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 .
Status of Claims
Claims 1, 15-16 and 24 have been amended. Claims 1-12, 15-18, 20 and 24 have been examined.
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.
Claim(s) 1-12, 16-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Gurkan et al., WO 2018/170412 (Pub Date: 09/20/2018, hereinafter “Gurkan” IDS) in view of Yang et al. (Appl. Rheol. 21, 2011, 63890, pages 1-5, hereinafter “Yang”) and Garcia et al. (Chapter 17 - In vitro blood flow behaviour in microchannels with simple and complex geometries. In Applied Biological Engineering - Principles and Practice. InTech. p. 393-416, 2012).
Regarding claim 1, Gurkan teaches throughout the publication a microfluidic system for measuring cell adhesion (paragraph 0007), the system comprising:
a gas impermeable housing including at least one microchannel defining at least one cell adhesion region (paragraphs 0012 and 0082), the at least one cell adhesion region being provided with at least one capturing agent that adheres a cell of interest to a surface of the at least one microchannel when a fluid sample containing cells is passed through the at least one microchannel (paragraphs 0083 and 0091), wherein at least the capturing agent includes at least one of E- Selectin, P-Selectin, intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1) or endothelial cells functionalized to the surface of the microchannel (paragraphs 0079, 0110 and 0221); and
an imaging system for measuring the adherence of cells of interest adhered by the at least one capturing agent to the surface of the at least one microchannel when the fluid sample is passed therethrough (paragraph 0127),
wherein viscosity of the sample is measured (paragraph 0170).
However, Gurkan does not explicitly teach that the imaging system includes a control unit for determining viscosity of the fluid sample and the viscosity of the fluid sample is determined by measuring the mean flow velocity of the fluid sample using particle image velocimetry of the fluid as it passes through the microchannel.
Yang teaches throughout the publication a non-contact method for liquid viscosity measurement in a capillary tube (abstract). More specifically, Yang teaches the use of digital image processing to capture the test liquid flow behavior in the capillary via a camera and then calculate the viscosity based on the digital image processing (page 2, left column, second paragraph). Furthermore, Yang teaches that if one can deduce the mean flow velocity from the dynamic image of the flow, then viscosity can easily be identified (page 2, right column). As described on pages 3-4, image data can be collected from a camera and transferred to a computer and processed by digital image processing software such that the viscosity of the test liquid can be calculated after determining the mean velocity from the digital imaging processing.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to incorporate for viscosity measurements in the system of Gurkan, digital image processing procedures using mean flow velocity to determine viscosity as taught by Yang because it would have been desirable to use a technique that has been demonstrated for several types of liquids and allows for simplicity, low cost and good practical value (Yang, page 5, right column). One skilled in the art would have had a reasonable expectation of success in using the digital image processing technique of Yang to determine the mean flow velocity and thus the viscosity of samples of Gurkan since Gurkan teaches the use of a viscometer for measuring viscosity and Yang teaches the cumbersome performance of standard viscometers are insufficient to meet the requirements for point-of-care blood measurement while new approaches using digital image processing promote flexibility and simplify the procedures (Yang, page 2, left column).
While Gurkan in view of Yang do not specifically teach the use of particle image velocimetry of the fluid perfused through the microchannel to measure the velocity, Garcia teaches throughout the publication the use of digital imaging processing methods such as particle image velocimetry to study flow properties of blood within microsystems (page 393, first paragraph). More specifically, Garcia teaches that the flow volume is imaged and then by using a PIV cross-correlation method, it is possible to obtain velocity fields of the working fluid (page 393, last paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to modify the imaging system and methods of Gurkan in view of Yang by incorporating particle image velocimetry methods to determine velocity as taught by Garcia because it would have been desirable to have the potential to obtain three-dimensional information about the fluid flow and also to obtain accurate flow-field measurements thus making it possible to study complex blood flow phenomena (Garcia, page 395).
Regarding claim 2, Gurkan teaches they system wherein the at least one microchannel comprising multiple microchannels, the microchannels being fluidly isolated from each other (paragraphs 0078).
Regarding claim 3, Gurkan teaches the system wherein the fluid comprising blood and the cells of interest being red blood cells (paragraph 0008).
Regarding claim 4, Gurkan teaches the system further comprising a micro-gas exchanger for controlling the oxygen content of the blood prior to delivering the blood to the at least one microchannel (see reference claim 4).
Regarding claim 5, Gurkan teaches the system wherein the micro-gas exchanger providing hypoxic blood to the at least one microchannel (see reference claim 5).
Regarding claim 6, Gurkan teaches the system wherein the at least one microchannel having a width that continuously changes in a direction of fluid flow therethrough (see reference claim 6).
Regarding claim 7, Gurkan teaches the system wherein the microchannel having a convergent and divergent cross-sectional area along the direction of flow (see reference claim 7).
Regarding claim 8, Gurkan teaches the system wherein the shear stress on fluid flowing through the microchannel decreasing along the length of the microchannel (see reference claim 8).
Regarding claim 9, Gurkan teaches the system wherein the capturing agent being covalently immobilized to surfaces of each microchannel with a cross-linker (see reference claim 9).
Regarding claim 10, Gurkan teaches the system wherein the cross-linker being GMBS (paragraph 0125).
Regarding claim 11, Gurkan teaches the system further including a pressure pump and a reservoir that is in fluid communication the at least one microchannel, reservoir including a blood sample and the pressure pump configured to provide pressure to reservoir such that the blood sample flows through the at least one microchannel at a physiologically relevant shear stress value (paragraph 0224).
Regarding claim 12, Gurkan teaches the system wherein the physiologically relevant shear stress value is about 0.5 dyne/cm2 to about 1 dyne/cm2 (paragraph 0224).
Regarding claim 16, Gurkan teaches throughout the publication methods and systems comprising:
providing a gas impermeable housing including at least one microchannel defining at least one cell adhesion region (paragraphs 0012 and 0082), the at least one cell adhesion region being provided with at least one capturing agent that adheres a cell of interest to a surface of the at least one microchannel when a fluid sample containing cells is passed through the at least one microchannel (paragraphs 0083 and 0091), wherein at least the capturing agent includes at least one of E- Selectin, P-Selectin, intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1) or endothelial cells functionalized to the surface of the microchannel (paragraphs 0079, 0110 and 0221);
perfusing a fluid sample containing the blood cells through the at least one microchannel at a physiologically relevant shear stress rate (paragraph 0224); and
measuring adherence of the blood cells to the at least one capturing agent when the fluid sample is passed therethrough, wherein the adherence of the blood cells is measured using an imaging system (paragraph 0127 and see reference claim 1).
Additionally, Gurkan teaches that the biochip device can be used to analyze adhesive properties of RBCs and WBCs that can be used to monitor disease severity, treatment response sand treatment effectiveness in a clinically meaningful way (paragraphs 0078 and 0098). More specifically, Gurkan teaches the device and imaging system can quantify the adhered cells in each channel to measure the efficacy of a therapeutic treatment administered to a subject from which the cells are obtained (paragraph 0103), which reads on the limitations of measuring efficacy of therapeutic agent that is added to at least the fluid sample prior to perfusion through the at least one microchannel since the therapeutic treatment is added to the fluid sample through administration to the patient and therefore before perfusion through the microchannel.
However, Gurkan does not explicitly teach determining the viscosity of the fluid sample with imaging system, wherein the imaging system provides particle image velocimetry of the fluid perfused through the microchannel and includes a control unit for determining viscosity of the fluid sample, wherein the viscosity of the fluid sample is determined by measuring the mean flow velocity of the fluid sample using particle image velocimetry of the fluid as it passes through the microchannel.
Yang teaches throughout the publication a non-contact method for liquid viscosity measurement in a capillary tube (abstract). More specifically, Yang teaches the use of digital image processing to capture the test liquid flow behavior in the capillary via a camera and then calculate the viscosity based on the digital image processing (page 2, left column, second paragraph). Furthermore, Yang teaches that if one can deduce the mean flow velocity from the dynamic image of the flow, then viscosity can easily be identified (page 2, right column). As described on pages 3-4, image data can be collected from a camera and transferred to a computer and processed by digital image processing software such that the viscosity of the test liquid can be calculated after determining the mean velocity from the digital imaging processing.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to incorporate for viscosity measurements in the system of Gurkan, digital image processing procedures using mean flow velocity to determine viscosity as taught by Yang because it would have been desirable to use a technique that has been demonstrated for several types of liquids and allows for simplicity, low cost and good practical value (Yang, page 5, right column). One skilled in the art would have had a reasonable expectation of success in using the digital image processing technique of Yang to determine the mean flow velocity and thus the viscosity of samples of Gurkan since Gurkan teaches the use of a viscometer for measuring viscosity and Yang teaches the cumbersome performance of standard viscometers are insufficient to meet the requirements for point-of-care blood measurement while new approaches using digital image processing promote flexibility and simplify the procedures (Yang, page 2, left column).
While Gurkan in view of Yang do not specifically teach the use of particle image velocimetry of the fluid perfused through the microchannel to measure the velocity, Garcia teaches throughout the publication the use of digital imaging processing methods such as particle image velocimetry to study flow properties of blood within microsystems (page 393, first paragraph). More specifically, Garcia teaches that the flow volume is imaged and then by using a PIV cross-correlation method, it is possible to obtain velocity fields of the working fluid (page 393, last paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to modify the imaging system and methods of Gurkan in view of Yang by incorporating particle image velocimetry methods to determine velocity as taught by Garcia because it would have been desirable to have the potential to obtain three-dimensional information about the fluid flow and also to obtain accurate flow-field measurements thus making it possible to study complex blood flow phenomena (Garcia, page 395).
Regarding claim 17, Gurkan teaches the method wherein the fluid sample comprises blood and the cells being red blood cells and/or white blood cells (see reference claim 3).
Regarding claim 18, Gurkan teaches the method wherein the adherence of the blood cells is measured under at least one normoxic or hypoxic conditions (paragraph 0200).
Regarding claim 20, Gurkan teaches the method wherein the physiologically relevant shear stress value is about 0.5 dyne/cm2 to about 1 dyne/cm2 (paragraph 0224).
Claim(s) 15 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Gurkan et al., WO 2018/170412 (Pub Date: 09/20/2018, hereinafter “Gurkan” IDS) in view of Yang et al. (Appl. Rheol. 21, 2011, 63890, pages 1-5, hereinafter “Yang”) and Garcia et al. (Chapter 17 - In vitro blood flow behaviour in microchannels with simple and complex geometries. In Applied Biological Engineering - Principles and Practice. InTech. p. 393-416, 2012), as applied to claims 1 and 16 above (hereinafter “Modified Gurkan”) and further in view of Townsend et al. (Electroanalysis 2019, 31, pages 1409-1415).
Regarding claims 15 and 24, while Modified Gurkan teaches a fibronectin coated surface of the microchannel (paragraphs 0079), the references fail to teach that the capturing agent includes endothelial cells that are provided in the at least one microchannel by culturing the endothelial on a fibronectin coated surface of the microchannel under continuous flow of the culture medium through the at least one microchannel.
Townsend teaches throughout the publication a microfluidic device that can be used to detect interactions between blood cells and endothelial cells (abstract). More specifically, Townsend teaches endothelial cells can be immobilized on chip and achieved by endothelial cell culture using a collagen coating (page 1411, left column, first full paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to modify the surface of the microchannel of Modified Gurkan to incorporate endothelial cells as a capturing agent as taught by Townsend because it would have been desirable to study interactions between red blood cells and endothelial cells to extend device functionality and provide further information on the mechanisms and by products of the reaction (Townsend, abstract). Although Modified Gurkan in view of Townsend does not explicitly teach that the endothelial cells are provided in the channel by culturing the cells on a fibronectin surface of the microchannel under continuous flow of the culture medium through the at least one microchannel, such limitation is drawn to a product by process limitation. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (See MPEP 2113). In the instance case, the product of the product by process limitation (endothelial capture agent) is the same as the product of the prior art teachings of Modified Gurkan in view of Townsend and thus the claim in unpatentable even though the endothelial cells of Townsend were immobilized by a different process.
Response to Arguments
Applicant’s arguments filed 01/08/2026 have been considered but are found to be moot in view of the new grounds of rejection applied to the newly amended claims. Garcia teaches that particle image velocimetry is a well-known digital imaging processing tool and thus it would have been obvious to incorporate this methodology into the systems and methods of Gurkan in view of Yang, as described above, in order to determine velocity and use the measured velocity for subsequent viscosity measurements.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M GIERE whose telephone number is (571)272-5084. The examiner can normally be reached M-F 8:30-4:30.
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/REBECCA M GIERE/Primary Examiner, Art Unit 1677
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