriate position, such as in the droplet generating portion 62, to effect ejection of a free flying drop let out of the orifice 44 upon actuation thereof (interpreting actuators as controllers; constrictions; and verify single file transport of cells, claim 1) (col 8, lines 17-22). Figures 2 and 3 are shown below:
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Koltay teaches a negative pressure gradient between the manifold and ambient causes the droplets to be deflected into the manifold as shown in Figure 5a, such that the droplets containing undesired cells or particles can be directed into the manifold, which can represent a waste position, where once the sensor detects the target cell or particle, the suction mechanism of the manifold 140 is deactivated and the selected cell or particle is ejected to the prescribed position on the target carrier 114 (interpreted as ejecting the cell to a well plate or a waste receptacle, claim 1) (col 10, lines 52-60; and Figure 5a). Figure 5a is shown below:
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Koltay teaches that as long as a desired property of cells or particles is not detected, the shutter 130 is controlled to be in the position shown in Figure 7a, and droplets 52 are ejected to the shutter 130, which can be a waste position, such that upon detection of a desired property, the shutter 130 is moved into the position shown in Figure 7b and a droplet 52 having a cell/particle with the desired property is ejected onto the target carrier 114 (interpreted as ejecting into waste or into a target carrier encompassing a well plate, claim 1) (col 10, lines 33-40; and Figure 7). Koltay teaches a single-cell or particle detection for recognizing or analyzing and/or sorting the target cell or particle can be performed from a continuous cell or particle stream by using optical or impedance sensing means that are located within the region of interest, wherein the sensing element is embedded within the droplet generator using an electrode pair fabricated along the sidewalls or on the channel, a wave-guide apparatus with a photo-detector, or using an externally mounted vision system as a sensing device (interpreted as encompassing detection devices in sequence, claim 1) (col 11, lines 9-18). Koltay teaches that cells/particles of different sizes can be easily sorted by printing them to different locations such as into different wells of a micro-well plate (interpreted as a microwell plate, claim 1) (col 11, lines 43-46). Koltay teaches a non-transitory computer readable medium programmed with a program code executable on a computing device, wherein the program code is effective to derive the information on cells or particles from an output of a sensor device and to control an apparatus for dispensing one or more cells or particles confined in a free flying droplet, to direct an ejected droplet to a first position or a second position depending on the derived information (interpreted as a controller configured to receive outputs, determine the characteristics of the cells, generate signals, etc., claim 1) (col 15, claim 21; and col 16, claim 21). Koltay teaches an amplification system and a computer for analysis of the signals, where the flow cell enabling the liquid stream can use a sheath fluid and carries and aligns the cells so that they pass single file, i.e. one by one, through a light beam for sensing; and the measuring system commonly uses measurement of impedance or conductivity or makes use of optical systems, which can comprise lamps (mercury, xenon), high-power water-cooled lasers (such as argon, krypton or dye lasers), low power air-cooled lasers (e.g., argon lasers at a wavelength of 488 nm, red-HeNe lasers at a wavelength of 633 nm, green-HeNe lasers or HeCd lasers (UV)), diode lasers (blue, green, red, violet) for providing light signals, wherein the detector and analog-to-digital conversion system generates Forward Scatter (FSC), Side Scatter (SSC); as well as, fluorescence signals from light and converts them into electrical signals that can be processed by a computer (interpreting the computer processing as a controller, and comprising a database; and interpreting the light beams, optical systems, various lasers, lamps, and conversion system as signal generators, claims 1 and 8) (col 1, lines 29-45).
Koltay teaches an electrode pair fabricated along the side-walls or on the channel, a wave-guide apparatus with a photo-detector, or an externally mounted vision system as a sensing device (interpreting electrodes, waveguides, detectors, and vision systems as a filter per detection device configured to generate an electrical field specific to a detection device, claim 1) (col 11, lines 13-17).
Regarding claim 2, Koltay teaches a controller 30 is provided to control the operation of the apparatus, and to this end, is connected to the droplet generating device 10, the device 16, 18 for detecting information, and the means 20 for directing, wherein the first position can be a target position and the second position can be a waste position or vice versa (interpreted as a controller, claims 1-3 and 8) (col 6, lines 6-11). Koltay teaches that impedance measurements and/or optical analysis are used to measure properties of cells circulating in the main micro-channel, where cells or particles are identified according to pertinent characteristics, detected electrically and/or optically, in particular by criteria of size, cytoplasmic conductivity and/or membrane capacitance, such that depending on the measurement results, the device can be programmed for parametering an ejection device case by case; and when a particle which verifies specific criteria is detected, a pressure pulse is applied to the second channel and a droplet is ejected via the ejection orifice (interpreted as cell characteristics such as size, conductivity, permittivity, etc.; cell ejector; and at the end of the channel, claim 2) (col 2, lines 48-57). Koltay teaches that optical images obtained by a camera can be evaluated with impedance measurement results to determine the size and shape of the cell, as well as its electrical properties simultaneously (interpreted as characteristics including impedance, claim 2) (col 11, lines 66-67; and col 12, lines 1-3).
Regarding claim 3, Koltay teaches a controller 30 is provided to control the operation of the apparatus, and to this end, is connected to the droplet generating device 10, the device 16, 18 for detecting information, and the means 20 for directing, wherein the first position can be a target position and the second position can be a waste position or vice versa (interpreted as a controller, claims 1-3 and 8) (col 6, lines 6-11). Koltay teaches that a device for detecting or measuring means is applicable that can determine information on cells/particles within the observation volume, such as the status of the cell suspension inside the droplet generator in terms of at least one of number, size, position, type, color, or any other property of the cells/particles inside the observation volume of the droplet generator (interpreted as any characteristic including type of cell, claim 3) (col 6, lines 46-53). Koltay teaches that intrinsic cell or particle properties like chemical content, cell state, cell type, DNA content, etc., or extrinsic characteristics like viability, size, shape, etc., can be deduced from the recorded data acquired (interpreted as size, and cell type, claims 2 and 3) (col 12, lines 48-51). Koltay teaches a program product comprising program code executable on a computing device, wherein the program code is effective to derive the information on the cells or particles from an output of a sensor device and to control an apparatus as mentioned above to direct an ejected droplet to the first position or the second position depending on the detected information (interpreted as a controller configured to receive outputs, determine the characteristics of the cells, generate signals, to direct the ejector, a filter device per detection device to generate an electric field, etc.; a sensor; and computer database, claim 1) (col 3, lines 57-63).
Regarding claims 4-6, Koltay teaches that single-cell or particle detection for recognizing or analyzing and/or sorting the target cell or particle can be performed from a continuous cell or particle stream by using optical or impedance sensing means that are located within the region of interest, wherein the sensing elements can be embedded within the droplet generator using an electrode pair fabricated along the sidewalls or on the channel, a wave-guide apparatus with photo-detector, or using an externally mounted vision systems as a sensing device (interpreted as electrodes to apply an electric field; sensors; configured to measure impedance; within the constriction of detection device; and outside of the constriction of the detection device, claims 1 and 4-6) (col 11, lines 9-18).
Regarding claim 8, Koltay teaches that characteristic property studies can be performed and database records can be kept (interpreted as a database) (col 12, lines 46-47). Koltay teaches that the database can include the position of deposited cells together with a related properties profile, such that this database can be used to trace the temporal condition of an individual deposited cell or particle especially during post-harvesting analysis (interpreted as mapping, claim 8) (col 13, lines 6-10).
Koltay does not specifically exemplify a constrictions of each of the detection devices varies in shape (claim 7, in part).
Regarding claim 7, Sharei teaches a microfluidic system for causing perturbations in a cell membrane, the system including a microfluidic channel defining a lumen and being configured such that a cell suspended in a buffer can pass therethrough, wherein the microfluidic channel includes a cell-deforming constriction, wherein a diameter of the constriction is a function of the diameter of the cell (interpreted as multiple constrictions, claims 1 and 7) (Abstract). Sharei teaches passing the solution includes passing the solution through the plurality of microfluidic channels arranged in one series and parallel (interpreted as a plurality of detection devices in sequence, claim 1) (col 5, lines 11-14). Sharei teaches that Figure 1A shows a microfluidic system wherein cells are exposed to the delivery material (payload) after passing through the constriction; and Figure 1B shows cells exposed to the delivery material (payload) passing through-out the process by suspending the cells in a solution that includes the delivery material (payload), wherein cells are exposed to the delivery material before and after passing through the constriction (col 9, lines 48-46; and Figures 1a and 1b). Figures 1A and 1B are shown below:
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Sharei teaches that Figures 5 and 6 are photographs of a microfluidic system (col 9, lines 54-55; and Figures 5 & 6). Figures 5 and 6 are shown below:
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Sharei teaches that the configuration of the constriction 15 can be customized to control the constriction of the cell 20, thereby controlling the pressure applied to the cell 20; and the diameters of the constrictions 15 can be varied to adjust the pressure applied to the cells and how quickly that pressure is applied/released, such that the length of the constriction 15 can also be varied to adjust the amount of pressure applied to the cell (interpreted as varying the constriction shape, size and length; and a filter device to generate different electric fields, claims 1 and 7) (col 12, lines 23-31; Figures 1-3). Sharei teaches that multiple constrictions can be placed in parallel and/or series, wherein the perturbation in the cell is a breach in the cell that allows material from outside the cell to move into the cells, such as a hole, tear, cavity, aperture, pore, break, gap and/or perforation (interpreted as constrictions in series or parallel; and a plurality of detection devices; and a plurality of sensors, claims 1 and 4-7) (col 11, lines 60-64). Sharei teaches that the invention is based on the surprising discovery that a controlled injury, such as subjecting a cell to a constriction, rapid stretching, rapid compression, or pulse of high shear rate, leads to uptake of molecules into the cytoplasm of the cell from the surrounding cell medium, such that the invention features a vector-free microfluidic platform for direct-to-cytosol intracellular delivery of materials, wherein a compound or composition, to a eukaryotic cell, wherein the device is useful to deliver desired molecules into target cells while preserving the viability of the cells (col 1, lines 46-56; and col 2, lines 7-10). Sharei teaches that the diameter of the constriction is substantially 20 to 99% of the diameter of the cell passing therethrough, wherein a cross-section of the channel is selected from the group consisting of circular, elliptical, an elongated slit, square, hexagonal, and triangular (interpreted as a constriction can comprise a variety of shapes and sizes, claim 7) (col 4, lines 21-26). Sharei teaches that the device and methods are amenable to any cell type, the size of the constricted portion is tailored to the cell to be treated (interpreted as a constriction can comprise a variety of shapes and sizes, claim 7) (col 5, lines 38-40). Sharei teaches that the system 5 can operate using electrical and/or optical sensors can be used to measure cell properties such as fluorescence (interpreted as a plurality of detection devices in sequence, claims 1 and 4-7) (col 14, lines 48-53). Sharei teaches that Figure 6 shows a photograph of a parallel configuration of the system 5 that includes filters at the inlet of each of the channels 10 (interpreted as a filter device per detection device, claim 1) (col 15, lines 5-7; and Figure 6).
Sharei teaches that other configurations of the system 5 can also include sorters including pretreatment/post treatment modules, and/or sensor modules (e.g., optical, electrical, and magnetic) (interpreted as ejecting; a plurality of sensors within and outside of the constriction; signal generators; and filter devices per detection device, claims 1 and 4-6) (col 15, lines 14-16). Sharei teaches that Figure 12 is a schematic diagram of the microfluidic system; and Figure 13 shows that the operating pressure is varied by varying the length and/or the width of the constriction 15 (interpreted as varying the size of the constrictions, claim 7) (col 9, line 65; col 16, lines 45-47; and Figures 12 and 13). Figures 12 and 13 are shown below:
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Sharei teaches that the system can be implemented in series with a Fluorescence Activated Cell Sorting (FACS) module to enable the delivery and sorting of the desired cells on the same system in real-time, wherein various pretreatment and post-sort assaying techniques can also be deployed, thus enabling the development of continuous, high-throughput assays for drug screening and diagnostics (interpreting FACS sorting as ejecting, claim 1) (col 18, lines 2-10). Sharei teaches that the various implementations can provide one or more clinical and research capabilities including the quantitative delivery of drugs to cell models for improved screening and dosage studies (col 6, lines 40-41). Sharei teaches that Figure 38 shows a device modified by incorporated electrodes on either side of the constriction by photolithographic patterning and Au deposition to introduce a localized electrical field into the channel thereby combining cell deformation with electroporation, wherein capacitance across the constriction is measured and correlated to cell transit time (e.g., its deformation rate) (interpreted as electrodes/sensors in the channel/outside the channel, claims 4-6) (col 11, lines 3-8; col 44, lines 16-21; and Figure 38). Sharei teaches that cells were analyzed on an LSR Fortessa (BD Biosciences) or FACS Canto (BD Biosciences) equipped with a high throughput sampling robot, wherein the 405 nm and 488 nm lasers were used for the excitation of the desired fluorophores, such as propidium iodide (live/dead stain), fluorescein and pacific blue signals were detected using 695 nm long pass, 530/30 and 450/50 filters respectively, such that data analysis was conducted using FACS Diva (BD Biosciences) and FlowJo software (interpreted as devices; interpreting fluorophores and lasers as signal generators; 530/30 and 450/50 filters as filter devices that generate electric fields that are different; and computers including databases, claim 1) (col 32, lines 21-31). Sharei teaches that Figure 42 illustrates several example fields of application such as regenerative medicine, immunology, imaging and sensing, cancer vaccines and cancer research (col 11, lines 21-24; and Figure 42). Figures 38 and 42 (in part) are shown below:
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Sharei teaches that Figure 38 illustrates alternate device structures including a bright field micrograph combining a constriction and electrodes, wherein electrodes can be incorporated near the constriction, which can couple deformation and electroporation to enable delivery effects to yield enhanced system performance, wherein electrodes can be placed on either side of a constriction and the change in capacitance between the two electrodes is measured as the cell passes through (interpreting electrodes as filter devices that generate an electrical field, claim 1) (col 43, lines 56-60; col 54, lines 16-21; col 55, lines 35-38; and Figure 38).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of a microfluidic system that causes a cell to uptake molecules into the cytoplasm as exemplified by Sharei,
it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods and devices for detecting information on cells/particles by passing the cells/particles through a microfluidic channel, and influencing and/or analyzing a stream of single cells using dielectrophoresis techniques as disclosed by Koltay to include the microfluidic system for deforming cells using one or more channels including a series of constrictions of varied sizes and/or lengths as taught by Sharei with a reasonable expectation of success detecting the properties of particular cells and/or particular cell types; in enhancing uptake of molecules into the cell cytoplasm for the quantitative delivery of drugs to cell models for improved screening and dosage studies; and/or in sorting and/or ejecting the cells having specific desired properties and/or that fulfil predetermined conditions such as optical properties and/or impedance properties into a target position such as a well-plate for further analysis and/or downstream applications.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Response to Remarks
Applicant’s remarks filed February 2, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Koltay does not teach the amended structural components including a signal generator and filter devices per detection device-that enable the different electric fields to be applied at each detection device; and Koltay’s sensing areas are not sequential detection devices (Applicant Remarks, pg. 12, last partial paragraph; and pg. 13, first partial paragraph); (b) the claims are fundamentally different. As described in the specification, "each detection device (104) may apply different electrical fields such that the cell preparation system (100) is not just replicating a detection, but is detecting based on different parameters, where the same cell is subjected to different electric fields at sequential detection devices to determine different characteristics (such as elasticity, conductivity, and permittivity), is not taught by Koltay (Applicant Remarks, pg. 13, first full paragraph); and (c) Sharie’s constrictions are designed to cause controlled injury to cells for molecule uptake, not for cell characterization with different electric fields. Moreover, Sharei teaches that "the system operates as a purely mechanical system without applying any electrical fields." Sharei, paragraph [0108]; and because the references address fundamentally different problems and lacks motivation to combine because Koltay addresses dispensing cells in droplets with detection near an orifice, while Sharei addresses intracellular delivery (Applicant Remarks, pg. 14, first and second full paragraphs).
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As noted in MPEP 2112.01(I),
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that Koltay does not teach the amended structural components including a signal generator and filter devices per detection device-that enable the different electric fields to be applied at each detection device; and Koltay’s sensing areas are not sequential detection devices, is not found persuasive. As an initial matter, the components of the system in claim 1 are very broadly recited (e.g., a signal generator, a filter device, etc.); and instant claim 1 does not recite how each of the components is related one to the other. The Examiner contends that the combined references of Koltay and Sharei teach all of the limitations of the claims. To that end –
Koltay teaches:
A light beam for sensing; and a measuring system that commonly uses measurement of impedance or conductivity or makes use of optical systems, which can comprise:
lamps (mercury, xenon),
high-power water-cooled lasers,
low power air-cooled lasers (e.g., argon lasers at a wavelength of 488 nm, red-HeNe lasers at a wavelength of 633 nm, green-HeNe lasers or HeCd lasers (UV)), diode lasers for providing light signals, wherein
the detector and analog-to-digital conversion system generates Forward Scatter (FSC), Side Scatter (SSC); as well as,
fluorescence signals from light and converts them into electrical signals that can be processed by a computer
(interpreting the light beams, optical systems, various lasers, lamps, and conversion system as signal generators, claim 1) (col 1, lines 29-45).
A preparation measuring channel area to influence and separate the particle by dielectrophoresis, a having at least two sensing areas arranged in series, and a sorting area having electrode devices for sorting particles identified in the measuring channel area (interpreted as a filter per detection device configured to generate an electrical field specific to a detection device; and interpreting devices arranged in series as sequential sensing devices, claim 1) (col 2, lines 1-7).
A piezoelectric actuating device (interpreted as a filter per detection device configured to generate an electrical field specific to a detection device, claim 1) (col 13, claim 1, line 64).
An electrode pair fabricated along the side-walls or on the channel, a wave-guide apparatus with a photo-detector, or an externally mounted vision system as a sensing device (interpreting electrodes, waveguides, photo-detectors, and vision systems as a filter per detection device configured to generate an different electrical fields specific to a detection device, claim 1) (col 11, lines 13-17).
Sharei teaches:
Configurations of the system 5 can include sorters including pretreatment/post treatment modules, and/or sensor modules including optical, electrical, and magnetic sensor modules (interpreting the sensor modules as signal generators, and as filter devices per detection device, claim 1) (col 15, lines 14-16).
Electrodes can be incorporated near the constriction, which can couple deformation and electroporation (interpreting electrodes as filter devices that generate an electrical field, claim 1) (col 43, lines 56-60).
Electrodes can be placed on either side of a constriction and the change in capacitance between the two electrodes is measured as the cell passes through (interpreting electrodes as filter devices that generate an electrical field, claim 1) (col 54, lines 16-21).
Regarding detection devices in sequence:
Multiple constrictions can be placed in parallel and/or in series (interpreted as sequential detection devices, claim 1).
One or more microfluidic channels arranged in series with one another (interpreted as sequential detection devices, claim 1) (col 19, lines 7-10).
The system can be implemented in series with a FACS module (interpreted as sequential detection devices, claim 1) (col 11, lines 60-62; and col 18, lines 2-4).
The combined references of Koltay and Sharei teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (b), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments; the broadly recited components of claim 1; and that there is no recitation indicating the positioning of the components relative one to another. MPEP 2112.01(II) indicates:
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty") (underline added).
Applicant’s assertion that Koltay does not teach detecting based on different parameters, where the same cell is subjected to different electric fields at sequential detection devices to determine different characteristics (such as elasticity, conductivity, and permittivity), is not found persuasive. It is noted that:
As previously indicated, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims.
The instant rejection is based on the combined references of Koltay and Sharei, and not based simply on the teachings of Koltay alone.
The claims are directed to a product; and not to a method of using the product.
Instant claim 1 does not recite that the system comprises cells, cells traveling through channels, cells passing through constrictions, applying different electric fields, signals being generated, sensor outputs, and/or a multi-characterization approach, where the same cell is subjected to different electric fields to determine different characteristics. There are no cells.
As noted supra, products of identical chemical composition cannot have mutually exclusive properties. Thus, the question becomes, what is inventive and/or novel about the cell preparation system described in the instant application. The combined references of Koltay and Sharei teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (c), regarding the teachings of Sharei and Applicant’s assertion of there being a lack of motivation to combine Koltay and Sharei, MPEP 2144(I) indicates:
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning) (underline added).
MPEP 2123(I) states:
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. See In re Heck, 699 F.2d 1331, 1332-33,216 USPQ 1038, 1039 (Fed. Cir. 1983); In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275,277 (CCPA 1968); Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); and Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (underline added).
Moreover, the Applicants are reminded that the motivation for combining the teachings of the prior art may be different from applicants’ motivation to make the disclosed compositions. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As an initial matter, it is noted that Sharei is directed to the limitations as recited in dependent claim 7. Additionally, Applicant’s specific argument is unclear. Applicant relies on paragraphs [0011] and [0108] of Sharei to argue that the references lack motivation to combine. Both Koltay and Sharei are issued US Patents, such that any citation to a teaching of Sharei should include a column number. However, Applicant’s response refers to specific paragraphs of Sharei. Thus, it is completely unclear what reference Applicant is using to support this argument. (See also, the Examiner’s response to Applicant’s argument in the Office Action mailed January 6, 2026)
Applicant’s specific argument is unclear to the Examiner. In response to what may be an argument that the cited prior art are all non-analogous art, MPEP 2141.01(a)(I) indicates a reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212. In the instant case, the references are from the same field of endeavor as the claimed invention (even if it addresses a different problem); and the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). The instant invention is directed to a cell preparation system comprising a waste receptacle, a well plate, a fluidic channel, an ejector, a plurality of detection devices, channels comprising a constriction, a pair of electrodes, a sensor, a signal generator, a filter device, and a controller. Koltay is directed to an apparatus comprising flow channels that can be used for dispensing one or more cells, detecting information on the cells located in an observation volume within a channel of the device, and directing a droplet to a first position or to a second position depending on the detected information. Sharei is directed to microfluidic systems for the perturbation of cells using mechanical deformation of the cells as they pass through a constriction; and measure changes that occur between electrode pairs including such characteristics as changes in cell size, shape, capacitance, viability, integrity, etc. Clearly, there is motivation to combine the cited references. Thus, the claims remain rejected.
New Objections/Rejections
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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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.
(2) Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (hereinafter “Cho”) (US Patent No. 10816550, issued October 27, 2020; previously published as WO2014062719, published April 24, 2014) in view of Sharei et al. (hereinafter “Sharei”) (US Patent No. 1069644, issued June 30, 2020; WO2013059343, filed October 17, 2012; of record).
Regarding claim 1, Cho teaches a cell detection systems, fluidic devices, structures and techniques related to particle, cell sorting, and detection in fluid, for example sorting specific subpopulations of cell types; as well as, a method of sorting particles including receiving a first detection signal that is associated with optical characteristics of a particle in the first channel; and a sorting channel of a plurality of second channels is determined based on the first detection signal, thereby determining the sorting of the particle into the sorting channel based on the optical characteristics of the particle, wherein a sorting signal for sorting the particle from the first channel into the sorting channel is transmitted; and a second detection signal is received that is associated with the presence of the particle in the sorting channel, such that the sorting of the particle from the first channel into the sorting channel is verified based on the second detection signal (interpreting sorting channels as an ejector; and a signal to eject a cell into a well plate or a waste receptacle, claim 1) (Abstract). Cho teaches in Figures 29A-29C illustrates the operation of the particle sorter of Figure 14, wherein Figure 29A illustrates a particle traveling directly from the main/source channel to the waste collection channel because the piezoelectric membrane does not move; Figure 29B illustrates a particle being sorted out to the sorting channel on the right when the piezoelectric membrane is deflected upward on receiving a sorting triggering signal; and Figure 29C illustrates a particle being sorted out to the sorting channel on the left when the piezoelectric membrane is deflected downward on receiving a sorting triggering signal (interpreted as comprising a waste receptacle; fluidic channels to transport cells; and a particle sorter as an ejector, claim 1) (col 7, lines 4-14; and Figure 29). Figures 29A-29C are shown below:
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Cho teaches in Figure 72A-72B illustrate modifications to a sorting channel (interpreted to show single file flow of cells, claim 1) (col 9, lines 51-53; and Figure 72A). Figure 72A is shown below:
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Cho teaches that a non-limiting example of a color filter that includes substantially discrete zones is illustrated in Figure 49A which illustrates signal intensity from discrete (e.g., bandpass) filers (interpreting bandpass filters as a filter device configured to generate an electrical signal, claim 1) (col 20, lines 24-26). Cho teaches that the zone widths can be regular or can vary, such that in color filter embodiments that include varying zone widths, the widths can be distributed in any suitable pattern, non-limiting examples of such patterns including periodic, chirp and pseudo-random patterns, wherein substantially opaque zones can be distributed in a pattern of varying width, and zones that transmit light can be distributed in a pattern of regular width (interpreted as varying channel width/constrictions, claim 1) (col 21, lines 25-29). Cho teaches that to further increase the throughput, it is further proposed to implement an integrated lens approach, a lens array creates a series of focal spots that are separated by less than 5 microns from each other, thus reducing the total width of the interrogation zone to be around 25 microns, wherein the design can potentially increase the throughput to 20-30K/s or about 100M particles per hour (interpreted as a interrogation of cells at a constriction in the channel, claim 1) (col 36, lines 7-16). Cho teaches a diaphragm can be in direct communication with the sorting volume, or with a deformable wall (not shown) of the source channel 5004 adjacent the sorting volume, such that during operation, the diaphragm 5006 can be rapidly filled/emptied, based on the sorting signal, to create lateral forces in the sorting volume that can push/pull the particle for sorting into a specific one of the destination channels 5010A-5010C (interpreted as constricting the channel using a diaphragm, claim 1) (col 58, lines 6-13). Cho teaches a first detection device 5012 can not only include detection components, but also additional components as necessary and/or desired for detection of the characteristics including fluorescence, wherein the first detection device 5012 can encompass excitation sources, coupling (e.g. optical fibers) and other (e.g. filters) optics, control electronics, and/or the like, such that if the characteristics include impedance as described above, the first detection device 5012 can encompass a pair of electrodes for generating an electrical signal that measures impedance within the first channel (interpreted as including a plurality of detection devices; impedance; controller; filters; signal generators; and comprising electrodes, claim 1) (col 54, lines 53-64). Cho teaches that a second detection device 5014 can be configured in a manner similar to or different than the first detection device 5012, wherein the second detection device 5014 is configured to at least detect the presence and/or volume of the particle in the destination channel 5010A, and to generate a second detection signal associated therewith, such that while the second detection signal can be of any suitable form (e.g. particle fluorescence, impedance, etc.) (interpreted as a plurality of detection devices that generate electrical signals different from the electric field of each other detection device; and configured to detect a cell, claim 1) (col 58, lines 28-35). Cho teaches that the first detection device 5012 detects a first detection signal that is associated with one or more characteristics, such as an optical characteristics of a particle in the source channel 5002, wherein the optical characteristic is selected from: fluorescence, phosphorescence, chemiluminescence, thermo-luminescence, reflectance, scattering (including forward scattering, large angle scattering, side scattering, and/or back scattering), and/or the like including one or more fluorescence signals as the first from the particles as they pass through the first volume of the source channel 5004 (interpreted as signal generators, claim 1) (col 55, lines 12-27). Cho teaches that Figure 17 shows multiple parameter detection is achieved by applying COlor-Space-Time (COST) coding technology, which allows for detection of 12 or more different fluorescent wavelengths of light emanating from the microfluidic detector 1710 can support the detection of multiple (e.g., 20 or more) fluorescent wavelengths of light emanating from a microfluidic detector using a single detector (interpreted as a plurality of devices; and sensors, claim 1) (col 29, lines 61-67; and col 30, lines 1-4). Cho teaches that a particle 1898 such as a cell in the sample fluid flowing through the sensing region 1840 emits light that sequentially passes through the optical apertures along the input fluidic channel at different positions at different times, such that he light received by the waveguides 1852, 1854, 1856 and 1858 can be collected by an optical detector (e.g., a PMT, such as the optical detector 1714), wherein the waveguide 1852 can conduct light of all wavelengths emitted by the particles 1898; and waveguides 1854, 1856 and 1858 are optical filter waveguides with optical transmission bands that are respectively centered at different center transmission frequencies, such that the waveguides 1854, 1856 and 1858 can produce different filtered optical transmission signals with different optical spectral bands centered at the different center transmission frequencies (interpreted as a plurality of devices in sequence (sequential); interpreting filters and waveguides as filters devices per detection device; and sensors, claim 1) (col 30, lines 26-40; and Figure 18). Figure 18 is shown below:
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Cho teaches that the system also includes a controller configured to process the signal generated by the detector and control actuation of the piezoelectric membrane (interpreted as comprising a controller coupled to the detection devices configured to receive outputs, claim 1) (col 2, lines 58-61). Cho teaches in Figure 27 illustrates that the controller is responsible for real-time gating/decision and PZT control, wherein piezoelectric actuator 2818 operates to cause a flow disturbance to fluid in the actuation area 2811 in response to a control signal such as a voltage control signal from a controller or driver as illustrated (interpreted as configured to determine whether cells are single file; and activating the ejector, claim 1) (col 38, lines 64-67; and Figure 27). Cho teaches the analysis of cells including CTC cells regarding the nature of metastatic disease, diagnosis, prognosis of a neoplasm, progression of treatment, and development of personalized cancer therapy (col 12, lines 1-10). Cho teaches that the system can improve detection and downstream molecular analysis and sequencing of single cancer cells, as well as, personalized diagnosis and treatment, and improved electronics and detection speeds all embedded on disposable and manufacturable chips (col 72, lines 39-41).
Regarding claim 2, Cho teaches that the first detection device 5012 detects a first detection signal that is associated with one or more characteristics, such as an optical characteristics of a particle in the source channel 5002, wherein the optical characteristic is selected from: fluorescence, phosphorescence, chemiluminescence, thermoluminescence, reflectance, scattering (including forward scattering, large angle scattering, side scattering, and/or back scattering), and/or the like including one or more fluorescence signals as the first from the particles as they pass through the first volume of the source channel 5004 (interpreted as configured to determine impedance, elasticity, conductivity, etc., claims 1 and 2) (col 55, lines 12-27). Cho teaches that a second detection device 5014 can be configured in a manner similar to or different than the first detection device 5012, wherein the second detection device 5014 is configured to at least detect the presence and/or volume of the particle in the destination channel 5010A, and to generate a second detection signal associated therewith, such that while the second detection signal can be of any suitable form (e.g. particle fluorescence, impedance, etc.) (interpreted as a plurality of detection devices that generate electrical signals different from the electric field of each other detection device; and configured to detect a cell, claim 1) (col 58, lines 28-35). Cho teaches that the second detection device is associated with one or more of fluorescence, reflectance, impedance, and/or the like, as discussed in detail earlier, such that the second detection signal permits at least an impedance measurement, and Figure 51B illustrates an exemplary impedance measurement 5104 of the second volume when the particle passes through it, wherein the measurement can be characterized by the 'width' of the disturbance (1 millisecond in this case) (col 58, lines 38-47).
Regarding claim 3, Cho teaches that a light emitting sample ( e.g., a particle or a cell) can transiently occupy positions A, B, C and D as it passes through the fluidic channel (e.g., a microfluidic channel) thereby generating multiple signals per sample, wherein the waveform of these signals is determined by the transmission spectra of the optical filters and the characteristics of the sample, such that the combined optical signals of a sample can be digitally processed to determine the type of the particle and whether to sort the particle into a separate channel in a fluorescence-activated cell sorter system (interpreted as determining a type of cell based on a different characteristic, claim 3) (col 44, lines 20-29). Cho teaches that a visualization tool allows a user to analyze detection data and identify particular particles or types of particles flowing through the device (e.g., 4811) (interpreted as determining a type of cell based on a different characteristic, claim 3) (col 49, lines 14-17).
Regarding claim 4, Cho teaches that the sorted particle 7210 can generate an impedance signal upon detection by a sensor 7214C, as disclosed in the embodiment of Figure 50 as element 5014C (interpreting the sensor to be an impedance sensor, claim 4) (col 78, lines 43-45). Cho teaches that the second detection device is associated with one or more of fluorescence, reflectance, impedance, and/or the like, as discussed in detail earlier, such that the second detection signal permits at least an impedance measurement, and Figure 51B illustrates an exemplary impedance measurement 5104 of the second volume when the particle passes through it, wherein the measurement can be characterized by the 'width' of the disturbance (1 millisecond in this case) (interpreted as an impedance sensor, claim 4) (col 58, lines 38-47).
Regarding claim 5, Cho teaches that the sorter 6200 also includes, as the first detection device an impedance measuring apparatus 6202 that includes electrodes 6202A, 6202B defining a second detection volume 6206 in the channel 6210 (interpreting the electrodes to be sensors within the constriction area, claim 5) (col 63, lines 11-13). Figure 62A is shown below:
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Regarding claim 6, Cho teaches electrodes formed on the bottom substrate across the downstream sorting channels from the sorting junction are designed to produce electrical signals detecting impedance change at the region when a cell, bead, or particle passes by, thus confirming/verifying a successful sorting event (interpreted as electrodes disposed outside of the constriction, claim 6) (col 66, lines 39-44). Cho also teaches in Figure 63A, electrodes 6302A and 6302B are outside of the channel constriction, claim 6) (Figure 63A). Figure 63A is shown below:
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Regarding claim 7 (in part), Cho teaches that the zone widths can be regular or can vary, such that in color filter embodiments that include varying zone widths, the widths can be distributed in any suitable pattern, non-limiting examples of such patterns including periodic, chirp and pseudo-random patterns, wherein substantially opaque zones can be distributed in a pattern of varying width, and zones that transmit light can be distributed in a pattern of regular width (interpreted as varying channel width/constrictions; and wherein constriction shapes can vary, claim 7) (col 21, lines 25-29). Cho teaches that to further increase the throughput, it is further proposed to implement an integrated lens approach, a lens array creates a series of focal spots that are separated by less than 5 microns from each other, thus reducing the total width of the interrogation zone to be around 25 microns, wherein the design can potentially increase the throughput to 20-30K/s or about 100M particles per hour (interpreted as a interrogation of cells at a constriction in the channel; and wherein constriction shapes can vary, claim 7) (col 36, lines 7-16). Cho teaches a diaphragm can be in direct communication with the sorting volume, or with a deformable wall (not shown) of the source channel 5004 adjacent the sorting volume, such that during operation, the diaphragm 5006 can be rapidly filled/emptied, based on the sorting signal, to create lateral forces in the sorting volume that can push/pull the particle for sorting into a specific one of the destination channels 5010A-5010C (interpreted as constricting the channel using a diaphragm, claim 1) (col 58, lines 6-13).
Regarding claim 8, Cho teaches that the PMT 1714 upon sensing of the light in turn output signals indicative of the sensed light to National Instruments Lab View-based software 1716 (available from National Instruments Corp. of Austin, Tex.), which in turn provides data to personal computer 1718 (notwithstanding the representation provided in Figure 14, the software 1716 can be considered implemented on the personal computer) (interpreted as comprising a database; and referencing a database, claim 8) (col 29, lines 53-60). Cho teaches that the processor and driver 3450 can be in communication with a computer 3448 for receiving user input, such that it generates a presence signal indicative of the presence of a particle of interest passing a predetermined location in the input channel, and generates the control signal for the piezoelectric actuator 3418 in response to the presence signal (interpreted as comprising a database, claim 8) (col 40, lines 17-23).
Cho does not specifically exemplify a plurality of constrictions (claim 7, in part).
Regarding claim 7 (in part), Regarding claim 7, Sharei teaches a microfluidic system for causing perturbations in a cell membrane, the system including a microfluidic channel defining a lumen and being configured such that a cell suspended in a buffer can pass therethrough, wherein the microfluidic channel includes a cell-deforming constriction, wherein a diameter of the constriction is a function of the diameter of the cell (interpreted as multiple constrictions, claims 1 and 7) (Abstract). Sharei teaches the size/diameter of the constricted portion for processing of a human egg is between 6.2 μm and 8.4 μm, although larger and smaller constrictions are possible (diameter of a human ovum is approximately 12 μm) (interpreted as constrictions of different shapes, claim 7) (col 2, lines 49-50).
Sharei teaches passing the solution includes passing the solution through the plurality of microfluidic channels arranged in one series and parallel (interpreted as a plurality of detection devices in sequence, claim 1) (col 5, lines 11-14). Sharei teaches that Figure 1A shows a microfluidic system wherein cells are exposed to the delivery material (payload) after passing through the constriction; and Figure 1B shows cells exposed to the delivery material (payload) passing through-out the process by suspending the cells in a solution that includes the delivery material (payload), wherein cells are exposed to the delivery material before and after passing through the constriction (col 9, lines 48-46; and Figures 1a and 1b). Figures 1A and 1B are shown below:
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Sharei teaches that Figures 5 and 6 are photographs of a microfluidic system (col 9, lines 54-55; and Figures 5 & 6). Figures 5 and 6 are shown below:
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Sharei teaches that the configuration of the constriction 15 can be customized to control the constriction of the cell 20, thereby controlling the pressure applied to the cell 20; and the diameters of the constrictions 15 can be varied to adjust the pressure applied to the cells and how quickly that pressure is applied/released, such that the length of the constriction 15 can also be varied to adjust the amount of pressure applied to the cell (interpreted as varying the constriction shape, size and length; and a filter device to generate different electric fields, claims 1 and 7) (col 12, lines 23-31; Figures 1-3). Sharei teaches that multiple constrictions can be placed in parallel and/or series, wherein the perturbation in the cell is a breach in the cell that allows material from outside the cell to move into the cells, such as a hole, tear, cavity, aperture, pore, break, gap and/or perforation (interpreted as a plurality of constrictions in series or parallel; and a plurality of detection devices; and a plurality of sensors, claims 1 and 4-7) (col 11, lines 60-64). Sharei teaches that the invention is based on the surprising discovery that a controlled injury, such as subjecting a cell to a constriction, rapid stretching, rapid compression, or pulse of high shear rate, leads to uptake of molecules into the cytoplasm of the cell from the surrounding cell medium, such that the invention features a vector-free microfluidic platform for direct-to-cytosol intracellular delivery of materials, wherein a compound or composition, to a eukaryotic cell, wherein the device is useful to deliver desired molecules into target cells while preserving the viability of the cells (col 1, lines 46-56; and col 2, lines 7-10). Sharei teaches that the diameter of the constriction is substantially 20 to 99% of the diameter of the cell passing therethrough, wherein a cross-section of the channel is selected from the group consisting of circular, elliptical, an elongated slit, square, hexagonal, and triangular (interpreted as a constriction can comprise a variety of shapes and sizes, claim 7) (col 4, lines 21-26). Sharei teaches that the device and methods are amenable to any cell type, the size of the constricted portion is tailored to the cell to be treated (interpreted as a constriction can comprise a variety of shapes and sizes, claim 7) (col 5, lines 38-40). Sharei teaches that the system 5 can operate using electrical and/or optical sensors can be used to measure cell properties such as fluorescence (interpreted as a plurality of detection devices in sequence, claims 1 and 4-7) (col 14, lines 48-53). Sharei teaches that Figure 6 shows a photograph of a parallel configuration of the system 5 that includes filters at the inlet of each of the channels 10 (interpreted as a filter device per detection device, claim 1) (col 15, lines 5-7; and Figure 6).
Sharei teaches that other configurations of the system 5 can also include sorters including pretreatment/post treatment modules, and/or sensor modules (e.g., optical, electrical, and magnetic) (interpreted as ejecting; a plurality of sensors within and outside of the constriction; signal generators; and filter devices per detection device, claims 1 and 4-6) (col 15, lines 14-16). Sharei teaches that Figure 12 is a schematic diagram of the microfluidic system; and Figure 13 shows that the operating pressure is varied by varying the length and/or the width of the constriction 15 (interpreted as varying the size of the constrictions, claim 7) (col 9, line 65; col 16, lines 45-47; and Figures 12 and 13). Figures 12 and 13 are shown below:
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Sharei teaches that the system can be implemented in series with a Fluorescence Activated Cell Sorting (FACS) module to enable the delivery and sorting of the desired cells on the same system in real-time, wherein various pretreatment and post-sort assaying techniques can also be deployed, thus enabling the development of continuous, high-throughput assays for drug screening and diagnostics (interpreting FACS sorting as ejecting, claim 1) (col 18, lines 2-10). Sharei teaches that the various implementations can provide one or more clinical and research capabilities including the quantitative delivery of drugs to cell models for improved screening and dosage studies (col 6, lines 40-41). Sharei teaches that Figure 38 shows a device modified by incorporated electrodes on either side of the constriction by photolithographic patterning and Au deposition to introduce a localized electrical field into the channel thereby combining cell deformation with electroporation, wherein capacitance across the constriction is measured and correlated to cell transit time (e.g., its deformation rate) (interpreted as electrodes/sensors in the channel/outside the channel, claims 4-6) (col 11, lines 3-8; col 44, lines 16-21; and Figure 38). Sharei teaches that cells were analyzed on an LSR Fortessa (BD Biosciences) or FACS Canto (BD Biosciences) equipped with a high throughput sampling robot, wherein the 405 nm and 488 nm lasers were used for the excitation of the desired fluorophores, such as propidium iodide (live/dead stain), fluorescein and pacific blue signals were detected using 695 nm long pass, 530/30 and 450/50 filters respectively, such that data analysis was conducted using FACS Diva (BD Biosciences) and FlowJo software (interpreted as devices; interpreting fluorophores and lasers as signal generators; 530/30 and 450/50 filters as filter devices that generate electric fields that are different; and computers including databases, claim 1) (col 32, lines 21-31). Sharei teaches that Figure 42 illustrates several example fields of application such as regenerative medicine, immunology, imaging and sensing, cancer vaccines and cancer research (col 11, lines 21-24; and Figure 42). Figures 38 and 42 (in part) are shown below:
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Sharei teaches that Figure 38 illustrates alternate device structures including a bright field micrograph combining a constriction and electrodes, wherein electrodes can be incorporated near the constriction, which can couple deformation and electroporation to enable delivery effects to yield enhanced system performance, wherein electrodes can be placed on either side of a constriction and the change in capacitance between the two electrodes is measured as the cell passes through (interpreting electrodes as filter devices that generate an electrical field, claim 1) (col 43, lines 56-60; col 54, lines 16-21; col 55, lines 35-38; and Figure 38).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of using a microfluidic system to subject cells to mechanical deformation as exemplified by Sharei, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system, methods, and fluidic devices including detectors, filters, channels, FACS, processors, etc. for differentiating different cell types in a sample by their physical and/or biological properties as disclosed by Cho, to include the microfluidic system comprising one or more channels comprising a series of constrictions that can vary in number, size and/or shape as taught by Sharei with a reasonable expectation of success in integrating microfluidics and optics on the same device to enhance system functionality and sensitivity, while reducing costs; in identifying and sorting cells that comprise specific biological and/or physical characteristics, wherein these selected cells can undergo controlled injury to produce intracellular delivery vehicles; and/or for the quantitative delivery of drug therapies to a patient including the delivery of personalized cancer therapies.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Conclusion
Claims 1-8 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684