DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
2. Applicant’s amendments filed on 10/29/2025 have been entered. Claims 1, 11, 18, 22-24, 26, 32 and 39 have been amended. Claim 10 has been canceled. Claims 1-3, 7-8, 11, 13-14, 16-18, 22-24, 26, 32, 39, 42, and 44 are pending in this application, with claims 1, 18 and 39 being independent.
Response to Arguments
3. Applicant’s arguments, see page 6, filed 10/29/2025, with respect to the claim objections have been fully considered and are persuasive. The amendments to the claims are sufficient to overcome the informalities of the previous claims; thus the objections to these claims have been withdrawn.
4. Applicant's arguments filed on 10/29/2025, with respect to the 102&103 rejections have been fully considered but are moot in view of the new grounds of rejection.
Examiner notes that independent claims 1, 18 and 39 have been amended to include new limitation. Examiner finds these limitations to be unpatentable as can be found in below detail action.
In light of the current Office Action, the Examiner respectfully submits that independent claims 1, 7 and 15 are rejected in view of newly discovered reference(s) to Akazawa (US-2021/0110536-A1).
On Applicant's Remarks, the Applicant argues that the dependent claims are not taught by the prior art, insomuch as they depend from claims that are not taught by the prior art. Examiner respectfully disagrees with these arguments, for the reasons discussed below.
Claim Rejections - 35 USC § 103
5. 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.
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.
6. Claims 1-3 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Adey et al., (“Adey”) [US-2018/0128714-A1] in view of Vink et al., (“Vink”) [US-2018/0225872-A1], further in view of Akazawa, (“Akazawa”) [US-2021/0110536-A1]
Regarding claim 1, Adey discloses a system for transferring pathologist markings (Adey- Figs. 1, 3 and ¶0076, at least disclose an exemplary computer-based tissue dissection instrument (or system) 100, an exemplary computer-implemented method, and an exemplary clinical workflow residing on a workflow module 320 (FIG. 3), for meso-dissection of biological specimens and tissue slides in accordance with the present disclosure […] a separate computer and monitor can be used), comprising:
an imaging device for imaging a stained slide and an unstained slide (Adey- ¶0003, at least discloses either stained or unstained paraffin embedded tissue sections may be dissected for further molecular or genomic analysis; Fig. 3 and ¶0086, at least disclose The camera 325 captures desired images of the slides);
a display for displaying one or more images of the stained slide and the unstained slide (Adey- ¶0003, at least discloses either stained or unstained paraffin embedded tissue sections may be dissected for further molecular or genomic analysis; ¶0082, at least discloses monitor; Figs. 27, 29-31 depicting various screen shots of images of slides comprising a reference slide 2625; ¶0143, at least discloses the reference slide 2625 can be the first cut of an FFPE block that has an H&E stain);
a first application used in aligning the one or more images of the stained slide or the unstained slide (Adey- Figs. 25, 30 and ¶0143, at least disclose the steps 2545 and 2550 of the workflow 2500 for respectively aligning the reference slide 2625 with the various sample slides 465, 466, 467, and for drawing or annotating the areas of interest (“AOIs”) […] the reference slide 2625 can be the first cut of an FFPE block that has an H&E stain […] The reference slide 2625 is then aligned to the tissues on the serial slides, which is a crucial step to identify the AOIs 3000), and
wherein said aligning the one or more images is performed manually based on visual cues (Adey- ¶0146, at least discloses The transfer and alignment of the reference slide image onto the sample slides 465, 466, 467, 468 can be done manually by the user or automatically by the workflow 2500; ¶0141, at least discloses the term “hotspots” refers to the sections of the tissue sample that needs to be captured in a higher resolution. The hotspots are also status indicators and they indicate if the tissue has been captured or not, and if the user checked the alignment and areas of interest on each tissue sample 406 [Wingdings font/0xE0] the sections of the tissue sample captured in a higher resolution and the hotspots are also status indicators suggests “visual cues”); and
a second application used in transferring a digital marking of one or more features (Adey- Figs. 30-31 and ¶0145-0146, at least disclose Once the reference slide is aligned with the first tissue sample slide 465, the AOIs 3000 are subsequently transferred on to the remaining sample slides 466, 467, 468 by the software of workflow 2500. The transfer and alignment of the reference slide image onto the sample slides 465, 466, 467, 468 can be done manually by the user or automatically by the workflow 2500).
Adey does not explicitly disclose wherein said aligning comprises positioning and/or orienting the one or more images of the stained slide or the unstained slide, and wherein said aligning the one or more images is performed manually by an operator based on visual cues without using image registration algorithms.
However, Vink discloses
positioning and/or orienting the one or more images of the stained slide or unstained slide (Vink- Fig. 10 and ¶0191-0192, at least disclose the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52. Alternatively, the sample slide 14 can be placed in front of the display 52, in particular of the top surface 54 of the display 52. The relative position between sample slide 14 and the display 52 can be fixed. In an example, the display 52 can highlight a region 56, where the slide 14 is to be arranged […] the sample slice 18 is arranged on a transparent substrate 30 of the sample slide 14. The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18 [Wingdings font/0xE0] region 56 provides the spatial reference for positioning and orienting sample slice 18 relative to the markings of reference slide 12 for transferring annotation 22 and removing region 48 from the stained and annotated reference slide 12).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey to incorporate the teachings of Vink, and apply the spatial reference for positioning and orienting sample slice into Adey’s teachings for positioning and/or orienting the one or more images of the stained slide or the unstained slide.
Doing so would facilitate a transformation of information provided at the reference slide to a sample slide, wherein the reference slide and the sample slide contain slices of the same biological material block.
The prior art does not explicitly disclose, but Akazawa discloses
said aligning the one or more images is performed manually by an operator based on visual cues without using image registration algorithms (Akazawa- ¶0042, at least discloses When the operator sets the culture plate 13 including a cell 14 at a predetermined position and performs predetermined operations with the input unit 30; Fig. 3 and ¶0054, at least disclose It is desirable that the position, the direction, the size, etc., of a cell are exactly the same between a pair of the IHM phase image and the stained fluorescent image […] it is inevitable that the position, the direction, the size, etc., of a cell differ between the IHM phase image and the stained fluorescent image. Therefore, the image alignment processing unit 52 performs image processing, such as, e.g., translating, rotating, enlarging, and reducing one of images to align both the images (Step S12). Generally, it is preferable to perform the image processing so as to align the stained fluorescent image with reference to the IHM phase image in which a cell is more clearly visible. This alignment operation may be performed manually by the operator while referring to, for example, an edge of a well, a mark on a culture plate, or the like, or may be automatically performed with a predetermined algorithm [Wingdings font/0xE0] suggests alignment operation may be performed manually by the operator without using image registration algorithms).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey/Vink to incorporate the teachings of Akazawa, and apply the alignment operation may be performed manually by the operator into imaging a stained slide and an unstained slide, as taught by Adey/Vink in order a first application used in aligning the one or more images of the stained slide or the unstained slide, wherein said aligning comprises positioning and/or orienting the one or more images of the stained slide or the unstained slide, and wherein said aligning the one or more images is performed manually by an operator based on visual cues without using image registration algorithms.
Doing so would provide a cell image analysis method and a cell analysis device capable of satisfactorily observing a shape of a cell non-invasively.
Regarding claim 2, Adey in view of Vink and Akazawa, discloses the system of claim 1, and further discloses wherein the second application is used in transferring the digital marking of the one or more features from an image of the stained slide to an image of the unstained slide (Adey- and ¶0143, at least discloses The reference slide can be equated to a map with coordinates that identify the areas of interest 3001, 3002, 3003, 3004 (collectively referred to as AOI or AOIs 3000); Fig. 31 and ¶0147, at least disclose a screen shot 3100 that shows the various AOIs 3001, 3002, 3003, 3004 (or 3000) projected onto the tissue sample slide 465).
Regarding claim 3, Adey in view of Vink and Akazawa, discloses the system of claim 1, and further discloses wherein the second application is used in transferring the digital marking of the one or more features (see Claim 2 rejection for detailed analysis), and does not explicitly disclose transferring the digital marking of the one or more features into coordinates for use in further processing.
However, Vink discloses
transferring the digital marking of the one or more features into coordinates for use in further processing (Vink- 0175, at least disclose reference coordinates are determined for the reference slide 12, and reference coordinates are transferred to sample coordinates for the sample slide 14, in order to determine on the basis of the transformation a spatial link. Preferably, the determination unit 40 is configured to perform this determination).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey/Akazawa to incorporate the teachings of Vink, and apply the reference coordinates into transferring the digital marking of the one or more features, as taught by Adey/Akazawa for transferring the digital marking of the one or more features into coordinates for use in further processing.
The same motivation that was utilized in the rejection of claim 1 applies equally to this claim.
Regarding claim 7, Adey in view of Vink and Akazawa, discloses the system of claim 3, and further discloses wherein further processing comprises one or more downstream processes that include at least a dissection (Adey - 0019, at least discloses the user can use different buffer solutions for the extraction process, allowing the user to closely integrate the dissection process with a downstream tissue extraction process, thus reducing the number of steps and improving the tissue extraction times. The workflow enables the user to verify that the dissection buffer solution was collected using color recognition) or separation of a portion of a biological specimen (Adey - 0183, at least discloses initiating a dissection, by the instrument, of one or more biological specimens based on the annotations).
Regarding claim 8, Adey in view of Vink and Akazawa, discloses the system of claim 1, wherein the first application is a metrology software program used for inspection of physical properties of the stained slide or the unstained slide (Adey- ¶0012, at least discloses the instrument and the workflow provide the user with the ability to control all aspects of the dissection process […] The workflow permits the user to input the tissue thickness and nucleic density of the tissue samples. With this input, the workflow can actively monitor how much volume or nucleic concentration is collected, and can alert the user when the minimum amount of buffer solution is collected based on the user's predetermined preferences Viewing in real time the reference and serial cut selection; ¶0080, at least discloses the real time viewing [inspection] of the reference and serial cut selection; the dissection across multiple serial selections at one time; and changing the lighting conditions, focus, iris to identify and compare key cellular tissue sections on a slide; Fig. 29 and ¶0139-0141, at least disclose screen shot associated with a “Sample View” step 2540 of the workflow 2500 [metrology software program] […] At this step 2540, the user can create, delete, or duplicate “hotspots” on the reference slide 2625. As used herein, the term “hotspots” refers to the sections of the tissue sample that needs to be captured in a higher resolution), and/or wherein the second application is a marking software program used in digitally marking the one or more features (Adey- Figs. 30-31 and ¶0144-0146, at least disclose The objective is to collect as much volume of the tissue sample 406 as possible from the AOIs, to be analyzed in various downstream applications [marking software program] […] Once the reference slide is aligned with the first tissue sample slide 465, the AOIs 3000 are subsequently transferred on to the remaining sample slides 466, 467, 468 by the software of workflow 2500. The transfer and alignment of the reference slide image onto the sample slides 465, 466, 467, 468 can be done manually by the user or automatically by the workflow 2500).
7. Claim 11, 13-14 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Adey in view of Vink, further in view of Akazawa, still further in view of Yeung et al., (“Yeung”) [US-2019/0390252-A1]
Regarding claim 11, Adey in view of Vink and Akazawa, discloses the system of claim 1, and further discloses wherein the orienting of the one or more images of the stained slide or the unstained slide (see Claim 10 rejection for detailed analysis) and does not explicitly disclose, but Yeung discloses comprises one or more operations of a pan, a rotate, a zoom, or a mirror image of the one or more images of the stained slide or the unstained slide (Yeung- ¶0014, at least discloses an image overlay engine configured to map the overlay the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are rotated and aligned), or wherein the one or more images of the stained slide or the unstained slide are overlaid on one another to obtain an alignment of the one or more images of the stained slide or the unstained slide (Yeung- ¶0014, at least discloses an image overlay engine configured to map the overlay the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are rotated and aligned; ¶0020, at least discloses overlaying the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are aligned).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey/Vink/Akazawa to incorporate the teachings of Yeung, and apply the mapping the overlay and the sample are rotated and aligned into Adey/Vink/Akazawa’s teachings in order the orienting of the one or more images of the stained slide or unstained slide comprises one or more operations of a pan, a rotate, a zoom, or a mirror image of the one or more images of the stained slide or unstained slide, or wherein the one or more images of the stained slide or unstained slide are overlaid on one another to obtain an alignment of the one or more images of the stained slide or unstained slide.
Doing so would useful for separating and isolating regions of interest (ROI) and regions of non-interest (RONI) in the substrate, e.g., biological substrates such as histology specimen.
Regarding claim 13, Adey in view of Vink and Akazawa the system of claim 1, and does not explicitly disclose, but Yeung discloses wherein the one or more features comprises one or more dots, straight or curve lines, or a polyline (Yeung- Fig. 6 and ¶0176, at least disclose an exemplary slide 600 with undesired “X” regions 602 marked and a region of interest (ROI) 604 (e.g., an “S” region) [curve lines] between the “X” regions 602), and wherein the second application is used in recognizing the one or more dots or lines, or the polyline (Yeung- Fig. 6 and ¶0176-0177, at least disclose an exemplary slide 600 with undesired “X” regions 602 marked and a region of interest (ROI) 604 (e.g., an “S” region) [curve lines] between the “X” regions 602 […] FIG. 7 illustrates a process where undesired “X” regions 712 and 714 are removed from a slide 720 by overlaying a mask 700 over the slide 720. For example, a mask slide 710 may be prepared having undesirable “X” regions 702, 704 and desirable “S” region 706 delineated. For example, the “X” regions 702, 704 and the “S” region 706 may be determined by the processes described above), and converting the one or more dots or lines, or the polyline into the digital marking of the one or more features (Yeung- ¶0009, at least discloses digitalize a pen marking into a digital marking, (c) perform an object based or other algorithm to match marking coordinates on a substrate to the associated substrates, (d) extract marked sample ROI into a container; ¶0144, at least discloses marking may be manually transferred via path 3. For example, in path 3 direct marking transfer from submission substrate(s) are not available, and require a pathologist to manually perform digital marking on each associated substrate individually; ¶0167, at least discloses an easy-to-use digital annotation tool and object-based algorithm to match digital marking across substrates while maintaining the specimen's morphology that eliminates the need to generate sets of Unstained Substrates (USS) for manual microdis section).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey/Vink/Akazawa to incorporate the teachings of Yeung, and apply the digital marking into Adey/Vink/Akazawa’s teachings in order the one or more features comprises one or more dots, straight or curve lines, or a polyline, and wherein the second application is used in recognizing the one or more dots or lines, or the polyline, and converting the one or more dots or lines, or the polyline into the digital marking of the one or more features.
Doing so would useful for separating and isolating regions of interest (ROI) and regions of non-interest (RONI) in the substrate, e.g., biological substrates such as histology specimen.
Regarding claim 14, Adey in view of Vink, Akazawa and Yeung, discloses the system of claim 13, and further discloses wherein the one or more features are drawn manually by an operator (Yeung- ¶0144, at least discloses marking may be manually transferred via path 3. For example, in path 3 direct marking transfer from submission substrate(s) are not available, and require a pathologist to manually perform digital marking on each associated substrate individually; ¶0167, at least discloses an easy-to-use digital annotation tool and object-based algorithm to match digital marking across substrates while maintaining the specimen's morphology that eliminates the need to generate sets of Unstained Substrates (USS) for manual microdis section).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Adey to incorporate the teachings of Yeung, and apply the manually perform digital marking into Adey’s teachings in order the one or more features are drawn manually by an operator.
The same motivation that was utilized in the rejection of claim 13 applies equally to this claim.
Regarding claim 16, Adey in view of Vink, Akazawa and Yeung, discloses the system of claim 13, and further discloses wherein the one or more images of the stained slide comprises a low-resolution image of the stained slide (Adey- ¶0144, at least discloses Once the tissue dissection instrument 100 is initialized, the workflow 2500 proceeds to step 2515 to capture a low resolution image of the stage 400 and to read the various barcodes, as described earlier, using the barcode reader 830; Fig. 29 and ¶0139, at least disclose In the event that the reference slide 2625 is mounted on the stage 400, the user has the ability to capture a low resolution reference image, and thus leaves the “Import Reference” field blank in the corresponding setup page).
Regarding claim 17, Adey in view of Vink, Akazawa and Yeung, discloses the system of claim 16, and further discloses wherein one or more boundary edges or corners of the low-resolution image is used (Adey- ¶0144, at least discloses Once the tissue dissection instrument 100 is initialized, the workflow 2500 proceeds to step 2515 to capture a low resolution image of the stage 400 and to read the various barcodes, as described earlier, using the barcode reader 830; Fig. 29 and ¶0139, at least disclose In the event that the reference slide 2625 is mounted on the stage 400, the user has the ability to capture a low resolution reference image, and thus leaves the “Import Reference” field blank in the corresponding setup page; Yeung- ¶0178, at least discloses At the front face of this portion, there can be one or plurality of cutting edges that will dissect tissue from the slide during the rotations of the milling tool; ¶0180, at least discloses The distal cutting region can have an inner lumen used to collect tissue ROI and has one or plurality of cutting edges radially dispose at the front face) in the recognizing and in the converting of the one or more dots or lines, or the polyline into the digital marking of the one or more features (see Claim 13 rejection for detailed analysis).
8. Claims 18, 22 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Vink et al., (“Vink”) [US-2018/0225872-A1] in view of Akazawa, (“Akazawa”) [US-2021/0110536-A1]
Regarding claim 18, Vink discloses a method for digitally transferring markings (Vink- Fig. 14 and ¶0219-0225, at least disclose a method 65), comprising:
obtaining an image of a stained slide under an imager (Vink- ¶0023, at least discloses the reference slice is a stained slice of the object, and the sample slice is an unstained or differently stained slice of the object; Fig. 14 and ¶0220, at least disclose a digital reference image 26 of a reference slide 12 comprising a reference slice 16 of an object 10 comprising biological material is provided; ¶0091, at least discloses reference slice 16 is stained, in particular when the reference image 26 is generated);
displaying the image of the stained slide onto a display (Vink- Fig. 14 and ¶0221, at least disclose a digital annotation 22 in the reference image 26 is provided; ¶0140, at least discloses at least one annotation 22 can be digitally applied to the digital image of the reference slide 12, in order to form the digital reference image 26 of the reference slide 12 including its digital annotation 22 [Wingdings font/0xE0] suggests displaying the digital reference image (image of the stained slide) onto a display);
aligning the image of the stained slide with an unstained slide (Vink- Fig. 10 and ¶0191-0192, at least disclose the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52. Alternatively, the sample slide 14 can be placed in front of the display 52, in particular of the top surface 54 of the display 52. The relative position between sample slide 14 and the display 52 can be fixed. In an example, the display 52 can highlight a region 56, where the slide 14 is to be arranged […] the sample slice 18 is arranged on a transparent substrate 30 of the sample slide 14. The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18 [Wingdings font/0xE0] region 56 provides the spatial reference for aligning the image of the sample slice 18 [unstained slide] relative to the markings of reference slide 12 [stained slide] for transferring annotation 22 and removing region 48 from the stained and annotated reference slide 12); and
transferring one or more markings from the image of the stained slide to the unstained slide (Vink- Fig. 14 and ¶0225, at least disclose step 76, the annotation 22 is physically illustrated at the annotation position 42 at the sample slide 14 in view of preceding steps 70-74);
Vink does not explicitly discloses wherein the aligning is performed manually based on visual cues, without using image registration algorithms.
However, Akazawa discloses
the aligning is performed manually based on visual cues, without using image registration algorithms (Akazawa- ¶0042, at least discloses When the operator sets the culture plate 13 including a cell 14 at a predetermined position and performs predetermined operations with the input unit 30; Fig. 3 and ¶0054, at least disclose It is desirable that the position, the direction, the size, etc., of a cell are exactly the same between a pair of the IHM phase image and the stained fluorescent image […] it is inevitable that the position, the direction, the size, etc., of a cell differ between the IHM phase image and the stained fluorescent image. Therefore, the image alignment processing unit 52 performs image processing, such as, e.g., translating, rotating, enlarging, and reducing one of images to align both the images (Step S12). Generally, it is preferable to perform the image processing so as to align the stained fluorescent image with reference to the IHM phase image in which a cell is more clearly visible. This alignment operation may be performed manually by the operator while referring to, for example, an edge of a well, a mark on a culture plate, or the like, or may be automatically performed with a predetermined algorithm [Wingdings font/0xE0] suggests alignment operation may be performed manually by the operator without using image registration algorithms).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink to incorporate the teachings of Akazawa, and apply the alignment operation may be performed manually by the operator into imaging a stained slide and an unstained slide, as taught by Vink for aligning the image of the stained slide with an unstained slide, wherein the aligning is performed manually based on visual cues, without using image registration algorithms.
Doing so would provide a cell image analysis method and a cell analysis device capable of satisfactorily observing a shape of a cell non-invasively.
Regarding claim 22, Vink in view of Akazawa, discloses the method of claim 18, and further discloses the method comprising marking the image of the stained slide prior to transferring the one or more markings (Vink- ¶0049, at least discloses the reference slide has been marked with a region of interest and an annotation, which can be associated with the region of interest. If such reference slide is scanned, the respective reference image contains the information about the marked region of interest as well as the annotation, too; ¶0175, at least discloses reference coordinates are determined for the reference slide 12, and reference coordinates are transferred to sample coordinates for the sample slide 14, in order to determine on the basis of the transformation a spatial link), wherein marking the image of the stained slide (As discussed above) comprises drawing one or more features on the display (Vink- Fig. 10 and ¶0188-0192, at least disclose the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52 […] the display 52 can highlight a region 56, where the slide 14 is to be arranged […] the display 52 can project light on the sample slide 14, such that the annotation 22 and/or the removing region 48 are displayed in or on the sample slide 14. Preferably, the sample slice 18 is arranged on a transparent substrate 30 of the sample slide 14. The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18).
Regarding claim 39, Vink discloses a system for transferring pathologist markings (Vink- Figs. 5-6, 10 and ¶0098-0102, at least disclose the apparatus 32 […] The sample providing unit 36 is configured to provide a digital sample image 28 of a sample slide 14 comprising a sample slice 18 of the object 10), comprising:
an imaging device for imaging a stained slide or an unstained slide (Vink- Figs. 5-6 and ¶0102, at least disclose The sample providing unit 36 is configured to provide a digital sample image 28 of a sample slide 14 [unstained slide] comprising a sample slice 18 of the object 10; ¶0112, at least discloses the sample providing unit 36 can be connected to a camera 46, wherein the camera 46 is adapted to generate a digital sample image 28 of the sample slide 14);
a display for displaying one or more images of the stained slide or the unstained slide (Vink- Fig. 10 and ¶0188-0192, at least disclose a display 52 to project light onto sample slide 14 for visually illustrating the annotation 22 and/or the removing region 48 […] the display 52 may be formed as an LCD display […] the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52);
a mechanical stage/scaffold for positioning or orienting the stained slide with respect to the unstained slide to enable physical marking of the unstained slide (Vink- Fig. 10 and ¶0191-0192, at least disclose the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52. Alternatively, the sample slide 14 can be placed in front of the display 52, in particular of the top surface 54 of the display 52. The relative position between sample slide 14 and the display 52 can be fixed. In an example, the display 52 can highlight a region 56, where the slide 14 is to be arranged […] the sample slice 18 is arranged on a transparent substrate 30 of the sample slide 14. The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18 [Wingdings font/0xE0] region 56 provides the spatial reference for positioning and orienting sample slice 18 relative to the markings of reference slide 12 [stained slide] for transferring annotation 22 and removing region 48 from the stained and annotated reference slide 12); and
an application used to digitally draw one or more features based on the physical marking (Vink- Fig. 10 and ¶0192, at least disclose The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18.) and transfer the features into coordinates to be used for further processing (Vink- ¶0175, at least discloses reference coordinates are determined for the reference slide 12, and reference coordinates are transferred to sample coordinates for the sample slide 14, in order to determine on the basis of the transformation a spatial link. Preferably, the determination unit 40 is configured to perform this determination).
Vink does not explicitly disclose the mechanical stage/scaffold is operated manually to position or orient the stained slide with respect to the unstained slide based on visual cues without using image registration algorithms.
However, Akazawa discloses
operated manually to position or orient the stained slide with respect to the unstained slide based on visual cues without using image registration algorithms (Akazawa- ¶0042, at least discloses When the operator sets the culture plate 13 including a cell 14 at a predetermined position and performs predetermined operations with the input unit 30; Fig. 3 and ¶0054, at least disclose It is desirable that the position, the direction, the size, etc., of a cell are exactly the same between a pair of the IHM phase image and the stained fluorescent image […] it is inevitable that the position, the direction, the size, etc., of a cell differ between the IHM phase image and the stained fluorescent image. Therefore, the image alignment processing unit 52 performs image processing, such as, e.g., translating, rotating, enlarging, and reducing one of images to align both the images (Step S12). Generally, it is preferable to perform the image processing so as to align the stained fluorescent image with reference to the IHM phase image in which a cell is more clearly visible. This alignment operation may be performed manually by the operator while referring to, for example, an edge of a well, a mark on a culture plate, or the like, or may be automatically performed with a predetermined algorithm [Wingdings font/0xE0] suggests alignment operation may be performed manually by the operator without using image registration algorithms).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink to incorporate the teachings of Akazawa, and apply the alignment operation may be performed manually by the operator into imaging a stained slide and an unstained slide, as taught by Vink in order a mechanical stage/scaffold for positioning or orienting the stained slide with respect to the unstained slide to enable physical marking of the unstained slide, wherein the mechanical stage/scaffold is operated manually to position or orient the stained slide with respect to the unstained slide based on visual cues without using image registration algorithms.
Doing so would provide a cell image analysis method and a cell analysis device capable of satisfactorily observing a shape of a cell non-invasively.
9. Claims 23, 26 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Vink in view of Akazawa, further in view of Yeung et al., (“Yeung”) [US-2019/0390252-A1]
Regarding claim 23, Vink in view of Akazawa, discloses the method of claim 22, and further discloses wherein marking the image of the stained slide (see Claim 22 rejection for detailed analysis), and does not explicitly disclose, but Yeung discloses the method comprises:
drawing one or more dots, straight or curve lines, or a polyline on the display (Yeung- Fig. 6 and ¶0176, at least disclose an exemplary slide 600 with undesired “X” regions 602 marked and a region of interest (ROI) 604 (e.g., an “S” region) [curve lines] between the “X” regions 602);
recognizing, via an application, the one or more drawn dots or lines, or the drawn polyline (Yeung- Fig. 6 and ¶0176-0177, at least disclose an exemplary slide 600 with undesired “X” regions 602 marked and a region of interest (ROI) 604 (e.g., an “S” region) [curve lines] between the “X” regions 602 […] FIG. 7 illustrates a process where undesired “X” regions 712 and 714 are removed from a slide 720 by overlaying a mask 700 over the slide 720. For example, a mask slide 710 may be prepared having undesirable “X” regions 702, 704 and desirable “S” region 706 delineated. For example, the “X” regions 702, 704 and the “S” region 706 may be determined by the processes described above); and
converting the one or more recognized dots or lines, or the recognized polyline into one or more digital markings (Yeung- ¶0009, at least discloses digitalize a pen marking into a digital marking, (c) perform an object based or other algorithm to match marking coordinates on a substrate to the associated substrates, (d) extract marked sample ROI into a container; ¶0144, at least discloses marking may be manually transferred via path 3. For example, in path 3 direct marking transfer from submission substrate(s) are not available, and require a pathologist to manually perform digital marking on each associated substrate individually; ¶0167, at least discloses an easy-to-use digital annotation tool and object-based algorithm to match digital marking across substrates while maintaining the specimen's morphology that eliminates the need to generate sets of Unstained Substrates (USS) for manual microdis section).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink/Akazawa to incorporate the teachings of Yeung, and apply the digital marking into Vink/Akazawa’s teachings for drawing one or more dots, straight or curve lines, or a polyline on the display; recognizing, via an application, the one or more drawn dots or lines, or the drawn polyline; and converting the one or more recognized dots or lines, or the recognized polyline into one or more digital features.
Doing so would useful for separating and isolating regions of interest (ROI) and regions of non-interest (RONI) in the substrate, e.g., biological substrates such as histology specimen.
Regarding claim 26, Vink in view of Akazawa, discloses the method of claim 18, and further discloses the method comprising:
re-orienting the unstained slide is performed manually by an operator based on visual cues without using image registration algorithms (Akazawa- ¶0042, at least discloses When the operator sets the culture plate 13 including a cell 14 at a predetermined position and performs predetermined operations with the input unit 30; Fig. 3 and ¶0054, at least disclose It is desirable that the position, the direction, the size, etc., of a cell are exactly the same between a pair of the IHM phase image and the stained fluorescent image […] it is inevitable that the position, the direction, the size, etc., of a cell differ between the IHM phase image and the stained fluorescent image. Therefore, the image alignment processing unit 52 performs image processing, such as, e.g., translating, rotating, enlarging, and reducing one of images to align both the images (Step S12). Generally, it is preferable to perform the image processing so as to align the stained fluorescent image with reference to the IHM phase image in which a cell is more clearly visible. This alignment operation may be performed manually by the operator while referring to, for example, an edge of a well, a mark on a culture plate, or the like, or may be automatically performed with a predetermined algorithm [Wingdings font/0xE0] suggests alignment operation may be performed manually by the operator without using image registration algorithms).
The prior art does not explicitly disclose, but Yeung discloses
overlaying the unstained slide on top of the image of the stained slide with the one or more digital markings (Yeung- ¶0009, at least discloses digitalize a pen marking into a digital marking; 0014, at least discloses an image overlay engine configured to map the overlay the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are rotated and aligned; ¶0020, at least discloses overlaying the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are aligned);
re-orienting the unstained slide to align and superimpose the one or more digital markings onto the unstained slide (Yeung- ¶0009, at least discloses digitalize a pen marking into a digital marking; ¶0014, at least discloses an image overlay engine configured to map the overlay the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are rotated and aligned; ¶0020, at least discloses overlaying the marker image onto the second image such that image outlines of the first affixed sample and the second affixed sample are aligned); and
marking the unstained slide (Yeung- ¶0133, at least discloses Methods for Digitally Marking ROIs on Unstained Substrates; ¶0167, at least discloses provide an easy-to-use digital annotation tool and object-based algorithm to match digital marking across substrates while maintaining the specimen's morphology that eliminates the need to generate sets of Unstained Substrates (USS) for manual microdis section);
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink to incorporate the teachings of Akazawa and Yeung, and apply the alignment operation may be performed manually by the operator and overlaying the marker image into Vink’s teachings for overlaying the marker image.
Doing so would useful for separating and isolating regions of interest (ROI) and regions of non-interest (RONI) in the substrate, e.g., biological substrates such as histology specimen.
Regarding claim 32, Vink in view of Akazawa and Yeung, discloses the method of claim 26, and further discloses wherein the re-orienting (see Claim 26 rejection for detailed analysis) comprises placing the unstained slide on a scaffold that lies on top of the display and aligning the unstained slide with the image of the stained slide by positioning the scaffold (Vink- Fig. 10 and ¶0191-0192, at least disclose the sample slide 14 is arranged on the display 52, in particular on a top surface 54 of the display 52. Alternatively, the sample slide 14 can be placed in front of the display 52, in particular of the top surface 54 of the display 52 […] the sample slice 18 is arranged on a transparent substrate 30 of the sample slide 14. The display 52 can therefore be configured to illuminate the annotation 22 and/or the removing region 48 at the sample slice 18 [Wingdings font/0xE0] region 56 provides the spatial reference for positioning and orienting sample slice 18 relative to the markings of reference slide 12 for transferring annotation 22 and removing region 48 from the stained and annotated reference slide 12), wherein the scaffold is operated manually by a user (Akazawa- ¶0054, at least discloses This alignment operation may be performed manually by the operator while referring to, for example, an edge of a well, a mark on a culture plate, or the like, or may be automatically performed with a predetermined algorithm [Wingdings font/0xE0] suggests alignment operation may be performed manually by the operator).
10. Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Vink in view of Akazawa, further in view of Yeung et al., (“Yeung”) [US-2019/0390252-A1], still further in view of Adey et al., (“Adey”) [US-2018/0128714-A1]
Regarding claim 24, Vink in view of Akazawa and Yeung, discloses the method of claim 23, and further discloses wherein one or more boundary edges or comers of the image is used in the recognizing and in the converting of the one or more dots or lines, or the polyline into the one or more digital markings (Yeung- Fig. 6 and ¶0176-0178, at least disclose an exemplary slide 600 with undesired “X” regions 602 marked and a region of interest (ROI) 604 (e.g., an “S” region) [curve lines] between the “X” regions 602 […] FIG. 7 illustrates a process where undesired “X” regions 712 and 714 are removed from a slide 720 by overlaying a mask 700 over the slide 720. For example, a mask slide 710 may be prepared having undesirable “X” regions 702, 704 and desirable “S” region 706 delineated. For example, the “X” regions 702, 704 and the “S” region 706 may be determined by the processes described above […] At the front face of this portion, there can be one or plurality of cutting edges that will dissect tissue from the slide during the rotations of the milling tool; ¶0180, at least discloses The distal cutting region can have an inner lumen used to collect tissue ROI and has one or plurality of cutting edges radially dispose at the front face [one or more boundary edges or comers of the image]; ¶0009, at least discloses digitalize a pen marking into a digital marking, (c) perform an object based or other algorithm to match marking coordinates on a substrate to the associated substrates, (d) extract marked sample ROI into a container; ¶0144, at least discloses marking may be manually transferred via path 3. For example, in path 3 direct marking transfer from submission substrate(s) are not available, and require a pathologist to manually perform digital marking on each associated substrate individually; ¶0167, at least discloses an easy-to-use digital annotation tool and object-based algorithm to match digital marking across substrates while maintaining the specimen's morphology that eliminates the need to generate sets of Unstained Substrates (USS) for manual microdis section [converting of the one or more dots or lines, or the polyline into the one or more digital features]).
The prior art does not explicitly disclose, but Adey discloses
wherein the image of the stained slide is a low-resolution image of the stained slide (Adey- ¶0144, at least discloses Once the tissue dissection instrument 100 is initialized, the workflow 2500 proceeds to step 2515 to capture a low resolution image of the stage 400 and to read the various barcodes, as described earlier, using the barcode reader 830; Fig. 29 and ¶0139, at least disclose In the event that the reference slide 2625 is mounted on the stage 400, the user has the ability to capture a low resolution reference image, and thus leaves the “Import Reference” field blank in the corresponding setup page).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink/Akazawa/Yeung to incorporate the teachings of Adey, and apply the low resolution reference image into Vink/Akazawa/Yeung’s teachings in order the image of the stained slide is a low-resolution image of the stained slide and wherein one or more boundary edges or comers of the low-resolution image is used in the recognizing and in the converting of the one or more dots or lines, or the polyline into the one or more digital features.
Doing so would provide precise, automated, quantifiable, and serial microdissection of slide-mounted biological specimen.
11. Claims 42 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Vink et al., (“Vink”) [US-2018/0225872-A1] in view of Akazawa, (“Akazawa”) [US-2021/0110536-A1], further in view of Adey et al., (“Adey”) [US-2018/0128714-A1]
Regarding claim 42, Vink in view of Akazawa, discloses the system of claim 39, and does not explicitly disclose, but Adey discloses wherein the application is a metrology software program used for inspection of physical properties of the stained slide or the unstained slide (Adey- ¶0012, at least discloses the instrument and the workflow provide the user with the ability to control all aspects of the dissection process […] The workflow permits the user to input the tissue thickness and nucleic density of the tissue samples. With this input, the workflow can actively monitor how much volume or nucleic concentration is collected, and can alert the user when the minimum amount of buffer solution is collected based on the user's predetermined preferences Viewing [inspection] in real time the reference and serial cut selection; ¶0080, at least discloses the real time viewing [inspection] of the reference and serial cut selection; the dissection across multiple serial selections at one time; and changing the lighting conditions, focus, iris to identify and compare key cellular tissue sections on a slide; Fig. 29 and ¶0139-0141, at least disclose screen shot associated with a “Sample View” step 2540 of the workflow 2500 [metrology software program] […] At this step 2540, the user can create, delete, or duplicate “hotspots” on the reference slide 2625. As used herein, the term “hotspots” refers to the sections of the tissue sample that needs to be captured in a higher resolution).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink/Akazawa to incorporate the teachings of Adey, and apply the real time viewing of the reference into Vink/Akazawa’s teachings in order the application is a metro logy software program used for inspection of physical properties of the stained slide or the unstained slide.
Doing so would provide precise, automated, quantifiable, and serial microdissection of slide-mounted biological specimen.
Regarding claim 44, Vink in view of Akazawa, discloses the system of claim 39, and does not explicitly disclose, but Adey discloses wherein further processing comprises one or more downstream processes that include at least a dissection (Adey - 0019, at least discloses the user can use different buffer solutions for the extraction process, allowing the user to closely integrate the dissection process with a downstream tissue extraction process, thus reducing the number of steps and improving the tissue extraction times. The workflow enables the user to verify that the dissection buffer solution was collected using color recognition) or separation of a portion of a biological specimen (Adey - 0183, at least discloses initiating a dissection, by the instrument, of one or more biological specimens based on the annotations).
It would have been obvious to one of ordinary in the art before the effective filing date of the claimed invention to have modified Vink/Akazawa to incorporate the teachings of Adey, and apply the dissection process into Vink/Akazawa’s teachings in order the one or more downstream processes that include at least a dissection or separation of a portion of a biological specimen.
Doing so would provide precise, automated, quantifiable, and serial microdissection of slide-mounted biological specimen.
Conclusion
12. 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.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL LE whose telephone number is (571)272-5330. The examiner can normally be reached 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kent Chang can be reached at (571) 272-7667. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL LE/Primary Examiner, Art Unit 2614