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 .
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 cited rejections 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.
Applicant's response, filed on 09/23/2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Priority
This application is a CON of 16/347,104 (filed 5/2/2019) which is a 371 of PCT/US2017/059979 (filed 11/3/2017) which claims benefit of 62/526,177 (filed 6/28/2017), claims benefit of 62/430,094 (filed 12/5/2016), claims benefit of 62/416,775 (filed 11/3/2016) and claims benefit of 62/416,773 (filed 11/3/2016).
Drawings
The drawings received on 11/27/2019. These drawings are accepted.
Status of the Claims
Claims 1-21 are pending, claims 4 and 6-7 are withdrawn, claims 1 and 5 are amended and claims 1-3,5 and 8-21 are examined below. Claims 1-3,5 and 8-21 are rejected.
Withdrawn Rejections/Objections
The rejection of claim 5 under 35 U.S.C. §112(b), in the Office action mailed 07/02/2025is withdrawn in view of the amendments filed 09/23/2025.
The rejection of claims 1, 8-10, 12-13 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8-9 of co-pending US application No. 16347104 (reference application), in the Office action mailed 07/02/2025 is withdrawn in view of the Terminal Disclaimer filed 09/23/2025.
Regarding 35 USC 101
Claims 1-3, 5, 8-14 and 18-21 are patent-eligible under 35 U.S.C. 101 because independent claim 1 recites a particular machine of an actuator. The claims are implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b). Therefore, the judicial exception is integrated into a practical application under Step 2A, 2nd prong of the 101 analysis.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) 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.
Claims 1 - 3, 5, 8 -14, and 19-20 are rejected under 35 U.S.C. § 103 as being unpatentable over Allbritton (U.S. Pat. Pub. 2015/0251151, as cited on the 03/16/2020 IDS Document), in view of Tanke ("The use of computers for quantitative cell analysis." World Journal of Urology 8 (1990): 154-158; published 1990, as cited on the 07/02/2025 892 form) and Ogunniyi ("Screening individual hybridomas by microengraving to discover monoclonal antibodies." Nature protocols vol. 4,5: 767-82, published 2009; as cited in the 09/05/2024 IDS Document), as evidenced by GenePix Pro (GenePix Pro User’s Guide and Tutorial. Axon Instruments, Inc. (2003), pages 1-108, as cited on the attached 892 form)).
Regarding claim 1, Allbritton teaches the claim limitation of i) using a system, imaging a microwell array comprising a plurality of cell rafts at a first time subsequent to a plurality of cells having been seeded into the microwell array, and at one or more times later than the first time, to identify at least one selected cell raft that contains a cell undergoing a cellular process with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Allbritton teaches the claim limitation of the system comprising: an imaging device configured for obtaining the images of the microwell array with “Data were collected by a cooled CCD camera” (para. [0089]) and “Transillumination and fluorescence microscopy were performed using an inverted microscope (TE300, Nikon). Imaging of GFP-expressing cells was performed using a standard fluorescein filter set.” (para. [0091]).
Allbritton teaches the claim limitation of an actuator configured for releasing the cell rafts from the microwell array with “In another embodiment of a motorized device for a release needle assembly, a collar made from a suitable material such as plastic or metal is designed to fit around a microscope objective to which is attached a carrier assembly for a needle. (FIG. 17). The needle has a ninety degree bend and is clamped into the carrier assembly such that the elbow of the needle remains at a suitable distance from the carrier assembly to ensure that the carrier assembly does not obstruct the view of the microraft array through the microscope objective. The carrier assembly is mounted to a collar that can either be tightened around the microscope objective or can be designed and manufactured to a dimension that provides a friction fit to the microscope objective. A motor having a screw drive is attached to the collar, and the screw drive engages the carrier by means of a threaded aperture so that the carrier can be translated through one axis of motion into and out of the field of view allowing alignment of the needle to the center of the field of view. Translation of the needle in the z-axis to release a microraft from an array is accomplished by movement of the microscope objective through the focusing mechanism of the microscope.” (Para. [0188]).
Allbritton teaches the claim limitation of a mechanical cell raft collector with “A first aspect of the invention is an apparatus for collecting or culturing cells or cell colonies. The apparatus comprises a common substrate formed from a flexible resilient polymeric material and having a plurality of wells formed therein; and a plurality of rigid cell carriers releasably connected to said common substrate, with said carriers arranged in the form of an array, and with each of said carriers resiliently received in one of said wells.” (Para. [0008]).
Allbritton teaches the claim limitation of obtaining the images of the microwell array using the imaging device with “Data were collected by a cooled CCD camera” (para. [0089]) and with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Allbritton teaches the claim limitation of identifying, by analyzing the images of the microwell array, the at least one selected cell raft that contains a cell undergoing a cellular process with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Allbritton teaches the claim limitation of controlling the actuator to release the selected cell raft from the microwell array with “FIG. 5. Release of individual rafts from the array by needle release. (A) Experimental setup of the needle release system. The needle was fixed on a transparent polycarbonate block, and the position of the needle was controlled by an x-y-z manipulator. The manipulator was installed on the stage of an inverted microscope. (B) Micrographs of needles used for release (from top to bottom): tungsten carbide, anodized steel, tungsten. The scale bar is 100 μm. (C) Shown is an array of square molded rafts (50 μm side, 15 um height, 25 μm spacing). The rafts marked with an asterisk were released as shown in (E). (D) The fluorescence image of the raft array in (C). The polymer solution used to form the rafts was mixed with 100 ppm of rhodamine B in order to visualize the rafts by fluorescence microscopy. (E) The four rafts marked in (C) were sequentially released with a needle. (F) The fluorescence image of the raft array in (E). After release, the four rafts dropped from the array into the collection dish.” (para. [0016]) and with “Probe or microneedle movement can be provided by any suitable means, such as a miniaturized piezoelectric driver (Physique Instrumente GmbH, P-563) (FIG. 1) or similar piezoelectric device. Typically, these devices can travel up to 5 cm in the forward or reverse direction with velocities up to 200 m/s and step sizes as little as 5 um, while generating forces up to 0.2 N. The devices can be controlled by a 5V TTL signal. The microneedle is supported on the piezo-driven rod and an XYZ microstage by any suitable means, such as custom mounts or clamps. Movement of the microneedle is in some embodiments controlled using a standard digital board interfaced via Metamorph (Molecular Devices) or uManager (http://www.micro-manager.org/) software. If the piezomotor proves insufficient for a particular application, DC motor (for example, Pololu Robotics & Electronics, Las Vegas, Nev.) can be utilized using similar mounting and control software.” (para. [0059]).
Allbritton teaches the claim limitation of controlling the mechanical cell raft collector to collect the selected cell raft after release from the microwell array and controlling the mechanical cell raft collector to deposit the selected cell raft at the mapped location of the collection plate with Figure. 14 Scheme for the magnetic collection of microrafts. Fig. 14 depicts the released of a microraft and collecting the microraft in a collection plate and with “Microrafts on an inverted array were released from the top by means of previously used procedures (see, e.g., Y. Wang et al., Lab Chip 10, 2917-24 (2010). Additionally, magnetic rafts were released with a needle from below the array and magnetically collected against gravity onto a collection plate. The microraft array attached to the release chamber with culture media enclosed within the chamber by a collection plate was directly placed upright on a microscope stage. The release needle, an anodized steel microneedle with a 150 nm base diameter and 17.5 nm tip diameter (Fine Science Tools, Foster City, Calif.) was either bound to a PDMS block or bent at a 90° angle and attached to an XYZ micromanipulator with a polycarbonate brace. The needle tip was positioned between the center of the microscope objective and the microraft of interest. Individual microrafts were released from the PDMS mold by raising the needle to puncture the PDMS and eject the selected microraft. Following release the micromanipulator was lowered to its original position. Released microrafts were drawn to the collection plate by a permanent magnet held above the cassette. The magnet was kept over the collection substrate to retain microrafts as the collection plate is gently lifted off the microraft cassette.” (Para. [0162]).
Allbritton teaches the claim limitation of ii) using the system, releasing the at least one selected cell raft that contains the cell undergoing the cellular process; and iii) using the system, collecting the at least one selected cell raft at the mapped location of the collection plate with Figure. 14 Scheme for the magnetic collection of microrafts. Fig. 14 depicts the released of a microraft and collecting the microraft in a collection plate.
For Claim 1 also see: the Allbritton reference teaches a method comprising: 1) imaging a microwell array with a plurality of cell rafts a first time and one time later than the first time (before and after cell release, page 2, [0020], line 2++, page 17, [0186], line 20++) to identify selected cell raft that contains a cell undergoing a cellular process (no specific “cellular process” is claimed/defined, therefore any fluorescent cells meets claim limitation, Fig. 9); ii) releasing the selected cell rafts (page 3, left column, line 1++, Fig. 9); and iii) collecting the selected cell raft (page 3, left column, line 2++ and Fig. 9) as indicated in the 12/19/2022 office action.
Allbritton teaches the use of fully automated microscope (page 5, [0056], line 10++) and software for mounting and controlling (page 5, [0059], line 13++), and suggest automated system using image recognition to guide cell release (page 1, [0004], line 22++), and method of sorting/collecting culture cells (title and abstract) wherein sorting cell based on antibody affinity (page 1, [0005], last line) and use of eGFP expressing HeLa cells (page 2, [0020]++, page 10, [0110]++) sorted from wild-type HeLa cells under microscopy. However, Allbritton does not explicitly teach a computer system comprising at least one processor and memory and storing a location of the selected cell raft on the microwell array, and assigning the selected cell raft to a mapped location of a collection plate based on analyzing the images of the microwell array of claim 1. These limitations are taught by Tanke and Ogunniyi.
Tanke teaches a computer system comprising at least one processor and memory with “…three examples of the use of computers in cell analysis: (1) their current role in flow cytometry, with emphasis on the measurement of DNA ploidy using pulse processing; (2) the combined use of CCD cameras and computers as powerful instruments for analysis of absorption and fluorescence images; and (3) their incorporation in routine microscopes to create a highly optimized microscope environment (HOME).” (Page 154, col. 2, para. 5)
Ogunniyi teaches the claim limitation of storing a location of the selected cell raft on the microwell array, and assigning the selected cell raft to a mapped location of a collection plate to which the selected cell raft will be deposited, the mapped location based on analyzing the images of the microwell array with Figure 2 Design of an array of microwells for microengraving (Page 29) and Figure 2 Caption (Pages 29-30). Figure 2 shows (a) Schematic representation of the top-left corner of the array showing a network of microchannels and 4 × 4 groups of blocks containing microwells…” (Fig.2 Caption) and “To determine the location of cells producing antibodies of interest in GenePix Pro, a template for the spatial arrangement of the microwells is generated and superimposed on the image. The format for these templates is a GenePix Array List (GAL); these files can be edited in a text editor or a spreadsheet application to assign a unique name to each well in the array (e.g., block number, column number and row number). Alignment of the template to the scanned image is most easily achieved using the reference channel that highlights all captured mouse IgG.” (Page 8, para. 4). Ogunniyi teaches “Position the micromanipulator such that the tip of the capillary is positioned at the mouth of the well of interest. Lower the tip approximately halfway into the well. Aspirate to pick up cells from well.” (page 20, number 68) and “Lower the capillary tip into a well of the preloaded 96-well plate and dispense the tip contents into the well.” (page 20, number 70). Because a GenePix Array List (GAL) is used to map the locations of the well, the cells deposited into the well would have a mapped location with block number, column number and row number as depicted in Fig. 2.
It would have been prima facia obvious to combine the teachings of Allbritton and Tanke to arrive at the claimed invention. Tanke discusses that the combined use of CCD cameras and computers provides for powerful instruments for the analysis of absorption and fluorescence images and their incorporation in routine microscopes creates for a highly optimized microscope environment. A person of ordinary skill in the art would have been motivated to modify the method of Allbritton to include a computer with a processor and memory in combination with CCD cameras and microscopes as taught by Tanke to better analyze florescence images. Furthermore, there would have been a reasonable expectation of success, since both Allbritton and Tanke teach methods that pertain to the utilization of CCD cameras and microscopes to analyze cells.
It would have also been prima facia obvious to combine the teachings of Allbritton and Ogunniyi to arrive at the claimed invention. Ogunniyi’s method of coding facilitates the unambiguous determination of the position of a block and well within the array during micromanipulation (Page 5, Para. 3). A person of ordinary skill in the art would have been motivated to modify the method of Allbritton by including the method for storing and mapping the location of the cell of interest on a microwell array as taught by Ogunniyi to facilitate unambiguous determination of well position. Furthermore, there would have been a reasonable expectation of success, since both Allbritton and Ogunniyi teach methods that pertain to the utilization of microwells to analyze cells.
Regarding claim 2, Allbritton teaches the claim limitation of wherein the at least one selected cell raft that contains the cell undergoing the cellular process is an individual cell or a clonal colony of cells with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Regarding claim 3, Allbritton teaches the claim limitation of wherein the individual cell or the clonal colony of cells harbors or has been exposed to a specific transgene, a siRNA, or a small molecule with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Regarding claim 5, Allbritton teaches the claim limitation of wherein the plurality of cells are from a diverse cell population and the at least one selected cell raft that contains the cell undergoing the cellular process is an individual cell or a clonal colony of cells isolated based on temporal characteristics with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
For Claims 2-3 and 5 also see: the Allbritton reference teaches the selected cell raft contains individual cell or a clonal colony of cells (page 3, left column, line 5++, Fig. 9) with unique temporal characteristics: GFP expression (Fig. 9, for claim 5) and been exposed to a small molecule: in CO2 incubator (page 3, left column, line 1++, for claim 3) as indicated in the 12/19/2022 office action.
Regarding claim 8, Allbritton teaches the claim limitation of wherein identifying the at least one selected cell raft comprises detecting, for each cell raft, a marker depicted in a sub-image of the cell raft and gating the cell rafts based on detecting the marker with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]) and “Transillumination and fluorescence microscopy were performed using an inverted microscope (TE300, Nikon). Imaging of GFP-expressing cells was performed using a standard fluorescein filter set.” (Para. [0091]).
Regarding claim 9, Allbritton teaches the claim limitation of wherein the detection of the marker is based on intensity of a color channel, a size, or both with “FIG. 4. Fluorescence of films of SU-8 photoresist (50-μm thickness), 1002F photoresist (50-μm thickness), 1009F resin (50-μm thickness), and PDMS (120-μm thickness) using common microscopy filter sets. Films of varying thickness were coated onto glass slides. The fluorescence intensity of the films was measured using a fluorescein filter set (hatched bars), a TRITC filter set (white bars), or a Cy5 filter set (black bars).” (para. [0015]).
Regarding claim 10, Allbritton teaches the claim limitation of monitoring a localization pattern or an abundance of the marker, or both, within the at least one selected cell by the imaging of the microwell array with “Magnetic microrafts were developed with these polymers and coated with a non-magnetic polymer to provide a barrier between the magnetic film and plated cells. Additional layers of polymer added over pre-existing microrafts remained isolated within the PDMS microwells even after the addition of a forth polymer. Magnetic microrafts were released from the PDMS frame and magnetically collected with an external magnet. Cells grown on magnetic rafts were imaged with traditional transmitted light and fluorescence microscope, as well as confocal microscope. The growth and localization of cells on these microrafts with untreated poly(styrene-co-acrylic acid) (PS-AA) surfaces was monitored. Finally, single cells attached to magnetic microrafts were sorted and magnetically collected.” (Para. [0151]).
Regarding claim 11, Allbritton teaches the claim limitation of wherein the localization pattern of the marker within the at least one selected cell is monitored in response to a stimulus to the plurality of cells with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
For Claim 11 also see: the Allbritton reference teaches monitoring selected cell response to a stimulus to the plurality of cells (“stimulus” is not claimed/defined to be distinct from light/laser source for GFP detection, page 8, right column, line 2++) as indicated in the 12/19/2022 office action.
Regarding claim 12, Allbritton teaches the claim limitation of wherein the marker is detected with an optically detectable probe with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]) and “Transillumination and fluorescence microscopy were performed using an inverted microscope (TE300, Nikon). Imaging of GFP-expressing cells was performed using a standard fluorescein filter set.” (Para. [0091]).
Regarding claim 13, Allbritton teaches the claim limitation of wherein the optically detectable probe comprises: i) a dye, alone or in combination with one or more chemical or affinity moieties, or ii) a gene expressing the marker engineered to include a fluorescent motif, a green fluorescent protein, an antigen, a HisX6, an enzymatic activity, a luciferase, or an alkaline phosphatase with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020])
For Claims 8-10 and 12-13 also see: the Allbritton reference teaches detecting (with an optically probe: GFP, page 8, right column, line 1++, for claims 12-13) for each cell raft a marker depicted a sub-image of the cell raft and gating (using filter set, page 8, right column, line 2++) the cell rafts based on detecting the marker: GFP marker (page 8, right column, line 2++) based on intensity of a color channel: red (for claim 9) and monitoring an abundance of the marker: GFP (page 2, [0015], line 5++, for claim 10) as indicated in the 12/19/2022 office action.
Regarding claim 14, Allbritton teaches the claim limitation of wherein the one or more chemical or affinity moieties comprises a nucleic acid with complementary sequence to the marker sequence or an antibody against the marker protein with “In some embodiments, one or more biologically active molecules is applied to or coated on the rafts (particularly, the top surface or layer of the raft). Different rafts in the same device may be coated with the same, or a different, molecule. Examples of such biomolecules include, but are not limited to, a peptide, a protein, a carbohydrate, a nucleic acid, a lipid, a polysaccharide, a hormone, an extracellular matrix molecule, a cell adhesion molecule, a natural polymer, an enzyme, an antibody, an antigen, a polynucleotide, a growth factor, a synthetic polymer, polylysine, a drug, etc., including combinations thereof. Coating may be carried out by any suitable technique, including but not limited to simple adsorption and covalent coupling…” (Para. [0066]).
Regarding claim 19, Allbritton teaches the claim limitation of wherein obtaining the images of the microwell array comprises illuminating the at least one cell raft with light of a specified wavelength and detecting a fluorescence signature of the cellular process with “The carriers (also referred to as “rafts” herein) can be formed of any suitable material. The rafts are, in some embodiments, preferably transparent or semitransparent (e.g., visually transparent, optically transparent, optically transparent at certain wavelengths, and/or optionally containing elements or features that magnifies, reflects, refracts, absorbs or otherwise distorts light or certain wavelengths of light as light passes therethrough, etc.) A variety of polymers and other materials can generally satisfy the requirements for the microcarriers or rafts.” (Para. [0051).
For Claim 19 also see: the Allbritton reference teaches illuminating the cell raft with light of a specified wavelength and detecting a fluorescence signature of the cellular process because GFP fluorescence signal is detected (page 8, Fig. 5B) and presenting a graph (page 10, [0109]++) as indicated in the 12/19/2022 office action.
Regarding claim 20, Allbritton teaches the claim limitation of wherein the fluorescence signature is a result of the cell undergoing the cellular process expressing an enhanced green fluorescent protein (EGFP) reporter gene with “FIG. 9. Isolation of colonies of eGFP-expressing cells. (A) Transmitted light image of HeLa cells on an array. (B) Fluorescent image of the cells shown in (A). (C) Raft with eGFP-expressing cells was released from the array. Shown is a transmitted light image immediately after collection. (D) Shown is the fluorescence image of the cells and raft shown in (C). (E) Shown is the same raft in collection well shown in (C) 6 days after collection. The cells have expanded into a colony of >200 cells. (F) The fluorescence image of the raft and collection well shown in (E).” (para. [0020]).
Allbritton does not explicitly teach wherein the analyzing of the one or more images of the microwell array comprises: identifying and storing a size of the microwell array; identifying and storing an optimal focus position and an optimal exposure for the microwell array; and sectioning the microwell array using the processor and storing a translation required to match a set of microwells to a field of view of claim 15. However, this limitation is taught by Ogunniyi.
Regarding claim 15, Ogunniyi teaches the claim limitation of wherein the analyzing of the one or more images of the microwell array comprises: identifying and storing a size of the microwell array; identifying and storing an optimal focus position and an optimal exposure for the microwell array; and sectioning the microwell array using the processor and storing a translation required to match a set of microwells to a field of view with Figure 2 Design of an array of microwells for microengraving (Page 29) and Figure 2 Caption (Pages 29-30). Figure 2 shows (a) Schematic representation of the top-left corner of the array showing a network of microchannels and 4 × 4 groups of blocks containing microwells…” (fig. 2 Caption) and “To determine the location of cells producing antibodies of interest in GenePix Pro, a template for the spatial arrangement of the microwells is generated and superimposed on the image. The format for these templates is a GenePix Array List (GAL); these files can be edited in a text editor or a spreadsheet application to assign a unique name to each well in the array (e.g., block number, column number and row number). Alignment of the template to the scanned image is most easily achieved using the reference channel that highlights all captured mouse IgG.” (Page 8, para. 4).
Ogunniyi teaches identifying and storing an optimal focus position and an optimal exposure for the microwell array; and sectioning the microwell array using the processor and storing a translation required to match a set of microwells to a field of view with “To determine the location of cells producing antibodies of interest in GenePix Pro, a template for the spatial arrangement of the microwells is generated and superimposed on the image. The format for these templates is a GenePix Array List (GAL); these files can be edited in a text editor or a spreadsheet application to assign a unique name to each well in the array (e.g., block number, column number and row number). Alignment of the template to the scanned image is most easily achieved using the reference channel that highlights all captured mouse IgG.” (Page 8, para. 4). GenePix Pro is evidence that Ogunniyi teaches identifying and storing an optimal focus position and an optimal exposure for the microwell array because GenePix Pro allows for changing the focus position and saving the settings (page 39 of GenePix Pro User’s Guide and Tutorial).
It would have been prima facia obvious to combine the teachings of Allbritton and Ogunniyi to arrive at the claimed invention. Ogunniyi’s method of coding facilitates the unambiguous determination of the position of a block and well within the array during micromanipulation (Page 5, Para. 3). A person of ordinary skill in the art would have been motivated to modify the method of Allbritton by including the method of identifying and storing the size and translation of the microwell array to match a set of microwells to a field of view as taught by Ogunniyi to facilitate unambiguous determination of well position. Furthermore, there would have been a reasonable expectation of success, since both Allbritton and Ogunniyi teach methods that pertain to the utilization of microwells to analyze cells.
Claims 16, 18 and 21 are rejected under 35 U.S.C. § 103 as being unpatentable over Allbritton (U.S. Pat. Pub. 2015/0251151), in view of Tanke ("The use of computers for quantitative cell analysis." World Journal of Urology 8 (1990): 154-158; published 1990, as cited on the 07/02/2025 892 form) and Ogunniyi ("Screening individual hybridomas by microengraving to discover monoclonal antibodies." Nature protocols vol. 4,5: 767-82, published 2009; as cited in the 09/05/2024 IDS Document), as evidenced by GenePix Pro (GenePix Pro User’s Guide and Tutorial. Axon Instruments, Inc. (2003), pages 1-108, as cited on the attached 892 form)), as applied to claims 1- 3, 5, 8 -14 and 19-20 above and in further view of Lamprecht ("CellProfiler™: free, versatile software for automated biological image analysis." Biotechniques 42.1 (2007): 71-75; published 2007, as cited on the 07/02/2025 892 form).
Allbritton, Tanke and Ogunniyi are applied to claims 1 - 3, 5, 8 -14 and 19-20 as discussed above.
Allbritton does not explicitly teach wherein the identifying of the at least one selected cell raft comprises: segmenting, using the processor, the plurality of rafts of the microwell array; and counting, using the processor, cell nuclei per raft for the plurality of rafts of claim 16; wherein analyzing the images comprises storing the images and associating each of the images with a respective capture time of the image of claim 17; and wherein identifying, by analyzing the images of the microwell array, the at least one selected cell raft that contains the cell undergoing the cellular process comprises presenting, in a graphical user interface, a graph of the fluorescence signature in the images over time to provide a temporal evolution of the cellular process of claim 21. However, these limitations are taught by Lamprecht.
Regarding claim 16, Lamprecht teaches the claim limitation of wherein the identifying of the at least one selected cell raft comprises: segmenting, using the processor, the plurality of rafts of the microwell array; and counting, using the processor, cell nuclei per raft for the plurality of rafts. Lamprecht teaches "Here we describe the use of the open-source software, CellProfiler™, to automatically identify and measure a variety of biological objects in images. The software automatically identifies objects in digital images, counts them, and records a full spectrum of measurements for each object, including location within the image, size, shape, color in-tensity, degree of correlation between colors, texture (smoothness), and number of neighbors. Small numbers of images can be processed automatically on a personal computer, and hundreds of thousands can be analyzed using a computing cluster." (Abstract). Lamprecht provides the details specific to CellProfiler. Lamprecht teaches that images can be processed automatically on a personal computer, and hundreds of thousands can be analyzed using a computing cluster, which corresponds to the recited a computer system comprising at least one processor and memory.
Regarding claim 18, Lamprecht teaches the claim limitation of wherein analyzing the images comprises storing the images and associating each of the images with a respective capture time of the image with “Figure 3, E–G were prepared using MDA-MB-435 cells and imaged at the time points indicated…” (Page 71, col. 3, para.2). Lamprecht teaches that images can be processed automatically on a personal computer, and hundreds of thousands can be analyzed using a computing cluster, which can store the images.
For Claim 18 also see: the Allbritton reference inherently teaches storing the images and associating each of the images with a respective capture time of the image (computer inherently store the images and related information including capture time, page 8, [0092]) as indicated in the 12/19/2022 office action.
Regarding claim 21, Lamprecht teaches the claim limitation of wherein identifying, by analyzing the images of the microwell array, the at least one selected cell raft that contains the cell undergoing the cellular process comprises presenting, in a graphical user interface, a graph of the fluorescence signature in the images over time to provide a temporal evolution of the cellular process with Figure 1F depicts The red intensity (vertical axis) and size (horizontal axis) of each colony on the plate (Page 72). Lamprecht teaches "Here we describe the use of the open-source software, CellProfiler™, to automatically identify and measure a variety of biological objects in images. The software automatically identifies objects in digital images, counts them, and records a full spectrum of measurements for each object, including location within the image, size, shape, color in-tensity, degree of correlation between colors, texture (smoothness), and number of neighbors. Small numbers of images can be processed automatically on a personal computer, and hundreds of thousands can be analyzed using a computing cluster." (Abstract). Lamprecht provides the details specific to CellProfiler. Lamprecht teaches that images can be processed automatically on a personal computer, and hundreds of thousands can be analyzed using a computing cluster, which corresponds to the recited a computer system comprising at least one processor and memory.
For Claim 21 also see: the Allbritton reference teaches illuminating the cell raft with light of a specified wavelength and detecting a fluorescence signature of the cellular process because GFP fluorescence signal is detected (page 8, Fig. 5B) and presenting a graph (page 10, [0109]++) as indicated in the 12/19/2022 office action.
It would have been prima facia obvious to combine the teachings of Allbritton and Lamprecht to arrive at the claimed invention. Lamprecht’s easy to use open-source software, CellProfiler™, can automatically identify and measure a variety of biological objects in images (Abstract). A person of ordinary skill in the art would have been motivated to modify the system of Allbritton to incorporate Lamprecht's CellProfiler software to automatically and easily identify and measure cells. Furthermore, there would have been a reasonable expectation of success, since Allbritton and Lamprecht teach methods that pertain to the analysis of cells.
Claim 17 is rejected under 35 U.S.C. § 103 as being unpatentable over Allbritton (U.S. Pat. Pub. 2015/0251151), in view of Tanke ("The use of computers for quantitative cell analysis." World Journal of Urology 8 (1990): 154-158; published 1990; as cited on the 07/02/2025 892 form) and Ogunniyi ("Screening individual hybridomas by microengraving to discover monoclonal antibodies." Nature protocols vol. 4,5: 767-82, published 2009; as cited in the 09/05/2024 IDS Document), as evidenced by GenePix Pro (GenePix Pro User’s Guide and Tutorial. Axon Instruments, Inc. (2003), pages 1-108; as cited on the attached 892 form), as applied to claims 1 - 3, 5, 8 -14 and 19-20 above and in further view of Forero-Vargas ("Image processing methods for automatic cell counting in vivo or in situ using 3D confocal microscopy." Published 2011, as cited on the 07/02/2025 892 form).
Allbritton, Tanke and Ogunniyi are applied to claims 1 - 3, 5, 8 -14 and 19-20 as discussed above.
Allbritton does not teach wherein the counting of the cell nuclei further comprises performing, using the processor, a watershed transform to define the cell nuclei relative to a fluorescence threshold of claim 17. However, this limitation is taught by Forero-Vargas.
Regarding claim 17, Forero-Vargas teaches the claim limitation of wherein the counting of the cell nuclei further comprises performing, using the processor, a watershed transform to define the cell nuclei relative to a fluorescence threshold with “Watershed based algorithms are frequently employed for contour detection and cell segmentation (Beucher & Lantuejoul, 1979; Vincent & Soille, 1991), some employing different distance functions to separate the objects (Lockett & Herman, 1994; Malpica, 1997). In this way, cells are separated by defining the watershed lines between them.” (page 193, para. 3).
It would have been prima facia obvious to combine the teachings of Allbritton and Forero-Vargas to arrive at the claimed invention. Forero-Vargas discusses that watershed transform is applied to images for contour detection and cell segmentation (page 193, para. 3). A person of ordinary skill in the art would have been motivated to combine Allbritton and Forero-Vargas to include using a watershed transform algorithm for images to better identify cells for counting and analysis. Furthermore, there would have been a reasonable expectation of success, since Allbritton and Forero-Vargas teach methods that pertain to the analysis of cells.
Response to 35 USC 103 Argument filed 09/23/2025, pages 7-12
Applicant amended claims 1 and 5.
Applicant argues that Ogunniyi, Allbritton, Tanke, Lamprecht, and Forero-Vargas do not teach, suggest, or render obvious the claim limitation of "assigning the selected cell raft to a mapped location of a collection plate to which the selected cell raft will be deposited, the mapped location based on analyzing the images of the microwell array," as recited in amended independent claim 1.
In response, Applicants' remarks have been fully considered and are not persuasive. Ogunniyi teaches the claim limitation of storing a location of the selected cell raft on the microwell array, and assigning the selected cell raft to a mapped location of a collection plate to which the selected cell raft will be deposited, the mapped location based on analyzing the images of the microwell array with Figure 2, Design of an array of microwells for microengraving (Page 29) and Figure 2 Caption (Pages 29-30). Figure 2 shows (a) Schematic representation of the top-left corner of the array showing a network of microchannels and 4 × 4 groups of blocks containing microwells…” (Fig. 2 Caption) and “To determine the location of cells producing antibodies of interest in GenePix Pro, a template for the spatial arrangement of the microwells is generated and superimposed on the image. The format for these templates is a GenePix Array List (GAL); these files can be edited in a text editor or a spreadsheet application to assign a unique name to each well in the array (e.g., block number, column number and row number). Alignment of the template to the scanned image is most easily achieved using the reference channel that highlights all captured mouse IgG.” (Page 8, para. 4). Ogunniyi teaches using a GenePix Array List (GAL) to assign block number, column number and row number to the microwell that corresponds to a map of the well locations within the microwell array. Ogunniyi teaches “Position the micromanipulator such that the tip of the capillary is positioned at the mouth of the well of interest. Lower the tip approximately halfway into the well. Aspirate to pick up cells from well.” (page 20, number 68) and “Lower the capillary tip into a well of the preloaded 96-well plate and dispense the tip contents into the well.” (page 20, number 70). Because a GenePix Array List (GAL) is used to map the locations of the well, the cells deposited into the well would have a mapped location with block number, column number and row number as depicted in Fig. 2.
Applicants also argues that the cited references, Ogunniyi, Allbritton, Tanke, Lamprecht, and Forero-Vargas, do not teach, suggest, or render obvious at least the features of "identifying and storing an optimal focus position and an optimal exposure for the microwell array; and sectioning the microwell array using the processor and storing a translation required to match a set of microwells to a field of view," as recited in dependent claim 15.
In response, Applicants' remarks have been fully considered and are not persuasive. Ogunniyi teaches identifying and storing an optimal focus position and an optimal exposure for the microwell array; and sectioning the microwell array using the processor and storing a translation required to match a set of microwells to a field of view with “To determine the location of cells producing antibodies of interest in GenePix Pro, a template for the spatial arrangement of the microwells is generated and superimposed on the image. The format for these templates is a GenePix Array List (GAL); these files can be edited in a text editor or a spreadsheet application to assign a unique name to each well in the array (e.g., block number, column number and row number). Alignment of the template to the scanned image is most easily achieved using the reference channel that highlights all captured mouse IgG.” (Page 8, para. 4). GenePix Pro is evidence that Ogunniyi teaches identifying and storing an optimal focus position and an optimal exposure for the microwell array because GenePix Pro allows for changing the focus position and saving the settings (page 39 of GenePix Pro User’s Guide and Tutorial).
Conclusion
No claims are allowed.
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 KETTIP KRIANGCHAIVECH whose telephone number is (571)272-1735. The examiner can normally be reached 8:30am-5:00pm EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D. Riggs can be reached at (571) 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/K.K./E