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 .
Claim Status
Applicant’s amendment filed on October 28, 2025 is acknowledged. Currently, claims 83-102 are pending. Claims 83, 91-92, 94, 101, and 102 have been amended.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 28, 2025 is in compliance with the provisions of 27 CFR 1.97. Accordingly, the information disclosure statement is being considered and attached by the examiner.
Response to Arguments
Applicant’s arguments, filed October 28, 2025, regarding the 102 rejections are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Frenz in view of Wilkinson.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 83-86 and 88-93, 96-97, and 99-102 are rejected under 35 U.S.C. 103 as being unpatentable of Frenz et al., WO 2020123316, (hereinafter “Frenz”) in view of Wilkinson et al., US 20160302870 A1, (hereinafter “Wilkinson”).
Regarding claim 83, Frenz teaches a method for detecting fiducials associated with an array, the method comprising:
receiving, by a data processor ([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), first array image data comprising a first array image comprising an array and an array fiducial ([pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) ([pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein an array fiducial is a fiducial marker);
receiving, by the data processor ([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), second array image data comprising a second array image comprising an overlay of the array with a sample and the array fiducial ([pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) ([pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein an array fiducial is a fiducial marker), wherein the sample obscures the array fiducial in the overlay ([pg. 126] “An image of the substrate and the tissue section can be obtained, and the position of the fluorophore within the tissue section image can be determined (e.g., by reviewing an optical image of the tissue section overlaid with the fluorophore detection).” wherein the array fiducial is the fluorophore);
determining, by the data processor ([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), a location of the array fiducial in the first array image based on a first coordinate system ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a first coordinate system is the alignment sub-system);
determining, by the data processor ([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), a location of the sample in the second array image based on the first coordinate system ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a second coordinate system is the alignment sub-system);
([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), ([pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings and the sample is a substrate); and
providing, by the data processor ([pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the array fiducial is fiducial markings and the sample is a substrate).
Frenz does not specifically disclose comparing the location of the array fiducial in the first array image and the location of the sample in the second array image; and providing the location of the array fiducial relative to the location of the sample based on the comparing.
However, Wilkinson teaches comparing the location of the array fiducial in the first array image and the location of the sample in the second array image; and providing the location of the array fiducial relative to the location of the sample based on the comparing ([0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a step to compare the location of the array fiducial and the location of the sample of Wilkinson in the method for detecting fiducials associated with an array of Frenz to ensure the precision of alignment between the array fiducial and sample.
Regarding claim 84, Frenz in view of Wilkinson teaches the method of claim 83, wherein the first array image is taken when the sample is not in contact with the array and wherein the second array image is taken when the sample is in contact with the array (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.” wherein the first array image that is taken when the sample is not in contact with the array is the captured biological analyte on a second array wherein the first array can be removed).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 85, Frenz in view of Wilkinson teaches the method of claim 83, wherein the first array image and the second array image are taken when the sample is in contact with the array (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.” wherein the first and second array images that are taken when the sample is in contact with the array are the captured biological samples that are contacted with two or more arrays).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 86, Frenz in view of Wilkinson teaches the method of claim 85, wherein the first array image is acquired at a first focal depth so as to exclude the sample from the first array image, and wherein the second array image is acquired at a second focal depth as to include the sample overlaid with the array (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) (Frenz - [pg. 361] “For example, control unit 2228 can adjust the position of sample 2208 or feature array 2214 relative to the position of the incident light, and also with respect to the focal plane of the incident light (if the incident light is focused).” wherein a first and second focal depth are the adjusted focal planes) (Frenz - [pg. 126] “An image of the substrate and the tissue section can be obtained, and the position of the fluorophore within the tissue section image can be determined (e.g., by reviewing an optical image of the tissue section overlaid with the fluorophore detection).” wherein the array is the fluorophore).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 88, Frenz in view of Wilkinson teaches the method of claim 83, wherein the first array image further comprises a first instrument fiducial (Frenz - [pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein a first instrument fiducial is a fiducial marker), the method further comprising
receiving, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the second array image data further comprising the first instrument fiducial in the second array image (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) (Frenz - [pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein the first instrument fiducial is a fiducial marker), wherein the sample obscures the array fiducial and the first instrument fiducial in the overlay (Frenz - [pg. 126] “An image of the substrate and the tissue section can be obtained, and the position of the fluorophore within the tissue section image can be determined (e.g., by reviewing an optical image of the tissue section overlaid with the fluorophore detection).” wherein the array fiducial and the first instrument fiducial is the fluorophore);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial relative to the first instrument fiducial in the first array image based on the first coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the first instrument fiducial is fiducial markings and a first coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the sample relative to the first instrument fiducial in the second array image based on a second coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the first instrument fiducial is fiducial markings and a second coordinate system is the alignment sub-system); and
comparing, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the first array image and the location of the sample in the second array image (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings and the sample is a substrate) (Wilkinson - [0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 89, Frenz in view of Wilkinson teaches the method of claim 83, wherein the first array image further comprises a first applied fiducial (Frenz - [pg. 126] “In some embodiments, fiducial markers can be precisely placed in the field of view (e.g., at known locations on a substrate). In this instance, a fiducial marker can be stamped, attached, or synthesized on the substrate and contacted with a biological sample.” wherein the first applied fiducial is a fiducial marker), the method further comprises
receiving, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the second array image data further comprising the first applied fiducial in the second array image (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) (Frenz - [pg. 126] “In some embodiments, fiducial markers can be precisely placed in the field of view (e.g., at known locations on a substrate). In this instance, a fiducial marker can be stamped, attached, or synthesized on the substrate and contacted with a biological sample.” wherein the first applied fiducial is a fiducial marker), wherein the sample obscures the array fiducial and the first applied fiducial in the overlay (Frenz - [pg. 126] “An image of the substrate and the tissue section can be obtained, and the position of the fluorophore within the tissue section image can be determined (e.g., by reviewing an optical image of the tissue section overlaid with the fluorophore detection).” wherein the array fiducial and the first applied fiducial is the fluorophore; wherein it is obvious to one of ordinary skill in the art for the sample to obscure the array fiducial and the first applied fiducial in the overlay because Frenz teaches reviewing an optical image of the tissue section overlaid with the fluorophore detection so an image of the substrate and tissue section can be obtained.);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial relative to the first applied fiducial in the first array image based on the first coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the first applied fiducial is fiducial markings and a first coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the sample relative to the first applied fiducial in the second array image based on the second coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the first applied fiducial is fiducial markings and a second coordinate system is the alignment sub-system); and
comparing, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the first array image and the location of the sample in the second array image (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings and the sample is a substrate) (Wilkinson - [0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 90, Frenz in view of Wilkinson teaches the method of claim 89, wherein the first applied fiducial is one of a stamp, a sticker, a drawing, or a laser etching located on a substrate on which the array and the array fiducial are located (Frenz - [pg. 126] “In some embodiments, fiducial markers can be precisely placed in the field of view (e.g., at known locations on a substrate). In this instance, a fiducial marker can be stamped, attached, or synthesized on the substrate and contacted with a biological sample.” wherein the first applied fiducial is a fiducial marker).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 91, Frenz in view of Wilkinson teaches the method of claim 90, wherein the first applied array fiducial is formed from a material including a dye, a chemical, a contrast agent, or a nanoparticle (Frenz - [pg. 127] “For example, a fiducial marker can be a nanoparticle, e.g., a nanorod, a nanowire, a nanocube, a nanopyramid, or a spherical nanoparticle.” wherein the first applied array fiducial is a fiducial marker).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 92, Frenz in view of Wilkinson teaches the method of claim 91, wherein the material forming the first array fiducial improves a visible contrast of the first applied array fiducial (Frenz - [pg. 127] “For example, a fiducial marker can be a nanoparticle, e.g., a nanorod, a nanowire, a nanocube, a nanopyramid, or a spherical nanoparticle.” wherein the first applied array fiducial is a fiducial marker) (Frenz - [pg.152] “In some embodiments, special types of nanoparticles with more than one distinct physical property can be used to make the beads physically distinguishable.”).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 93, Frenz in view of Wilkinson teaches the method of claim 83, wherein the first array image is acquired from a substrate comprising the array, the array fiducial, and at least one spacer (Frenz - [pg. 72] “For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array,”) (Frenz - [pg. 24] “This system can include (shown as a rectangle, from left to right): a biological sample, optional spacer of oil or air, optional buffer, substrate comprising probes, optional spacer of oil or air, and optional buffer.”), the method further comprising
receiving, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the second array image data further comprising the at least one spacer in the overlay in the second array image (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) (Frenz - [pg. 24] “This system can include (shown as a rectangle, from left to right): a biological sample, optional spacer of oil or air, optional buffer, substrate comprising probes, optional spacer of oil or air, and optional buffer.”), wherein a location of the sample is associated with the second coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a second coordinate system is the alignment sub-system);
registering, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the first array image to the second array image by aligning the location of the array fiducial and the location of the sample in a common coordinate system comprising the first coordinate system and the second coordinate system, the common coordinate system further comprising the location of the array fiducial and the location of the sample (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a common coordinate system comprising the first coordinate system and the second coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the first array image based on the common coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the common coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the sample in the second array image based on the common coordinate system (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the common coordinate system is the alignment sub-system); and
comparing, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the first array image and the location of the sample in the second array image using the common coordinate system (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings, the sample is a substrate, and the common coordinate system is the alignment sub-system) (Wilkinson - [0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
The motivation for combining Frenz and Wilkinson is the same motivation as used for claim 83.
Regarding claim 96, the claim recites similar limitations to claim 85 but in the form of a system. Therefore, claim 96 recites similar limitations to claim 85 and is rejected for similar rationale and reasoning (see the analysis for claim 85 above).
Regarding claim 97, the claim recites similar limitations to claim 86 but in the form of a system. Therefore, claim 97 recites similar limitations to claim 86 and is rejected for similar rationale and reasoning (see the analysis for claim 86 above).
Regarding claim 99, the claim recites similar limitations to claim 89 but in the form of a system. Therefore, claim 99 recites similar limitations to claim 89 and is rejected for similar rationale and reasoning (see the analysis for claim 89 above).
Regarding claim 100, the claim recites similar limitations to claim 90 but in the form of a system. Therefore, claim 100 recites similar limitations to claim 90 and is rejected for similar rationale and reasoning (see the analysis for claim 90 above).
Regarding claim 101, the claim recites similar limitations to claim 91 but in the form of a system. Therefore, claim 101 recites similar limitations to claim 91 and is rejected for similar rationale and reasoning (see the analysis for claim 91 above).
Regarding claim 102, the claim recites similar limitations to claim 92 but in the form of a system. Therefore, claim 102 recites similar limitations to claim 92 and is rejected for similar rationale and reasoning (see the analysis for claim 92 above).
Claims 87, 94- 95, and 98 are rejected under 35 U.S.C. 103 as being unpatentable of Frenz et al., WO 2020123316, (hereinafter “Frenz”) in view of Wilkinson et al., US 20160302870 A1, (hereinafter “Wilkinson”) in view of Abbey et al., US 20220091307, (hereinafter “Abbey”).
Regarding claim 87, Frenz in view of Wilkinson teaches the method of claim 85, wherein the first array image is acquired (Frenz - [pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) (Frenz - [pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein an array fiducial is a fiducial marker).
Frenz in view of Wilkinson does not specifically disclose at a first illumination causing a contrast of the sample to be lower than a contrast, and at a second illumination causing a contrast of the sample to be higher than a contrast.
However, Abbey teaches at a first illumination causing a contrast of the sample to be lower than a contrast, and at a second illumination causing a contrast of the sample to be higher than a contrast ([0027] “The image formed from the light emitted from the sample by fluorescence can be formed in a first time period, and the colour contrast image can be formed in a second time period. In some embodiments, illuminating the sample with light so that said light interacts with the sample and sample holder can include using a first illumination spectrum in the first time period, and a second illumination spectrum in the second time period. The first illumination spectrum can be selected on the basis of a fluorescence property of the sample.” wherein a first illumination causing a contrast of the sample to be lower than a contrast is a first illumination spectrum in the first time period and a second illumination causing a contrast of the sample to be higher than a contrast is a second illumination spectrum in the second time period where the sample is illuminated; It is obvious to one of ordinary skill in the art that distinct illumination periods with respective contrasts can be used to illuminate certain areas of interest because Abbey teaches distinct illumination periods with associating contrasts to illuminate the sample and sample holder respectively).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the array fiducial detecting method of Frenz in view of Wilkinson with distinct illumination periods and associating contrasts of Abbey to illuminate the sample and the array fiducial respectively.
Regarding claim 94, Frenz in view of Wilkinson teaches the method of claim 87, wherein the second array image is acquired a substrate comprising the array, the array fiducial, and at least one spacer visible in the second array image acquired (Frenz - [pg. 72] “For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array,”) (Frenz - [pg. 24] “This system can include (shown as a rectangle, from left to right): a biological sample, optional spacer of oil or air, optional buffer, substrate comprising probes, optional spacer of oil or air, and optional buffer.”), the method further comprising
receiving, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), second array image data comprising a second array image acquired (Frenz - [pg. 72] “For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array,”) (Frenz - [pg. 24] “This system can include (shown as a rectangle, from left to right): a biological sample, optional spacer of oil or air, optional buffer, substrate comprising probes, optional spacer of oil or air, and optional buffer.”);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the second array image acquired (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a first coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the sample in the second array image acquired (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a second coordinate system is the alignment sub-system);
registering, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the second array image acquired at the (Frenz - [pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a common coordinate system comprising the first coordinate system and the second coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the second array image acquired (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings and the common coordinate system is the alignment sub-system);
determining, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the sample in the second array image acquired (Frenz - [0027] “The image formed from the light emitted from the sample by fluorescence can be formed in a first time period, and the colour contrast image can be formed in a second time period. In some embodiments, illuminating the sample with light so that said light interacts with the sample and sample holder can include using a first illumination spectrum in the first time period, and a second illumination spectrum in the second time period. The first illumination spectrum can be selected on the basis of a fluorescence property of the sample.”) (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the sample is a substrate and the common coordinate system is the alignment sub-system); and
comparing, by the data processor (Frenz - [pg. 362] “In some embodiments, control unit 2228 includes an electronic processor and software instructions that are readable by the electronic processor, and cause the processor to carry out the steps describe herein.”), the location of the array fiducial in the second array image acquired (Frenz - [pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings, the sample is a substrate, and the common coordinate system is the alignment sub-system) (Wilkinson - [0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
Frenz in view of Wilkinson does not specifically disclose the first illumination and the second illumination.
However, Abbey teaches the first illumination and the second illumination ([0027] “The image formed from the light emitted from the sample by fluorescence can be formed in a first time period, and the colour contrast image can be formed in a second time period. In some embodiments, illuminating the sample with light so that said light interacts with the sample and sample holder can include using a first illumination spectrum in the first time period, and a second illumination spectrum in the second time period. The first illumination spectrum can be selected on the basis of a fluorescence property of the sample.”).
The motivation for combining Frenz, Wilkinson and Abbey is the same motivation as used for claim 87.
Regarding claim 95, Frenz teaches a system for detecting fiducials associated with an array, the system comprising:
a sample holder comprising
a first retaining mechanism configured to retain a first substrate received within the first retaining mechanism, the first substrate comprising a sample ([pg. 358] “Within chamber 2202, a first holder 2204 holds a first substrate 2206 on which a sample 2208 is positioned. Sample chamber 2202 also includes a second holder 2210 that holds a second substrate 2212 with an array of features 2214, as described above.” wherein a first retaining mechanism is a first holder), and
a second retaining mechanism configured to retain a second substrate received within the second retaining mechanism, the second substrate comprising an array and an array fiducial ([pg. 358] “Within chamber 2202, a first holder 2204 holds a first substrate 2206 on which a sample 2208 is positioned. Sample chamber 2202 also includes a second holder 2210 that holds a second substrate 2212 with an array of features 2214, as described above.” wherein a second retaining mechanism is a second holder and an array and an array fiducial are an array of features), the sample holder configured to adjust a location of the first substrate relative to the second substrate to cause all or a portion of the sample to be aligned with the array ([pg. 359] “To initiate interaction between sample 2208 and feature array 2214, the sample and array are brought into spatial proximity. To facilitate this step, second holder 2210—under the control of control unit 2228—can translate second substrate 2212 in any of the x-, y-, and z-coordinate directions. In particular, control unit 2228 can direct second holder 2210 to translate second substrate 2212 in the z-direction so that sample 2208 contacts, or nearly contacts, feature array 2214.”);
a first computing device communicatively coupled to the microscope and to the sample holder, the computing device comprising a display, a data processor, and a non-transitory computer readable storage medium storing computer readable and executable instructions ([pg. 391] “The network 3130 can include one or more computer servers, which can enable distributed computing, such as cloud computing.” wherein a first computing device is the network)) ([pg. 362] “FIG. 22C is a schematic diagram showing one example of control unit 2228, including an electronic processor 2280, a memory unit 2282, a storage device 2284, and an input/output interface 2286. Processor 2280 is capable of processing instructions stored in memory unit 2282 or in storage device 2284, and to display information on input/output interface 2286.”) ([pg. 362] “Memory unit 2282 stores information. In some embodiments, memory unit 2282 is a computer-readable medium.”), which when executed cause the data processor to perform operations comprising
receiving first array image data comprising a first array image of the second substrate, the first array image comprising the array and the array fiducial ([pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) ([pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein an array fiducial is a fiducial marker);
receiving second array image data comprising a second array image comprising an overlay of the sample of the first substrate and the array of the second substrate, and the array fiducial of the second substrate ([pg. 72] “In some embodiments, the biological sample is contacted with two or more arrays (e.g., flexible arrays, as described herein). For example, after a subcellular region is permeabilized and a biological analyte from the subcellular region is captured on a first array, the first array can be removed, and a biological analyte from a different subcellular region can be captured on a second array.”) ([pg. 125] “In some embodiments, a fiducial marker can be present on a substrate to provide orientation of the biological sample. In some embodiments, a microsphere can be coupled to a substrate to aid in orientation of the biological sample.” wherein an array fiducial is a fiducial marker), wherein the sample obscures the array fiducial in the overlay ([pg. 126] “An image of the substrate and the tissue section can be obtained, and the position of the fluorophore within the tissue section image can be determined (e.g., by reviewing an optical image of the tissue section overlaid with the fluorophore detection).” wherein the array fiducial is the fluorophore);
determining the location of the array fiducial in the first array image based on a first coordinate system ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a first coordinate system is the alignment sub-system);
determining the location of the sample in the second array image based on the first coordinate system ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein a second coordinate system is the alignment sub-system);
comparing ([pg. 359] “Alignment sub-system 2230 can be implemented in a variety of ways. In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212.” wherein the array fiducial is fiducial markings and the sample is a substrate); and
providing ([pg. 359] “In some embodiments, for example, alignment sub-system 2230 includes an imaging unit that obtains one or more images showing fiducial markings on first substrate 2206 and/or second substrate 2212. Control unit 2218 analyzes the image(s) to determine appropriate translations of second substrate 2212 in the x- and/or y-coordinate directions to ensure that sample 2208 and feature array 2214 are aligned prior to translation in the z-coordinate direction.” wherein the array fiducial is fiducial markings and the sample is a substrate).
Frenz does not specifically disclose comparing the location of the array fiducial in the first array image and the location of the sample in the second array image; and providing the location of the array fiducial relative to the location of the sample based on the comparing.
However, Wilkinson teaches comparing the location of the array fiducial in the first array image and the location of the sample in the second array image; and providing the location of the array fiducial relative to the location of the sample based on the comparing (Wilkinson - [0015] “The method further includes comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone and, based on comparison results, determining an indication of precision of alignment of the instrument in the surgical procedure on the portion of the bone relative to the designed alignment of the instrument to the portion of the bone.” wherein comparing the location of the array fiducial to the location of the sample is comparing the three-dimensional spatial position and orientation of the instrument relative to the portion of the bone with a designed alignment of the instrument to the portion of the bone).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a step to compare the location of the array fiducial and the location of the sample of Wilkinson in the method for detecting fiducials associated with an array of Frenz to ensure the precision of alignment between the array fiducial and sample.
Frenz in view of Wilkinson does not specifically disclose a microscope operatively coupled to the sample holder, the microscope configured to view the first substrate and the second substrate within the sample holder and to acquire image data associated with the sample and/or the array.
However, Abbey teaches a microscope operatively coupled to the sample holder, the microscope configured to view the first substrate and the second substrate within the sample holder and to acquire image data associated with the sample and/or the array ([0035] “The system can include a reflected light microscope having an image forming system, and an illumination system, and sample holder having an upper surface and a lower surface, the upper surface having a plasmonic layer associated therewith, the plasmonic layer including a periodic array of sub-micron structures. The system can include an image capture system to generate at least one image of the sample.” wherein the first and second substrates are the samples).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the array fiducial detecting method of Frenz in view of Wilkinson to have a microscope coupled to the sample holder of Abbey to ensure stability and protection of the samples.
Regarding claim 98, the claim recites similar limitations to claim 87 but in the form of a system. Therefore, claim 98 recites similar limitations to claim 87 and is rejected for similar rationale and reasoning (see the analysis for claim 87 above).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/AMANDA H PEARSON/Examiner, Art Unit 2666
/EMILY C TERRELL/Supervisory Patent Examiner, Art Unit 2666
/EMILY C TERRELL/Supervisory Patent Examiner, Art Unit 2666