GDETAILED 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 – 50 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 – 50 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 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 – 50 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 – 50 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 – 50 are directed to judicial exceptions because claims 30 – 50 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 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 determine if the subject will respond to a cancer therapy selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission; and
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.
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 cancer therapy for the subject based on an analysis of a sample of a breast tumor of a 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
integrating the tumor aggressivity and the immunological activity based on an interaction term; and
administering the selected cancer therapy to the subject.
Claim 30 recites the combination of limitations identified in bold as “determining 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,” and “combining the Proliferative Index score and the Immunescore to determine if the subject will respond to a cancer therapy 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 cancer therapy for the subject based on an analysis of a sample of a breast tumor of a 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 “integrating the tumor aggressivity and the immunological activity based on an interaction term.” A broadest reasonable interpretation of this 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 are recite judicial exceptions under Step 2A, Prong One.
Dependent claims 31 – 41 and 43 – 50 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 – 50, 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 the 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 a mean 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 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, and “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. At best, each combination 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 – 50 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 – 50 are 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 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 determine if the subject will respond to a cancer therapy selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission; and
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.
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 cancer therapy for the subject based on an analysis of a sample of a breast tumor of a 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
integrating the tumor aggressivity and the immunological activity based on an interaction term; and
administering the selected cancer therapy 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 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.” Claim 42 recites the additional limitations identified in bold as “method of treating a subject for breast cancer” and the selected cancer therapy.” 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 and the field of use and technological environment. See MPEP 2106.04(d)(2). Furthermore, MPEP 2106.05(a) states: “In determining patent eligibility, examiners should consider whether the claim ‘purport(s) to improve the functioning of the computer itself’ or ‘any other technology or technical field.’… [A]n improvement in the abstract idea itself is not an improvement in technology.” 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 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 – 50 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 – 50 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 – 50 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 – 50, the Office carries over its determination from Step 2A, Prong Two that claims 31 – 41 and 43 – 50 further recite additional limitations and claims 31 – 41 and 43 – 50 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 – 50 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 – 50 are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 30 – 31, 33 – 35, 38 – 39, and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gutin (U.S. Pub. No. 2020/0283855 A1).
Regarding independent claim 30, Gutin 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:
determining a Proliferative Index score based on a level of one or more genes from Table 6 in a tissue sample from the subject (Paragraphs [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “determining 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 activities in Gutin (Paragraphs [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 and 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 an Immunescore based on a level of one or more genes from Table 4 in the tissue sample (Paragraphs [0064] – [0073] 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 [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.).);
combining the Proliferative Index score and the Immunescore to determine if the subject will respond to a cancer therapy selected from standard radiation therapy, radiotherapy intensification, radiotherapy de-intensification, or radiotherapy omission (Paragraphs [0022], [0027], [0041], and [0064] – [0073] of Gutin. In the instant application, the broadest reasonable interpretation of “combining the Proliferative Index score and the Immunescore” reads on the activity in Gutin (Paragraphs [0022], [0027], [0041], and [0064] – [0073]) of combining the expression levels of the genes (i.e., UBE2C, STC2, TOP2A, AURKA, CYBRD1, ADRA2A, SCUBE2, PGR, PTGER3, etc.) and the genes (i.e., UBE2C, EPHX2, CCND1, STC2, CELSR2, IL6ST, INPP4B, etc.)) and generating a combined score indicative of a prognosis or prediction of an outcome of a patient undergoing radiation therapy.); and
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 (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.).
Regarding claim 31, Gutin 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 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 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 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 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 teaches the limitations identified in bold as “the Proliferative Index score is based on a mean level of the 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 a mean 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], [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 the 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 a mean 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], [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 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.).
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 32, 40, 42 – 43, 45 – 46, and 49 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin, and further in view of Harbeck (U.S. Pub. No. 2006/0084056 A1).
Regarding claim 32, Gutin as 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 as 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]).
Regarding independent claim 42, Gutin 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 cancer therapy for the subject based on an analysis of a sample of a breast tumor of a subject (Paragraphs [0041], [0059], and [0116] – [0118] of Gutin. In the instant application, the broadest reasonable interpretation of “selecting a cancer therapy for the subject based on an analysis of a sample of a breast tumor of a 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
integrating the tumor aggressivity and the immunological activity based on 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 selected cancer therapy 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 as 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 as modified by 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 as modified by 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 as 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.).
Claims 36 – 37 are rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin and applied to claim 30, and further in view of Sandler (U.S. Pub. No. 2022/0111044 A1).
Regarding claim 36, Gutin as 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 as 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 as 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 (Paragraph [0087]), in order to provide improved immunotherapies for treating cancers (Paragraph [0003]).
Claim 44 is rejected under 35 U.S.C. 103(a) as being unpatentable over Gutin as modified by Harbeck and applied to claim 42, and further in view of Chang (U.S. Pub. No. 2022/0033912 A1).
Regarding claim 44, Gutin as modified by 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 as modified by 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 as modified by Harbeck and applied to claim 42, and further in view of Racioppi (U.S. Pub. No. 2019/0167776 A1).
Regarding claim 47, Gutin as modified by 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 as modified by 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 as modified by 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 as modified by 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]).
Conclusion
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/V.C.I./Examiner, Art Unit 3686
/DEVIN C HEIN/Examiner, Art Unit 3686