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 .
This is a NON FINAL REJECTION in response to applicant’s claim amendments and arguments field March 27, 2026. Claims 1, 4, 11, 12, and 14 are currently amended. Claims 8-10, 16, and 18-20 are canceled from consideration. Claims 1-7, 11-15, 17, and 21-23 are pending review in this correspondence.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 27, 2026 has been entered.
Response to Amendment
Rejection of claims 1-5, 7, and 11-15 as being unpatentable over Lueerssen et al (WO 2010/142954 A1 – reference will be made to US Pub No. 2012/0156675 A1) in view of Aminova et al (Aminova O, Disney MD. A microarray-based method to perform nucleic acid selections. Methods Mol Biol. 2010;669:209-24. doi: 10.1007/978-1-60761-845-4_17. PMID: 20857369; PMCID: PMC3840795) is withdrawn in view of applicant’s claim amendments.
Rejection of claims 6 and 17 as being unpatentable over Lueerssen et al (WO 2010/142954 A1 – reference will be made to US Pub No. 2012/0156675 A1) and Aminova et al (Aminova O, Disney MD. A microarray-based method to perform nucleic acid selections. Methods Mol Biol. 2010;669:209-24. doi: 10.1007/978-1-60761-845-4_17. PMID: 20857369; PMCID: PMC3840795) in view of Di Carlo (US prov no. 61/382,841, filed 9/14/2010; See US PGPub 2013/0171628 A1) is withdrawn in view of applicant’s amendments to claims 1 and 12.
Claim Objections
Claim 22 is objected to because of the following informalities: Applicant should consider the use of consistent terminology when referring to claimed subject matter (“targets” vs previously recited “targets of interest”). Appropriate correction is required.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-5, 7, 11-15, 22, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lueerssen et al (WO 2010/142954 A1 – reference will be made to US Pub No. 2012/0156675 A1) in view of Aminova et al (Aminova O, Disney MD. A microarray-based method to perform nucleic acid selections. Methods Mol Biol. 2010;669:209-24. doi: 10.1007/978-1-60761-845-4_17. PMID: 20857369; PMCID: PMC3840795), and further in view of Backhaus et al (US 2011/0124037 A1).
With respect to claim 1 Lueerssen discloses a method comprising:
Providing a chip (capture support, See Fig. 2 and Para. 0175) for receiving and retaining a sample derived from a tissue comprising a set of cells (See Para. 0146 for discussion of the cell types of interest, including tumor cells, heart cells, liver cells, etc.), wherein the chip comprises an array of addressable target capture locations having single-cell resolution (See Para. 0028 for discussion of how the capture support includes one or more wells that arranged to capture only a single cell);
Introducing the sample to the chip (See Para. 0175 for discussion of how a cell suspension is dispensed onto the surface of the capture support);
Introducing to the chip a plurality of affinity molecules that bind to targets of interest in the sample (See Para. 0175 for discussion of how the capture supports are modified to contain reagents such as antibodies to aid in capture of specific cells; Paras. 0084-0090 discuss how a single chamber can include a variety of immobilized binding reagents);
Generating by an imaging system (microscope, digital camera, and appropriate imaging software, See Para. 0175) an image of one or more of the affinity molecules bound to the targets of interest on the chip (See Paras. 0154-0156 for discussion of the use of a microscope to observe the cells within the device, and to generate images that may be used for diagnostic purposes and fault detection (accidental capture of two particles (e.g. cells), capture of contaminants, etc.), as well as for documentation purposes. Image analysis may be used to distinguish between different captured cell types; also see Para. 0175; Para. 0165 discusses how cell may be stained with fluorescently labelled antibodies or alternative dyes for more detailed characterization);
Performing in-situ hybridization of nucleic acids from the sample on a chip at addressable target capture locations of the array of addressable target capture locations (See Fig. 2 and Para. 0217 for discussion of how after lysis of the cells, hybridization of the cellular components and analytical components occurs, and some or all of the analysis can be performed in situ); and
Obtaining sequence data of the nucleic acids (See Paras. 0057, 0088, and 0095 of Lueerssen).
While Lueerssen discloses that detection may occur in situ within the device or may occur in a disassembled device (i.e. such as on the lid) (See Paras. 0128-0130), and that the support may be composed of hydrophilic and liquid permeable polymers inclusive of agarose and polyacrylamide gels, Lueerssen fails to disclose the step of retrieving nucleic acids derived from the sample from the chip.
Aminova teaches a microarray-based platform to perform nucleic acid selections (see abstract). Microarrays are advantageous platforms for screening and performing selections because of the small amounts of ligand and analyte required, and the ability of microarrays to probe thousands of interactions in parallel. These advantages are best illustrated in the widespread uses of microarrays, which include studying gene expression (17), and protein–protein (18), carbohydrate–protein (19), cell–ligand (20, 21), and small molecule–protein interactions (22–24). In order to develop a microarray-based method to complete selections, a microarray surface that is robust enough for ligand screening and allows bound RNAs to be harvested directly from the array surface is required. We found that the optimal surface is an agarose-coated microarray (25, 26). Bound RNAs can be harvested from the array surface by simple excision of the agarose from ligand-functionalized positions (27, 28). Additionally, agarose provides an inexpensive and three dimensional surface for high ligand loading. It can also be functionalized to provide a chemical handle for immobilization of a variety of reactive groups. Most importantly, by harvesting all ligand-bound RNAs via gel excision, kinetic biases found in resin-based selections may be mitigated (27) (See “Introduction”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the step of removing/harvesting bound nucleic acids from the agarose-coated array surface via gel excision, such as taught by Aminova, into the method of Lueerssen, in order to reduce and mitigate kinetic biases found in resin-based selections (See “Introduction” of Aminova).
The combination of Lueerssen and Aminova fails to teach storing, by the imaging system, locations on the chip of the one or more targets of interest.
Backhaus teaches a device for removing a cell and/or a cell colony from a cell culture is characterised by a microscope unit for microscopic scanning of the cell culture in combination with an image acquisition unit and an image evaluation unit for detecting the position of the cells and/or the cell colonies in the cell culture, a control and memory unit for storing the detected position of the cell and/or cell colony and a harvesting module having a removal tool for removing the cell and/or cell colony at the detected position of the cell and/or cell colony (See Para. 0051). In the process of cell detection and image processing, the user loads the feed receptacle with corresponding target plates, consumables and liquids and equips the microscope cross table with its starting plate in which the cell cultures to be harvested are located. These plates can be freely defined and calibrated in the image processing software. These plates can then be scanned (See Para. 0118). For scanning the table is moved in a pattern which corresponds to the image section of the optical camera system. The content of the complete plate can thus be scanned image by image. After one of these individual images has been scanned, a particle detection takes place immediately based on grey threshold values (and therefore on brightness differences). Corresponding mathematical filters can be used before this detection in order, for example, to optimize contrast or prepare the image for better detection. This detection is made image by image, i.e. during scanning. In this case, edge-overlapping particles are automatically identified by the software and combined to form one particle. This type of detection is therefore also designated as edge-overlapping detection. As a result, primarily only a so-called particle map remains which shows in binary form where and where not identified particles are located. Thus, image data need not be held expensively in the memory but merely a map of the detection result. Optionally, a reduced-size overview image can be produced and stored (See Para. 0119).
It would have been obvious to one of ordinary skill in the art before ethe effective filing date of the claimed invention to incorporate the step of storing, by the imaging system, locations on the chip of the one or more targets of interest, such as taught by Backhaus, into the of combined Lueersen and Aminova such that a map can be referenced which shows where identified particles are located (See Para. 0119 of Backhaus).
With respect to claim 2 the combination of Lueerssen, Aminova, and Backhaus teaches that the affinity molecule are antibodies (See Paras. 0175 and 0165 of Lueerssen)
With respect to claim 3 the combination of Lueerssen, Aminova, and Backhaus teaches that the antibodies comprise a fluorescent label (See Para. 0165 of Lueerssen)
With respect to claim 4 the combination of Lueerssen, Aminova, and Backhaus teaches profiling RNA or mRNA expressions of the sample (See Paras. 0057, 0088, and 0095 of Lueerssen).
With respect to claim 5 the combination of Lueerssen, Aminova, and Backhaus teaches generating a single cell analysis of the sample (See abstract and Para. 0008) of Lueerssen).
With respect to claim 7, the combination of Lueerssen, Aminova, and Backhaus teaches that introducing to the chip the plurality of affinity molecules comprises staining the sample by introducing a solution of conjugated antibodies to the tip (See Para. 0165 of Lueerssen for discussion of staining trapped cells with fluorescently labeled antibodies).
With respect to claim 11 the combination of Lueerssen, Aminova, and Backhaus teaches that the array comprises addressable target capture locations having a width from 5-200 micrometers (See Para. 0051 of Lueerssen for discussion of how the well diameter is 12-20 µm), and wherein the array of addressable target capture locations comprises 10,000 locations (See Para. 0057 of Lueerssen for discussion of 10,000 wells being arranged in a rectangular array).
With respect to claim 12 Lueerssen discloses a method comprising:
Providing a chip (capture support, See Fig. 2 and Para. 0175) for receiving and retaining a sample derived from a tissue comprising a set of cells (See Para. 0146 for discussion of the cell types of interest, including tumor cells, heart cells, liver cells, etc.), wherein the chip comprises an array with addressable locations for target capture (See Para. 0028 for discussion of how the capture support includes one or more wells that arranged to capture only a single cell);
Introducing the sample to the chip (See Para. 0175 for discussion of how a cell suspension is dispensed onto the surface of the capture support);
Introducing to the chip a plurality of affinity molecules that binds to targets of interest to the chip (See Para. 0175 for discussion of how the capture supports are modified to contain reagents such as antibodies to aid in capture of specific cells; Paras. 0084-0090 discuss how a single chamber can include a variety of immobilized binding reagents);
Performing in-situ hybridization on the chip (See Fig. 2 and Para. 0217 for discussion of how after lysis of the cells, hybridization of the cellular components and analytical components occurs, and some or all of the analysis can be performed in situ);
Imaging one or more of the affinity molecules bound to one or more of the targets of interest (See Paras. 0154-0156 for discussion of the use of a microscope to observe the cells within the device, and to generate images that may be used for diagnostic purposes and fault detection (accidental capture of two particles (e.g. cells), capture of contaminants, etc.), as well as for documentation purposes. Image analysis may be used to distinguish between different captured cell types; also see Para. 0175; Para. 0165 discusses how cell may be stained with fluorescently labelled antibodies or alternative dyes for more detailed characterization); and
Sequencing the nucleic acids (See Paras. 0057, 0088, and 0095 of Lueerssen).
While Lueerssen discloses that detection may occur in situ within the device or may occur in a disassembled device (i.e. such as on the lid) (See Paras. 0128-0130), and that the support may be composed of hydrophilic and liquid permeable polymers inclusive of agarose and polyacrylamide gels, Lueerssen fails to disclose the step of retrieving nucleic acids derived from the sample.
Aminova teaches a microarray-based platform to perform nucleic acid selections (see abstract). Microarrays are advantageous platforms for screening and performing selections because of the small amounts of ligand and analyte required, and the ability of microarrays to probe thousands of interactions in parallel. These advantages are best illustrated in the widespread uses of microarrays, which include studying gene expression (17), and protein–protein (18), carbohydrate–protein (19), cell–ligand (20, 21), and small molecule–protein interactions (22–24). In order to develop a microarray-based method to complete selections, a microarray surface that is robust enough for ligand screening and allows bound RNAs to be harvested directly from the array surface is required. We found that the optimal surface is an agarose-coated microarray (25, 26). Bound RNAs can be harvested from the array surface by simple excision of the agarose from ligand-functionalized positions (27, 28). Additionally, agarose provides an inexpensive and three dimensional surface for high ligand loading. It can also be functionalized to provide a chemical handle for immobilization of a variety of reactive groups. Most importantly, by harvesting all ligand-bound RNAs via gel excision, kinetic biases found in resin-based selections may be mitigated (27) (See “Introduction”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the step of removing/harvesting bound nucleic acids from the agarose-coated array surface via gel excision, such as taught by Aminova, into the method of Lueerssen, in order to reduce and mitigate kinetic biases found in resin-based selections (See “Introduction” of Aminova).
The combination of Lueerssen and Aminova fails to teach storing in an imaging system locations on the chip of the one or more targets of interest.
Backhaus teaches a device for removing a cell and/or a cell colony from a cell culture is characterized by a microscope unit for microscopic scanning of the cell culture in combination with an image acquisition unit and an image evaluation unit for detecting the position of the cells and/or the cell colonies in the cell culture, a control and memory unit for storing the detected position of the cell and/or cell colony and a harvesting module having a removal tool for removing the cell and/or cell colony at the detected position of the cell and/or cell colony (See Para. 0051). In the process of cell detection and image processing, the user loads the feed receptacle with corresponding target plates, consumables and liquids and equips the microscope cross table with its starting plate in which the cell cultures to be harvested are located. These plates can be freely defined and calibrated in the image processing software. These plates can then be scanned (See Para. 0118). For scanning the table is moved in a pattern which corresponds to the image section of the optical camera system. The content of the complete plate can thus be scanned image by image. After one of these individual images has been scanned, a particle detection takes place immediately based on grey threshold values (and therefore on brightness differences). Corresponding mathematical filters can be used before this detection in order, for example, to optimize contrast or prepare the image for better detection. This detection is made image by image, i.e. during scanning. In this case, edge-overlapping particles are automatically identified by the software and combined to form one particle. This type of detection is therefore also designated as edge-overlapping detection. As a result, primarily only a so-called particle map remains which shows in binary form where and where not identified particles are located. Thus, image data need not be held expensively in the memory but merely a map of the detection result. Optionally, a reduced-size overview image can be produced and stored (See Para. 0119).
It would have been obvious to one of ordinary skill in the art before ethe effective filing date of the claimed invention to incorporate the step of storing, by the imaging system, locations on the chip of the one or more targets of interest, such as taught by Backhaus, into the of combined Lueersen and Aminova such that a map can be referenced which shows where identified particles are located (See Para. 0119 of Backhaus).
With respect to claim 13 the combination of Lueerssen and Aminova teaches that the sample comprises cancer cells (See Para. 0146 of Lueerssen for discussion of how the cell types of interest can include tumor cells such as carcinomas, lymphomas, leukemic cells).
With respect to claim 14 the combination of Lueerssen and Aminova teaches that the chip comprises an array of addressable locations for target capture having a width from 5-200 micrometers (See Para. 0051 of Lueerssen for discussion of how the well diameter is 12-20 µm).
With respect to claim 15 the combination of Lueerssen and Aminova teaches sequencing the nucleic acids for providing RNA or mRNA expressions of the sample (See Paras. 0057, 0088, and 0095 of Lueerssen).
With respect to claim 21 the combination of Lueerssen, Aminova, and Backhaus teaches that the imaging system uses a first image to determine an address of one capture location for a cell of interest, and control imaging hardware to individually image the one capture location (See Paras. 0139-0141 of Backhaus for discussion of how the image processing software obtains information on position of the cell(s) of interest, and then takes an image of the particle(s) before an after harvesting).
With respect to claim 22 the combination of Lueerssen, Aminova, and Backhaus teaches that the targets of interest are target cells of the set of cells (See Para. 0175 for discussion of how a plurality of cells are in traduced to the capture support, and cells that fail to settle in a well are washed away; target cells are those that are bound to the well).
With respect to claim 23, the combination of Lueerssen, Aminova, and Backhaus teaches correolating, by the imaging system, one or more of the addressable target capture locations to the stored locations (See Para. 0051 of Backhaus for discussion of the use of the image acquisition unit and an image evaluation unit for detecting the position of the cells and/or the cell colonies in the cell culture, a control and memory unit for storing the detected position of the cell and/or cell colony).
Claim(s) 6 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lueerssen et al (WO 2010/142954 A1 – reference will be made to US Pub No. 2012/0156675 A1), Aminova et al (Aminova O, Disney MD. A microarray-based method to perform nucleic acid selections. Methods Mol Biol. 2010;669:209-24. doi: 10.1007/978-1-60761-845-4_17. PMID: 20857369; PMCID: PMC3840795), and Backhaus et al (US 2011/0124037 A1) in view of Di Carlo (US prov no. 61/382,841, filed 9/14/2010; See US PGPub 2013/0171628 A1).
Refer above for the combined teachings of Lueerssen, Aminova, and Backhaus.
With respect to claim 6, the combination of Lueerssen, Aminova, and Backhaus fails to teach the further step of permeabilizing the sample.
Di Carlo teaches a method of isolating cells (See abstract), wherein trapped cells are
sequentially prepared with a fixation agent and permeabilization agent and stained with
fluorescence antibodies. Cells were then washed and collected into a 96-well-plate for
characterization (See Para. 0071).
It would have been obvious to one of ordinary skill in the art at the time of filing to
incorporate the permeabilization step of Di Carlo into the method of combined Lueerssen, Aminova, and Backhaus for the purpose of better preparing a sample for subsequent imaging (See Para. 0071 of Di Carlo).
With respect to claim 17, although Lueerssen discloses that the cells may be fixed prior, during, or shortly after their capture using the cell capture device (See Para. 0176), the combination of Lueerssen, Aminova, and Backhaus fails to teach he further step of permeabilizing the sample.
Di Carlo teaches a method of isolating cells (See abstract), wherein trapped cells are
sequentially prepared with a fixation agent and permeabilization agent and stained with
fluorescence antibodies. Cells were then washed and collected into a 96-well-plate for
characterization (See Para. 0071).
It would have been obvious to one of ordinary skill in the art at the time of filing to
incorporate the permeabilization step of Di Carlo into the method of combined Lueerssen, Aminova, and Backhaus for the purpose of better preparing a sample for subsequent imaging (See Para. 0071 of Di Carlo).
Response to Arguments
Applicant's arguments filed March 27, 2026 have been fully considered but they are not persuasive.
APPLICANT ARGUES: “Lueerssen, Aminova, and DiCarlo do not teach or suggest any imaging system that can store a location on a chip for affinity molecules bound to targets of interest.
Lueerssen reports isolating individual cells in an apparatus for individual analysis of cell contents and states that "Single cells are captured, their contents are released, and the contents of individual cells are then analysed within a chamber containing suitable analytical components e.g. immobilised nucleic acid probes, immobilised antibodies, etc." US 2012/0156675, [0008]. Lueerssen state that device may include an image capturing element, such as a camera. Id., [011]]. However, Lueerssen does not teach or suggest that a location on a chip of targets of interest may be stored based on imaging affinity molecules that were bound to the sample.
Aminova reports a nucleic acid selection method in which a ligand-bound array is
incubated with an RNA library after which bound RNA library members are harvested by gel excision. Aminova, Abstract. Aminova does not teach or suggest any chip with an array of addressable target capture locations with single-cell resolution and also does not teach or suggest capturing a sample with a set of cells on any such chip (there being so such chip). Aminova does not teach or suggest any imaging system that stores a location on a chip at which affinity molecules bound to targets of interest.
Di Carlo reports a cell isolation system based on vortex trapping and states "cells 12 above a certain threshold or cutoff size... enter the expansion regions 30 and get caught or trapped within the re-circulating vortices." US 2013/0171628, [0048]. Di Carlo states that trapped cells "may be released from the expansion regions 30 by allowing the vortices to reduce in size and ultimately dissipate." Id., [0057]. Di Carlo does not teach or suggest any chip with an array of addressable target capture locations with single-cell resolution and also does not teach or suggest any imaging system that, for targets of interest found by imaging affinity molecules, stores location information, i.e., information about the location on the chip at which those targets of interest are found.
Factual analysis reveals that the asserted prior art does not disclose any image system that can store the location on a chip of targets of interest that were imaged via affinity molecules. Those references also do not teach or suggest a chip with an array of addressable target capture locations with single-cell resolution as recited in independent claims 1 and 12. ” (See pgs. 6-7 of applicant’s remarks/arguments).
EXAMINER’S RESPONSE: With regard to applicant’s assertion that the Lueerssen, Aminova, and DiCarlo do not disclose or teach any image system that can store the location on the chip of targets of interest that were imaged, the examiner has incorporated Backhaus into the rejection above to address the knowledge that storing imaged locations of particles of interest is well known in the art. The examiner disagrees with the applicant’s assertion that the cited prior art does not teach or suggest a chip with array of addressable target capture locations with single-cell resolution. Applicant has not provided any arguments as to why the prior art does not suffice to address this recitation, and as such, the examiner maintains that the cited prior art reasonably teaches that affinity molecules (i.e. fluorescent antibodies, see rejection above) are taught as being image to identify locations of targets of interest (i.e. well-bound cells in Lueerssen). Applicant might consider clarifying what is intended to be encompassed by the target capture locations being “addressable”.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRITTANY I FISHER whose telephone number is (469)295-9182. The examiner can normally be reached IFP.
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/BRITTANY I FISHER/Examiner, Art Unit 1796 April 3, 2026
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