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
Status of Claims
Claims 28-47 are pending and have been examined.
Priority
This application, Serial No. 18/251,598 (PGPub: US2024/0011888) was filed 05/03/2023. This application is a 371 of PCT/EP2021/079630 filed 10/26/2021. This application claims priority to foreign application EPO 20206259.2 filed 11/06/2020.
Information Disclosure Statements
The Information Disclosure Statements filed 05/03/2023 and 03/15/2024 have been considered by the Examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 31 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 31 recites “moved at an angle relative to a flow direction” and “angle relative” renders the claim indefinite. The term “angle” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While paragraph 0017 in the specification provides an example of an angle between 45 and 135 degrees, the claim has not provided a flow direction of carrier fluid to then be able to determine an angle relative to that to move the tissue sample.
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) 28-34, 36, 38 and 41-45 are rejected under 35 U.S.C. 103 as being unpatentable over Durack (US 2011/0003324, IDS) in view of El-Zehiry et al. (US 2019/0195774, Pub Date: 06/27/2019, hereinafter “Zehiry”, IDS).
Regarding claim 28, Durack teaches throughout the publication systems for the storage and preservation of an original tissue or cell sample on a microfluidic device (abstract). More specifically, Durack teaches a method of analyzing a tissue sample (paragraph 0042), the method comprising:
providing the tissue sample in a sample volume of a microfluidic system (Figure 4, sample well 406), wherein the tissue sample comprises a plurality of biological cells forming a continuous tissue material (paragraph 0043);
dissolving at least a part of the tissue sample into one or both of single cells and cell aggregates in a carrier fluid in the sample volume (paragraph 0044);
generating a flow of the carrier fluid from the sample volume to a measurement volume (Figure 4, analysis section 412) of the microfluidic system (paragraph 0045); and
utilizing the analysis section to an analyze the cells and for example, sort into different sample wells based on differing characteristics of the cells.
However, Durack does not teach that the analysis section takes a first phase shift image of the cells in the measurement volume with a quantitative phase- contrast microscope.
Zehiry teaches improved methods for detection of cell type using microfluidics and digital holographic microscopy (abstract). More specifically, Zehiry teaches flowing a medium comprising at least one cell into a microfluidic device, obtaining an image of the at least one cell in the microfluidic device by a digital holographic microscopic device, wherein the image is obtained with a depth of field of less than 6 μm, and determining the cell type of the at least one cell (paragraph 0011) such that the cells are flown past the digital holographic microscope device at a speed that allows for taking an image that is not blurred and with enough contrast (paragraph 0032) that allows for improved lateral resolution for more features of the cell to be detected such as phase changes (paragraph 0030). Finally, Zehiry teaches that the contrast is the result of scatter effects of subtle refractive index changes between the medium and cells as well as in between subcellular components. The quantitative and integral phase information of the subcellular components is related to the Mie scatter measurements of flow cytometry (paragraph 0026).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to incorporate within the analysis section in the method of Durack, a digital holographic microscope for taking phase shift images of cells as taught by Zehiry because it would have been desirable to allow for more features of the cell to be detected and allow for image analysis that allows performing hematology analysis of viable cells close to an in-vivo situation (Zehiry, paragraphs 0026 and 0030).
Regarding claim 29, Durack teaches the method wherein the tissue sample is dissolved by one or both of enzymatic digestion (paragraph 0043) or applying ultrasound (paragraph 0048) to the tissue sample.
Regarding claim 30, Durack teaches the method further comprising moving the tissue sample relative to an outlet of the sample volume that is in fluid communication with the measurement volume while dissolving the tissue sample (see paragraph 0044, digestion pulls the cell sample from the tissue for introduction into the analysis section).
Regarding claim 31, although Durack in view of Zehiry do not specifically teach that the tissue sample is moved at an angle relative to a flow direction of the carrier fluid in the sample volume, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value for a result effective variable. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation” Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). “No invention is involved in discovering optimum ranges of a process by routine experimentation.” Id. at 458, 105 USPQ at 236-237. The “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” Since applicant has not disclosed that the specific limitations recited in instant claim 31 are for any particular purpose or solve any stated problem, and the prior art teaches that sheath flow travels along with the sample fluid based on the dimensions and configuration of the fluid flow channels. Absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the microfluidic art.
Regarding claims 32-33, while Durack in view of Zehiry do not explicitly teach the method wherein the first phase shift image of the one or both of single cells and cell aggregates in the measurement volume is taken when the tissue sample is at a first position relative to the outlet of the sample volume; and the method further comprises taking a second phase shift image of the one or both single cells and cell aggregates in the measurement volume when the tissue sample is at a second position relative to the outlet of the sample volume or alternatively, wherein the first phase shift image is taken at a first point in time while dissolving the tissue sample; and the method further comprises taking a third phase shift image of the one or both of single cells and cell aggregates in the measurement volume at a second point in time while dissolving the tissue sample, Zehiry teaches that the DHM image collection can vary based on speed at which the sample is flowing past the microscope, illumination time, dimensions of the channels, etc. (paragraphs 0032-0038). As such, it would be obvious to take more than one image of the cells at varying relative locations based on the desire parameters for analysis as described above by Zehiry.
Regarding claim 34, while Durack does not specifically teach that the invention provides an imaging marker in the carrier fluid for labelling the one or both of single cells and cell aggregates, Durack describes in the background section that fluorescent material can be used to label target cells to identify specific subsets of desired cells (paragraphs 0004-0005). Therefore, it would be obvious to incorporate within the method of Durack, imaging markers as described by Durack in order to identify and count desired cells from a subset of targeted cell types (paragraphs 0004-0005).
Regarding claim 36, Durack in view of Zehiry teaches the method further comprising determining a cell type of one or more cells from the first phase shift image (Zehiry, paragraph 0016).
Regarding claim 38, Durack in view of Zehiry teach a microfluidic system for analyzing a tissue sample comprising a plurality of biological cells forming a continuous tissue material using a method according to claim 28 (as described above), the microfluidic system comprising:
a sample volume (Figure 4, sample well 406) configured to receive the tissue sample through an insertion opening (paragraph 0043, tissue 404 placed into well 406);
an input port that is in fluid communication with the sample volume and configured to receive a carrier fluid (paragraph 0044, port 414);
a measurement volume in fluid communication with the sample volume via a microfluidic transport channel (Figure 4, analysis section 412; paragraphs 0044-0046); and
a detection window for taking phase shift images of cells in the measurement volume using a quantitative phase-contrast microscope (teachings of DHM of Zehiry, for example, paragraph 0028, a window is inherently present with an incorporated microscope).
Regarding claim 41, Durack teaches an input channel connecting the input port with the sample volume (see Figure 4). While Durack does not specifically teach that openings of the input and transport channels are arranged on opposing sidewalls of the sample volume and aligned with each other along a direction of flow of the input channel, it would have been obvious to one skilled in the art to modify the channel arrangement and orientation based on the desired design choice.
Regarding claim 42, Durack in view of Zehiry teach the system further comprising a cell sorter that is configured to sort single cells based on cell type (Durack, paragraphs 0046-0047) or hydrodynamic properties of the cells (Zehiry, for example, paragraph 0069).
Regarding claim 43, Durack in view of Zehiry teach a device for analyzing a tissue sample comprising a plurality of biological cells forming a continuous tissue material using a method according to claim 28 (see rejection above), the device comprising:
a mount configured to receive a microfluidic system comprising a sample volume configured to receive the tissue sample and a measurement volume in fluid communication with the sample volume (Durack, for example, paragraph 0034, substrate);
a quantitative phase-contrast microscope configured to take phase shift images of cells in the measurement volume (Zehiry, paragraphs 0011-0016 and 0026-0032); and
a controller configured to control means for dissolving at least a part of the tissue sample into one or both of single cells and cell aggregates in a carrier fluid in the sample volume and for generating a flow of the carrier fluid from the sample volume to the measurement volume (Durack, paragraph 0043, external machine applied the chemicals to dissociate the cells for analysis).
Regarding claim 44, Durack teaches the device further comprising an ultrasound source that is configured to apply ultrasound to the sample volume of the microfluidic system, wherein the controller is configured to control the ultrasound source to dissolve at least a part of the tissue sample by applying ultrasound to the tissue sample in the sample volume (paragraph 0048, external machine also controls application of vibratory energy to the device by ultrasonic acoustic methods such as a piezoelectric acoustic device).
Regarding claim 45, Durack teaches the device comprising a microfluidics unit that is configured to supply a fluid to the sample volume (See Figure 4), wherein the controller is configured to control the microfluidics unit to dissolve at least a part of the tissue sample by supplying a dissolving fluid comprising enzymes for an enzymatic digestion of the tissue sample to the sample volume (paragraph 0043).
Claim(s) 35 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Durack (US 2011/0003324, IDS) in view of El-Zehiry et al. (US 2019/0195774, Pub Date: 06/27/2019, hereinafter “Zehiry”, IDS), as applied to claims 28, 38 and 43 above (hereinafter “Modified Durack”), and further in view of Shutze et al. (US 2018/0023111, Pub Date: 01/25/2018, hereinafter “Shutze”, IDS).
Regarding claim 35, Modified Durack teaches the method as described above but fails to teach the method performing molecular spectroscopy on the one or both of single cells and cell aggregates. Shutze teaches that cells can be imaged in not only two dimensions but also three dimensions by means of DHM and/or spectroscopy (paragraph 0015). It would have been obvious to one skilled in the art to incorporate within the method of Modified Durack, spectroscopy analysis as taught by Shutze because it would have been desirable to further characterize the cells while not leading to destruction of the cells (Shutze, paragraph 0021).
Regarding claim 37, while Modified Durack does not specifically teach the method further comprising one or both of hydrodynamic and viscoelastic focusing of the one or both of single cells and cell aggregates in the measurement volume, Shutze teaches that flow in the channel may be stopped for measurement to be performed and a centering in the channel can be performed by hydrodynamic focusing (paragraph 0060). It would have been obvious to one skilled in the art to incorporate within the method of Modified Durack, hydrodynamic focusing as taught by Shutze because it would have been desirable to allow ideal spatial positioning of the cells in the channel for analysis (Shutze, paragraph 0060).
Claim(s) 39-40 and 46-47 are rejected under 35 U.S.C. 103 as being unpatentable over Durack (US 2011/0003324, IDS) in view of El-Zehiry et al. (US 2019/0195774, Pub Date: 06/27/2019, hereinafter “Zehiry”, IDS), as applied to claims 38 and 43 above (hereinafter “Modified Durack”), and further in view of Smythe et al. (US 2017/0175522, Pub Date: 06/22/2017, hereinafter “Smythe”).
Regarding claims 39-40 and 46-47, Modified Durack teaches the system and device as described above but does not teach that the system/device comprise a piston that is configured to be moved within the sample volume for moving the tissue sample in the sample volume, wherein the piston comprises a cover member that is configured to seal off the insertion opening and to slide along the sample volume for moving the tissue sample along the sample volume, further comprising an actuator and controller configured to control the actuator to move the movable element within the sample volume for moving the tissue sample within the sample volume.
Smythe teaches microfluidics for providing a flow of fluid through a microfluidic flow line (abstract). More specifically, Smythe teaches actuation of a piston to pull or push fluid through the components of the system and the piston has a precision actuation mechanism (e.g., a lead screw or ball screw) that allows for precise control of volumetric flow during piston-driven flow processes (paragraphs 0079-0080). As seen in Figure 3B, piston 2025 includes a cover configured to seal off the insertion opening. Furthermore, Smythe teaches that operation of the pistons can be performed by a processing system (paragraph 0149). This piston is additionally fluidically interfaced with the microfluidic line to deliver fluids throughout the system (paragraph 0004).
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was filed to incorporate within the device/system of Durack, a piston controlled by actuator and controller that allows for fluid manipulation and fluidic control in relation to inlets and channels as taught by Smythe because it would have been desirable to allow computer controlled fluid movements for accuracy and greater user control over processes of the system/device.
Double Patenting
Claims 28, 37 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25 and 40 of copending Application No. 18/291,952 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because regarding instant claims 28 and 37, application 952 recites a method for detecting cell aggregates of biological cells using a quantitative phase-contrast microscope, the method comprising: preparing a suspension comprising biological cells from a sample; generating a flow of the suspension along a microfluidic channel to one or both of viscoelastically and hydrodynamically focus cell aggregates in the suspension in a focal plane of the quantitative phase-contrast microscope; taking one or more phase shift images of the biological cells in the suspension using the quantitative phase-contrast microscope; and identifying cell aggregates in the one or more phase shift images, wherein the sample is a whole blood sample or a blood fraction sample and identifying cell aggregates in the one or more phase shift images comprises identifying platelet aggregates in the one or more phase shift images (see reference claim 25).
Additionally, reference claim 40 reads on instant claim 43.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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