DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/22/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered and attached by the examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 19 is rejected under 35 U.S.C. 101 because the claimed invention is directed to nonstatutory subject matter. Claim 19 is non-statutory under the most recent interpretation of the Interim Guidelines regarding 35 U.S. C.101 because: the computer program product claimed is not positively disclosed in the specification as a statutory only embodiment and is not limited to non-transitory media. The broadest reasonable interpretation of a claim drawn to a computer readable medium (also called machine readable medium and other such variations) typically covers forms of non-transitory tangible media and transitory propagating signa Is per se in view of the ordinary and customary meaning of computer readable media, particularly when the specification is silent. See MPEP 2111.01. When the broadest reasonable interpretation of a claim covers a signal per se, the claim must be rejected under 35 U.S.C. § 101 as covering non-statutory subject matter. See In re Nuijten, 500 F.3d 1346, 1356-57 (Fed. Cir. 2007) transitory embodiments are not directed to statutory subject matter and Interim Examination Instructions for Evaluating Subject Matter Eligibility Under 35 U.S.C. § 101, Aug. 24, 2009; p. 2. To overcome this rejection, the claim may be amended to recite "A non-transitory computer readable medium comprising"
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-5, 7-8, 11-13, 16-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Kramer (U.S. Patent Pub. No. 2012/0236120) in view of Mouton (U.S. Patent Pub. No. 2021/0343015).
Regarding Claim 1, Kramer teaches a method comprising:
receiving a plurality of images of a sample, the plurality of images comprising a plurality of z-stacks (¶30 The imager 201 and the motorized stage 207 are used to capture a Z-stack of images of a sample on the motorized stage 207,) wherein each z-stack in the plurality of z-stacks represents at least a portion of a volume of the sample (¶31 A Z-stack is a series of images captured at incremental steps in the Z plane or along the Z-axis. The incremental steps in the Z-plane can be, for example, about 0.1 .mu.m, but can be selected in larger or smaller increments depending on the system capabilities; ¶32 the Z-stacks can be captured after a user manually outlines (by selecting or clicking via a user interface) anatomically defined reference spaces in a low magnification (-2.5x objective))
for each z-stack in the plurality of z-stacks:
determining a focus score for each image within the z-stack; and (¶34 the processor 203 can be configured to perform steps for identifying a top and a bottom boundary of each image of the Z-stack by performing a depth of focus analysis to determine just-out-of-focus focal planes of images within the Z-stack, the just-out-of-focus focal planes establishing boundaries with no interpolation between images within the Z-stack of images; ¶43 From the Z-stack of images, a top image slice of the Z-stack is located (S301) and a focus function is applied to identify a just-out-of-focus optical plane (S302). The identified just-out-of-focus optical plane is set as a top surface boundary of the next image slice below the top image (S303). With decision step S304, as long as the next image slice is not the last slice in the stack (e.g., the bottom slice), the steps S302, S303, and S304 are performed in a loop so that the focus function is applied to identify the just-out-of-focus optical plane for each next image slice and the identified just-out-of-focus optical plane is set as the top surface boundary of the next image slice that follows.)
determining a thickness of the z-stack based on the focus scores (¶43 Once the bottom slice is located, the focus function is then applied from the bottom slice back to the top slice by performing a loop of steps S305, S306, and S306 in which the identified just-out-of-focus optical plane is set as the bottom surface boundary of the next consecutive image of the Z-stack until the next image slice is the top image slice of the Z-stack. The boundaries of the slices can be identified in this manner. The results of the identification can then be used to calculate thickness of each slice and facilitate probe placement in subsequent methods; this method also teaches the axial bounds of the z-stack.)
Kramer does not explicitly disclose determining, based on the determined thicknesses, axial bounds of the sample.
Mouton is in the same field of art of image analysis. Further, Mouton teaches determining, based on the determined thicknesses, axial bounds of the sample (¶161 Another argument in favor of high power is that the optical fractionator method requires section thickness measurements which are determined manually and automatically by thin focal plane scanning through the z-axis to find the upper and lower optical planes of each section.)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Kramer by determining thickness based on the axial bounds that is taught by Mouton; thus, one of ordinary skilled in the art would be motivated to combine the references to obtain accurate and efficient stereology-based estimates of the number and size of biological objects (e.g., cells) in tissue sections (Mouton ¶6).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 2, Kramer in view of Mouton discloses the method of claim 1, wherein the plurality of z-stacks represents a plurality of fields of view taken of the sample (Kramer, ¶32 The Z-stack of images is then acquired according to the step increment and buffer at the selected X-Y location. In addition, with further user assistance, multiple Z-stacks can be collected by repeating the steps at different systematic-random locations through the X-Y plane of the reference space.)
Regarding Claim 3, Kramer in view of Mouton discloses the method of claim 1, wherein determining a focus score comprises determining a Tenengrad of each image in the z-stack (Kramer, ¶91 The Z-stacks described with respect to Table 2 were used in evaluating the focus functions of the example studies; see photo below)
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Regarding Claim 4, Kramer in view of Mouton discloses the method of claim 3, wherein the determined focus scores for each z-stack in the plurality of z-stacks represents a curve (Kramer, ¶41 Moreover, in contrast to the typical autofocus algorithms that are directed to finding the maximal point of focus as required for stereology studies, embodiments of the invention are directed to finding the just-out-of-focus focal plane. As opposed to a smooth change to an apex for finding the depth of maximum focus, the ideal focus-curve algorithm for the stereology applications of embodiments of the invention will have sharp changes (bends) from unfocused to focused and from focused to unfocused.)
Regarding Claim 5, Kramer in view of Mouton discloses the method of claim 4, wherein determining the thickness of the z-stack comprises measuring a width of the curve (Kramer, Figs. 8; ¶116 It should be understood that the focus function studies here are directed to locating the just-out-of-focus planes, and not the optical plane of peak focus. The approaches directed to the optical plane of peak focus are based on the idea that focus functions behave like Gaussian curves near their peaks; and are based on the knowledge that the logarithm of a Gaussian is quadratic, enable fitting of a parabolic curve between adjacent images to determine optimal peak focus along the focus curve.)
Regarding Claim 7, Kramer in view of Mouton discloses the method of claim 1, further comprising applying a filter to the determined thicknesses (Mouton, ¶48 finding the correct locations is often not an easy task because (1) these edge pixels are not always easily detectable because of low contrast and signal to noise ratio; and (2) the presence of artifacts and non-cells create spurious edges. The first issue can be addressed with a filter that smooths the transition locations using the calculated transition locations before and after. This step ensures that if enough edge pixels are detected correctly, a missing/incorrectly detected edge pixel will be recovered. To minimize the adverse effect of spurious edges in the first phase of each iteration, a rougher smoothing filter can be used to smooth those values and others values further from their smoothed values.)
Regarding Claim 8, Kramer in view of Mouton discloses the method of claim 7, wherein the filter comprises a smoothing filter (Mouton, ¶48 The first issue can be addressed with a filter that smooths the transition locations using the calculated transition locations before and after.)
Regarding Claim 11, Kramer in view of Mouton discloses the method of claim 1, further comprising determining a maximum thickness of the sample based on the determined thicknesses, wherein the imageable volume is based on the maximum thickness (Mouton, ¶37 FIG. 7 shows an example of an algorithm (Algorithm 1) according to the present invention. Filtering regions based on a maximum size can be considered, as seen in line 6 of Algorithm 1. The filter can increase segmentation accuracy but should not change the results for nucleus detection accuracy on previous cytology datasets.)
Regarding Claim 12, Kramer in view of Mouton discloses the method of claim 11, wherein the imageable volume is based on about 100% to about 120% of the maximum thickness (Mouton, ¶38 clump segmentation can follow nucleus detection and segmentation. In clump segmentation, the cell clumps (cellular masses that contain urothelial cells) are segmented from the background (100% of the cell is used). Generally, the background in each EDF image is uniformly bright and the pixels of the foreground are darker, but have more variation.)
Regarding Claim 13, Kramer in view of Mouton discloses the method of claim 1, further comprising imaging a volume based on the determined axial bounds of the sample (Kramer, ¶42 In one embodiment, the top, bottom and thickness of biological objects of interest are determined by locating the in-focus optical planes at the upper and lower surfaces of stained biological objects of interest and then locating the start and end through tissue sections along the Z-axis of stained biological objects of interest.)
Regarding Claim 16, Kramer in view of Mouton discloses the method of claim 1, wherein the plurality of images is received from an optics module comprising a camera and an objective (Kramer, ¶37 The Stereologer.TM. assists biomedical researchers in a number of tasks using high-resolution microscopy equipped with hardware (motorized x-y-z stage, camera) and software compatible with Macintosh or PC computer platforms. The Stereologer.TM. can automatically capture sets of Z-stacks of images with a step size as small as 0.01 micrometers at systematic randomly generated probe positions on the X-Y plane of a tissue section.)
Regarding Claim 17, Kramer in view of Mouton discloses the method of claim 1, wherein the sample comprises a tissue sample (Kramer, ¶37 The Stereologer.TM. assists biomedical researchers in a number of tasks using high-resolution microscopy equipped with hardware (motorized x-y-z stage, camera) and software compatible with Macintosh or PC computer platforms. The Stereologer.TM. can automatically capture sets of Z-stacks of images with a step size as small as 0.01 micrometers at systematic randomly generated probe positions on the X-Y plane of a tissue section.)
Regarding claim 19, claim 19 has been analyzed with regard to claim 1 and is rejected for the same reasons of obviousness as used above as well as in accordance with Kramer further teaching on: A computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor (Kramer, ¶76 It should be appreciated by those skilled in the art that computer readable media include removable and non-removable structures/devices that can be used for storage of information, such as computer readable instructions, data structures, program modules, and other data used by a computing system/environment… Computer readable media should not be construed or interpreted to include any propagating signals.)
Regarding claim 20, claim 20 has been analyzed with regard to claim 1 and is rejected for the same reasons of obviousness as used above as well as in accordance with Kramer further teaching on: A system comprising: an image database; and a computing node comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor (Kramer, ¶28 A processor 203 can control the system and perform instructions stored in the memory 204. The memory 204 may also be used for storing images captured by the imager.)
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Kramer (U.S. Patent Pub. No. 2012/0236120) in view of Mouton (U.S. Patent Pub. No. 2021/0343015) in view of Zhang (U.S. Patent Pub. No. 2022/0084305).
Regarding Claim 6, Kramer in view of Mouton teaches the method of claim 5.
Kramer in view of Mouton does not explicitly disclose wherein measuring the width comprises measuring from a first inflection point to a second inflection point that is adjacent to the first inflection point.
Zhang is in the same field of art of image analysis. Further, Zhang teaches wherein measuring the width comprises measuring from a first inflection point to a second inflection point that is adjacent to the first inflection point (Zhang 2022/0084305 ¶423 The processing device 120 may determine a first dividing point (also referred to as first inflection point) between the high-attenuation range and the intermediate range based on the ratio Area.sub.H and/or a second dividing point between the intermediate range and the low-attenuation range based on the ratio Area.sub.L according to Equation (3) and Equation (4), respectively:
x1=f.sub.L Min+Area.sub.H×HistogramSpan (3)
x2=nPos−Area.sub.L×HistogramSpan (4),
where x1 refers to the first dividing point, x2 refers to the second dividing point, f.sub.L Min denotes the minimum gray value of the first image, HistogramSpan denotes the width of a grayscale histogram of the target region.)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Kramer in view of Mouton by measuring a width using inflection points that is taught by Zhang; thus, one of ordinary skilled in the art would be motivated to combine the references to improve image processing accuracy and/or efficiency (Zhang¶3).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Kramer (U.S. Patent Pub. No. 2012/0236120) in view of Mouton (U.S. Patent Pub. No. 2021/0343015) in view of Steinert (U.S. Patent Pub. No. 2024/0135565).
Regarding Claim 9, Kramer in view of Mouton teaches the method of claim 7.
Kramer in view of Mouton does not explicitly disclose wherein the filter comprises a low pass filter.
Steinert is in the same field of art of image analysis. Further, Steinert teaches wherein the filter comprises a low pass filter (¶168 the application of a filter or a correction algorithm, with the result that the partial data record essentially contains image data without a background signal. By way of example, the filter can be a low-pass filter.)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Kramer in view of Mouton by using a low pass filter that is taught by Steinert; thus, one of ordinary skilled in the art would be motivated to combine the references to reduce artefacts (Steinert ¶17).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Regarding Claim 10, Kramer in view of Mouton in view of Steinert discloses the method of claim 7, wherein the filter comprises a rolling ball filter (Steinert, ¶169 The effect of a rolling ball algorithm is similar to that of a low-pass filter, which is to say low-frequency components are removed from the image data, but the rolling ball filter acts locally on the image data and globally like the low-pass filter.)
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Kramer (U.S. Patent Pub. No. 2012/0236120) in view of Mouton (U.S. Patent Pub. No. 2021/0343015) in view of Liu (U.S. Patent Pub. No. 2022/0269058).
Regarding Claim 18, Kramer in view of Mouton teaches the method of claim 1 .
Kramer in view of Mouton does not explicitly disclose wherein the sample is translucent. Examiner believes that this limitation would be well known to someone with ordinary skill in the art. However, examiner still looks to Liu to explicitly teach a translucent tissue sample.
Liu is in the same field of art of image analysis. Further, Liu teaches wherein the sample is translucent (¶122 The translucent biological sample 124 can be obtained from a specimen and then immersed in a medium. The translucent biological sample 124 can be an optically cleared tissue or a naturally translucent tissue.)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Kramer in view of Mouton by [new***] that is taught by Liu; thus, one of ordinary skilled in the art would be motivated to combine the references to successfully operate high-resolution light-sheet microscopes (Liu ¶4).
Thus, the claimed subject matter would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Allowable Subject Matter
Claims 14-15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 14, no prior art teaches further comprising determining the lateral bounds of the sample based on the determined thicknesses.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DUSTIN BILODEAU whose telephone number is (571)272-1032. The examiner can normally be reached 9am-5pm.
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/DUSTIN BILODEAU/Examiner, Art Unit 2664
/JENNIFER MEHMOOD/Supervisory Patent Examiner, Art Unit 2664