DETAILED ACTION
Applicant’s response, filed 01 Dec. 2025 and entered 02 Jan. 2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02 Jan. 2026 has been entered.
Status of Claims
Claim 13 is cancelled.
Claims 1-12 and 14-20 are pending.
Claims 1-12 and 14-20 are rejected.
Priority
The effective filing date of the claimed invention is 08 May 2020.
Claim Objections
The objection to claims 1, 4, and 16 in the Office action mailed 07 Aug. 2025 has been withdrawn in view of claim amendments received 07 Aug. 2025.
Claim Interpretation
Claims 1 and 16 recite “based on a user selection through the display device that selects information associated with the target items, marking a first visual representation in a region of the pathology slide image corresponding to the selected information”. Claims 1 and 16 only require a step of marking a first visual representation in a region of the pathology slide information corresponding to the selected information, but do not require a step of selecting the information through the display device. Therefore the limitation “based on a user selection through the display device that selects information associated with the target items” is interpreted to be a product by process limitation which defines the process in which the selected information was previously obtained. See MPEP 2113 I. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.
Claim 4 recites “…wherein the ROI extraction model is trained to output a reference ROI upon input of at least one of…”, which is a product by process limitation interpreted to describe the process in which the ROI extraction model was previously trained. See MPEP 2113 I. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-12 and 14-20 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendment.
Claims 1 and 16, and claims dependent therefrom, recite “determining/determine, based on a proportion of the immune phenotypes among the plurality of ROIs, an overall immune phenotype of the pathology slide image”. Claims 1 and 16 then output the “overall immune phenotype” with the distribution map overlaid on the pathology slide. Applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the above claim limitations relating to the “overall immune phenotype” in the application as filed. See MPEP 2163.04 I.
A review of Applicant’s specification does not mention the term “overall immune phenotype” or any similar terms related to an immune phenotype for the entire pathology slide image. Instead, Applicant’s specification discloses “a tumor proportion score (TPS) and/or a combined proportion score (CPS), which are information related to the expression of PD-L1, based on a specific threshold”, but does not relate these to an “overall immune phenotype”, particular for the entire slide image determined for a proportion of immune phenotypes. Applicant’s specification also discusses an “immune phenotype proportion” at para. [0103]-[0104] and FIG. 8, with FIG. 8 depicting proportions for each of the three immune phenotypes of immune-desert, immune excluded, and inflamed; however this does not disclose determining an overall immune phenotype for the slide image based on these proportions as claimed.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitation above recited in claims 1-12 and 14-20 to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-12 and 14-20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claims 1 and 16, and claims dependent therefrom, are indefinite for recitation of “… determining immune phenotypes for the plurality of ROIs in the pathology slide image, based on at least one of a density…within a cancer area or a stroma area of the corresponding ROI”. Given the claims determine immune phenotypes for the plurality of ROIs, it is unclear which ROI “the corresponding ROI” is referring to, and thus which cancer area or stroma area the immune phenotypes are intended to be based on. It is further unclear if Applicant intends to determine an immune phenotype for each of the plurality of ROIs (as suggested by “the corresponding ROI”) or if Applicant intends to collectively determine “immune phenotypes” corresponding to the plurality of ROIs. Clarification is requested via claim amendment. For purpose of examination, the limitation will be interpreted to mean either (1) determining an immune phenotype for each of the plurality of ROIs or (2) immune phenotypes for the ROIs based on information within a cancer area or stroma area of an ROI.
Claim 5, and claims dependent therefrom, are indefinite for recitation of “the immune phenotype” in lines 4 and 6. Claim 1, from which claim 5 depends, recites “determining immune phenotypes for the plurality of ROIs” and “determining…an overall immune phenotype” at the bottom of pg. 2 to the top of pg. 3 of the claims. Therefore, it is unclear if “the immune phenotype” of claim 5 is referring to the overall immune phenotype or one of the immune phenotypes of the immune phenotype. If “the immune phenotype” is intended to refer to one of the immune phenotypes it is further unclear which immune phenotype is being referenced. For purpose of examination, the immune phenotype is interpreted to refer to any determined immune phenotype.
Response to Arguments
Applicant's arguments filed 01 Dec. 2025 regarding 35 U.S.C. 112(b) have been fully considered but they are not persuasive because they do not pertain to the new grounds of rejection set forth above.
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.
Claims 1-12 and 14-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1 and 15-16 being representative) is directed to a method, product, and system for providing information associated with an immune phenotype. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claims 1, 15, and 16 recite the following steps which fall under the mental processes and/or mathematical concept groupings of abstract ideas:
detecting/detect one or more target items including at least one of immune cells, tumor cells, a cancer area and a stroma area in the pathology slide image…by:…detecting…the one or more target items in the pathology slide image…
dividing/divide the pathology slide image into a plurality or regions of interest (ROIs) of a predetermined size;
determining/determine immune phenotypes for the plurality of ROIs in the pathology slide image, based on at least one of a density, a number, or a spatial distribution of the detected immune cells within a caner area or a stroma area of the corresponding ROI;
determining/determine, based on a proportion of the immune phenotypes among the plurality of ROIs, an overall immune phenotype of the pathology slide image;
generating/generate an immune phenotype distribution map representing the immune phenotypes for the plurality of ROIs;
based on a user selection through the display device that selects information associated with the target items, marking/mark a first visual representation in a region of the pathology slide image corresponding to the selected information;
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, the step of detecting target items, including particular cell types, encompasses analyzing different stain colors of a pathology slide image to infer cell types, which is a mental process similar to what a histologist would perform. The step of dividing the slide image into regions of interest (ROI) encompasses analyzing an image and determining boundaries on the image around areas of interest, which is a mental process. Determining immune phenotypes for the ROIs based on a density of detected immune cells within a caner or stroma area of an ROI amounts to a mere analysis of data involving, for example, determining an ROI is immune excluded if density of immune cells is low. Determining an overall immune phenotype based on a proportion of the immune phenotypes can be practically performed in the mind by, for example, classifying the image as immune excluded if a certain proportion of ROIs are immune excluded. Furthermore, generating an immune phenotype distribution map representing the phenotypes for the ROIs can be practically performed in the mind aided with pen and paper by, for example, organizing phenotype scores into a heat map. Last, marking a first visual representation in a region of the pathology slide image corresponding to selected information encompasses analyzing selected information and annotating a visual representation of a region, which can be practically performed in the mind aided with pen and paper. Overall, the mental process recited in the claims is analogous a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). That is, other than reciting the above limitations are performed by a computing device or processor, nothing precludes the steps from being practically performed in the mind. Therefore, these limitations recite a mental process. See MPEP 2106.04(a)(2) III.
Dependent claims 2-5, 8, 11, 14, 17, and 20 further recite an abstract idea and/or further limit the abstract idea of claims 1 or 16. Dependent claims 2-4 further limit the obtaining of information for the one or more ROIs, which are part of the abstract idea of claim 1. Dependent claim 4 further recites a mathematical concept of using an ROI extraction model that takes detection results as input to determine information associated with the image. Dependent claims 5 and 17 further recite the mental process of generating an image including a visual representation corresponding to the immune phenotype, where the immune phenotype includes at least one of immune inflamed, immune excluded, or immune desert. Dependent claims 8 and 20 further recites the mental process of obtaining one or more immune phenotype scores for the one or more ROIs, wherein the scores include at least one of a score for immune inflamed, a score for immune excluded, or a score for immune desert, and generating the image including a second visual representation corresponding to one or more immune phenotype scores. Dependent claim 11 further recites the mental process of obtaining a feature associated with one or more immune phenotypes for the one or more ROIs, the feature vector associated with the one or more immune phenotypes includes at least one of a statistical value or a vector. Dependent claim 14 further recites the mental process of generating an image indicative of the detection result.
The claims further recite the law of nature of a natural correlation between the presence of immune or tumor cells, including cell densities, distributions or numbers, in a tissue sample and an immune phenotype, similar to the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals. See MPEP 2106.04(b). Therefore, claims 1-12 and 14-20 recite an abstract idea and law of nature.. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 2-5, 8, 11, 17, and 20 do not recite any elements in addition to the judicial exception.
The additional elements of claims 1 and 15-16 include:
acquiring, by the at least one computing device, the pathology slide image digitized by a whole-slide imaging scanner (claims 1 and 15);
using an artificial neural network model stored in the memory and executed by the processor …with the artificial neural network model (claims 1 and 15)/ with the artificial neural network model (claim 16);
inputting the pathology slide image into the artificial neural network (i.e. data input);
outputting/output, through the display device, the overall immune phenotype and the immune phenotype distribution map overlaid on the pathology slide image;
a computing device comprising a processor, a memory, and display device (claims 1 and 16); and
a non-transitory computer-readable medium (claim 15).
The additional elements of dependent claims 6-7, 9-10, 12, 14, and 18-19 include:
outputting/output the plurality of ROIs in the pathology slide image together with the image including the visual representation (claims 6, 9, 12, 18);
the outputting includes overlaying/overlay the image including the visual representation on the plurality of ROIs in the pathology slide image (claims 7, 10, and 19); and
outputting the image indicative of the detection result for one or more target items (claim 14);
The additional elements of a processor, memory, non-transitory computer-readable medium, inputting data, and outputting data or an image (i.e. displaying data) are generic computer components and/or processes. The additional elements also recite an artificial neural network to perform the abstract idea of detecting target items. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). With further regard to the use of the artificial neural network, the additional elements merely serves to generally link the abstract idea of detecting target items of an image to the technological environment of neural networks, which is not sufficient to integrate the recited judicial exception into a practical application. See MPEP 2106.05(h).
Furthermore, the additional element of outputting information, including one or more ROIs overlayed with a visual representation only serves to output data generated by the abstract idea, which amounts to insignificant extra-solution activity.
Last, it is not apparent that the additional elements, alone or in combination with the judicial exception, improves computer technology or any other technology. Applicant’s specification at pg. 2 lines 3-12 disclose a user (e.g. doctor, patient, and the like) may be provided with immune response information through a pathology slide image to aid in predicting the response of a user to an immune checkpoint inhibitor, which reflects an improvement in the abstract idea (e.g. providing better information) rather than an improvement to technology.
Therefore, the additionally recited elements merely invoke computers as a tool and/or amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-12 and 14-20 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Dependent claims 2-5, 8, 11, 17, and 20 do not recite any elements in addition to the judicial exception. The additional elements of claims 1, 6-7, 9-10, 12, 14-16, and 18-19 are identified above.
First, the additional elements of a processor, memory, non-transitory computer-readable medium, inputting data, outputting data or an image (i.e. displaying data), and neural networks are conventional computer components and/or processes. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Further regarding a neural network that takes images as input to make a classification, this additional element is well-understood, routine, and conventional, as supported by Madabhushi (Image analysis and machine learning in digital pathology: Challenges and opportunities, 2016, Medical Image Analysis, pg. 170-175; previously cited). Madabhushi reviews the use of computational image analysis tools for digital pathology images (Abstract), and discloses over the last decade, digital pathology has transformed computational image research and discloses a more recent class of approaches utilize deep learning techniques of neural networks to process digital pathology images (pg. 171, col. 1, para. 3 to pg. 171, col. 2, para. 3-6; Fig. 1).
The additional element of outputting an image with information overlayed in a pathology slide image is well-understood, routine, and conventional. This position is supported by Parra et al. (State-of-the-Art of Profiling Immune Contexture in the Era of Multiplexed Staining and Digital Analysis to Study Paraffin Tumor Tissues, 2019, Cancers, 11, 247, pg. 1-23; previously cited). Parra reviews the profiling of immune contexture in multiplex staining and digital analysis of images (Abstract). Parra discloses that multiplexed imaging platforms have arisen as important tools to provide information about the cancer microenvironment, citing 5 different studies (pg. 1, para. 1), and further discloses a plurality of commercially available, well-known, image analysis software packages which allow overlaying information over the images (Table 2, e.g. color; pg. 12, para. 1). Parra discloses further discloses multiplex immunofluorescence microphotography with images overlayed with information on different cell types (Figure 4-5), and can align information from various images of regions of interest (pg. 11, para. 3).
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 01 Dec. 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks the operations of the claim provide a “user with an image…”and enable the user to intuitively recognize the information associated with immune phenotype for region, and instead of analyzing the whole pathology slide image, only processing is performed on the ROIs while excluding regions where is analysis is unnecessary, such that computer resources, processing costs, and the like can be minimized, and thus the claims include meaningful limitations that solve a real problem with a solution necessarily rooted in computer technology, similar to DDR Holdings (Applicant’s remarks at pg. 13, para. 4 to pg. 14, para. 1). Applicant further remarks that consequently, the claims include meaningful limitations that solve a real problem with a solution that improves the functioning of a terminal and provides an improved user interface for the terminal to increase efficiency and accuracy of using the terminal, similar to Core Wireless (Applicant’s remarks at pg. 15, para. 2). Applicant further remarks that these limitations when taken as an ordered combination, provide unconventional steps that confine claim 1 to a particular useful application and improve the way devices provide information, and thus claims 1 and 16 recite patent eligible subject matter (Applicant’s remarks at pg. 15, para. 2).
This argument is not persuasive. First, it is noted an improvement cannot be provided by the judicial exception alone. See MPEP 2106.05(a). Furthermore, in computer-related technologies, the examiner should determine whether the claim purports to improve computer capabilities or, instead, invokes computers merely as a tool. Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, 1336, 118 USPQ2d 1684, 1689 (Fed. Cir. 2016). Furthermore, examples the courts have found may not be sufficient to show an improvement in computer-functionality include: Arranging transactional information on a graphical user interface in a manner that assists traders in processing information more quickly, Trading Technologies v. IBG LLC, 921 F.3d 1084, 1093-94, 2019 USPQ2d 138290 (Fed. Cir. 2019). Examples the courts have indicated may show an improvement to computer functionality include: an improved user interface for electronic devices that displays an application summary of unlaunched applications, where the particular data in the summary is selectable by a user to launch the respective application. Core Wireless Licensing S.A.R.L., v. LG Electronics, Inc., 880 F.3d 1356, 1362-63, 125 USPQ2d 1436, 1440-41 (Fed. Cir. 2018).
In the instant case, simply analyzing less information by processing regions of interest does not improve computer technology, but rather uses a generic computer to process less information. Therefore, the alleged improvement is provided by the abstract idea of determining the ROIs and generating the immune phenotypes of the ROIs, rather than an additional element of the claim. This is not analogous to the claims in DDR Holdings, where the claims were directed to a modification of conventional Internet hyperlink protocol to dynamically produce a dual-source hybrid webpage.
While Applicant alleges the instant claims provide an improved user interface, similar to Core Wireless, the claims in Core Wireless displayed provided an improvement to computer technology by specifically requiring the display of an application summary of unlaunched applications, where the particular data in the summary is selectable by a user to launch the respective application (see MPEP 2106.05(a)), which is an additional element providing particular functionality to the user interface that provided the improvement. In contrast, the instant claims merely output the overall immune phenotype and the immune phenotype distribution map overlaid on a pathology slide image, which is analogous to the claims in Trading Technologies, cited above, by arranging information on a display in a manner that merely assists a user in processing information more quickly, which is not an improvement to computer technology.
Overall, the claims merely use a computer as a tool to perform the abstract idea, as discussed in the above rejection, and the alleged improvement amounts to an improvement in the abstract idea (e.g. providing better information), which is not an improvement to technology. See MPEP 2106.05(a).
Applicant remarks that similar to claim 3 of Example 47, the pending claims are directed to providing information associated with an immune phenotype for a pathology slide image, and similar to claim 3, the devices provide only information on features that had either great or little information on the output result, rather than providing information on all features (Applicant’s remarks at pg. 15, para. 3 to pg. 16, para. 2).
This argument is not persuasive. As discussed above, simply analyzing less information by processing regions of interest does not improve computer technology, but rather uses a generic computer to process less information; the alleged improvement is provided by the abstract idea of determining the ROIs and generating the immune phenotypes of the ROIs, rather than an additional element of the claim. Claim 3 of example 47 in contrast, recited the additional elements of “dropping the one or more malicious network packets in real time; and (f) blocking future traffic from the source address”, which integrate the recited judicial exception of detecting anomalies into a practical application.
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.
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.
Claims 1-12 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Gaire (2019) in view of Saltz (2018). Any newly recited portion is necessitated by claim amendment.
Cited references:
Gaire et al., US 2021/0343009 A1, effectively filed 23 Oct. 2019 (previously cited); and
Saltz et al., US 2020/0388029 A1, filed 30 Nov. 2018 (previously cited).
Regarding claims 1 and 15-16, Gaire discloses a method for providing information on a biomedical state, including immunophenotyping, of a tissue sample using image-based classification (Abstract; [0001]-[0004), a system comprising a memory, processor, and display device for carrying out the method (FIG. 1), and a memory storing instructions for the method (FIG. 1; [0200]), where in the method comprises the following steps:
Gaire discloses acquiring a digital pathology slide image (claim 1).
Gaire discloses detecting immune cells and tumor cells (i.e. the one or more target items) in the pathology slide image using a connected component analysis and edge detection routines in order to identify pixel blobs representing cells ([0202]) (i.e. detecting one or more target items including at least one of immune cells, tumor cells… in the pathology slide image…).
Gaire discloses identifying sub-areas, including tumor areas, of the image (i.e. regions of interest), and that the sub-area may be of a pre-defined size or may be automatically detected ([0140], e.g. sub-area annotated as tumor-region [0216], e.g. sub-area of pre-defined size; [0239], e.g. multiple tumor regions identified).
Gaire discloses determining, for the tumor regions, spatial distributions of immune cells represented by a number of CD8+ cells closer to any tumor cell than a given radius r for multiple r’s (i.e. multiple immune phenotypes) based on a number of immune cells in each circular region around each tumor cell (i.e. a cancer area) defined by a given radius r in a tumor region (i.e. a number of cells in a cancer area of a corresponding region of interest) ([0140], e.g. only tumor cells in tumor regions analyzed; [0190]; [0223]; FIG. 7A, e.g. a plurality of immune phenotypes at each radius r).
Gaire discloses determining a biomedical state of the tissue sample comprising an immune-phenotype for the sample (i.e. the overall immune phenotype of the image) based on a proximity score determined from the number circular regions around a tumor cell having an observed number of immune cells within a given radius from the tumor cell greater or less than an expected number of immune cells in a reference distribution (FIG. 7B; [0229]-[0230]). The proximity score is based on a proportion of the spatial distributions of immune cells for each r (i.e. the immune phenotypes) (e.g. “the number of CD8+ T-cells closer than r” for each r in FIG. 8) being different than a reference (FIG. 7B and FIG. 8, e.g. see area-based delta score, which is a proportion of the immune phenotypes). In the interest of compact prosecution, it is also noted that Saltz identifies global patterns of lymphocyte infiltrating regions of a tumor based on a proportion of tumor regions identified as lymphocyte infiltrating, which demonstrates determining overall immune phenotypes based on a proportion of immune phenotypes of regions ([0313]; Table 3).
Gaire discloses generating an image indicative of the immune phenotypes (FIG. 1, e.g. plot generation and display; FIG. 3-4; [0202]-[0203]; [0216]), wherein the image visually represents colors depicting the distribution and proximities of different cell types of immune and tumor cells (i.e. the immune phenotype distribution map) (Figure 3, e.g. see cell distributions and images; [0202], e.g. monochromatic images derived with a color for each cell type). Given the image represents the distribution and proximities of the immune and tumor cells, this is considered to represent the immune phenotypes corresponding to the proximities of immune cells to a tumor cell discussed above.
Gaire discloses displaying (i.e. outputting) the generated image on a display device (claim 19; [0141]-[0142]; [0216]), wherein the outputted image includes monochromatic images from the pathology slide image to generate an image specific to a particular cell biomarker for an immune cell ([0202]-[0203]; [0206], e.g. generated images #118 displayed; FIG. 3), which shows overlaying the image including the immune phenotype distribution map (e.g. colors for immune vs tumor cell types) on the pathology slide image. Gaire further discloses displaying the overall immune phenotype above the pathology slide image, with the phenotype distribution map overlaid on the slide image (FIG. 3).
Gaire does not disclose the following limitations:
Further regarding claims 1 and 15-16¸ Gaire does not disclose detecting the one or more target items uses an artificial neural network stored in memory and executed by the processor by: inputting the pathology slide image into the artificial neural network, and detecting, with the artificial neural network, the one or more target items in the pathology slide image.
However, Saltz discloses a method for quantifying immune cells for clinical pathology in pathology images (Abstract), which comprises using a neural network to detect cancer cell and lymphocyte nuclei (i.e. immune cells and tumor cells) and tumor lymphocyte infiltrated (TIL) regions (i.e. cancer area) ([0084]; [0132], e.g. autoencoder detects nuclei [0141]; [0166]). Saltz further discloses the neural network takes a pathology slide image as input and detects the cell nuclei and TIL regions in the image (FIG. 1C; FIG. 2A-C). Saltz discloses the neural network was trained to predict the nuclei and TIL regions (i.e. label information) from 50x50 micron patches from slide tissue images (i.e. at least one portion of pathology slide images) ([0168]). Saltz further discloses the deep learning technique allows expert practitioners to identify and quantify image features and formulate higher-order relationships that have prognostic value, and that the method is scalable and cost-effective for computational staining ([0021]-[0022]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Gaire to have utilized the neural network of Saltz to detect the immune and tumor cells, as shown by Saltz, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Gaire and Saltz to utilize a scalable and cost-effective approach for computational staining, that facilitates expert practitioners in identifying image features that have prognostic value, as shown by Saltz ([0021]-[0022]). This modification would have had a reasonable expectation of success given Gaire also detects immune cells and tumor cells (i.e. the one or more target items) in the pathology slide image using a connected component analysis and edge detection routines to identify pixel blobs representing cells ([0202]), such that the neural network methods of detecting cell nucleic of Saltz is applicable to Gaire.
Further regarding claims 1 and 15-16, Gaire does not disclose the overall immune phenotype is overlayed on the ROIs in the pathology slide image.
However, the limitation of overlaying the overall immune phenotype on the ROIs is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to displaying the second visual representation directly on top of the region, as shown by Gaire (FIG. 3 and 9). Therefore, the image of Gaire would perform equally as well in labeling or providing information on the region of interest and such a modification fails to patentably distinguish over Gaire.
Last regarding claims 1 and 15-16, Gaire does not disclose, based on a user selection through the display device that selects information associated with the target items, marking a first visual representation in a region of the pathology slide image corresponding to selected information.
However, as discussed above, Saltz discloses a method for quantifying immune cells for clinical pathology in pathology images (Abstract). Saltz further discloses that a pathologist may choose a TIL-map editing tool from a user interface, select an image, and pan and zoom to view image regions, in addition to editing a heatmap overlay using lymphocyte sensitivity and using various sliders that allow the pathologist to change the threshold values to determine if a patch should be classified as lymphocyte-infiltrated or not for finer-grain editing of individual patches ([0266]). Saltz further discloses the pathologist can use the “Markup Edit” function to mark up specific patches and label them ([0266]).
It would have been prima facie obvious, to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of Gaire to have marked a visual representation of a region of a pathology slide based on selected information for the target items, as shown by Salts, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Gaire and Saltz to allow for finer-grain editing of individual patches of the image, as shown by Satlz ([0266]). This modification would have had a reasonable expectation of success because both Gaire and Saltz receive, analyze, and display pathology slide images.
Regarding claim 2¸ Gaire further discloses determining the regions of interest by manually or automatically annotating a “tumor region” in the image wherein the cells are identified (i.e. the target items were detected) by identifying a sub-area in which only detected cells identifying a particular biomarker lie within the sub-area ([0140]).
Regarding claim 3, Gaire discloses determining the ROIs for which information associated with the immune phenotype is obtained, comprises detection regions where only cells expressing a particular biomarker lie within the region (i.e. satisfy a condition associated with the one or more target items/detected cells) ([0140]).
Regarding claim 4, while Gaire discloses the regions of interest can be manually or automatically annotated and may be of a pre-defined size ([0141]; [0216]), Gaire does not disclose inputting at least one of the detection result for the one or more target items or the pathology slide image to a region-of-interest (ROI) extraction model and outputting, from the ROI extraction model, the one or more ROIs, wherein the ROI extraction model is trained to output a reference ROI upon input of at least one of the detection result from one or more target items for a reference pathology slide image or the reference pathology slide image.
However, Saltz further discloses utilizing a convolution neural network (CNN) for generating and outputting regions of tumor infiltrating lymphocytes (TIL) (i.e. extracted regions of interest) ([0024], e.g. density of TILs used to classify regions of interest; [0105] [0109]-[0111]; [0214] FIG. 6 and 7B, e.g. TIL region). Saltz discloses the CNN (i.e. ROI extraction model) takes the pathology slide image as input ([0039] and FIG. 3A) and further discloses the CNN is trained to output a ROI upon input of a reference pathology slide image (FIG. 5). Saltz discloses the CNN takes as input and classifies image patches of a pre-determine size to detect the tumor infiltrating lymphocyte regions ([0110]). Saltz further discloses the generated TIL maps are useful in generating prognostic values in diagnosis or related classifications ([0019]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have further modified the method of Gaire to have utilized a ROI extraction model to determine regions of interest, as shown by Saltz above. One of ordinary skill in the art would have been motivated to combine the methods of Gaire and Saltz to have provided regions of interest useful in generating prognostic values in diagnosis or related classifications, as shown by Saltz ([0019]), given Gaire uses cell type and density information in these regions to obtain immune cell information as discussed above ([0036], [0068]; [0140], [0202]-[0203], [0239]; FIG. 3-6 and 10). This modification would have had a reasonable expectation of success given Gaire also analyses information in regions of interest, such that the ROI extraction model of Saltz is applicable to the method of Gaire.
Regarding claims 5 and 17, Gaire further discloses obtaining information on each region being immune infiltrated, immune excluded, or immune desert (i.e. obtaining the immune phenotype of immune inflamed, immune excluded, or immune desert) (Figure 3; [0222]).
Gaire further discloses generating a second visual representation of the immune phenotype, including CD8A+ cell densities and a separate plot of the immune cell distribution (FIG. 9), in addition to the colors for different cell types of immune and tumor cells and overall immune phenotype (Figure 3, e.g. see cell density graph in addition to distribution overlaid on image [0202], FIG. 9, e.g. CD8A+ density display in addition to image).
Regarding claims 6 and 18, Gaire further discloses displaying the tumor region together with the second visual representation of immune phenotypes (Fig. 3 and FIG. 9).
Regarding claims 7 and 19, while Gaire discloses displaying the CD8A+ cell density directly below the second visual representation of immune phenotypes ([0202]-[0203]; [0206], e.g. generated images #118 displayed; [02016]; FIG. 9 also see “CD8A+ density” next to region images), Gaire does not disclose the second visual representation is overlayed on the one or more ROIs in the pathology slide image.
However, the limitation of overlaying the second visual representation on the ROI is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to displaying the second visual representation directly below the region, as shown by Gaire (FIG. 3 and 9). Therefore, the image of Gaire would perform equally as well in labeling or providing information on the region of interest and such a modification fails to patentably distinguish over Gaire.
Regarding claims 8 and 20¸ Gaire discloses obtaining an immune phenotype score for a tumor region ([0018]-[0020], e.g. combined score based on distribution of A and B cells; [0021],e.g. see definitions of A and B cells), wherein the score is for immune inflamed, immune excluded, or immune deserted (FIG. 3; [0134], e.g. combined score indicates immune-cell infiltration state).
Gaire discloses generating an image including a second visual representation of the CD8A+ cell density in addition to the proximity score (FIG. 9), which correspond to the immune phenotype score ([0020], e.g. proximity score used in combined score).
Regarding claim 9, Gaire further discloses displaying the tumor region together with the second visual representation of the immune phenotype score (([0202]-[0203]; [0206], e.g. generated images #118 displayed; [02016]; FIG. 9 see proximity score and density below images).
Regarding claim 10¸ while Gaire discloses displaying the tumor region directly below the second visual representation of immune phenotypes ([0202]-[0203]; [0206], e.g. generated images #118 displayed; [02016]; FIG. 9 also see “proximity score” next to region images), Gaire does not disclose the second visual representation is overlayed on the ROIs in the pathology slide image.
However, the limitation of overlaying the second visual representation on the ROI is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to displaying the second visual representation directly below the regions, as shown by Gaire (FIG. 3 and 9). Therefore, the image of Gaire would perform equally as well in labeling or providing information on the region of interest and such a modification fails to patentably distinguish over Gaire.
Regarding claim 11¸ Gaire discloses obtaining an immune phenotype score (i.e. a feature) for tumor regions ([0018]-[0020], e.g. combined score based on distribution of A and B cells; [0021],e.g. see definitions of A and B cells), wherein the score (i.e. feature) is associated with a delta between an observed and relative distribution of tumor and immune cells (i.e. a statistical value) ([0018], e.g. proximity score representing the delta [0020], e.g. combined score includes proximity score; FIG. 3; [0134], e.g. combined score indicates immune-cell infiltration state).
Regarding claim 12, Gaire further discloses displaying the tumor regions together with image of a proximity score which corresponds to the immune phenotype score associated with the immune phenotypes (FIG. 9; [0020]).
Regarding claim 14, Gaire further discloses generating and outputting an image indicative of the detected immune and tumor cells (FIG. 3, e.g. see stained cells on top row; [0202], e.g. color information in image).
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 01 Dec. 2025 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that Gaire does not disclose or suggest “determining, based on a proportion of the immune phenotypes among the plurality of ROIs, an overall immune phenotype” because Gaire detects tumor cells and immune cells from a tissue sample and generates and displays digital images with results of the analysis, and thus at best discloses generating color information for detecting tumor cells and immune cells from a tissue sample (Applicant’s remarks at pg. 17, , para. 2 to pg. 18, para. 2). Applicant remarks that Satlz does not remedy the deficiencies of Gaire (Applicant’s remarks at pg. 18, para. 3 to 5).
This argument is not persuasive, particularly in view of newly cited portions of Gaire applied above. Gaire does not simply generate color information for tumor cells and immune cells and then display images with these results as alleged by Applicant. Gaire does disclose identifying tumor and immune cells, also referred to as the A-type and B-type cells respectively, in an image ([0021]). However, Gaire also discloses methods of analyzing both the proximity of immune cells to the tumor cells and analyzing immune cell densities to determine a final, combined score of an immune phenotype ([0020]-[0022]; FIG. 3). As explained in the above rejection, Gaire discloses determining a plurality of spatial distributions of immune cells in the regions of interest based on a number of CD8+ cells closer to any tumor cell than a given radius r for multiple r’s ([0140], e.g. only tumor cells in tumor regions analyzed; [0190]; [0223]; FIG. 7A, e.g. a plurality of immune phenotypes at each radius r). The spatial distributions of immune cells from tumor cells are considered immune phenotypes (FIG. 7A). Each spatial distribution is determined based on a number of immune cells within a cancer area (i.e. a specified distance away from the tumor cell) of a region of interest, as claimed, given only tumor cells within a tumor region are analyzed ([0140}]).
Gaire then discloses determining a biomedical state of the tissue sample comprising an immune-phenotype for the sample (i.e. the overall immune phenotype of the image) based on a proximity score determined from the spatial distributions including the number circular regions around a tumor cell having an observed number of immune cells within a given radius from the tumor cell greater or less than an expected number of immune cells in a reference distribution (FIG. 7B; [0229]-[0230]). The proximity score is based on a proportion of the spatial distributions of immune cells for each r (i.e. the immune phenotypes) (e.g. “the number of CD8+ T-cells closer than r” for each r in FIG. 8) being different than a reference (FIG. 7B and FIG. 8, e.g. see area-based delta score, which is a proportion of the immune phenotypes).
Last, Saltz is not relied upon to teach the determination of an overall immune phenotype. Although, it is noted that Saltz does also identify global patterns of lymphocyte infiltrating regions of a tumor based on a proportion of tumor regions identified as lymphocyte infiltrating ([0313]; Table 3).
Applicant remarks that claim 16 recites features similar to the features of claim 1, and dependent claims 2-12, 14-15, and 17-20 are patentable due to their respective dependencies and due to additional features, and thus the rejection should be withdrawn (Applicant’s remarks at pg. 19, para. 1-2).
This argument is not persuasive for the reasons discussed above for claim 1, and because Applicant does not provide any particular arguments regarding the additional features of the dependent claims.
Double Patenting
The provisional rejection of claims 1-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/463,912 (reference application) in the Office action mailed 02 Sept. 2025 has been withdrawn in view of claim amendments received 01 Dec. 2025 and claim amendments received in the reference application. The patent applications are patentably distinct in view of the amendments.
The provisional rejection of claims 1-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/463,962 (reference application) in the Office action mailed 02 Sept. 2025 has been withdrawn in view of claim amendments received 01 Dec. 2025. The patent applications are patentably distinct in view of the amendments.
The rejection of claims 1-4, 11-12, and 14-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. US 12,205,288 B2 (reference application) in view of Saltz (2018) in the Office action mailed 02 Sept. 2025 has been withdrawn in view of claim amendments received 01 Dec. 2025. The patent applications are patentably distinct in view of the amendments.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685