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 .
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/ US18/22888 filed on 03/16/2018, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/596,630 filed on 12/08/2017, 62/570,380 filed on 10/10/2017 and 62/472,437 filed on 03/16/2017.
Status of the claims
Claims 1, 4-5, 9, 16-20, 38-39, and 42 are pending. Claims 19-20, 38-39, and 42 are withdrawn. Claims 2-3, 6-8, 10-15, 21-37, and 40-41 are cancelled. Claims 1, 4-5, 9, and 16-18 are examined below.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Viovy et al., US9939439B2 (09/06/2013; see PTO-892, 10/17/2025), in view of Alapan et al. Dynamic deformability of sickle red blood cells in microphysiological flow. Technology. 2016 Jun 19;4(02):71-9 (see PTO-892, 10/17/2025) and Zhang et al. Neurite outgrowth on well-characterized surfaces: preparation and characterization of chemically and spatially controlled fibronectin and RGD substrates with good bioactivity. Biomaterials. 2005 Jan 1;26(1):47-61 (see PTO-892, 05/16/2024).
Regarding claims 1, 9 and 16, Viovy teaches a microfluidic system comprising at least one channel for the flow of fluid having an inlet, an outlet and a longitudinal axis extending between the inlet and the outlet, said channel comprising a capture zone, and the cross section of the channel orthogonal to the longitudinal axis of the channel increasing in size in the capture zone (variable width microchannel having divergent cross-sectional area along the direction of flow; Viovy, column 3, lines 24-29). Viovy further teaches that the channels means microstructures suitable for the circulation/flow of fluids (constant continuous flow) and that they are usually closed over the whole of the travel of the fluids and that the substrate may be made from glass, silicon, ceramic, metal or polymeric/plastics material and may be covered with a cover of the same nature or a flexible material (housing; Viovy, column 8, lines 54-64) Viovy further teaches that the capture zone of the channel comprises magnetic particles (Viovy, column 3, lines 39-40) and that the magnetic particles are stabilized in the capture zone (adhesion region; Viovy, column 6, lines 16-17). Viovy further teaches that the magnetic particles carry ligands (capturing agents; Viovy, column 6, line 49) and that ligands designates the species or a function able to bond reversibly or irreversibly to another species and may be nucleic acids, polypeptides, amino acids and others (Viovy, column 19, lines 14-23). Viovy further teaches that the global form of the channel is an asymmetric diamond shape or a symmetrical diamond shape (convergent and divergent cross-sectional area; Viovy, sheet 1 of 7, Figures 2A and 2F).
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As such Viovy teaches a divergent cross-sectional area between an inlet port (4) of the variable width microchannel and the convergent cross-sectional area and the microchannel has a width that increased in the divergent cross-sectional area. Viovy further teaches that it is possible to provide several capture zones along a channel or several channels in the microfluidic system (Viovy, column 20, lines 3-4). Viovy further teaches that the channels have at least one dimension that is less than 500 µm, less than 100 µm or less than 50 µm (Viovy, column 8, lines 49-50). Viovy further teaches that the samples are fluids and that these may be body fluids (Viovy, column 18, lines 43-45) and further that the invention makes it possible to capture cells in a medium and the cells in question may be red blood cells (Viovy, column 21, lines 1-13). As such, because Viovy does teach capture of red blood cells, i.e., capturing agent that is capable of adhering red blood cells, Viovy addresses a capture agent that adheres red blood cells in a fluid sample containing blood (the sample is not a recited structural component of the claimed device itself, rather is a sample on which the device is used). Viovy further teaches that the capture zone is closed on one of its sides by a transparent material having a thickness compatible with high-resolution microscopic observation, forming a window (Viovy, column 11, lines 32-38) and also that the system comprises a detection means such as an optical detection means (Viovy, column 15, lines 53-55).
Viovy does not teach that the microchannel is configured to simulate physiological shear rate gradients of microcirculatory blood flow at a constant flow. Viovy does not teach that the fluid sample experiences a continuously variable shear rate gradient during the continuous flow and that mean flow velocity and shear stress of the sample decreases along the length of flow while a flow rate is constant. Viovy does not teach a capturing agent that is covalently immobilized to a surface with a cross-linker GMBS nor an imaging system configured to measure the morphology and/or quantity of red blood cells adhered by the capturing agent.
Alapan teaches a microfluidic channel with immobilized fibronectin (claim 9) to mimic size scale and bulk flow velocities of post-capillary venules using whole blood to show red blood cell adhesion and deformability measured at a single cell level in sickle cell disease blood sampled examined in microfluidic channels mimicking microvasculature and that the channels mimic the size scale (50 µm) of post-capillary venules (Alapan, page 2 of 10, lines 4-14). Alapan further teaches that fibronectin plays a role in red blood cell adhesion to the endothelial wall (Alapan, page 1 of 10, 3rd paragraph, line 5-page 2 of 10, line 1 and Figure 1). Alapan further teaches attaching the fibronectin with the cross-linker agent GMBS (claim 16; Alapan, page 6 of 10, ‘Surface Chemistry’, line 7-11). Alapan further teaches that fibronectin was immobilized on microfluidic channel surfaces to mimic in part endothelial wall characteristics (Alapan, page 2 of 10, 4th paragraph, lines 1-2). Alapan further teaches assembling a glass slide with a Poly(methyl methacrylate) structure to form a microchannel (Alapan, page 6 of 10, ‘Methods’, lines 6-9).
Alapan further teaches placing the microfluidic system on an Olympus IX83 inverted motorized microscope stage for high resolution live single cell image recording and analysis (Alapan, page 2 of 10, ‘Results’, lines 10-12). Alapan further teaches analyzing aspect ratio and deformability of red blood cells in three conditions (imaging system to measure morphology of red blood cells; Alapan, page 2 of 10, 2nd column, 2nd paragraph, lines 1-2). Alapan further teaches determination of cell adhesion sites by outlining individual red blood cells in three consecutive frames in deformable and non-deformable red blood cells (Alapan, page 5 of 10, Figure 4, legend, lines 1-3) and that a greater number of adhesion sites in a subpopulation of sickled red blood cells may play a role in deformability of adhered cells in microvasculature which has been shown to correlate with hemolysis (Alapan, page 4 of 10, ‘Discussion’, line16-page 5 of 10, line 5).
Zhang teaches immobilizing fibronectin to a surface using a heterobifunctional crosslinker (Zhang, Abstract, lines 4-5). Zhang further teaches that the heterobifunctional crosslinker GMBS can be used to create fibronectin patterned surfaces in order to spatially control the protein immobilization and cell adhesion on substrates (Zhang, page 58, ‘3.8. AFM and TOF-SIMS analysis of FN-patterned surfaces’, lines 1-4). Zhang further teaches that the substrate is glass (Zhang, page 49, ‘2.3. Cleaning of the glass substrates’, line 1).
Regarding the limitation that the fluid sample experiences a continuously variable shear rate gradient during the continuous flow and that mean flow velocity and shear stress of the sample decreases along the length of flow while a flow rate is constant. As explained previously in detail above, the device as taught by Viovy comprises a divergent cross-sectional area between an inlet port (4) of the variable width microchannel and the convergent cross-sectional area and the microchannel has a width that increased in the divergent cross-sectional area. The shape of the device results in a continuously variable shear rate gradient during the continuous flow and mean flow velocity and shear stress of the sample decrease along the length of flow while a flow rate is constant due to the divergent channel as taught by Viovy. Further, Viovy teaches channels that are less than 100 µm or less than 50 µm, which according to Alapan mimics the size (50 µm) of post-capillary venules.
The prior art device structurally meets the claim because Alapan teaches that microfluidic channels measuring 50 µm mimic microvasculature and Viovy teaches channels that are less than 100 µm or less than 50 µm. As such Viovy teaches microfluidic channels that mimic microcirculatory blood flow.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the microfluidic biochip of Viovy by covalently immobilizing fibronectin with a cross-linker such as GMBS to the channel (Fibronectin being capable of binding red blood cells) because of the teaching of Alapan that fibronectin immobilized to a microfluidic channel mimics in part endothelial wall characteristics and the teaching of Zhang that a cross-linker such as GMBS can be used to create fibronectin patterned surfaces in order to spatially control protein immobilization and cell adhesion on substrates.
One having ordinary skill in the art would have a reasonable expectation of success in immobilizing fibronectin using GMBS as a crosslinker because of the teaching of Viovy that the microchannel can be made from glass and the teaching of success of both Alapan and Zhang in attaching fibronectin using GMBS to a glass channel.
It would have further been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the microfluidic biochip system of Viovy by adding an imaging system configured to measure the morphology and/or quantity of red blood cells as taught by Alapan because of the teaching of Alapan that this allows frame by frame analysis of red blood cell deformation, which in turn allows for determination of adhesion sites and adhesion sites correlate with hemolysis in sickle cell disease.
One having ordinary skill in the art would have had a reasonable expectation of success because of the teaching of that the capture zone is closed on one of its sides by a transparent material having a thickness compatible with high-resolution microscopic observation and also that the system comprises a detection means such as an optical detection means and the success of Alapan using a microscope for recording and analysis of the sample.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Viovy in view of Alapan and Zhang as applied to claim 1 above, and further in view of Harink et al. Microtiter plate-sized standalone chip holder for microenvironmental physiological control in gas-impermeable microfluidic devices. Lab on a Chip. 2014;14(11):1816-20 (PTO-892, 06/28/2023) and Sun et al. New insights into sickle cell disease: a disease of hypoxia. Current opinion in hematology. 2013 May 1;20(3):215-21 (PTO-892, 05/16/2024).
Regarding claim 4, Viovy and the cited art above teaches a microfluidic biochip device substantially as claimed.
Viovy does not teach a micro-gas exchanger being provided for controlling the oxygen content prior to delivering the blood to the microchannel.
Harink teaches a microfluidic system comprising a system which allows gas tension control (Harink, page 1816, 4th paragraph, lines 5-7) particularly meant for microfluidic platforms (Harink, page 1819, ‘Conclusions’, lines 1-2). Harink further teaches two different chip designs connected to the device by two or four different supply channels (Harink, page 1818, lines 1-7). Harink further teaches that gas exchange is ensured through the microfluidic connections with the chip inside the closed chip holder and by controlling the flow rate the residence time of the medium (sample) inside the tubing (micro gas exchanger), the gas equilibrium is reached before the sample enters the chip (controlling the oxygen content prior to delivering the blood to the microchannel; Harink, page 1817, 3rd paragraph, lines 1-8). Harink further teaches that this configuration does not create shear stress from the gas exchange in the microfluidic channel (Harink, page 1818, lines 10-11) Harink further teaches a complete system comprising a microfluidic chip and allowing gas-tension control, which can mimic physiological conditions, such as oxygen deprivation, also known as hypoxia (Harink, page 1816, 3rd paragraph, lines 4-8 and page 1817, lines 1-6).
Sun teaches that in sickle cell disease hypoxia leads to the polymerization of hemoglobin and the deformation and sickling of red blood cells, which leads to vaso-occlusion and abnormal erythrocyte-endothelial interactions. Further acute tissue hypoxia and chronic organ damage will be induced resulting in a malicious cycle contribution to sickle cell disease progression and hypoxia is a critical player in this cycle (Sun, page 215, lines 11-22).
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 have added to the device as taught by the combination of Viovy and the cited art, a gas exchanger as taught by Harink, because the configuration as taught by Harink mimics physiological conditions, such as oxygen deprivation or hypoxia. One having ordinary skill in the art would have been motivated to do so because of the teaching of Sun that hypoxia leads to the polymerization of hemoglobin and the deformation and sickling of red blood cells and can lead to abnormal interactions between red blood cells. In summary, it would have been obvious to have modified the device for the study of sickle cell red blood cells, as taught by the cited art, to add a microgas exchanger, in order to allow the ability to control oxygen to imitate hypoxic conditions because it was known that in sickle cell disease hypoxia leads to the polymerization of hemoglobin and the deformation and sickling of red blood cells, which leads to vaso-occlusion and abnormal erythrocyte-endothelial interactions; therefore one would be interested in controlling these conditions (motivated to add a micro-gas exchanger) to more accurately reflect the conditions in the body such that the investigation of the sickle cell red blood cells would be more relevant to the disease in relation to hypoxia.
One having ordinary skill in the art would have had a reasonable expectation of success, because of the teaching of Harink, that the gas exchanger is designed particularly for use with microfluidic platforms, without adding shear stress, and that the gas exchange system is connected to the microfluidic device with two supply channels.
Regarding claim 5, Viovy and the cited art above teaches a microfluidic biochip device substantially as claimed.
Viovy fails to teaches the device of claim 4, where the micro-gas exchanger provides hypoxic blood.
Harink teaches a microfluidic system comprising a system which allows gas tension control as discussed previously above (Harink, page 1816, 4th paragraph, lines 5-7).
Harink further teaches a device comprising a sample in reduced (4%) oxygen condition, whereas the hypoxic medium (blood) was provided before entering the microfluidic device (Harink, page 1819, ‘Hypoxia assay’, see 2nd paragraph).
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 have modified the device of Viovy and the cited art to comprise a micro-gas exchanger, because the micro gas exchanger allows for rendering a sample hypoxic before it enters the channel without adding shear stress to the physiological range of shear stress in the device of Viovy and further because of the teaching of Sun that hypoxia leads to the polymerization of hemoglobin and the deformation and sickling of red blood cells and can lead to abnormal interaction between red blood cells and other cells, as discussed previously in detail above.
One having ordinary skill in the art would have had a reasonable expectation of success, because of the reasons discussed above in claim 4, the same reasoning applies for claim 5.
Claims 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Viovy, in view of Alapan, and Zhang as applied to claim 1 above, and further in view of Zhu H, et al. Optofluidic fluorescent imaging cytometry on a cell phone. Analytical chemistry. 2011 Sep 1;83(17):6641-7 (of record, see PTO-892, 06/28/2023).
Regarding claims 17 and 18, Viovy and the cited art above, teaches a microfluidic biochip device substantially as claimed.
Viovy and the cited art above teach an imaging system substantially as claimed.
Viovy fails to teach an optical attachment member for connecting the housing to a cellular phone. Viovy further fails to teach an imaging system comprising a lens, a diffuser, a light emitting diode (LED) and an LED holder, and software usable by the cellular phone configured to quantify the adhered cells of interest.
Zhu teaches using a cell phone to enable specific and sensitive analysis of samples from microfluidic devices (Zhu, page 6641, 2nd paragraph, line 11). Zhu further teaches software for setting up virtual counters at specific cross sections of the chamber, which allows to more accurately count the number of cells passing through the microfluidic chamber (quantify adhered cells at variable shear gradients; Zhu, page 6644, see 3rd paragraph). Zhu further teaches a cell phone optical attachment, comprising a simple lens, a plastic color filter (diffuser), and inexpensive light emitting diodes as part of the attachment (LED holder; Zhu, page 6641, column 2, lines 1-6). Still further, Zhu teaches that their imaging system is compact, lightweight, and cost-effective and might be especially useful for rapid and sensitive imaging of bodily fluids in resource limited locations (Zhu, page 6646, see Conclusion).
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 have modified the device of Viovy to comprise an imaging system comprising software to quantify the adhered cells of interest because of the teaching of Zhu that using software for setting up virtual counters at specific cross sections of the chamber allows for a more accurate count of the number of cells. It would have further been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the device of Viovy to comprise an imaging system comprising an optical attachment connected to a cell phone, comprising a simple lens, a plastic color filter, and an inexpensive LED because of the teaching of Zhu that this kind of system is compact, lightweight, and cost effective and might be especially useful in resource limited locations.
One having ordinary skill in the art would have a reasonable expectation of success, because Zhu demonstrates successful use of the optical system with a microfluidic device.
Response to Arguments
Applicant's arguments filed 01/19/2026 have been fully considered but they are not persuasive. Applicant argues, starting on page 2, that claim 1 is not obvious over the prior art and that the office action fails to provide a reasonable rationale to modify Viovy to include at least one cell adhesion region being provided with a capturing agent covalently immobilized to the surface of a microchannel.
Applicant argues that Viovy teaches a microfluidic system using magnetic particles that have ligands in the capture zone and that Viovy does not provide any indication that there would be any benefit to using a capturing agent covalently immobilized to the surface of the microchannel, rather that the channel is coated with an epoxy-dimethylacrylamide polymer before a test to prevent adsorption of particles and proteins to the channel and that there is no indication that the microchannel could be used to study cell adhesion.
This argument is not persuasive.
The motivation to modify the device of Viovy is not derived from the teaching of Viovy but rather from the teaching of Alapan and Zhang. Alapan teaches a microchannel comprising immobilized fibronectin as well as motivation to modify the device of Viovy with fibronectin (in order to study sickle cell disease by studying red blood cell adhesion and deformability in microfluidic channels mimicking microvasculature). Regarding the argument (page 4 of arguments) that the device is coated with a polymer before a test, the coating is applied to the device and then rinsed before application of the sample (Viovy, column 24, lines 37-43) and as such is not part of the device as taught by Viovy.
Applicant further argues, starting on page 5, that Alapan teaches a microfluidic system for the study of red blood cells under no flow, flow, and at detachment instant and at uniform flow across the channel and does not suggest a microchannel designed to have a variable width.
In response to applicant's arguments against the references individually, 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). In the instant case, Viovy teaches a microfluidic device of variable width which is modified by immobilizing fibronectin on its surface as taught by Alapan. The combination of the prior art teaches a microfluidic channel of varying width designed such that mean flow velocity and shear stress of the fluid sample decrease along the length while the flow rate remains constant comprising fibronectin immobilized on the channel surface.
Applicant further argues, starting on page 6, that the Office Action fails to provide a reasonable rationale to modify Viovy as Viovy does not teach a capturing agent covalently immobilized to a surface of a microchannel. Applicant argues that Viovy teaches the use of magnetic particles to bind to an analyte so that the microfluidic system can capture, sort, extract, purify, analyze, identify, or cultivate analytes from a fluid. Applicant further argues that the capturing agent immobilized to a microchannel surface could not be easily manipulated like the magnetic particles and would have less surface/area for exposure. Further, according to applicant, the divergent cross section of the microchannel in Viovy is used in combination with the magnetic field so that the magnetic particles are retained in the capture zone and therefor one of ordinary skill in the art would have no reason to use the microchannel with a divergent cross sectional area with a capturing agent adhered to a surface because said capturing agent would not be moving during flow like the magnetic particles.
This argument is not persuasive.
Viovy teaches the microchannel with a divergent cross sectional zone and channels that are less than 100 µm or less than 50 µm, which according to Alapan mimics the size (50 µm) of post-capillary venules. One of ordinary skill in the art would then be motivated by Alapan to modify the device of Viovy in order to study red blood cell adhesion in a microchannel the mimics microvasculature in order to be able to study red blood cells in sickle cell disease at a single cell level (see above). As such one of ordinary skill in the art would be motivated to modify the microfluidic channel of Viovy by immobilizing fibronectin on the channel surface. Further, Viovy teaches that the invention can in particular make it possible to capture cells in a medium to identify or lyse them (Viovy, column 21, lines 1-2). As such, the modifying the device of Viovy by replacing the magnetic beads with immobilized fibronectin would not invalidate the purpose of the device of Viovy because immobilizing fibronectin on the device of Viovy would also allow one to identify cells in a sample applied to the device.
Regarding the argument that Alapan does not teach a varying width microchannel (page 7 of arguments), as explained previously in detail above, Viovy teaches the varying width microchannel, whereas Alapan is relied on to modify the varying width microchannel of Viovy by immobilizing fibronectin on the channel surface.
For the reasons explained above, the argument on page 8 that the Office Action’s rationale to modify Viovy to include a capturing agent is merely conclusory and does not support a prima facie finding of obviousness is not persuasive.
Regarding the argument that claims 4 and 5 as well as 17 and 18 are allowable because they depend on claim 1, as explained previously in detail above, claim 1 is not allowable and therefore the argument is moot.
For all the reasons above, the arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEFANIE J KIRWIN whose telephone number is (571)272-6574. The examiner can normally be reached Monday - Friday 7.30 - 4 pm.
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/Soren Harward/Primary Examiner, TC 1600
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