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 November 28, 2024, January 15, 2025, May 9, 2025 and March 17, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 12 and 16 are objected to because of the following informalities:
Claim 12, line 4, “(a) a tumor core (TC) region of a sample of the tumor, and (b) an invasive margin (IM) region or a peri- tumoral (PT) region of a sample of the tumor;” should read “(i) a tumor core (TC) region of the sample of the tumor, and (ii) an invasive margin (IM) region or a peri- tumoral (PT) region of the sample of the tumor;”
Claim 16, line 2 “in in” should read “in”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2 and 5-9 (and claims 10-11) are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Antecedent Basis:
Claim 7 recites the limitation "the labeled cells" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation "the ROI" in line 6. There is insufficient antecedent basis for this limitation in the claim.
Claims 10-11 are further rejected for inheriting the rejection of claim 9, while also failing to cure the deficiency.
General Indefiniteness:
Claim 2, line 1, states “wherein the ROI is identified in a digital image of a first serial section of the test sample.” Claim 2, depends on claim 1, however claim 1 already claims “(a) annotating a region of interest (ROI) on a digital image of a test sample.” It is unclear if the digital image in claim 2 is the same as that of claim 1, or if this is a newly acquired image. For the sake of examination, claim 2 will be interpreted as the digital image being the same image as in claim 1.
A similar issue and analysis is applied to claims 5 and 6 which both state, “wherein the ROI is identified in a digital image of a first serial section of the test sample.”
Claim 7, line 1 states, “wherein the cell densities of the feature vector”. Claim 7 depends on claim 1 and claim 1 only states determining one cell density in line 6. It is unclear whether there is one density or multiple. For the sake of examination, the examiner will interpret claim 7 as “wherein the cell density of the feature vector.”
Claim 8, line 1 states, “wherein the cell densities of the feature vector”. Claim 8 depends on claim 1 and claim 1 only states determining one cell density in line 6. It is unclear whether there is one density or multiple. For the sake of examination, the examiner will interpret claim 8 as “wherein the cell density of the feature vector.”
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.
Claim(s) 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015/124737 to Ventana Medical Systems (hereinafter Ventana), and further in view of Hermitte, F. (2016). Biomarkers immune monitoring technology primer: Immunoscore® Colon. Journal for ImmunoTherapy of Cancer, 4(1). https://doi.org/10.1186/s40425-016-0161-x (hereinafter Hermitte).
Regarding independent claim 1, Ventana discloses A method (abstract, “This disclosure describes methods, kits, and systems for scoring the immune response to cancer through examination of tissue infiltrating lymphocytes (TILs)”) comprising:
(a) annotating a region of interest (ROI) on a digital image of a test sample of a colorectal tumor (paragraph 0005, “Methods, kits, and systems for scoring cancer through examination of tissue infiltrating lymphocytes (TILs) are disclosed in which a panel of CD3, CD8, CD20, and FoxP3 was found to be useful as a prognostic marker across a number of cancers, including high risk melanoma, colorectal cancer, and breast cancer.” paragraph 0102, “for each case, manual cell counts and regional annotation were taken”),
(b) detecting CD3+ cells in at least a portion of the ROI (paragraph 0102, “for each case, manual cell counts and regional annotation were taken” paragraph 0014, “An image analysis algorithm and/or system has been developed that automatically computes an immune score from a set images of multiplex IHC slides and/or fluorescent stained slides. The image analysis algorithm involves a computer-implemented method for counting a number of types of cells in a single tissue specimen that has been stained with a multiplex assay”… “ classify the detected cells as at least one of false positive cells, CD3 only T-cells, CD3 and CD8 T-cells, FP3 T-cells; and CD20 B-cells; counting a number of each different type of cell classified;”);
Ventana fails to explicitly disclose as further recited. However, Hermitte discloses wherein the ROI comprises a tumor core (TC) region or an invasive margin (IM) or a peritumoral (PT) region (page 1, right column, second paragraph, “After image processing validation by an independent reviewer,
densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”);
(c) obtaining a CD3+ cell density within the ROI (Page 1, right column, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported; i.e., the densities of CD3 and CD8 are derived by division over the entire ROI).”); and
(d) applying a non-linear continuous scoring function to a feature vector comprising the CD3+ cell density to obtain an immune context score (ICS) for the tumor (page 1, right column, third paragraph, “Briefly, for each marker (CD3 & CD8) and each zone (CT & IM), densities distributions have been established on the study training set; for each parameter of a tested sample (CD3, CDS, CT, IM), a percentile is derived from. these distributions. An average percentile is calculated based on these 4, values. The Immunoscore'" is reported as IS-0, 1 - 2 - 3 - 4 based on the following average percentile classes respectively: [0 %; 10 %] - [>10 %; 25 %] - [>25 %; 70 %] - [>70 %; 95%] - [>95 %; 100%];” page 1, left column, “The Immunoscore® assay for Colon Cancer OS Colon) is the first standardized immune-based assay for the classification of cancer;” classification based on the score is read as using the score to determine a prognosis).
Ventana is directed toward “s methods, kits, and systems for scoring the immune response to cancer through examination of tissue infiltrating lymphocytes (TILs) (abstract).” Hermitte is directed toward “The Immunoscore® assay for Colon Cancer (IS Colon) is the first standardized immune-based assay for the classification of cancer. It assesses the host immune response to Colon Cancer (CC) by measuring intra- and peri tumoral T cell infiltration in formalin-fixed paraffin embedded (FFPE) tissue sections (page 1, left column).” As can be easily seen by one of ordinary skill in the art before the effective filing date of the claimed invention, Ventana and Hermitte are directed toward similar methods of endeavor of cancer scoring. Further, one of ordinary skill in the art before the effective filing date would be easily aware when multiple physicians are communicating about a cancer diagnosis, it would be helpful to have a standard that applies so miscommunications are prevented. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermitte in order to utilize a standardized immune-based assay for the classification of cancer (page 1, left column).
Regarding dependent claim 2, the rejection of claim 1 is incorporated herein. Additionally, Ventana further discloses wherein the ROI is identified in a digital image of a first serial section of the test sample (being that a “whole slide image” scanner is used (page 16, line 3); page 13, line 27, “Initial evaluation was conducted with a high power microscope field [Olympus BX51], … The number of positive cells has been evaluated by counting them in 5 peritumoral and 5 intratumoral non-overlapping fields using X400 magnification;” non-overlapping fields are read as the tiles found in serial imaging), wherein the first serial section is stained with hematoxylin and eosin (paragraph 0038, “. In one embodiment, specifically staining includes the application of a primary stain that selectively stains portions of the sample through adhesion associated with hydrophobicity, intercalation, or other non-recognition associations. For example, hematoxylin and eosin staining [H&E staining] is well known in the art.”), and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3 (paragraph 0038, “For example, hematoxylin and eosin staining [H&E staining] is well known in the art;” abstract, “a panel of CD3, CDS, CD20, and FoxP3 was found to be useful as a prognostic marker” Paragraph 0050, “To generate multi-spectral images, a multi-spectral imaging system [such as a fluorescent microscope or scanner [e .g., a whole slide scanner] is used to obtain the multi-spectral fluorescent images;” whole slide scanners are well known in the art to capture images of tissue sections tile by tile in a line scanning fashion and then registering those images back together).
Regarding dependent claim 3, the rejection of claim 1 is incorporated herein. Additionally, Hermitte further discloses further comprising detecting CD8+ cells in at least a portion of the ROI (Page 1, right column, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported; i.e., the densities of CD3 and CD8 are derived by division over the entire ROI).”); and
obtaining a CD8+ cell density within the ROI (Page 1, right column, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported; i.e., the densities of CD3 and CD8 are derived by division over the entire ROI).”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell presence in specific areas can correlate to different disease stages. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 4, the rejection of claim 3 is incorporated herein. Additionally, Hermitte further discloses wherein the feature vector further comprises the CD8+ cell density (Page 1, right column, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported; i.e., the densities of CD3 and CD8 are derived by division over the entire ROI).”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages (i.e. density is a determination of a count of cells within a specified area). Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 5, the rejection of claim 3 is incorporated herein. Additionally, Ventana further discloses wherein the ROI is identified in a digital image of a first serial section of the test sample (being that a “whole slide image” scanner is used (page 16, line 3); page 13, line 27, “Initial evaluation was conducted with a high power microscope field [Olympus BX51], … The number of positive cells has been evaluated by counting them in 5 peritumoral and 5 intratumoral non-overlapping fields using X400 magnification;” non-overlapping fields are read as the tiles found in serial imaging), wherein the first serial section is stained with hematoxylin and eosin (paragraph 0038, “. In one embodiment, specifically staining includes the application of a primary stain that selectively stains portions of the sample through adhesion associated with hydrophobicity, intercalation, or other non-recognition associations. For example, hematoxylin and eosin staining [H&E staining] is well known in the art.”), and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3 and with CD8 (paragraph 0038, “For example, hematoxylin and eosin staining [H&E staining] is well known in the art;” abstract, “a panel of CD3, CDS, CD20, and FoxP3 was found to be useful as a prognostic marker” Paragraph 0050, “To generate multi-spectral images, a multi-spectral imaging system [such as a fluorescent microscope or scanner [e .g., a whole slide scanner] is used to obtain the multi-spectral fluorescent images;” whole slide scanners are well known in the art to capture images of tissue sections tile by tile in a line scanning fashion and then registering those images back together).
Regarding dependent claim 6, the rejection of claim 3 is incorporated herein. Additionally, Ventana further discloses wherein the ROI is identified in a digital image of a first serial section of the test sample (being that a “whole slide image” scanner is used (page 16, line 3); page 13, line 27, “Initial evaluation was conducted with a high power microscope field [Olympus BX51], … The number of positive cells has been evaluated by counting them in 5 peritumoral and 5 intratumoral non-overlapping fields using X400 magnification;” non-overlapping fields are read as the tiles found in serial imaging), wherein the first serial section is stained with hematoxylin and eosin (paragraph 0038, “. In one embodiment, specifically staining includes the application of a primary stain that selectively stains portions of the sample through adhesion associated with hydrophobicity, intercalation, or other non-recognition associations. For example, hematoxylin and eosin staining [H&E staining] is well known in the art.”), and wherein the ROI is automatically registered to a digital image of at least a second serial section and a third serial section of the test sample, wherein the second serial section is stained with CD3 and the third serial section is stained with CD8 (paragraph 0038, “For example, hematoxylin and eosin staining [H&E staining] is well known in the art;” abstract, “a panel of CD3, CDS, CD20, and FoxP3 was found to be useful as a prognostic marker” Paragraph 0050, “To generate multi-spectral images, a multi-spectral imaging system [such as a fluorescent microscope or scanner [e .g., a whole slide scanner] is used to obtain the multi-spectral fluorescent images;” whole slide scanners are well known in the art to capture images of tissue sections tile by tile in a line scanning fashion and then registering those images back together).
Regarding dependent claim 7, the rejection of claim 1 is incorporated herein. Additionally, Hermitte further discloses wherein the cell densities of the feature vector are derived from an area cell density obtained by dividing the quantity of the labeled cells in the ROI by the area of the ROI (Page 1, right column, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported; i.e., the densities of CD3 and CD8 are derived by division over the entire ROI).”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages (i.e. density is well known to be a determination of a count of cells within a specified area). Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 8, the rejection of claim 1 is incorporated herein. Additionally, Hermitte further discloses wherein the cell densities of the feature vector are derived from a mean or median area cell density of a plurality of control regions of the ROI (page 1, right column, paragraph 3, “page 1, right column, third paragraph, “Briefly, for each marker (CD3 & CD8) and each zone (CT & IM), densities distributions have been established on the study training set; for each parameter of a tested sample (CD3, CDS, CT, IM), a percentile is derived from these distributions. An average percentile is calculated based on these 4, values.”).
Claim(s) 12-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ventana, and further in view of Hermitte and WO 2015121465 (hereinafter WO ‘465).
Regarding independent claim 12, Ventana discloses A method of prognosing a chemo-naive stage II colorectal cancer patient having a tumor (abstract, “This disclosure describes methods, kits, and systems for scoring the immune response to cancer through examination of tissue infiltrating lymphocytes (TILs);” paragraph 0005, “Methods, kits, and systems for scoring cancer through examination of tissue infiltrating lymphocytes (Tlls) are disclosed in which a panel of CD3, CDS, CD20, and FoxP3 was found to be useful as a prognostic marker across a number of cancers, including high risk melanoma, colorectal cancer, and breast cancer;” The method of Ventana is directed at prognosing colorectal cancer (among other cancers), and as such, stage II colorectal cancer could be evaluated) t
(a) calculating a feature vector for a sample of the tumor, wherein the feature vector comprises a density of CD3+ lymphocytes in one or more of: (a) a tumor core (TC) region of a sample of the tumor, and (b) an invasive margin (IM) region or a peri-tumoral (PT) region of a sample of the tumor (paragraph 0104, “observed a range of immune responses, both in terms of different cell types and in terms of number of cells. In addition, immune cells were located in different regions of the tissue, such as: stroma only, at the invasive margin of the tumor, and in the tumor center.” paragraph 0015, “CD3 detected in blue C exemplarily indicated by an arrow indicated with "B" in FIG. KB” abstract, “tissue infiltrating lymphocytes include detecting CD3;” paragraph 0007, “the immunological data [the type, density, and location of immune cells within the tumor samples]”);
(c) prognosing the patient on the basis of the ICS (paragraph 0014, “An image analysis algorithm and/or system has been developed that automatically computes an immune score from a set images of multiplex IHC slides and/or fluorescent stained slides;” paragraph 0008, “We propose an immune scoring based on the type, density and location of lymphocyte infiltrates as a novel prognostic factor,”).
Ventana fails to explicitly disclose as further recited. However, Hermitte discloses (b) applying a continuous scoring function to the feature vector to obtain an immune context score (ICS) (Page 1, right column, the feature vectors are ROIs e.g., CT or IM; “The Immunoscore'" is reported as IS-0, 1 - 2 - 3 - 4 based on the following average percentile classes respectively: [0 %; 10 %] - [>10 %; 25 %] - [>25 %; 70 %] - [>70 %;95%] -[>95 %; 100%].”); and
Ventana is directed toward “s methods, kits, and systems for scoring the immune response to cancer through examination of tissue infiltrating lymphocytes (TILs) (abstract).” Hermitte is directed toward “The Immunoscore® assay for Colon Cancer (IS Colon) is the first standardized immune-based assay for the classification of cancer. It assesses the host immune response to Colon Cancer (CC) by measuring intra- and peri tumoral T cell infiltration in formalin-fixed paraffin embedded (FFPE) tissue sections (page 1, left column).” As can be easily seen by one of ordinary skill in the art before the effective filing date of the claimed invention, Ventana and Hermitte are directed toward similar methods of endeavor of cancer scoring. Further, one of ordinary skill in the art before the effective filing date would be easily aware when multiple physicians are communicating about a cancer diagnosis, it would be helpful to have a standard that applies so miscommunications are prevented. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermitte in order to utilize a standardized immune-based assay for the classification of cancer (page 1, left column).
Ventana and Hermitte in the combination fail to explicitly disclose as further recited. However, WO ‘465 discloses A method of prognosing a chemo-naive stage II colorectal cancer patient having a tumor that is determined to be mismatch repair proficient (pMMR) (page 8, line 28, “FIG. 8 shows Kaplan-Meier curves for chemo-naive stage II CRC subjects (T3+T4) stratified by mis-match repair proficient (pMMR), mis-match repair deficient (dMMR), pMMR/GIV-positive, pMMR/GIV-negative, using the GIV-fl Predictive Score scoring algorithm shown in Table 7.;” page 55, line 3, “For the classification, a chemo-naive patient population was used to estimate the coefficients, and the linear predictor(Lp) is that which gives us the maximum sensitivity and specificity as a cut-point for high and low risk.” abstract, “Method (M1) for analyzing a stage II mismatch repair proficient (pMMR) colorectal cancer (CRC) sample obtained from a subject”)
As noted above, Ventana and Hermitte are directed toward similar methods of endeavor of cancer scoring. Further, WO ‘465 is directed toward, “ methods of analyzing stage II colorectal cancer (CRC) samples (such as those that are mis-match repair proficient, pMMR) (abstract).” As can be easily seen by one of ordinary skill in the art before the effective filing date of the claimed invention, Ventana, Hermitte and WO ‘465 are all directed toward similar methods of endeavor of cancer analysis. Further, WO ‘465 allows for diagnosis specifically as related to pMMR colorectal cancer. It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of WO ‘465 in order to ensure the method can be applied to additional specified cancer types.
Regarding dependent claim 13, the rejection of claim 12 is incorporated herein. Additionally, Hermitte further discloses wherein the feature vector further comprises a density of CD8+ lymphocytes in the IM region or the PT region of the sample (page 1, right column, second paragraph, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 14, the rejection of claim 12 is incorporated herein. Additionally, Hermitte further discloses wherein the feature vector further comprises a density of CD3+ lymphocytes in a tumor core (TC) region of the sample (page 1, right column, second paragraph, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 15, the rejection of claim 12 is incorporated herein. Additionally, Hermitte further discloses wherein the feature vector consists essentially of the density of CD3+ lymphocytes in the IM region or the PT region of the sample (page 1, right column, second paragraph, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Regarding dependent claim 16, the rejection of claim 12 is incorporated herein. Additionally, Hermitte further discloses wherein the feature vector consists essentially of the density of CD3+ lymphocytes in in the IM or PT region (page 1, right column, second paragraph, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”); and the density of CD3+ lymphocytes in the TC region of the sample (page 1, right column, second paragraph, “After image processing validation by an independent reviewer, densities of CD3 and CD8 positive lymphocytes in the 2 regions of interest (ROis) CT or IM regions are reported.”).
One of ordinary skill in the art before the effective filing date of the claimed invention would easily understand cell metrics in specific areas can correlate to different disease stages. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of Hermite in order to allow for analyzing cells as related to a specific disease or diagnosis of interest.
Claim(s) 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Ventana, Hermitte and WO ‘465 as applied to claim 12 above, and further in view of WO 2015164501 (hereinafter WO ‘501).
Regarding dependent claim 17, the rejection of claim 12 is incorporated herein. Additionally, Ventana, Hermitte and WO ‘465 fails to explicitly disclose wherein the prognosing of the patient on the basis of the ICS comprises integrating the ICS with one or more clinical variables.
However, WO ‘501 discloses wherein the prognosing of the patient on the basis of the ICS comprises integrating the ICS with one or more clinical variables (paragraph 00136, “In some embodiments one or more of the clinical variables (e.g., tumor size and node status) can be combined into a clinical score (e.g., nomogram score), which can then be combined with one or more of the gene expression scores score to yield a combined score;” paragraph 0016, “determining at least one clinical parameter for the patient (e.g., age, tumor size, node status, tumor stage)”).
As noted above, Ventana, Hermitte and WO ‘465 are directed toward similar methods of endeavor of cancer analysis. Further, WO ‘501 is directed toward “a molecular classification of cancer and particularly to molecular markers for cancer prognosis and methods of use thereof (paragraph 0002).” As can be easily seen by one of ordinary skill in the art before the effective filing date of the claimed invention, Ventana, Hermitte, WO ‘465 and WO ‘501 are all directed toward similar methods of endeavor of cancer analysis. Further, one of ordinary skill in the art before the effective filing date of the claimed invention would easily understand when determining a patient’s cancer prognosis, many patient features are relevant. For example, a patient of an older age may have a different prognosis than one of a younger age. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of WO ’501 in order to take patient features into account when analyzing cancer in a patient..
Regarding dependent claim 18, the rejection of claim 17 is incorporated herein. Additionally, WO ‘501 further discloses wherein the clinical variables (paragraph 00136, “In some embodiments one or more of the clinical variables (e.g., tumor size and node status) can be combined into a clinical score (e.g., nomogram score), which can then be combined with one or more of the gene expression scores score to yield a combined score”) include each of age of the patient (paragraph 0016, “determining at least one clinical parameter for the patient (e.g., age, tumor size, node status, tumor stage)”), sex of the patient, sidedness of the tumor, and number of lymph nodes harvested from the patient.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of WO ’501 in order to classify cancer according to multiple different variables in order to get the most accurate diagnosis and prognosis.
Regarding dependent claim 19, the rejection of claim 18 is incorporated herein. Additionally, WO ‘501 in the combination further discloses wherein the clinical variables and the ICS are integrated by a model combination (a model combination: paragraph 00136, “In some embodiments one or more of the clinical variables (e.g., tumor size and node status) can be combined into a clinical score (e.g., nomogram score), which can then be combined with one or more of the gene expression scores score to yield a combined score”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teaching of WO ’501 in order to classify cancer according to multiple different models combined to determine the most accurate output.
Regarding dependent claim 20, the rejection of claim 18 is incorporated herein. Additionally, Ventana, Hermite, WO ‘465 and WO ‘501 in the combination fail to explicitly disclose wherein the clinical variables and the ICS are integrated by a covariate combination.
However, utilizing covariate combinations would be well known by one of ordinary skill in the art before the effective filing date of the claimed invention. Covariate combinations provide the benefits of improving precision, power and interpretability. Thus, it would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in order to modify the teachings of Ventana, Hermite, WO ‘465 and WO ‘501 to incorporate covariate combinations so that the system is more accurate as a whole.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-3, 5-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 29 of U.S. Patent No. 11,250,566 (hereinafter US ‘566). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application is more broad in scope compared to claims 1-5 and 29 of US ‘566.
Claim 1: Regarding claim 1, see the chart below for the comparison between claim 1 of the instant application and claim 1 of US ‘566. As can be seen below, claim 1 of the instant application is more broad in scope compared to claim 1 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 1 of US ‘566.
Instant Application - Claim 1
US '566 - Claim 1
Notes
A method comprising:
A method comprising:
Verbatim
(a) annotating a region of interest (ROI) on a digital image of a test sample of a colorectal tumor, wherein the ROI comprises a tumor core (TC) region or an invasive margin (IM) or a peritumoral (PT) region;
(a) annotating a region of interest (ROI) on a digital image of a test sample of a colorectal tumor, wherein the ROI comprises a tumor core (TC) region or an invasive margin (IM) or a peritumoral (PT) region;
Verbatim
(b) detecting CD3+ cells in at least a portion of the ROI;
(b) detecting CD3+ cells in at least a portion of the ROI;
Verbatim
(c) obtaining a CD3+ cell density within the ROI; and
(c) obtaining a CD3+ cell density within the ROI;
Verbatim
(d) detecting CD8+ cells in at least a portion of the ROI;
(e) obtaining a CD8+ cell density within the ROI; and
(d) applying a non-linear continuous scoring function to a feature vector comprising the CD3+ cell density to obtain an immune context score (ICS) for the tumor.
(f) applying a non-linear continuous scoring function to a feature vector comprising the CD3+ cell density to obtain an immune context score (ICS) for the tumor, wherein the non-linear continuous scoring function is derived from a Cox proportional hazard model of formula 1: ICS cox=exp(b 1 X 1 +b 2 X 2 + . . . b 2 X 2) Formula 1 wherein: X1, X2, . . . Xp are independent variables, the independent variables including the CD3+ cell density and the CD8+ cell density and/or a combination of the CD3+ cell density and the CD8+ cell density for the ROI; and b1, b2 . . . bp are constants extrapolated for each of the independent variables.
Instant application more broad
Claim 2: Regarding claim 2, see the chart below for the comparison between claim 8 of the instant application and claim 2 of US ‘566. As can be seen below, claim 2 of the instant application is more broad in scope (when incorporating dependency) compared to claim 2 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 2 of US ‘566.
Instant Application - Claim 2
US '566 - Claim 2
Notes
The method of claim 1, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3.
The method of claim 1, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3 and with CD8.
Instant application more broad
Claim 3: Regarding claim 3, see the chart below for the comparison between claim 3 of the instant application and claim 1 of US ‘566. As can be seen below, claim 3 of the instant application is more broad in scope (when incorporating dependency) compared to claim 1 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 1 of US ‘566.
Instant Application - Claim 3
US '566 - Claim 1
Notes
The method of claim 1, further comprising detecting CD8+ cells in at least a portion of the ROI;
… (d) detecting CD8+ cells in at least a portion of the ROI;
Verbatim
and obtaining a CD8+ cell density within the ROI.
… (e) obtaining a CD8+ cell density within the ROI; and
Verbatim
Claim 5: Regarding claim 5, see the chart below for the comparison between claim 5 of the instant application and claim 2 of US ‘566. As can be seen below, claim 5 of the instant application is more broad in scope (when incorporating dependency) compared to claim 2 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 2 of US ‘566.
Instant Application - Claim 5
US '566 - Claim 2
Notes
The method of claim 3, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3 and with CD8.
The method of claim 1, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section of the test sample, wherein the second serial section is stained with CD3 and with CD8.
Verbatim
Claim 6: Regarding claim 6, see the chart below for the comparison between claim 6 of the instant application and claim 3 of US ‘566. As can be seen below, claim 6 of the instant application is more broad in scope (when incorporating dependency) compared to claim 3 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 3 of US ‘566.
Instant Application - Claim 6
US '566 - Claim 3
Notes
The method of claim 3, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section and a third serial section of the test sample, wherein the second serial section is stained with CD3 and the third serial section is stained with CD8.
The method of claim 1, wherein the ROI is identified in a digital image of a first serial section of the test sample, wherein the first serial section is stained with hematoxylin and eosin, and wherein the ROI is automatically registered to a digital image of at least a second serial section and a third serial section of the test sample, wherein the second serial section is stained with CD3 and the third serial section is stained with CD8.
Verbatim
Claim 7: Regarding claim 7, see the chart below for the comparison between claim 7 of the instant application and claim 4 of US ‘566. As can be seen below, claim 7 of the instant application is more broad in scope (when incorporating dependency) compared to claim 4 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 4 of US ‘566.
Instant Application - Claim 7
US '566 - Claim 4
Notes
The method of claim 1, wherein the cell densities of the feature vector are derived from an area cell density obtained by dividing the quantity of the labeled cells in the ROI by the area of the ROI.
The method of claim 1, wherein the cell densities of the feature vector are derived from an area cell density obtained by dividing the quantity of the labeled cells in the ROI by the area of the ROI.
Verbatim
Claim 8: Regarding claim 8, see the chart below for the comparison between claim 8 of the instant application and claim 5 of US ‘566. As can be seen below, claim 8 of the instant application is more broad in scope (when incorporating dependency) compared to claim 5 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 5 of US ‘566.
Instant Application - Claim 8
US '566 - Claim 5
Notes
The method of claim 1, wherein the cell densities of the feature vector are derived from a mean or median area cell density of a plurality of control regions of the ROI.
The method of claim 1, wherein the cell densities of the feature vector are derived from a mean or median area cell density of a plurality of control regions of the ROI.
Verbatim
Claim 9: Regarding claim 9, see the chart below for the comparison between claim 9 of the instant application and claim 29 of US ‘566. As can be seen below, claim 9 of the instant application is more broad in scope (when incorporating dependency) compared to claim 29 of US ‘566. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 29 of US ‘566.
Instant Application - Claim 9
US '566 - Claim 29
Notes
A method of prognosing a stage II colorectal cancer patient, the method comprising:
Claim 24: 24. The method of claim 23, further comprising prognosing the patient on the basis of the ICS.
Claim 29: The method of claim 24, wherein the patient is chemo-naïve and the colorectal tumor is determined to be mismatch repair proficient (pMMR).
Substantially the same
calculating an immune context score (ICS) for a sample of a tumor obtained from the patient, the ICS being calculated according to Formula 2:
Claim 23: wherein the continuous scoring function derived from the Cox proportional hazard model is a function according to formula 2:
Substantially the same
ICScox = exp(-b1* CD3AD – b2 * CD8AD + b3 * CD3AD * CD8AD) (Formula 2)
wherein:
Claim 23: ICS cox=exp(−b 1 *CD3AD −b 2 *CD8AD +b 3 *CD3AD *CD8AD) Formula 2
wherein:
verbatim
CD3AD is an area density of CD3+ cells of the ROI,
CD3AD is a CD3+ cell density of the ROI,
verbatim
CD8AD is an area density of CD8+ cells of the ROI, and
CD8AD is a CD8+ cell density of the ROI, and
verbatim
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of colorectal cancer patients.
Substantially the same
Claims 9 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 11 respectively of U.S. Patent No. 11,783,478 (hereinafter US ‘478). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application is more broad in scope (when incorporating dependency) compared to claim 5 and 11 of US ‘478.
Claim 9: Regarding claim 9, see the chart below for the comparison between claim 9 of the instant application and claim 5 of US ‘478. As can be seen below, claim 9 of the instant application is more broad in scope (when incorporating dependency) compared to claim 5 of US ‘478. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 5 of US ‘478.
Instant application - Claim 9
US '478 - Claim 5
Notes
A method of prognosing a stage II colorectal cancer patient, the method comprising:
Claim 1: A method of prognosing a patient having a stage II colorectal tumor, the method comprising:
… (d) prognosing the patient at least in part on the basis of the ICS.
Substantially the same
calculating an immune context score (ICS) for a sample of a tumor obtained from the patient, the ICS being calculated according to Formula 2:
The method of claim 1, wherein the non-linear continuous scoring function derived from the Cox proportional hazard model comprises a function according to formula 2:
Substantially the same
ICScox = exp(-b1* CD3AD – b2 * CD8AD + b3 * CD3AD * CD8AD) (Formula 2)
wherein:
ICScox=exp(-b1*CD3D-b2*CD8D+b*CD3D*CD8D)Formula2 wherein:
verbatim
CD3AD is an area density of CD3+ cells of the ROI,
CD3D is the density of CD3+ cells of the ROI,
Verbatim
CD8AD is an area density of CD8+ cells of the ROI, and
CD8D is the CD8+ cell density of the ROI, and
Verbatim
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of colorectal cancer patients, and wherein |b1|>|b2|>|b3|.
Substantially the same
Claim 12: Regarding claim 12, see the chart below for the comparison between claim 12 of the instant application and claim 11 of US ‘478. As can be seen below, claim 12 of the instant application is more broad in scope (when incorporating dependency) compared to claim 11 of US ‘478. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 11 of US ‘478.
Instant application - Claim 12
US '478 - Claim 11
Notes
A method of prognosing a chemo-naive stage II colorectal cancer patient having a tumor that is determined to be mismatch repair proficient (pMMR), the method comprising:
Claim 11: The method of claim 1, wherein the patient is chemo-naïve and the colorectal tumor is determined to be mismatch repair proficient (pMMR).
Claim 1: A method of prognosing a patient having a stage II colorectal tumor, the method comprising:
Substantially the same
(a) calculating a feature vector for a sample of the tumor, wherein the feature vector comprises a density of CD3+ lymphocytes in one or more of: (a) a tumor core (TC) region of a sample of the tumor, and (b) an invasive margin (IM) region or a peri- tumoral (PT) region of a sample of the tumor;
(a) obtaining:
(a1) a digital image of a tissue section of the stage II colorectal tumor stained for CD3; and
(a2) a digital image of a tissue section of the stage II colorectal tumor stained for at least one additional marker selected from a group consisting of CD8, CD4, FoxP3, CD45RA, and CD45RO;
(b) quantitating, on an image analysis system:
(b1) a CD3+ cell density within a region of interest (ROI) selected from a group consisting of a tumor core (TC) region, an invasive margin (IM) region, and/or a peritumoral (PT) region of the tissue section; and
(b2) a density of cells staining for the at least one additional marker within a ROI selected from a group consisting of a TC region, an IM region, and/or a PT region of the tissue section; and
Instant application more broad
(b) applying a continuous scoring function to the feature vector to obtain an immune context score (ICS); and
Claim 1: (c) applying a non-linear continuous scoring function to a feature vector comprising the CD3+ cell density and the density of cells staining for the at least one additional marker to obtain an immune context score (ICS) for the tumor, wherein the ICS is indicative of the prognosis of the patient, and wherein the non-linear continuous scoring function is derived from a Cox proportional hazard model of formula 1:
ICScox=exp(b1X1+b2X2+…bpXp)Formula1
wherein:
X1, X2, . . . Xp are independent variables, the independent variables including the CD3+ cell density and the density of cells staining for the additional marker and/or a combination of the CD3+ cell density and the density of cells staining for the additional marker for the ROI; and
b1, b2 . . . bp are constants extrapolated for each of the independent variables; and
Instant application more broad
(c) prognosing the patient on the basis of the ICS.
Claim 1: (d) prognosing the patient at least in part on the basis of the ICS.
verbatim
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 30 of U.S. Patent No. 12,154,275 (hereinafter US ‘275. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application is more broad in scope (when incorporating dependency) compared to claim 30 of US ‘275.
Claim 9: Regarding claim 9, see the chart below for the comparison between claim 9 of the instant application and claim 30 of US ‘275. As can be seen below, claim 9 of the instant application is more broad in scope (when incorporating dependency) compared to claim 30 of US ‘275. Therefore, any patent granted on the instant application would result in the unjustifiable timewise extension of the monopoly granted on claim 30 of US ‘275.
Instant application - Claim 9
US '275 - Claim 30
Notes
A method of prognosing a stage II colorectal cancer patient, the method comprising:
The method of claim 29, wherein the solid tumor is a stage II colorectal tumor,
Substantially the same
calculating an immune context score (ICS) for a sample of a tumor obtained from the patient, the ICS being calculated according to Formula 2:
the first ROI is an IM ROI or a PT ROI, and the continuous scoring function comprises a function according to formula 2:
Substantially the same
ICScox = exp(-b1* CD3AD – b2 * CD8AD + b3 * CD3AD * CD8AD) (Formula 2)
wherein:
ICScox=exp(−b 1*CD3D −b 2*CD8D +b 3*CD3D*CD8D) Formula 2
wherein:
verbatim
CD3AD is an area density of CD3+ cells of the ROI,
CD3AD is an area density of CD3+ cells of the ROI,
verbatim
CD8AD is an area density of CD8+ cells of the ROI, and
CD8AD is an area density of CD8+ cells of the ROI, and
verbatim
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
b1, b2, and b3 are constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
verbatim
Allowable Subject Matter
Claims 9-11 would be allowable if rewritten or amended to overcome the double patenting rejection(s) and 35 USC 112(b) rejections set forth in this Office action.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior arts of record teach methods of determining scoring for a tumor sample based on cellular properties.
However, none of them alone or in any combination teaches calculating immune context scores for stage II colorectal cancer patients using the Cox hazard model of formula 2, taking into account the area density of CD3 and CD8 cells in an ROI, and utilizing three constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
The closest prior art being previously cited Hermitte discloses methods of utilizing an Immunoscore assay for colon cancer (page 1, left column). The Immunoscore is a continuous score based on CD3 and CD8 markers and the tumor core and invasive margin (page 2, right column).
However, Hermitte fails to disclose calculating immune context scores for stage II colorectal cancer patients using the Cox hazard model of formula 2, taking into account the area density of CD3 and CD8 cells in an ROI, and utilizing three constants obtained from applying a Cox proportional hazard model to a dataset comprising recurrence-free survival data, CD3+ cell density data, and CD8+ cell density data obtained from a cohort of stage II colorectal cancer patients.
Contact
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/COURTNEY JOAN NELSON/Primary Examiner, Art Unit 2661
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