DETAILED ACTION
Acknowledgements
This office action is in response to the claims filed March 25, 2026.
Claims 60, 67-68, 72-75, and 79-88 are pending.
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 .
Response to Amendment(s)
Claims 60, 67-68, 72-75, and 79-88 are pending. Drawing objections have been overcome.
Information Disclosure Statement(s)
The information disclosure statement submitted 03/25/2026 was considered by examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 60, 67-68, 72-75, and 79-88 are rejected to under 35 U.S.C 101 as not being directed to eligible subject matter based on the grounds set out in detail below:
Independent Claims 60 and 79:
Eligibility Step 1 (does the subject matter fall within a statutory category?):
Independent claim 60 and 79 fall within the statutory category of method.
Eligibility Step 2A-1 (does the claim recite an abstract idea, law of nature, or natural phenomenon?): Independent claims 60 and 79 claimed invention is directed to an abstract idea without significantly more.
The claim elements which set forth the abstract idea in the independent claim 60:
A method of treating a subject, comprising steps of:(a) assessing a biomarker indicative of immune microenvironment status;
(b) selecting a treatment option based upon biomarker level;_
and (c) treating the subject according to the treatment option, wherein the assessing a biomarker includes:
(aa) assessing both:(i) subtype markers of a subtype selected from mesenchymal (M), mesenchymal stem-like (MSL), and combinations thereof;
and(ii) status markers of immunomodulatory (IM) status,
wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204, hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217;
and (bb) calculating an IO score by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy.
The claim elements which set forth the abstract idea in the independent claim 79:
A method comprising steps of:(a) receiving, data corresponding to levels of a plurality of markers indicative of immune microenvironment status for each of:
a subtype selected from M, MSL, and combinations thereof;
and an IM status, wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 13406751v1 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204,hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217;
(b) automatically determining, a classification of the subject as responsive to a first therapy (e.g. immunomodulation therapy) using the data received in step (a) to produce a numerical score;
and, optionally,(c) prescribing and/or administering the first therapy to the subject for treatment of the disease, wherein the numerical score is produced by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy.
The abstract idea is “certain methods of organizing human activity” by following rules and instructions to determine a treatment for a disease (see MPEP § 2106.04(a)(2))
Eligibility Step 2A-2 (does the claim recite additional elements that integrate the judicial exception into a practical application?): For Independent claims 60 and 79 judicial exception is not integrated into a practical application.
Independent claims 60 and 79 recites the additional claim elements below:
a computer
a processor of a computing device
Examiner takes the applicable considerations stated in MPEP 2106.04 (d) and analyzes them below in light of the instant applications disclosure and claim elements as a whole.
The additional elements, (a) and (b), are recited as executing the abstract idea and is merely recited as a general computer element as “apply-it” or an equivalent to analyze data
Accordingly, independent claims 60 and 79 as a whole do not integrate the recited abstract idea into a practical application (MPEP 2106.05(f) and 2106.04(d)(1).
Eligibility Step 2B (Does the claim amount to significantly more?): The independent claims do does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the computer element as analyzed above in step 2A prong 2, is merely applying the abstract idea and therefore, does not amount to significantly more. The claim is patent ineligible.
Dependent Claims 67-68, 72-75, and 80-88:
Eligibility Step 1 (does the subject matter fall within a statutory category?):
The dependent claims 67-68, 72-75, and 80-88 fall within the statutory category of method.
Eligibility Step 2A-1 (does the claim recite an abstract idea, law of nature, or natural phenomenon?): Dependent claims 67-68, 72-75, and 80-88 claimed invention is directed to an abstract idea without significantly more. The claims continue to limit the independent claim 60 and 79 abstract idea by (1) further limiting the assessment of biomarkers, (2) further limiting the gene data, (3) further limiting the treatment information, (4) further limiting the treatment option. Therefore, the dependent claims inherit the same abstract idea of “certain methods of organizing human activity” by following rules and instructions to determine a treatment for a disease (see MPEP § 2106.04(a)(2))
Eligibility Step 2A-2 (does the claim recite additional elements that integrate the judicial exception into a practical application?): For claims 67-68, 72-75, and 80-88 this judicial exception is not integrated into a practical application.
The dependent claims do not recite any additional elements not already recited in the independent claims thus purely treated as the abstract idea.
Accordingly, the dependent claims as a whole do not integrate the recited abstract idea into a practical application (MPEP 2106.05(f) and 2106.04(d)(1).
Eligibility Step 2B (Does the claim amount to significantly more?): The dependent claims do not include additional elements that amount to significantly more for the same reasons given in Prong 2. The claims are patent ineligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 60, 67, 68, 72, 73, and 79 are rejected to under 35 U.S.C. 103 as being unpatentable over Mitsiades et. al hereinafter (Mitsiades) (US20230075965Al) in view of Yeatman et. al (hereinafter Yeatman) (US20140031251A1)
As per claim 60, Mitsiades teaches:
A method of treating a subject, comprising steps of:(a) assessing a biomarker indicative of immune microenvironment status; (b) selecting a treatment option based upon biomarker level; and (c) treating the subject according to the treatment option, ([0005] discloses, “The present invention is based, at least in part, on the discovery that certain biomarkers determine the sensitivity or resistance of a subject to a type of immunotherapy. For example, some biomarkers disclosed herein allow more effective selection and treatment of subjects with immunotherapies that leverage natural killer (NK) cells” and see [0015] In some aspects, methods of treating a subject afflicted with a cancer include administering to the subject a therapeutically effective amount of an agent that modifies the copy number, the expression level, and/or the activity of one or more biomarkers listed in Table 1 or a fragment thereof, optionally in combination with an immunotherapy, optionally wherein the agent inhibits the copy number, the expression level, and/or the activity of one or more biomarkers listed in Table 1 or a fragment thereof.”)
However, Mitsiades does not explicitly teach:
wherein the assessing a biomarker includes:(aa) assessing both:(i) subtype markers of a subtype selected from mesenchymal (M), mesenchymal stem-like (MSL), and combinations thereof;
and (ii) status markers of immunomodulatory (IM) status, wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204, hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217;
and (bb) calculating, by means of a computer, an IO score by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy.
However, Yeatman does teach:
wherein the assessing a biomarker includes:(aa) assessing both:(i) subtype markers of a subtype selected from mesenchymal (M), mesenchymal stem-like (MSL), and combinations thereof; ([0011] discloses, “In one aspect, the invention provides a method for classifying a human Subject afflicted with a cancer type which is at risk of undergoing an epithelial cell-like to mesenchymal cell-like transition, as having a good prognosis or a poor prognosis, wherein said good prognosis indicates that said Subject is expected to have no distant metastases or no reoccurrence within five years of initial diagnosis of said cancer, and wherein said poor prognosis indicates that said Subject is expected to have distant metastases or a reoccurrence of cancer within five years of initial diagnosis of said cancer, the method comprising: (a) classifying cancer cells obtained from said human Subject as having mesenchymal cell-like qualities or epithelial cell-like qualities on the basis of the expression level of at least 5 of the genes for which markers are listed in any of TABLE 2A, TABLE 2B, TABLE 4A, TABLE 4B and/or at least one of the microRNAs listed in TABLE 9A and TABLE 9B; (b) classifying the human subject as having a good prognosis if the cancer cells are classified according to step (a) as having epithelial cell-like properties, or classifying the human Subject as having a poor prognosis if the cancer cells are classified according to step (a) as having mesenchymal cell-like properties; and (c) displaying or out putting to a user, user interface device, computer readable storage medium, or local or remote computer system the classification produced by said classifying step (b).”)
and (ii) status markers of immunomodulatory (IM) status, wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204, hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217; ([0061] discloses, “Generally, the invention provides signature marker sets (TABLES 2A, 2B, 4A, 4B, 9A, and 9B) whose expression levels within a cancer sample are correlated or anti correlated with the EMT status of the sample, and methods of use thereof.” And see table 9b which discloses has-mir-576 / examiner interprets EMT score as a narrower version of immunomodulatory status)
and (bb) calculating, by means of a computer, an IO score by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy. ([0076] discloses, “In another embodiment, the above method of deter mining the EMT status of a cancer sample obtained from a Subject to predict treatment response or assign treatment uses two "arms of the EMT signature, PC1 signature and/or MicroRNA signature markers. The “mesenchymal arm comprises the genes whose expression goes up with the tran sition of tissue to mesenchymal like cell characteristics (growth factor pathway activation (see TABLES 2A, 4A, and 9A)), and the “epithelial arm comprises the genes whose expression goes down with transition of tissue to mesenchy mal like cell characteristics (see TABLES 2B, 4B, and 9B).” and see comprising or consisting of 57 markers (see TABLE 9B).” and see [0077] discloses, “When comparing an individual sample with a stan dard or control, the expression value of marker X in the sample is compared to the expression value of marker X in the standard or control. For each gene in a set of inventive markers, log(10) ratio is created for the expression value in the individual sample relative to the standard or control. An EMT signature "score' is calculated by determining the mean log (10) ratio of the genes in the 'up' arm of the signature, here referred to as the “mesenchymal and then subtracting the mean log(10) ratio of the genes in the “down arm, here referred to as the “epithelial.” If the EMT signature score is above a pre-determined threshold, then the sample is considered to have a mesenchymal-like EMT status. In one embodiment of the invention, the pre-determined threshold is set at 0. The pre-determined threshold may also be the mean, median, or a percentile of EMT signature scores of a collection of samples or a pooled sample used as a standard of control. To determine if the EMT signature score is significant, an ANOVA calculation is performed (for example, a two tailed t-test, Wilcoxon rank-Sum test, Kolmogorov-Smirnov test, etc.), in which the expression values of the genes in the two opposing arms (Mesenchymal and Epithelial) are compared to one another. For example, if the two tailed t-test is used to determine whether the mean log(10) ratio of the genes in the “Mesenchymal arm is significantly different than the mean log(10) ratio of the genes in the “Epithelial arm, a p-value of expression values of the expression levels of the first plurality of genes and the second plurality of genes; and iii) Subtracting the mean differential expression value of the second plurality of genes from the mean differential expression value of the first plurality of genes to obtain the EMTSignature Score; (b) classifying the cancer cell sample as having mesenchymal cell-like properties if the obtained EMT Signature Score is at or above a first predetermined threshold and is statistically significant; or classifying said cancer cell sample as having epithelial cell-like properties if the obtained EMT Signature Score is at or below a second predetermined threshold and is statistically significant; wherein the human Subject is predicted to respond to the treatment if the cell sample is classified as having epithelial cell-like properties. Optionally, the EMT Signature Score and/or EMT classification status, i.e., mesenchymal cell-like properties or epithelial cell-like properties, is displayed; or output to a user, a user interface device, a computer readable storage medium, or a local or remote computer system.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings of predictive scores of what immunotherapy will be successful (see [0057] and [0102]) as previously cited with Yeatman’s teachings of utilizing a specific IO score, as previously cited, the motivation being Mitsiades’ is concerned with in para. [0004] the need in the field for a better understanding of why immunotherapies leveraging NK cells are effective or not effective, and for better clinical applications of such immunotherapies. Therefore combining with Yeatman’s IO score would improve prediction of which patients are most likely to benefit from immunotherapy and provide a more comprehensive assessment of the tumor immune microenvironment the complex ecosystem of cancer cells, immune cells, and other cells surrounding a tumor and does not render Mitsiades’ inoperable as a computer would still be able to use a predicative algorithm for this calculation thus a choice of what data to use.
As per claim 67, Mitsiades’ further teaches:
The method of claim 66, wherein the biomarker comprises an miRNA or comprises a collection of miRNAs present in blood. ([0379] discloses, “Accordingly, one aspect of the present invention relates to diagnostic assays for determining the amount and/or activity level of a biomarker described herein in the context of a biological sample ( e.g., blood, serum, cells, or tissue) to thereby determine whether an individual afflicted with a cancer is likely to respond to inhibitors of one or more biomarkers in Table 1 (e.g., B7-H6, HLA-E) and immunotherapy combination treatments, such as in a cancer.” And see [0067] discloses, “The "normal" copy number ( e.g., germline and/or somatic) of a biomarker nucleic acid or "normal" level of expression of a biomarker nucleic acid or protein is the activity/level of expression or copy number in a biological sample, e.g., a sample containing tissue, whole blood, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow, from a subject, e.g., a human, not afflicted with cancer, or from a corresponding noncancerous tissue in the same subject who has cancer.”)
As per claim 68, Mitsiades’ further teaches:
The method of claim 66, wherein the biomarker comprises an miRNA or comprises a collection of miRNAs present in a solid tumor. ([0279] discloses, “An alternative means for determining genomic copy number is comparative genomic hybridization. In general, genomic DNA is isolated from normal reference cells, as well as from test cells ( e.g., tumor cells) and amplified, if necessary. The two nucleic acids are differentially labeled and then hybridized in situ to metaphase chromosomes of a reference cell.”)
As per claim 72, Mitsiades’ further teaches:
The method of claim 60, wherein the treatment option comprises administration of one or more compounds. ([0123] discloses, “The term "therapeutic effect" refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal or human. The phrase "therapeutically-effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. In certain embodiments, a therapeutically effective amount of a compound will depend on its therapeutic index, solubility, and the like. For example, certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.”)
As per claim 73, Mitsiades’ further teaches:
The method of claim 72, wherein the subject is determined to have a tumor type sensitive to the one or more compounds. ( see pages 89-97 for example discloses, “Table B which Includes Table B, Table B2, and Table B3): Lists of Genes Identified by Genome-Scale CRISPR Screens to have Significant Enrichment (or. Conversely) Depletion of SgRNAs and by PRISM Studies to have Correlation of their Transcript Levels with NK Cell Sensitivity, or Conversely, Resistance” and see [0006] discloses, “In some aspects, methods of selecting a subject afflicted with cancer for treatment with an immunotherapy that primarily leverages either natural killer (NK) cells or T cells include detecting from the subject one or more values for one or more biomarkers listed in Table 1, which includes the biomarkers provided in the working examples, such as listed in Tables A-D; and selecting the subject for treatment with the immunotherapy based on the one or more values.” And see [0123] discloses, “The term "therapeutic effect" refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal or human. The phrase "therapeutically-effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. In certain embodiments, a therapeutically effective amount of a compound will depend on its therapeutic index, solubility, and the like. For example, certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.”)
As per claim 79, Mitsiades teaches:
A method comprising steps of:(a) receiving, by a processor of a computing device, data corresponding to levels of a plurality of markers for each of: a subtype selected from M, MSL, and combinations thereof; and an IM status;(b) automatically determining, by the processor, a classification of the subject as responsive to a first therapy (e.g. immunomodulation therapy) using the data received in step (a) to produce a numerical score; ( see table 1 and see [0070] discloses, “The term "diagnosing cancer" includes the use of the methods, systems, and code of the present invention to determine the presence or absence of a cancer or subtype thereof in an individual. The term also includes methods, systems, and code for assessing the level of disease activity in an individual.” And see [0344] discloses, “In another embodiment, immunotherapy comprises non-cell-based immunotherapies. In one embodiment, compositions comprising antigens with or without vaccine enhancing adjuvants are used. Such compositions exist in many well-known forms, such as peptide compositions, oncolytic viruses, recombinant antigen comprising fusion proteins, and the like. In still another embodiment, immunomodulatory interleukins, such as IL-2, IL-6, IL-7, IL-12, IL-17, IL-23, and the like, as well as modulators thereof ( e.g., blocking antibodies or more potent or longer lasting forms) are used. In yet another embodiment, immunomodulatory cytokines, such as interferons, G-CSF, imiquimod, TNFalpha, and the like, as well as modulators thereof ( e.g., blocking antibodies or more potent or longer lasting forms) are used. In another embodiment, immunomodulatory chemokines, such as CCL3, CCL26, and CXCL7, and the like, as well as modulators thereof ( e.g., blocking antibodies or more potent or longer lasting forms) are used. In another embodiment, immunomodulatory molecules targeting immunosuppression, such as STAT3 signaling modulators, NFkappaB signaling modulators, and immune checkpoint modulators, are used. The terms "immune checkpoint" and "anti-immune checkpoint therapy" are described above.” And see [0057] discloses, “The term "assigned score" refers to the numerical value designated for each of the biomarkers after being measured in a patient sample. The assigned score correlates to the absence, presence or inferred amount of the biomarker in the sample. The assigned score can be generated manually ( e.g., by visual inspection) or with the aid of instrumentation for image acquisition and analysis. In certain embodiments, the assigned score is determined by a qualitative assessment, for example, detection of a fluorescent readout on a graded scale, or quantitative assessment. In one embodiment, an "aggregate score," which refers to the combination of assigned scores from a plurality of measured biomarkers, is determined. In one embodiment the aggregate score is a summation of assigned scores. In another embodiment, combination of assigned scores involves performing mathematical operations on the assigned scores before combining them into an aggregate score. In certain, embodiments, the aggregate score is also referred to herein as the "predictive score." And see [0387] discloses, “An exemplary method for detecting the amount or activity of a biomarker described herein, and thus useful for classifying whether a sample is likely or unlikely to respond to inhibitors of one or more biomarkers in Table 1 (e.g., B7-H6, HLA-E) and immunotherapy combination treatments involves obtaining a biological sample from a test subject and contacting the biological sample with an agent, such as a protein-binding agent like an antibody or antigenbinding fragment thereof, or a nucleic acid-binding agent like an oligonucleotide, capable of detecting the amount or activity of the biomarker in the biological sample. In some embodiments, at least one antibody or antigen-binding fragment thereof is used, wherein two, three, four, five, six, seven, eight, nine, ten, or more such antibodies or antibody fragments can be used in combination (e.g., in sandwich ELISAs) or in serial. In certain instances, the statistical algorithm is a single learning statistical classifier system. For example, a single learning statistical classifier system can be used to classify a sample as a based upon a prediction or probability value and the presence or level of the biomarker. The use of a single learning statistical classifier system typically classifies the sample as, for example, a likely immunotherapy responder or progressor sample with a sensitivity, specificity, positive predictive value, negative predictive value, and/or overall accuracy of at least about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%0, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.” And see [0381] discloses, “The skilled artisan will also appreciated that, in certain embodiments, the methods of the present invention implement a computer program and computer system. For example, a computer program can be used to perform the algorithms described herein. A computer system can also store and manipulate data generated by the methods of the present invention which comprises a plurality of biomarker signal changes/profiles which can be used by a computer system in implementing the methods of this invention. In certain embodiments, a computer system receives biomarker expression data; (ii) stores the data; and (iii) compares the data in any number of ways described herein ( e.g., analysis relative to appropriate controls) to determine the state of informative biomarkers from cancerous or pre-cancerous tissue. In other embodiments, a computer system (i) compares the determined expression biomarker level to a threshold value; and (ii) outputs an indication of whether said biomarker level is significantly modulated (e.g., above or below) the threshold value, or a phenotype based on said indication.”)
And (c) prescribing and/or administering the first therapy to the subject for treatment of the disease. ([0006] discloses, “In some aspects, methods of selecting a subject afflicted with cancer for treatment with an immunotherapy that primarily leverages either natural killer (NK) cells or T cells include detecting from the subject one or more values for one or more biomarkers listed in Table 1, which includes the biomarkers provided in the working examples, such as listed in Tables A-D; and selecting the subject for treatment with the immunotherapy based on the one or more values.”)
However, Mitsiades does not explicitly teach:
indicative of immune microenvironment status for each of: a subtype selected from M, MSL, and combinations thereof; and an IM status, wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204, hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217;
wherein the numerical score is produced by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy.
However, Yeatman does teach:
indicative of immune microenvironment status for each of: a subtype selected from M, MSL, and combinations thereof; and an IM status, ([0011] discloses, “In one aspect, the invention provides a method for classifying a human Subject afflicted with a cancer type which is at risk of undergoing an epithelial cell-like to mesenchymal cell-like transition, as having a good prognosis or a poor prognosis, wherein said good prognosis indicates that said Subject is expected to have no distant metastases or no reoccurrence within five years of initial diagnosis of said cancer, and wherein said poor prognosis indicates that said Subject is expected to have distant metastases or a reoccurrence of cancer within five years of initial diagnosis of said cancer, the method comprising: (a) classifying cancer cells obtained from said human Subject as having mesenchymal cell-like qualities or epithelial cell-like qualities on the basis of the expression level of at least 5 of the genes for which markers are listed in any of TABLE 2A, TABLE 2B, TABLE 4A, TABLE 4B and/or at least one of the microRNAs listed in TABLE 9A and TABLE 9B; (b) classifying the human subject as having a good prognosis if the cancer cells are classified according to step (a) as having epithelial cell-like properties, or classifying the human Subject as having a poor prognosis if the cancer cells are classified according to step (a) as having mesenchymal cell-like properties; and (c) displaying or out putting to a user, user interface device, computer readable storage medium, or local or remote computer system the classification produced by said classifying step (b).”)
wherein the subtype markers and status markers comprise one or more miRNA species selected from: hsa-mir-511, hsa-mir-146b, hsa-mir-223, hsa-mir-148a, hsa-mir- 485, hsa-mir-29c, hsa-mir-4772, hsa-mir-32, hsa-let-7c, hsa-mir-299, hsa-mir-181d, hsa- mir-380, hsa-mir-889, hsa-mir-16-1, hsa-mir-192, hsa-mir-3613, hsa-mir-148b, hsa-mir- 6510, hsa-mir-134, hsa-mir-4677, hsa-mir-125b-2, hsa-mir-5586, hsa-mir-616, hsa-mir- 18a, hsa-mir-495, hsa-mir-27b, hsa-mir-942, hsa-mir-576, hsa-mir-133b, hsa-mir-204, hsa-mir-155, hsa-mir-10b, hsa-mir-3614, hsa-mir-487b, hsa-mir-29a, hsa-mir-330, hsa- mir-655, hsa-mir-19a, hsa-mir-146a, hsa-mir-181c, hsa-mir-379, hsa-mir-501, hsa-mir- 301a, hsa-mir-493, hsa-mir-140, hsa-mir-145, hsa-mir-23b, and hsa-mir-217;([0061] discloses, “Generally, the invention provides signature marker sets (TABLES 2A, 2B, 4A, 4B, 9A, and 9B) whose expression levels within a cancer sample are correlated or anti correlated with the EMT status of the sample, and methods of use thereof.” And see table 9b which discloses has-mir-576 / examiner interprets EMT score as a narrower version of immunomodulatory status)
wherein the numerical score is produced by weighting the subtype markers as likely to indicate non-responsiveness to immunomodulation therapy and the status markers as likely to indicate responsiveness to immunomodulation therapy.([0076] discloses, “In another embodiment, the above method of deter mining the EMT status of a cancer sample obtained from a Subject to predict treatment response or assign treatment uses two "arms of the EMT signature, PC1 signature and/or MicroRNA signature markers. The “mesenchymal arm comprises the genes whose expression goes up with the tran sition of tissue to mesenchymal like cell characteristics (growth factor pathway activation (see TABLES 2A, 4A, and 9A)), and the “epithelial arm comprises the genes whose expression goes down with transition of tissue to mesenchy mal like cell characteristics (see TABLES 2B, 4B, and 9B).” and see comprising or consisting of 57 markers (see TABLE 9B).” and see [0077] discloses, “When comparing an individual sample with a stan dard or control, the expression value of marker X in the sample is compared to the expression value of marker X in the standard or control. For each gene in a set of inventive markers, log(10) ratio is created for the expression value in the individual sample relative to the standard or control. An EMT signature "score' is calculated by determining the mean log (10) ratio of the genes in the 'up' arm of the signature, here referred to as the “mesenchymal and then subtracting the mean log(10) ratio of the genes in the “down arm, here referred to as the “epithelial.” If the EMT signature score is above a pre-determined threshold, then the sample is considered to have a mesenchymal-like EMT status. In one embodiment of the invention, the pre-determined threshold is set at 0. The pre-determined threshold may also be the mean, median, or a percentile of EMT signature scores of a collection of samples or a pooled sample used as a standard of control. To determine if the EMT signature score is significant, an ANOVA calculation is performed (for example, a two tailed t-test, Wilcoxon rank-Sum test, Kolmogorov-Smirnov test, etc.), in which the expression values of the genes in the two opposing arms (Mesenchymal and Epithelial) are compared to one another. For example, if the two tailed t-test is used to determine whether the mean log(10) ratio of the genes in the “Mesenchymal arm is significantly different than the mean log(10) ratio of the genes in the “Epithelial arm, a p-value of expression values of the expression levels of the first plurality of genes and the second plurality of genes; and iii) Subtracting the mean differential expression value of the second plurality of genes from the mean differential expression value of the first plurality of genes to obtain the EMTSignature Score; (b) classifying the cancer cell sample as having mesenchymal cell-like properties if the obtained EMT Signature Score is at or above a first predetermined threshold and is statistically significant; or classifying said cancer cell sample as having epithelial cell-like properties if the obtained EMT Signature Score is at or below a second predetermined threshold and is statistically significant; wherein the human Subject is predicted to respond to the treatment if the cell sample is classified as having epithelial cell-like properties. Optionally, the EMT Signature Score and/or EMT classification status, i.e., mesenchymal cell-like properties or epithelial cell-like properties, is displayed; or output to a user, a user interface device, a computer readable storage medium, or a local or remote computer system.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings of predictive scores of what immunotherapy will be successful (see [0057] and [0102]) as previously cited with Yeatman’s teachings of utilizing a specific IO score, as previously cited, the motivation being Mitsiades’ is concerned with in para. [0004] the need in the field for a better understanding of why immunotherapies leveraging NK cells are effective or not effective, and for better clinical applications of such immunotherapies. Therefore combining with Yeatman’s IO score would improve prediction of which patients are most likely to benefit from immunotherapy and provide a more comprehensive assessment of the tumor immune microenvironment the complex ecosystem of cancer cells, immune cells, and other cells surrounding a tumor and does not render Mitsiades’ inoperable as a computer would still be able to use a predicative algorithm for this calculation thus a choice of what data to use.
Claims 74, 75, 80, 81, 82, 83, 84, 85, 86, 87, and 88 are rejected to under 35 U.S.C. 103 as being unpatentable over Mitsiades et. al hereinafter (Mitsiades) (US20230075965Al) in view of Yeatman et. al (hereinafter Yeatman) (US20140031251A1) and in even further view of Keegan et. al (hereinafter Keegan (US20220011313Al)
As per claim 74, Mitsiades’ and Yeatman do not teach:
The method of claim 72, wherein the subject is determined to have a tumor type with a particular IO score that may change upon administration of the one or more compounds.
However, Keegan does teach:
The method of claim 72, wherein the subject is determined to have a tumor type with a particular IO score that may change upon administration of the one or more compounds. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings as previously cited, the motivation being Mitsiades is concerned with proper immunotherapies ([0004]) therefore it would be obvious to one of ordinary skill that the IO score may change with administration of one or more compounds.
As per claim 75, Mitsiades’ and Hyland do not teach:
The method of claim 74, wherein the treatment option further comprises co- administration or sequential administration of an additional or alternative therapy based upon change in IO score.
However, Keegan does teach:
The method of claim 74, wherein the treatment option further comprises co- administration or sequential administration of an additional or alternative therapy based upon change in IO score. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings as previously cited, the motivation being Mitsiades is concerned with proper immunotherapies ([0004]) therefore it would be obvious to one of ordinary skill that when the IO score may changes the therapy would change to meet new needs.
As per claim 80, Mitsiades and Yeatman do not explicitly teach:
The method of claim 60, wherein the treatment option comprises an immunomodulation therapy.
However, Keegan does teach:
The method of claim 60, wherein the treatment option comprises an immunomodulation therapy. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 81, Mitsiades and Yeatman does not explicitly teach:
The method of claim 80, wherein the immunomodulation therapy is selectively administered to subjects whose tumors have been determined to have IO scores above a certain threshold.
However, Keegan does teach:
The method of claim 80, wherein the immunomodulation therapy is selectively administered to subjects whose tumors have been determined to have IO scores above a certain threshold. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 82, Mitsiades and Yeatman does not explicitly teach:
The method of claim 81, wherein the immunomodulation therapy is selected from ICI therapy, CAR-T cell therapy, neoantigen vaccine therapy, or combinations thereof.
However, Keegan does teach:
The method of claim 81, wherein the immunomodulation therapy is selected from ICI therapy, CAR-T cell therapy, neoantigen vaccine therapy, or combinations thereof. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 83, Mitsiades and Yeatman does not explicitly teach:
The method of claim 82, wherein the immunomodulation therapy is ICI therapy.
However, Keegan does teach:
The method of claim 82, wherein the immunomodulation therapy is ICI therapy. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 84, Mitsiades and Yeatman does not explicitly teach:
The method of claim 75, wherein the additional therapy is selected to target gene pathways associated with negative IO scores.
However, Keegan does teach:
The method of claim 75, wherein the additional therapy is selected to target gene pathways associated with negative IO scores. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 85, Mitsiades and Yeatman does not explicitly teach:
The method of claim 75, wherein the treatment option is immunomodulation therapy.
However, Keegan does teach:
The method of claim 75, wherein the treatment option is immunomodulation therapy. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 86, Mitsiades and Yeatman does not explicitly teach:
The method of claim 85, wherein the immunomodulation therapy is ICI therapy and the additional therapy is not ICI therapy.
However, Keegan does teach:
The method of claim 85, wherein the immunomodulation therapy is ICI therapy and the additional therapy is not ICI therapy. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 87, Mitsiades and Yeatman does not explicitly teach:
The method of claim 85, wherein the immunomodulation therapy and additional therapy are co-administered.
However, Keegan does teach:
The method of claim 85, wherein the immunomodulation therapy and additional therapy are co-administered. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
As per claim 88, Mitsiades and Yeatman does not explicitly teach:
The method of claim 85, wherein the immunomodulation therapy and additional therapy are administered sequentially.
However, Keegan does teach:
The method of claim 85, wherein the immunomodulation therapy and additional therapy are administered sequentially. ([0014] discloses, “In some embodiments, comparing the levels of the one or more proteins in the initial and subsequent samples comprises determining ratios or percentage change between the levels in the initial and subsequent samples.” And see [0015] discloses, “In some embodiments, the methods further include determining an immuno-oncology (I-O) response score based on the levels, or ratios or percentage change between the levels in the initial and subsequent samples. In some embodiments, determining an I-O response score comprises applying principal component analysis or linear regression algorithm. In some embodiments, the methods include identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering further doses of the immune checkpoint inhibitor, or identifying a subject who has an I-O response score that is below a threshold, and selecting and optionally administering a therapy comprising further doses of the immune checkpoint inhibitor and at least one additional therapy, or a therapy not comprising the immune checkpoint inhibitor.” )
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Mitsiades’ teachings and Yeatman’s teachings with Keegan’s teachings for the same reasons given for claim 74.
Response to Arguments Regarding 35 U.S.C § 101 Rejection
The applicant argues on pages 1-2 of the submitted remarks that the rejection under 35 U.S.C § 101 should be withdrawn in light of the below arguments. The Office Action rejected previously examined claims 60-62, 64-69, and 71-79 under 35 U.S.C. § 101 as directed to ineligible subject matter. Specifically, the Office Action alleged that previously examined independent claims 60, 78, and 79 were directed to an abstract idea without significantly more and that previously examined dependent claims 61, 62, 64-69, and 71-77 did not recite any additional elements not already recited in the independent claims. Applicant respectfully traverses.
As noted by the examiner, previously examined claims 60, 78 and 79 satisfied Eligibility Step 1 as set forth by 35 U.S.C. §§ 101 and 100(b). Regarding Eligibility steps 2A and 2B, Applicant notes that previously examined claim 60 recited "[a] method of treating a subject" and for at least this reason was integrated into a practical application. Nevertheless, solely to advance prosecution, Applicant has amended claim 60 to recite a step of "treating the subject according to the treatment option". Previously examined claim 78 has been cancelled without prejudice, mooting the rejection of this claim. As noted in the Office Action, previously examined claim 79 recited an optional step of prescribing and/or administering the first therapy to the subject for treatment of the disease". Again, without conceding to the propriety of the rejection and solely to advance prosecution, Applicant has amended claim 79 to strike "optionally".
Accordingly, Applicant submits that the present claims recite patent-eligible subject matter under 35 U.S.C. § 101. Applicant respectfully requests that the rejection be withdrawn.
Examiner appreciates applicant’s arguments but does not find them persuasive. A claim reciting a judicial exception is not directed to the judicial exception if it also recites additional element(s) demonstrating that the claim as a whole integrates the exception into a practical application. One way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. The application or use of the judicial exception in this manner meaningfully limits the claim by going beyond generally linking the use of the judicial exception to a particular technological environment, and thus transforms a claim into patent-eligible subject matter. Such claims are eligible at Step 2A, because they are not "directed to" the recited judicial exception.
The particular treatment or prophylaxis consideration originated as part of the other meaningful limitations consideration discussed in MPEP § 2106.05(e) and shares the same legal basis in Supreme Court jurisprudence as that consideration. However, recent jurisprudence has provided additional guidance that is especially relevant to only a subset of claims, thus warranting the elevation of the particular treatment or prophylaxis consideration to become a stand-alone consideration in the Step 2A Prong Two analysis. Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 126 USPQ2d 1266 (Fed. Cir. 2018). The claims in Vanda recited a method of treating a patient having schizophrenia with iloperidone, a drug known to cause QTc prolongation (a disruption of the heart’s normal rhythm that can lead to serious health problems) in patients having a particular genotype associated with poor drug metabolism. 887 F.3d at 1121, 126 USPQ2d at 1269-70. In particular, the claims recited steps of: (1) performing a genotyping assay to determine if a patient has a genotype associated with poor drug metabolism; and (2) administering iloperidone to the patient in a dose range that depends on the patient’s genotype. Id. Although Vanda’s claims recited a law of nature (the naturally occurring relationship between the patient’s genotype and the risk of QTc prolongation) like the claims in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 101 USPQ2d 1961 (2012), the Federal Circuit distinguished them from the Mayo claims based on the differences in the administration steps. In particular, the court explained that Mayo’s step of administering a drug to a patient was performed in order to gather data about the recited laws of nature, and this step was thus ancillary to the overall diagnostic focus of the claims. 887 F.3d at 1134-35, 126 USPQ2d at 1280. In contrast, Vanda’s claims used the recited law of nature to more safely treat the patients with the drug, thereby reducing the patient’s risk of QTc prolongation. 887 F.3d at 1135, 126 USPQ2d at 1280. Accordingly, the court held Vanda’s claims eligible at the first part of the Alice/Mayo test (Step 2A) because the claims were not "directed to" the recited judicial exception. 887 F.3d at 1136, 126 USPQ2d at 1281.
Examples of "treatment" and prophylaxis" limitations encompass limitations that treat or prevent a disease or medical condition, including, e.g., acupuncture, administration of medication, dialysis, organ transplants, phototherapy, physiotherapy, radiation therapy, surgery, and the like. For example, an immunization step that integrates an abstract idea into a specific process of immunizing that lowers the risk that immunized patients will later develop chronic immune-mediated diseases is considered to be a particular prophylaxis limitation that practically applies the abstract idea. See, e.g., Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1066–68, 100 USPQ2d 1492, 1500-01 (Fed. Cir. 2011).
Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application.
Examiners may find it helpful to evaluate other considerations such as the mere instructions to apply an exception consideration (see MPEP § 2106.05(f)), and the field of use and technological environment consideration (see MPEP § 2106.05(h)), when making a determination of whether a treatment or prophylaxis limitation is particular or general.
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
Therefore, examiner notes the claims do not reflect or recite a particular treatment or prophylaxis as the claims are general and broad in the recitation as prescribing or administering, all independent claims are not of same scope, and furthermore the dependent claims give optionality to the types of immunotherapy or broadly state this therapy therefore not "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).
Examiner must maintain the 35 U.S.C 101 rejection.
Response to Arguments Regarding 35 U.S.C § 103 Rejections
Applicant argues on pages 2-4 of the remarks for claims rejected under 35 U.S.C § 103.
Applicant’s arguments with respect to the claims have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The 35 U.S.C rejection is maintained.
Prior Art not cited but made of record
Hyland et. al (hereinafter Hyland) (US12040048B2)
The method includes compressing numbers of reads data for targeted genes of a gene expression assay performed on a test sample. The targeted genes are organized into categories. Each category represents a functional context associated with the targeted genes in that category. The numbers of reads corresponding to targeted genes each category is compressed to form a compressed value for the category. The compressed value is compared to a baseline value for the category to determine an enrichment or a loss of a signature corresponding to the functional context of the category. The method may include analyzing information from multiple assays performed on the test sample, assigning a score value to each assay result and predicting a response to immune-oncology treatment based on the assigned scores.
US20240294643A1- Izar et. al
Methods of targeting CD58 signaling to enhance antitumor immunity and overcome resistance to checkpoint blockade therapy. Gene signatures associated with immune fitness were identified. Markers and therapeutic targets for such immunotherapy resistance.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ashley Elizabeth Evans whose telephone number is (571) 270-0110. The examiner can normally be reached Monday – Friday 8:00 AM – 5:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mamon Obeid can be reached on (571) 270-1813. The fax phone number for the organization where this application or proceeding is assigned 571-273-8300.
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/ASHLEY ELIZABETH EVANS/Examiner, Art Unit 3687
/MAMON OBEID/Supervisory Patent Examiner, Art Unit 3687
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