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 .
Status of the Claims
The office action is in response to the claims filed on November 26, 2025 for the application filed on January 24, 2025, which is a national stage of International Application No. PCT/US2023/070978 filed on July 25, 2023, which claims the benefit of Provisional Application Nos. 63/496,608 filed April 17, 2023, 63/479,049 filed January 9, 2023, 63/477,078 filed December 23, 2022, and 63/369,500 filed July 26, 2022. Claims 30 – 54 are currently pending and have been examined as discussed below.
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 30 – 54 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Examiners should determine whether a claim satisfies the criteria for subject matter eligibility by evaluating the claim in accordance with the flowchart in MPEP 2016(III).
Eligibility Step 1:
Under Step 1 of the 2019 Revised Patent Subject Matter Eligibility Guidance, it must be determined whether each claim as a whole falls within one of the statutory categories of invention (i.e., a process, machine, manufacture, or composition of matter). See MPEP 2106.03. In the instant application, claims 30 – 41 and 51 – 54 are directed to a method of treating a subject for breast cancer (i.e., a process), and claims 42 – 50 are directed to a method of treating a subject for breast cancer (i.e., a process).
While each one of claims 30 – 54 appears to fall within one or more statutory categories of invention, the Office has determined that the full eligibility analysis is required because there is doubt as to whether the applicant is effectively seeking coverage for a judicial exception itself. The eligibility of each claim is not self-evident at least because each claim as a whole did not appear to clearly improve a technology or computer functionality. To the contrary, each claim as a whole appeared to merely apply one or more judicial exceptions on a computer.
Accordingly, it has been determined that each one of claims 30 – 54 as a whole falls within one or more statutory categories under Step 1, and the Office proceeds with the full eligibility analysis (the Alice/Mayo test described in MPEP 2106(III)) as discussed below.
Eligibility Step 2A, Prong One:
Under Step 2A, Prong One of the 2019 Revised Patent Subject Matter Eligibility Guidance, it must be determined whether each claim is directed to one or more of the judicial exceptions (i.e., an abstract idea, law of nature, or natural phenomenon). See MPEP 2106.04(II)(A)(1). After evaluation, it has been determined that claims 30 – 54 are directed to judicial exceptions because claims 30 – 54 recite an abstract idea. (The Office will not determine that a claim is not directed to a judicial exception under Step 2A, Prong One for the mere reason that claim further recites one or more additional elements beyond the judicial exception.)
Independent claims 30 and 42 are determined to be directed to a judicial exception including an abstract idea (i.e., a mental process). Regarding claim 30, the mental process is represented by the limitations identified in bold as:
A method of treating a subject for breast cancer, comprising:
determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject;
determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample;
combining the Proliferative Index score and the Immunescore to generate an integrated score;
based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission; and
administering to the subject the selected cancer therapy
Regarding claim 42, the mental process is represented by the limitations identified in bold as:
A method of treating a subject for breast cancer, comprising:
selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject, wherein the analysis comprises:
determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk;
determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c); and
evaluating a treatment benefit of the selected treatment plan for the subject by integrating the tumor aggressivity and the immunological activity with an interaction term; and
administering the determined treatment plan to the subject.
Claim 30 recites the combination of limitations identified in bold as “determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject,” “determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample,” “combining the Proliferative Index score and the Immunescore to generate an integrated score,” and “based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission.” Claim 42 recites the combination of limitations identified in bold as “selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject,” “the analysis comprises: determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk,” “the analysis comprises: …. determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c),” and “the analysis comprises: … evaluating a treatment benefit of the selected treatment plan for the subject by integrating the tumor aggressivity and the immunological activity with an interaction term.” A broadest reasonable interpretation of each combination amounts to the activity of planning cancer therapy based on a patient’s genetic profile. This activity may be practically performed in the human mind using observation, evaluation, judgment, and opinion, and thus represents an abstract idea falling in the “mental process” grouping. There is nothing in each of claims 30 and 42 themselves that forecloses them from being performed by a human, mentally. with pen and paper, or even with generic computer components used as tools. Thus, this activity is an abstract idea in the "mental process" grouping.
Accordingly, claims 30 and 42 recite judicial exceptions under Step 2A, Prong One.
Dependent claims 31 – 41 and 43 – 54 are directed to one or more judicial exceptions (i.e., abstract idea exceptions) under Step 2A, Prong One of the full eligibility analysis as follows:
Regarding claims 31 – 41 and 43 – 54, the claims include the combinations of limitations identified in bold as “determining the Proliferative Index score comprises measuring an expression level of the one or more genes from Table 6 in the tissue sample, and/or wherein determining the Immunescore score comprises measuring an expression level of the one or more genes from Table 4 in the tissue sample” in claim 31, “the subject is at least 50 years old” in claims 32 and 43, “the tissue sample comprises a formalin fixed paraffin embedded tissue sample” in claim 33, “the tissue sample is from the subject prior to a treatment of the subject for the cancer” in claim 34, “a neoadjuvant immunotherapy” in claim 35, “stromal tumor-infiltrating lymphocytes around the tumor are not used in and/or available for analysis or used as part of the method” in claims 36 and 46, “using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 6 to determine the Proliferative Index score; and using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 4 to determine the Immunescore” in claim 37, “the Proliferative Index score is based on the level of one or more genes in at least one gene set selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on the level of one or more genes in at least one gene set selected from Table 4 and multiplying with the respective coefficient in Table 4” in claim 38, “the Proliferative Index score is based on a mean level of at least two genes in one or more gene sets selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on a mean level of at least two genes in one or more gene sets selected from Table 4 and multiplying with the respective coefficient in Table 4” in claim 39, “there is a high-risk of recurrence when the Proliferative Index score of the tissue sample is above a threshold between 60th to 95th percentile compared to a background population of representative tumors, and/or there is a low-risk of recurrence when the Proliferative Index score of the tissue sample is below a threshold below the 60th percentile compared to the background population of representative tumors” in claim 40, “combining the Proliferative Index and Immunescore based on an interaction term between the two” in claim 41, “when the tumor is classified as high-risk and the immunological activity is active, the treatment plan includes standard radiotherapy or radiotherapy omission, when the tumor is classified as high-risk and the immunological activity is inactive, the treatment plan includes radiotherapy intensification, when the tumor is classified as low-risk and the immunological activity is active, the treatment plan includes radiotherapy intensification, and when the tumor is classified as low-risk and the immunological activity is inactive, the treatment plan includes radiotherapy de-intensification” in claim 44, “a) high-risk when the Proliferative Index score of the sample is (i) above a threshold between the 60th to 95th percentile compared to a background population of representative tumors, or (ii) greater or equal to a median score of a background population of representative tumors, and/or low-risk when the Proliferative Index score of the sample is (i) below a threshold below the 60th percentile compared to the background population of representative tumors, or (ii) less than the median score of the background population of representative tumors” in claim 45, “the immunological activity is active when the sample comprises an activated tumor infiltrate comprising (i) a TILs score of ≥ 10%, and/or (ii) a positive staining for the expression of one or more of the checkpoint molecules” in claim 47, “the checkpoint molecules comprise PD-1 and/or PD-L1” in claim 48, “the tumor aggressivity comprises a histological grade of the sample of the tumor” in claim 49, “the analysis comprises determining a subtype of the tumor sample, wherein the subtype comprises Luminal A, Luminal B, HER2+, and triple negative/basal” in claim 50, “combining the integrated score and an age of the subject to generate a risk score; comparing the risk score of the subject to a representative background population to determine a risk category of the subject, the risk category selected from a low-risk group, a medium risk group, or a high risk group; and selecting the cancer therapy based on the risk category” in claim 51, “the subject falls into the high risk group, and the selected cancer therapy is intensified radiotherapy, or the subject falls into the medium risk group, and the selected cancer therapy is standard RT, or the subject falls into the low risk group, and the selected cancer therapy is RT de-intensification” in claim 52, “summing products of the mean level of at least two genes in two or more gene sets selected from Table 6 multiplied with the respective coefficient in Table 6 to determine the Proliferative Index score, and summing products of the mean level of at least two genes in two or more gene sets selected from Table 4 multiplied with the respective coefficient in Table 4 to determine the Immunescore” in claim 53, and “downgrading the selected cancer therapy based on the integrated score, wherein the breast cancer is grade III and the subject is 51-70 years old, or wherein the cancer is any histological grade and the subject is younger than 60 years old” in claim 54.. At best, each combination further defines the activity of planning cancer therapy based on a patient’s genetic profile. This activity may be practically performed in the human mind using observation, evaluation, judgment, and opinion, and thus represents an abstract idea falling in the “mental process” grouping. There is nothing in each of claims 31 – 41 and 43 – 54 themselves that forecloses them from being performed by a human, mentally. with pen and paper, or even with generic computer components used as tools.
Accordingly, claims 31 – 41 and 43 – 54 recite judicial exceptions under Step 2A, Prong One.
Eligibility Step 2A, Prong Two:
Claims 30 and 42 recite additional limitations beyond the judicial exceptions. Regarding claim 30, the additional limitations beyond the judicial exception are identified in bold as:
A method of treating a subject for breast cancer, comprising:
determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject;
determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample;
combining the Proliferative Index score and the Immunescore to generate an integrated score;
based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission; and
administering to the subject the selected cancer therapy.
Regarding claim 42, the additional limitations beyond the judicial exception are identified in bold as:
A method of treating a subject for breast cancer, comprising:
selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject, wherein the analysis comprises:
determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk;
determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c); and
evaluating a treatment benefit of the selected treatment plan for the subject by integrating the tumor aggressivity and the immunological activity with an interaction term; and
administering the determined treatment plan to the subject.
Claim 30 recites the additional limitations identified in bold as “a method of treating a subject for breast cancer” and “administering to the subject the selected cancer therapy.” Claim 42 recites the additional limitations identified in bold as “a method of treating a subject for breast cancer” and “administering the determined treatment plan to the subject.” Each of these elements is an additional limitation beyond the judicial exception (i.e., the mental process of planning cancer therapy based on a patient’s genetic profile). At best, looking at the combination of all additional elements and the judicial exception, the claim as a whole amounts to the activity of treating a subject for breast cancer.
The Office has determined that the administering step in each of claims 30 and 42 does not integrate the mental process into a practical application, but rather amounts to mere instructions to apply the mental process in a generic way, represent mere extra-solution activity, and does no more than generally link a judicial exception to a particular technological environment. The treatment limitation must be particular, i.e., specifically identified so that it does not encompass all applications of the judicial exception (planning cancer therapy based on a patient’s genetic profile). See MPEP 2106.04(d)(2) citing MPEP 2016.05(a), (f), (g), and (h). In the instant application, claim 30 recites the additional limitation of “administering to the subject the selected cancer therapy” in combination with the limitations of “based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission,” “combining the Proliferative Index score and the Immunescore to generate an integrated score,” “determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample,” and “determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject.” Claim 30 as a whole does not recite any computer components and thus does not improve the functioning of a computer itself. Claim 30 as a whole does not improve any other technology or technical field because it does not cover a particular solution to a problem or a particular way to achieve a desired outcome, but rather merely recites the idea of a solution or outcome at a high level of generality. See MPEP 2106.05(a). Claim 30 as a whole does not cover how the cancer therapy is selected based on the integrated score, how the cancer therapy is determined to be appropriate to reduce the subject's risk of local cancer recurrence, how the Proliferative Index score and the Immunescore are combined to generate the integrated score, how the Immunescore is determined based on the level of genes and their coefficients from Table 4, and how the Proliferative Index score is determined based on a level of genes and their associated coefficients from Table 6. Claim 42 recites the additional limitation of “administering the determined treatment plan” in combination with the limitations of “selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject, wherein the analysis comprises: c) determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk; d) determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c); and e) evaluating a treatment benefit of the selected treatment plan for the subject by integrating the tumor aggressivity and the immunological activity with an interaction term.” Claim 42 as a whole does not recite any computer components and thus does not improve the functioning of a computer itself. Claim 42 as a whole does not improve any other technology or technical field because it does not cover a particular solution to a problem or a particular way to achieve a desired outcome, but rather merely recites the idea of a solution or outcome at a high level of generality. See MPEP 2106.05(a). Claim 42 as a whole does not cover how the cancer therapy (i.e., in the step of administering to the subject the selected cancer therapy) is selected, how the selecting step comprises the evaluating step, how the tumor aggressivity is determined, how the tumor aggressivity and the immunological activity are integrated with an interaction term, how the Proliferative Index Score is determined, how the Proliferative Index Score is classified as high-risk, how the Proliferative Index Score is classified as low-risk, how the immunological activity is determined, how the Immunescore is determined, and any particular interaction term.
Regarding the consideration under MPEP 2106.05(g), each administering step is determined to add no more than insignificant extra-solution activities to the judicial exception. These limitations represent the well-known post-solution activity because each administering step represents an activity incidental to the primary process of each associated claim as a whole (i.e., planning cancer therapy based on a patient’s genetic profile) and thus those limitations are merely nominal or tangential additions to the claim. Regarding the consideration under MPEP 2106.05(h), the additional limitation, individually or in combination with any other limitations, also amount to merely indicating a field of use or technological environment (e.g., cancer treatment) in which to apply the judicial exception. Thus, the additional limitations fail to add an inventive concept to the claims.
Accordingly, in view of these considerations, the Office has determined that each one of claims 30 and 42 as a whole does not integrate the abstract idea exception into a practical application under Step 2A, Prong Two, and thus each claim as a whole is directed to a judicial exception under Step 2A.
Dependent claims 31 – 41 and 43 – 54 present additional information in tandem with further details regarding elements and the abstract idea from an associated one of independent claims 30 and 42 and are therefore directed to an abstract idea for similar reasons as given Under Step 2A, Prong One above. Claims 31 – 34, 36 – 41, and 43 – 54 do not recite any additional limitations beyond the abstract idea of planning cancer therapy based on a patient’s genetic profile. Claim 35 further recites an additional limitation, and this additional limitation fails to integrate the abstract idea into a practical application under Step 2A, Prong Two as follows:
Claim 35 recites the additional limitation identified in bold as “administering a neoadjuvant immunotherapy to the subject.” At best, the administering step is tantamount to the activity of merely administering a “suitable medication to a patient” and thus lacks particularity, such that each claim as a whole represents mere instructions to apply the abstract idea at a high level of generality. See MPEP 2106.05(a) and (f). Regarding the consideration under MPEP 2106.05(g), each administering step is determined to not add no more than insignificant extra-solution activities to the judicial exception. These limitations represent the well-known post-solution activity of data outputting because the claim as a whole represents an activity incidental to the primary process of the claim as a whole (i.e., planning cancer therapy based on a patient’s genetic profile) and thus those limitations are merely nominal or tangential additions to the claim. Regarding the consideration under MPEP 2106.05(h), the additional limitations, individually or in combination, also amount to merely indicating a field of use or technological environment in which to apply the judicial exception. Thus, the additional limitations fail to add an inventive concept to the claims.
Accordingly, in view of these considerations, the Office has determined that each one of claims 31 – 41 and 43 – 54 as a whole does not integrate the abstract idea exception into a practical application under Step 2A, Prong Two, and thus each claim as a whole is directed to a judicial exception under Step 2A.
Eligibility Step 2B:
Regarding independent claims 30 and 42, the Office carries over its identification of the additional elements (and combinations thereof) from Step 2A, Prong Two so as to apply the same additional elements in Step 2B. See MPEP 2106.05(II). The Office further carries over its conclusions from the considerations discussed in MPEP 2106.05(a) through (c), (e) through (h) in Step 2A, Prong Two so as to apply the same considerations in Step 2B.
Under Step 2B of the 2019 Revised Patent Subject Matter Eligibility Guidance, it must be determined whether the claim provides an inventive concept by determining if the claims include additional elements or a combination of elements that are sufficient to amount to significantly more than the judicial exception. After evaluation, there is no indication that an additional element or combination of elements are sufficient to amount to significantly more than the judicial exception. As discussed above with respect to integration of the abstract idea into a practical application, each claim as a whole does not provide an improvement to technology or technical field under MPEP 2106.05(a). The additional limitations amount to mere instructions to apply an abstract idea under MPEP 2106.05(f). Each claim as a whole represents the well‐understood, routine, and conventional functions of using Genomic-Adjusted Radiation Dose (GARD), a clinical model for genomic radiation dosing to allow the individualization of radiotherapy dose to tumor radiosensitivity and provide a framework to design genomically-guided clinical trials in radiation oncology. Using GARD to provide a framework to design genomically-guided clinical trials in radiation oncology is a well‐understood, routine, and conventional function as provided by NPL Scott.
Furthermore, looking at the limitations individually or as any ordered combination adds nothing that is not already present when looking at each claim as a whole. There is no indication that the individual elements or combinations of elements amount to an inventive concept.
Therefore, claims 30 and 42 are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Regarding claims 31 – 41 and 43 – 54, the Office carries over its determination from Step 2A, Prong Two that claims 31 – 41 and 43 – 54 further recite additional limitations and claims 31 – 41 and 43 – 54 do not recite additional elements so as to apply the same determination in Step 2B. See MPEP 2106.05(II). The Office further carries over its conclusions from the considerations discussed in MPEP 2106.05(a) through (c), (e) through (h) in Step 2A, Prong Two so as to apply the same considerations in Step 2B. The dependent claims merely present additional abstract information in tandem with further details regarding the elements from the independent claims and are, therefore, directed to an abstract idea for similar reasons as given above. Claims 31 – 34, 36 – 41, and 43 – 54 do not recite any additional limitations beyond the abstract idea of recommending an osteoporosis recovery program as a function of an individual’s predicted advancement of osteoporosis. Claim 35 further recites an additional limitation, and this additional limitation does not amount to significantly more than the judicial exception under Step 2B as follows:
Claim 35 as a whole does not provide an improvement to technology or technical field under MPEP 2106.05(a), but rather amounts to mere instructions to apply the abstract idea under MPEP 2106.05(f). The step of administering a neoadjuvant immunotherapy to the subject is recited at a high level of generality, such that the claim as a whole represents the well‐understood, routine, and conventional function of treating breast cancer (i.e., via GARD). Evidence that using GARD to provide a framework to design genomically-guided clinical trials in radiation oncology is well-understood, routine, and conventional is provided by NPL Scott.
Therefore, claims 31 – 41 and 43 – 54 are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 30 – 31, 33 – 35, 38 – 39, 41, 51, and 53 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin (U.S. Pub. No. 2020/0283855 A1) in view of Barnes (U.S. Pub. No. 2020/0234442 A1).
Regarding independent claim 30, Gutin teaches the limitations identified in bold as:
A method of treating a subject for breast cancer (Abstract and Paragraphs [0041] and [0065] of Gutin. In the instant application, the broadest reasonable interpretation of “method of treating a subject for breast cancer” reads on the administration in Gutin (Abstract and Paragraphs [0041] and [0065]) of radiation therapy for treating breast cancer.), comprising:
determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject (Paragraphs [0039] and [0064] – [0065] of Gutin. In the instant application, the broadest reasonable interpretation of “determining a tumor aggressivity of the breast cancer, wherein the tumor aggressivity comprises a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject” reads on the activity in Gutin (Paragraphs [0039] and [0064] – [0065], see also [0028] and [0066] – [0073]) of determining the score derived from the expression levels of marker genes (e.g., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) together with clinical data like tumor size, lymph node status or tumor grading (i.e., tumor aggressivity) as such variables coded as numbers in an equation.).
determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample (Paragraphs [0039] and [0064] – [0065] of Gutin. In the instant application, the broadest reasonable interpretation of “determining an Immunescore based on a level of one or more genes from Table 4 in the tissue sample” reads on the activities in Gutin (Paragraphs [0039] and [0064] – [0065], see also [0066] – [0073]) determining RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient and generating an expression score for the genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.).);
combining the Proliferative Index score and the Immunescore to generate an integrated score’ (Paragraph [0065] of Gutin. In the instant application, the broadest reasonable interpretation of “combining the Proliferative Index score and the Immunescore to generate an integrated score” reads on the activity in Gutin (Paragraph [0065], see also [0022], [0027], [0041], and [0064] and [0066] – [0073]) of combining the expression score (i.e., the expression levels of the genes, e.g., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.), and the clinical values (i.e., the genes, e.g., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) to generate the combined score indicative of a prognosis or prediction of an outcome of a patient undergoing radiation therapy.);
based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission (Paragraph [0065] of Gutin. In the instant application, the broadest reasonable interpretation of “the integrated score” reads on the combined score in Gutin (Paragraph [0065], see also [0022], [0027], [0041], and [0064] and [0066] – [0073]) indicative of a prognosis or prediction of an outcome of a patient undergoing radiation therapy.); and
administering to the subject the selected cancer therapy (Paragraphs [0041] – [0044] of Gutin. In the instant application, the broadest reasonable interpretation of “administering to the subject the selected cancer therapy” reads on the administration in Gutin (Paragraph [0041] – [0044], see also [0059] and [0116]) of radiation therapy.).
Gutin does not appear to explicitly disclose, but Barnes teaches the limitations identified in bold as “based at least on the integrated score, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission” (Paragraph [0232] of Barnes. In the instant application, the broadest reasonable interpretation of “based at least on …, selecting a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission” reads on the neoadjuvant or adjuvant treatment course in Barnes (Paragraph [0232], see also [0226]) including radiation therapy when subjects having a high risk of recurrence or progression as determined by an immune context score (optionally in combination with other diagnostic criteria) and not including radiation therapy when subjects having a low risk of recurrence or progression as determined by the immune context score (optionally in combination with other diagnostic criteria).).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin to include the activity of selecting, based at least on the integrated score, a cancer therapy appropriate to reduce the subject's risk of local cancer recurrence, wherein the cancer therapy is selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission, as taught by Barnes (Paragraph [0232]), in order to improve methods and compositions for isolating cell-free DNA, e.g., for use in liquid biopsies for early detection of cancer when the cancer is more susceptible to treatment (Paragraphs [0002] and [0005] of Barnes).
Regarding claim 31, Gutin in view of Barnes teaches the limitations identified in bold as “determining the Proliferative Index score comprises measuring an expression level of the one or more genes from Table 6 in the tissue sample, and/or wherein determining the Immunescore score comprises measuring an expression level of the one or more genes from Table 4 in the tissue sample” (Paragraphs [0035] and [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “determining the Proliferative Index score comprises measuring an expression level of the one or more genes from Table 6 in the tissue sample, and/or wherein determining the Immunescore score comprises measuring an expression level of the one or more genes from Table 4 in the tissue sample” reads on the activities in Gutin (Paragraphs [0035] and [0064] – [0073]) of measuring RNA expression level values of genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) in a tumor sample from a patient and measuring RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient.).
Regarding claim 33, Gutin in view of Barnes teaches the limitations identified in bold as “the tissue sample comprises a formalin fixed paraffin embedded tissue sample” (Paragraphs [0061] and [0078] of Gutin. In the instant application, the broadest reasonable interpretation of “the tissue sample comprises a formalin fixed paraffin embedded tissue sample” reads on the formalin-fixed paraffin embedded tumor sample in Gutin (Paragraphs [0061] and [0078]).).
Regarding claim 34, Gutin in view of Barnes teaches the limitations identified in bold as “the tissue sample is from the subject prior to a treatment of the subject for the cancer” (Paragraph [0103] of Gutin. In the instant application, the broadest reasonable interpretation of “the tissue sample is from the subject prior to a treatment of the subject for the cancer” reads on the sample in Gutin (Paragraph [0103]) from the subject prior to the administration of any therapy).
Regarding claim 35, Gutin in view of Barnes teaches the limitations identified in bold as “administering a neoadjuvant immunotherapy to the subject” (Paragraphs [0041] – [0042], [0060], and [0119] of Gutin. In the instant application, the broadest reasonable interpretation of “administering a neoadjuvant immunotherapy to the subject” reads on the activity in Gutin (Paragraphs [0041] – [0042], [0060], and [0119]) administering radiation therapy for cancer therapy in neoadjuvant mode).
Regarding claim 38, Gutin in view of Barnes teaches the limitations identified in bold as “the Proliferative Index score is based on the level of one or more genes in at least one gene set selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on the level of one or more genes in at least one gene set selected from Table 4 and multiplying with the respective coefficient in Table 4” (Paragraphs [0039], [0061], and [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “the Proliferative Index score is based on the level of one or more genes in at least one gene set selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on the level of one or more genes in at least one gene set selected from Table 4 and multiplying with the respective coefficient in Table 4” reads on the activities in Gutin (Paragraphs [0039], [0061], and [0064] – [0073]) determining RNA expression level values of genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) in a tumor sample from a patient, multiplying each expression level with a defined and specified coefficient, generating an expression score by combining the expression values for the genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.), determining RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient, multiplying each expression level with a defined and specified coefficient, and generating an expression score by combining the expression values for the genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.).).
Regarding claim 39, Gutin in view of Barnes teaches the limitations identified in bold as “the Proliferative Index score is based on a mean level of at least two genes in at least one or more gene sets selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on a mean level of at least two genes in one or more gene sets selected from Table 4 and multiplying with the respective coefficient in Table 4” (Paragraphs [0039], [0061], [0064] – [0073], [0103], and [0108] of Gutin. In the instant application, the broadest reasonable interpretation of “the Proliferative Index score is based on a mean level of at least two genes in at least one or more gene sets selected from Table 6 and multiplying with the respective coefficient in Table 6, and the Immunescore is based on a mean level of at least two genes in one or more gene sets selected from Table 4 and multiplying with the respective coefficient in Table 4” reads on the activities in Gutin (Paragraphs [0039], [0061], [0064] – [0073], [0103], and [0108]) determining RNA expression level values of genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) in a tumor sample from a patient, multiplying each expression level with a defined and specified coefficient, generating an expression score by combining the expression values for the genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.), determining RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient, multiplying each expression level with a defined and specified coefficient, and generating an expression score by combining the expression values for the genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.).).
Regarding claim 41, Gutin in view of Barnes teaches the limitations identified in bold as “combining the Proliferative Index and Immunescore based on an interaction term between the two” (Paragraphs [0135] – [0138] of Gutin. In the instant application, the broadest reasonable interpretation of “integrating the tumor aggressivity and the immunological activity based on an interaction term” reads on the activity in Gutin (Paragraphs [0135] – [0138]) of using the interaction term to combine and analyze the first dataset of 1120 patients from the ABCSG-8 cohort and the second dataset of 555 patients from the GEICAM cohort.).
Regarding claim 51, Gutin in view of Barnes and applied to claim 30 teaches the limitations identified in bold as “combining the integrated score and an age of the subject to generate a risk score; comparing the risk score of the subject to a representative background population to determine a risk category of the subject, the risk category selected from a low-risk group, a medium risk group, or a high risk group; and selecting the cancer therapy based on the risk category” (Paragraphs [0061], [0065], [0028], and [0232] of Barnes. In the instant application, the broadest reasonable interpretation of “risk” reads on the activities in Gutin (Paragraph [0065]) of developing recurrent neoplastic disease, in particular breast cancer. The broadest reasonable interpretation of “combining the integrated score and an age of the subject to generate a risk score; comparing the risk score of the subject to a representative background population to determine a risk category of the subject, the risk category selected from a low-risk group, a medium risk group, or a high risk group; and selecting the cancer therapy based on the risk category” reads on the activities in Barnes (Paragraphs [0028], [0061], and [0232], see also [0065], [0097] – [0099], and [0226]) of combining the immune context score with other diagnostic criteria (i.e., a score being a numerical derived from clinical data like age), applying the threshold on the combined score.to determine high and low risk (of developing recurrence), high, intermediate and low risk, or more risk, and determining the risk (of developing recurrence) without the subject receiving chemotherapy. The Office has determined that a person of ordinary skill in the art of computer-aided diagnosis for cancer therapy at the time of filing would understand that chemotherapy omission would be selected when there is low risk or no risk of cancer recurrence, and similarly radiotherapy would be omitted when there is low risk or no risk of cancer recurrence.).
Regarding claim 53, Gutin in view of Barnes and applied to claim 39 teaches the limitations identified in bold as “summing products of the mean level of at least two genes in two or more gene sets selected from Table 6 multiplied with the respective coefficient in Table 6 to determine the Proliferative Index score, and summing products of the mean level of at least two genes in two or more gene sets selected from Table 4 multiplied with the respective coefficient in Table 4 to determine the Immunescore” (Paragraphs [0039] and [0109] of Gutin. In the instant application, the broadest reasonable interpretation of “summing products of the mean level of at least two genes in two or more gene sets selected from Table 6 multiplied with the respective coefficient in Table 6 to determine the Proliferative Index score, and summing products of the mean level of at least two genes in two or more gene sets selected from Table 4 multiplied with the respective coefficient in Table 4 to determine the Immunescore” reads on the activity in Gutin (Paragraphs [0039] and [0109]) of combining the gene expression levels by multiplying each expression level (i.e., the mean levels of the one or more analyte biomarkers or the levels of the specific panel of analyte biomarkers and clinical variables) with a defined and specified coefficient and summing up such products to yield a score.).
Claims 32 and 40 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Barnes and applied to claim 30, and further in view of Harbeck (U.S. Pub. No. 2006/0084056 A1).
Regarding claim 32, Gutin in view of Barnes and applied to claim 30 does not appear to explicitly disclose, but Harbeck teaches the limitations identified in bold as “the subject is at least 50 years old” (Paragraph [0036] of Harbeck. In the instant application, the broadest reasonable interpretation of “the subject is at least 50 years old” reads on the patient in Harbeck (Paragraph [0036]) being greater than about 50 years of age.).
Regarding claim 40, Gutin in view of Barnes and applied to claim 30 does not appear to disclose, but Harbeck teaches the limitations identified in bold as “there is a high-risk of recurrence when the Proliferative Index score of the tissue sample is above a threshold between 60th to 95th percentile compared to a background population of representative tumors, and/or there is a low-risk of recurrence when the Proliferative Index score of the tissue sample is below a threshold below the 60th percentile compared to the background population of representative tumors” (Paragraph [0036] of Harbeck. The broadest reasonable interpretation of “there is a high-risk of recurrence when the Proliferative Index score of the tissue sample is above a threshold between 60th to 95th percentile compared to a background population of representative tumors, and/or there is a low-risk of recurrence when the Proliferative Index score of the tissue sample is below a threshold below the 60th percentile compared to the background population of representative tumors” reads on the activities in Harbeck (Paragraph [0036]) of measuring the level of uPA and the level of PAI-1 or the levels of mRNA encoding uPA and PAI-1 in said primary tumor tissue of said patient and classifying the patient as high risk if the level of uPA corresponds to above a cut-off value of at least about the 61st percentile, and classifying the patient as low risk if the level of uPA corresponds to levels below the cut-off value of at least about the 60th percentile.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin such that the subject is at least 50 years old, there is a high-risk of recurrence when the Proliferative Index score of the tissue sample is above a threshold between 60th to 95th percentile compared to a background population of representative tumors, and/or there is a low-risk of recurrence when the Proliferative Index score of the tissue sample is below a threshold below the 60th percentile compared to the background population of representative tumors, as taught by Harbeck (Paragraph [0036]), in order to provide specific methods for selecting treatment regimen in a cancer subject (Paragraph [0010]).
Claims 36 – 37 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Barnes and applied to claim 30, and further in view of Sandler (U.S. Pub. No. 2022/0111044 A1).
Regarding claim 36, Gutin in view of Barnes and applied to claim 30 does not appear to explicitly disclose, but Sandler teaches the limitations identified in bold as “stromal tumor-infiltrating lymphocytes around the tumor are not used in and/or available for analysis or used as part of the method” (Paragraph [0087] of Sandler. In the instant application, the broadest reasonable interpretation of “stromal tumor-infiltrating lymphocytes around the tumor are not used in and/or available for analysis or used as part of the method” reads on the high-risk nonimmunogenic tumors in Sandler (Paragraph [0087]) without TILs or PD-L1 expression not being susceptible to checkpoint therapy alone but being susceptible to vaccination as cell-mediated immunity induced against the tumor.).
Regarding claim 37, Gutin in view of Barnes and applied to claim 30 teaches the limitations of identified in bold as “using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 6 to determine the Proliferative Index score; and using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 4 to determine the Immunescore” (Paragraphs [0035] and [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “using the level of … genes from each gene set comprising the one or more genes from Table 6 to determine the Proliferative Index score; and using the level of … genes from each gene set comprising the one or more genes from Table 4 to determine the Immunescore” reads on the activities in Gutin (Paragraphs [0035] and [0064] – [0073]) of measuring RNA expression level values of genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) in a tumor sample from a patient and measuring RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient.).
Gutin in view of Barnes and applied to claim 30 does not appear to explicitly disclose, but Sandler the limitations of identified in bold as “using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 6 to determine the Proliferative Index score; and using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 4 to determine the Immunescore” (Paragraphs [0017] and [0019] of Sandler. In the instant application, the broadest reasonable interpretation of “using the level of at least the top 5 genes” reads on the activity in Sandler (Paragraphs [0017] and [0019]) of using he top 10 ranked differentially expressed genes for each cluster.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin such that stromal tumor-infiltrating lymphocytes around the tumor are not used in and/or available for analysis or used as part of the method, and to implement the activity of using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 6 to determine the Proliferative Index score; and using the level of at least the top 5 genes from each gene set comprising the one or more genes from Table 4 to determine the Immunescore, as taught by Sandler (Paragraphs [0017], [0019], and [0087]), in order to provide improved immunotherapies for treating cancers (Paragraph [0003]).
Claim 52 is rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Barnes and applied to claim 51, and further in view of Chang (U.S. Pub. No. 2022/0002815 A1).
Regarding claim 52, Gutin in view of Barnes and applied to claim 51 does not appear to explicitly disclose, but Chang teaches the limitations identified in bold as “the subject falls into the high risk group, and the selected cancer therapy is intensified radiotherapy, or the subject falls into the medium risk group, and the selected cancer therapy is standard RT, or the subject falls into the low risk group, and the selected cancer therapy is RT de-intensification” (Paragraph [0113] of Chang. In the instant application, the broadest reasonable interpretation of “the subject falls into the high risk group, and the selected cancer therapy is intensified radiotherapy, or the subject falls into the medium risk group, and the selected cancer therapy is standard RT, or the subject falls into the low risk group, and the selected cancer therapy is RT de-intensification” reads on the activities in Chang (Paragraph [0113]) of determining a subject to be at low risk of recurrence of breast cancer based on expression profiling and thus spared adjuvant radiotherapy and determining the subject to be at high risk of recurrence of breast cancer based on expression profiling and thus treated with radiation boost or adjuvant systemic therapy.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin to implement the subject falling into the high risk group, and the selected cancer therapy being intensified radiotherapy, or the subject falling into the medium risk group, and the selected cancer therapy being standard RT, or the subject falling into the low risk group, and the selected cancer therapy being RT de-intensification, as taught by Chang (Paragraph [0113]), in order to provide novel gene signatures that are prognostic for loco-regional recurrence and radiation sensitivity (Paragraph [0005] of Chang).
Claims 42 – 43, 45 – 46, and 49 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Barnes, and further in view of Harbeck (U.S. Pub. No. 2006/0084056 A1).
Regarding independent claim 42, Gutin in view of Barnes teaches the limitations identified in bold as:
A method of treating a subject for breast cancer (Abstract and Paragraph [0041] of Gutin. In the instant application, the broadest reasonable interpretation of “method of treating a subject for breast cancer” reads on the administration in Gutin (Abstract and Paragraph [0041]) of radiation therapy for cancer therapy.), comprising:
selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject (Paragraphs [0041], [0059], and [0116] – [0118] of Gutin. In the instant application, the broadest reasonable interpretation of “selecting a treatment plan for the subject based on an analysis of a sample of a breast tumor from the subject” reads on the activities in Gutin (Paragraphs [0041] and [0116] – [0118]) selecting and administering the therapy based on the marker genes being indicative of a good outcome of the patient.), wherein the analysis comprises:
determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk;
determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c) (Paragraphs [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “determining an immunological activity of the breast tumor from the sample, wherein the immunological activity comprises a) an Immunescore of the sample; b) a level of TILs in the sample; c) a level of checkpoint molecules in the sample; or d) any combination of a)-c)” reads on the activities in Gutin (Paragraphs [0064] – [0073]) determining RNA expression level values of genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.) in a tumor sample from a patient and generating an expression score by combining the expression values for the genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.).); and
evaluating a treatment benefit of the selected treatment plan for the subject by integrating the tumor aggressivity and the immunological activity with an interaction term (Paragraphs [0135] – [0138] of Gutin. In the instant application, the broadest reasonable interpretation of “integrating the tumor aggressivity and the immunological activity based on an interaction term” reads on the activity in Gutin (Paragraphs [0135] – [0138]) of using the interaction term to combine and analyze the first dataset of 1120 patients from the ABCSG-8 cohort and the second dataset of 555 patients from the GEICAM cohort.); and
administering the determined treatment plan to the subject (Paragraphs [0041] – [0044], [0059], and [0116] of Gutin. In the instant application, the broadest reasonable interpretation of “administering to the subject the cancer therapy selected upon the determination that the subject will respond to the selected cancer therapy based on combining the Proliferative Index score and the Immunescore” reads on the administration in Gutin (Paragraph [0041] – [0044]) of radiation therapy).
Gutin does not appear to explicitly disclose, but Harbeck teaches the limitation identified in bold as “determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk” (Paragraph [0036] of Harbeck. The broadest reasonable interpretation of “determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk” reads on the activities in Harbeck (Paragraph [0036]) of measuring the level of uPA and the level of PAI-1 or the levels of mRNA encoding uPA and PAI-1 in said primary tumor tissue of said patient and classifying the patient as high risk if the level of uPA corresponds to above a cut-off value of at least about the 61st percentile, and classifying the patient as low risk if the level of uPA corresponds to levels below the cut-off value of at least about the 60th percentile.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin to: implement the activity of determining a tumor aggressivity of the breast tumor from the sample, wherein the tumor aggressivity comprises a Proliferative Index score that classifies the tumor as high-risk or low-risk, as taught by Harbeck (Paragraph [0036]), in order to provide specific methods for selecting treatment regimen in a cancer subject (Paragraph [0010]).
Regarding claim 43, Gutin in view of Barnes and applied to claim 42 does not appear to explicitly disclose, but Harbeck teaches the limitations identified in bold as “the subject is at least 50 years old” (Paragraph [0036] of Harbeck. In the instant application, the broadest reasonable interpretation of “the subject is at least 50 years old” reads on the patient in Harbeck (Paragraph [0036]) being greater than about 50 years of age.).
Regarding claim 45, Gutin in view of Harbeck and applied to claim 42 teaches the limitations identified in bold as “wherein the tumor is classified as: a) high-risk when the Proliferative Index score of the sample is (i) above a threshold between the 60th to 95th percentile compared to a background population of representative tumors, or (ii) greater or equal to a median score of a background population of representative tumors, and/or low-risk when the Proliferative Index score of the sample is (i) below a threshold below the 60th percentile compared to the background population of representative tumors, or (ii) less than the median score of the background population of representative tumors” (Paragraphs [0036], [0103], and [0108] of Harbeck. In the instant application, the broadest reasonable interpretation of “wherein the tumor is classified as: a) high-risk when the Proliferative Index score of the sample is (i) above a threshold between the 60th to 95th percentile compared to a background population of representative tumors, or (ii) greater or equal to a median score of a background population of representative tumors, and/or low-risk when the Proliferative Index score of the sample is (i) below a threshold below the 60th percentile compared to the background population of representative tumors, or (ii) less than the median score of the background population of representative tumors” reads on the activity in Harbeck (Paragraphs [0036], [0103], and [0108]) of classifying the patient as high risk if the median level of uPA corresponds to above a cut-off value of at least about the 61st percentile, and classifying the patient as low risk if the median level of uPA corresponds to levels below the cut-off value of at least about the 60th percentile).
Regarding claim 46, Gutin in view of Harbeck and applied to claim 42 and teaches the limitations identified in bold as “the Proliferative Index score is based on an expression level of a first group of genes comprising one or more genes listed in Table 6, and wherein the Immunescore is based on an expression level of a second group of genes comprising one or more genes listed in Table 4” (Paragraphs [0035] and [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “determining the Proliferative Index score comprises measuring an expression level of the one or more genes from Table 6 in the tissue sample, and/or wherein determining the Immunescore score comprises measuring an expression level of the one or more genes from Table 4 in the tissue sample” reads on the activity in Gutin (Paragraphs [0035] and [0064] – [0073]) of measuring expression level of a gene directly (e.g., e.g. by obtaining a signal wherein the signal strength is correlated to the amount of mRNA transcripts of that gene) or indirectly (e.g., at a protein level).).
Regarding claim 49, Gutin in view of Barnes and applied to claim 42 teaches the limitations identified in bold as “the tumor aggressivity comprises a histological grade of the sample of the tumor” (Paragraph [0018] of Gutin. In the instant application, the broadest reasonable interpretation of “the tumor aggressivity comprises a histological grade of the sample of the tumor” reads on the histological origin in Gutin (Paragraph [0018]) including any grade, histomorphological feature, invasiveness, aggressiveness or malignancy of an affected tissue or cell aggregation, such as grade I cancer, grade II cancer, grade III cancer, malignant cancer and primary carcinomas.).
Claim 44 is rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Harbeck and applied to claim 42, and further in view of Chang (U.S. Pub. No. 2022/0033912 A1).
Regarding claim 44, Gutin in view of Harbeck and applied to claim 42 teaches the limitations identified in bold as “when the tumor is classified as high-risk and the immunological activity is active, the treatment plan includes standard radiotherapy or radiotherapy omission, when the tumor is classified as high-risk and the immunological activity is inactive, the treatment plan includes radiotherapy intensification, when the tumor is classified as low-risk and the immunological activity is active, the treatment plan includes radiotherapy intensification, and when the tumor is classified as low-risk and the immunological activity is inactive, the treatment plan includes radiotherapy de-intensification” (Paragraphs [0132] – [0134], [0172] – [0183], and Table 1 of Chang. In the instant application, the broadest reasonable interpretation of “when the tumor is classified as high-risk and the immunological activity is active, the treatment plan includes standard radiotherapy or radiotherapy omission, when the tumor is classified as high-risk and the immunological activity is inactive, the treatment plan includes radiotherapy intensification, when the tumor is classified as low-risk and the immunological activity is active, the treatment plan includes radiotherapy intensification, and when the tumor is classified as low-risk and the immunological activity is inactive, the treatment plan includes radiotherapy de-intensification” reads on the intensity-modulated radiation therapy (IMRT) in Chang (Paragraphs [0132] – [0134], [0172] – [0176], and Table 1) associated with the Average Genomic Risk (AGR) as the mean of the 15 signatures scores.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin in view of Harbeck such that, when the tumor is classified as high-risk and the immunological activity is active, the treatment plan includes standard radiotherapy or radiotherapy omission, when the tumor is classified as high-risk and the immunological activity is inactive, the treatment plan includes radiotherapy intensification, when the tumor is classified as low-risk and the immunological activity is active, the treatment plan includes radiotherapy intensification, and when the tumor is classified as low-risk and the immunological activity is inactive, the treatment plan includes radiotherapy de-intensification, as taught by Chang (Paragraphs [0132] – [0134] and [0176]), in order to provide use a whole transcriptome platform and the average of all the signatures, thereby produce results consistent with the best individual signatures and improve inter-signature variability (Paragraphs [0179] – [0181] of Chang).
Claims 47 – 48 and 50 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin in view of Barnes and applied to claim 42, and further in view of Racioppi (U.S. Pub. No. 2019/0167776 A1).
Regarding claim 47, Gutin in view of Harbeck and applied to claim 42 does not appear to explicitly disclose, but Racioppi teaches the limitations identified in bold as “the immunological activity is active when the sample comprises an activated tumor infiltrate comprising (i) a TILs score of ≥ 10%, and/or (ii) a positive staining for the expression of one or more of the checkpoint molecules” (Paragraph [0103] of Racioppi. In the instant application, the broadest reasonable interpretation of “the immunological activity is active when the sample comprises an activated tumor infiltrate comprising (i) a TILs score of ≥ 10%, and/or (ii) a positive staining for the expression of one or more of the checkpoint molecules” reads on the staining in Racioppi (Paragraph [0103]) of tumor-infiltrating E0771 tumors: 5×10.sup.6 cells suspension from dissected tumors were surface stained with PD-1 (i.e., checkpoint molecule).).
Regarding claim 48, Gutin in view of Harbeck and applied to claim 42 does not appear to explicitly disclose, but Racioppi teaches the limitations identified in bold as “the checkpoint molecules comprise PD-1 and/or PD-L1” (Paragraph [0060] of Racioppi. In the instant application, the broadest reasonable interpretation of “the checkpoint molecules comprise PD-1 and/or PD-L1” reads on the checkpoint inhibitors in Racioppi (Paragraph [0060]) include, without limitation, antibodies or other therapeutics targeting programmed cell death protein 1 (PD1, also known as CD279), programmed cell death 1 ligand 1 (PD-L1, also known as CD274).).
Regarding claim 50, Gutin in view of Harbeck and applied to claim 42 appears to explicitly disclose, but Racioppi teaches the limitations identified in bold as “determining a subtype of the tumor sample, wherein the subtype comprises Luminal A, Luminal B, HER2+, and triple negative/basal” (Paragraphs [0123] – [0125] and Table 2 of Racioppi. In the instant application, the broadest reasonable interpretation of “determining a subtype of the tumor sample , wherein the subtype comprises Luminal A, Luminal B, HER2+, and triple negative/basal” reads on the activity in Racioppi (Paragraphs [0123] – [0125] and Table 2) of determining gene expression to be low or high, correlated with molecular subtype: triple negative, luminal A, and luminal B.).
Therefore, it would have been obvious to one of ordinary skill in the art of computer-aided diagnosis systems at the time of filing to modify the system and method of Gutin in view of Harbeck to: implement the activity of the immunological activity is active when the sample comprises an activated tumor infiltrate comprising (i) a TILs score of ≥ 10%, and/or (ii) a positive staining for the expression of one or more of the checkpoint molecules, with the checkpoint molecules comprising PD-1 and/or PD-L1, and implement the activity of determining a subtype of the tumor sample, wherein the subtype comprises Luminal A, Luminal B, HER2+, and triple negative/basal, as taught by Racioppi (Paragraphs [0060], [0103], and [0123] – [0125] and Table 2), in order to use checkpoint inhibitors to treat cancer in a subject by inducing and/or enhancing an immune response in that subject (Paragraph [0059]).
Subject Matter Allowable Over the Prior Art
Claim 54 is determined to be allowable over the prior art. The prior art of record does not appear to disclose the limitation of "downgrading the selected cancer therapy based on the integrated score, wherein the breast cancer is grade III and the subject is 51-70 years old, or wherein the cancer is any histological grade and the subject is younger than 60 years old."
Response to Arguments
Applicant's arguments (Second Paragraph on Page 8 to Fourth Paragraph on Page 9 of the Amendment filed June 23, 2026) regarding the rejection of claims 30 – 50 under 35 U.S.C. § 101 have been fully considered and are moot in view of the new grounds of rejection necessitated by the amendment.
In the Amendment (Second Paragraph on Page 9), Applicant argued that amended claim 30 as a whole integrates any judicial exception into a practical application because “administering a cancer therapy selected based on a subject's integrated score, that is a combination of the Proliferative Index score and the Immunescore derived from the analysis of the subject's tissue sample, provides for individualized treatment to the subject that reduces the risk of local recurrence.” The Office respectfully disagrees.
The administering step in each of claims 30 and 42 does not integrate the mental process into a practical application, but rather amounts to mere instructions to apply the mental process in a generic way, represent mere extra-solution activity, and does no more than generally link a judicial exception to a particular technological environment. MPEP 2106.04(d)(2) states: “The treatment or prophylaxis limitation must be ‘particular,’ i.e., specifically identified so that it does not encompass all applications of the judicial exception.” See MPEP 2106.04(d)(2) citing MPEP 2016.05(a), (f), (g), and (h). For at least the reasons stated in the body of this Final Office Action, the administering step does not integrate the mental process into a practical application.
Applicant's arguments (Fifth Paragraph on Page 9 to Fourth Paragraph on Page 10 of the Amendment filed June 23, 2026) regarding the rejection of claims 30 – 31, 33 – 35, 38 – 39, and 41 under 35 U.S.C. § 102 have been fully considered and are moot in view of the new grounds of rejection necessitated by the amendment.
Applicant's arguments (Fifth Paragraph on Page 10 to First Paragraph on Page 15 of the Amendment filed June 23, 2026) regarding the rejections of claims 32, 36 – 37, 40, and 42 – 50 under 35 U.S.C. § 103 have been fully considered and are moot in view of the new grounds of rejection necessitated by the amendment.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/V.C.I./Examiner, Art Unit 3686
/DEVIN C HEIN/Examiner, Art Unit 3686
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