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 .
DETAILED ACTION
Status of Claims
The present Office Action is pursuant to Applicant’s communication on 08-30-2022. This application has PRO of 63496267 04/14/2023.
This application is a 371 of PCT/IL2021/050147 02/07/2021 PCT/IL2021/050147 has PRO 63/089,304 10/08/2020 PCT/IL2021/050147 has PRO 63/022,736 05/11/2020
PCT/IL2021/050147 has PRO 62/971,065 02/06/2020.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 12-21-2023, have been acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Patentability Summary
Independent claim(s) 1, 18 and dependent claim(s) 3, 5, 7, 9-10, 14-16, 20, 22, 24, 26-27, 29, 31-32 and 34-35 is/are directed to a technical solution to a technical problem associated with predicting a response in a target patient subjects to a specified therapy wherein said specified therapy in each of said subjects employs generation of a classifier suitable for predicting a response in the target patient to said specified therapy, wherein said sets of values are labeled with said labels based on receiving, for each of a plurality of subjects having a specified type of disease and receiving a specified therapy for treating said disease, (a) a first biological signature associated with a biological sample collected at a first time point relative to said specified therapy, and (b) a second biological signature associated with a biological sample collected at a second time point relative to said specified therapy, wherein each one of said first and second biological signatures.
Thus, based on the aforementioned summary, the combination of limitations corresponding to the aforementioned claim(s) is/are patent eligible.
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 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 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 for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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.
Claim(s) 1, 3, 5, 7, 9-10, 14-16, 18, 20, 22, 24, 26-27, 29, 31-32 and 34-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zitnik1 in view of Abraham (US 11,315,673).
Regarding claim(s) 1, 18, Zitnik discloses: A system for predicting a response in a target patient to a specified therapy, comprising:
receive, for each of a plurality of subjects having a specified type of disease and receiving a specified therapy for treating said disease, (a) a first biological signature associated with a biological sample collected at a first time point relative to said specified therapy, and (b) a second biological signature associated with a biological sample collected at a second time point relative to said specified therapy, wherein each one of said first and second biological signatures is selected from a list consisting of: a DNA profile, an RNA profile, a protein profile, a metabolomics profile, microbiome profile, a genomics profile, a transcriptomics profile, a cellular profile, an epigenomics profile, a post-translational modification-based profile, cellular profile, single-cell based analysis and a regulatory RNA profile, [Pages 77-81: gene expression profiles and single-cell analysis]
Regulating [b]-[c], Zitnik discloses calculation of a position weight matrix, a probabilistic model that scores how well a motif describes a sequence associated with transcription factors (TFs) and their binding sites in association with enhancers and promoter regions of DNA, TFs acting as master regulators that control access to DNA at said enhancers and promoter regions, mutation or alterations in TFs associated with upregulation of resistance proteins, TFs capable of being activated or silenced by environmental factors, altering binding patterns to enhance survival, a random forest being trained to predict transcription patterns. [Page 75-76]
Regarding [a]-[c], Zitnik does not explicitly disclose as disclosed by Abraham:
at least one hardware processor; and a non-transitory computer-readable storage medium having stored thereon program instructions, the program instructions executable by the at least one hardware processor to [33:1-67]:
calculate, for each of said plurality of subjects, a set of values representing a relation between said first and second biological signatures associated with said respective subject, (i.e., determining differentially expressed levels) [99:14-45: see Group 4 including PTEN2 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein] and
at a training stage, train a machine learning model on a training set comprising [112:34-113:20: training to predict benefit or lack of benefit of a therapeutic product, employing a random forest and class labels]:
said calculated sets of values, [59:1-60:35: expression levels] and
labels associated with an outcome of said specified therapy in each of said subjects, to generate a classifier suitable for predicting a response in a target patient to said specified therapy, wherein said sets of values are labeled with said labels (i.e., determining useful groups of biomarkers for predicting response or benefit employing machine learning modeling). [99:14-45: see Group 4 including PTEN3 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein, and wherein benefits including log rank p-values]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a]-[c], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 3, Zitnik-Abraham as a combination discloses: The system of claim 1, Abraham disclosing [a]: wherein said first and second biological signatures are each protein expression profiles, and said sets of values each comprise, with respect to each protein in said protein expression profiles, a ratio or a difference in the levels of expression of said protein in said first and second biological signatures, wherein said protein expression profile comprises expression values for at least two proteins. [99:14-45: see Group 4 including PTEN4 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein, and wherein benefits including log rank p-values]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 5, 22, Zitnik-Abraham as a combination discloses: The system of any one of claim 1, claim 18, Zitnik disclosing: wherein said program instructions are further executable to perform a dimensionality reduction stage with respect to said sets of values, to reduce the number of variables in each of said sets of values, and wherein said dimensionality reduction stage identifies a subset of principal proteins in each of said sets of values (i.e., based on data following an appropriate distribution, employing dimensionality reduction methods). [Page 78]
Regarding claim(s) 7, 24, Zitnik-Abraham as a combination discloses: The system of claim 5, claim 22, Abraham disclosing [a]: wherein said training set comprises only said subset of principal proteins in each of said sets of values. [99:14-45: see Group 4 including PTEN5 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein, and wherein benefits including log rank p-values]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 9, 26, Zitnik-Abraham as a combination discloses: The system of claim 1, claim 18, Abraham disclosing [a]: wherein each of said biological samples is one of: blood plasma, whole blood, blood serum, cerebrospinal fluid (CSF), and peripheral blood mononuclear cells (PBMCs). [88:33-34: a sample of a patient’s blood]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 10, Zitnik-Abraham as a combination discloses: The system of claim 1, Zitnik disclosing: wherein said specified type of disease is cancer. [Page 83]
Regarding claim(s) 14, Zitnik-Abraham as a combination discloses: The system of claim 1, Zitnik disclosing: wherein said predicting comprises an indication of secondary effects in said target subject (i.e., side effects). [Table 3]
Regarding claim(s) 15, 32, Zitnik-Abraham as a combination discloses: The system of claim 1, 31, Abraham disclosing [a]: wherein said program instructions are further executable to determine, based, at least in part, on said predicting, at least one of: continuing said specified therapy in said target subject, adjusting said specified therapy in said target subject, discontinuing said specified therapy in said target subject, and administering a different therapy to said target subject (i.e., changing a mode of treatment such using a course of treatment after standard-of-care therapies are no longer providing adequate efficiency).[41:1-42:2]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 16, Zitnik-Abraham as a combination discloses: The system of claim 1, Abraham disclosing [a]: wherein said specified therapy is an immunotherapy, wherein said immunotherapy is selected from anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, and both (i.e., employing immunotherapy such as anti-PD-L1). [114:15]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 20, Zitnik-Abraham as a combination discloses: The method of claim 18, Abraham disclosing [a]: wherein said first and second biological signatures are each protein expression profiles, and said sets of values each comprise, with respect to each protein in said protein expression profiles, a ratio of levels of expression of said protein in said first and second biological signatures, wherein said protein expression profile comprises expression values for at least two proteins. [99:14-45: see Group 4 including PTEN6 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein, and wherein benefits including log rank p-values]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 27, Zitnik-Abraham as a combination discloses: The method of claim 18, Zitnik disclosing: wherein said specified type of disease is a proliferative disease (i.e., cancer). [Page 83]
Regarding claim(s) 29, Zitnik-Abraham as a combination discloses: The method of claim 18, Abraham disclosing [a]: wherein said training set further comprises, with respect to at least some of said subjects, labels associated with clinical data (i.e., clinical data). [33:19]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 31, Zitnik-Abraham as a combination discloses: The method of claim 18, Abraham disclosing [a]: further comprising at an inference stage, applying said classifier to a target set of said values associated with a target subject, thereby predicting a response in said target subject to said specified therapy. [112:34-113:20: training to predict benefit or lack of benefit of a therapeutic product, employing a random forest and class labels]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 34, Zitnik-Abraham as a combination discloses: The method of claim 32, Abraham disclosing [a]: wherein adjusting said specified therapy or administering a different therapy to said target subject is determined by a method comprising:
determining differentially expressed proteins (DEPs) between responders and non-responders; [99:14-45: see Group 4 including PTEN7 and 59:1-60:35: expression levels capturing upregulation or higher transcription levels of a given protein, or downregulation capturing reduced transcription of a given protein, and wherein benefits including log rank p-values]
determining, in the sample obtained from said subject, one or more resistance associated proteins (RAPs), selected from the DEPs; [99:14-45: see Group 4 including PTEN and 59:1-60:35] and
identifying a therapy suitable for balancing the level of the one or more RAPs in said subject. [99:14-45: see Group 4 including PTEN and 59:1-60:35]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a]-[c], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Regarding claim(s) 35, Zitnik-Abraham as a combination discloses: The method of claim 32, Abraham disclosing [a]: wherein determining the one or more RAPs is by providing a probabilistic measurement of a distance of the DEP expression level from a defined group of samples selected from the responder group or the non-responder group, and wherein determining the one or more RAPs is by determining the expression distribution of each DEP in each of the responder and non-responder groups, fitting a probability density function for each group, and calculating for each subject, and based on the DEP expression of said subject, the probability of the DEP to be associated with one of the response groups. [99:14-45: see Group 4 including PTEN8 and 59:1-60:35]
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have modified Zitnik, including mechanism(s) [a], as taught by Abraham. One of ordinary skill would have been motivated to employ said mechanism(s) to identify resistance associated proteins that may impede treatment therapies for optimal cancer therapeutic treatments. [59:1-60:35, 112:34-113:20]
Conclusion
The prior art made of record9 and NOT relied upon is considered pertinent to applicant's disclosure: Shaked (US 11,155,614):
A method of treating a solid cancer in a subject in need thereof, the method comprising: measuring IL-1α, IL-1β or both in a biological sample obtained from said subject at a time of 20 hours or more after a session of treatment with radiotherapy, wherein said radiotherapy is external beam radiotherapy, to determine the level of circulating IL-1α, IL-1β or both in response to radiotherapy in said subject, wherein said biological sample is selected from blood plasma, whole blood, blood serum or peripheral blood mononuclear cells; obtaining a reference level for said circulating IL-1α, IL-1β or both in said subject before said session of treatment with said radiotherapy; establishing a fold-change in said circulating IL-1α, IL-1β or both from said reference level to said level in response to radiotherapy; determining said subject has a non-favorable response to said treatment with said radiotherapy if said fold-change is an increase of at least 1.5-fold; and treating said subject determined to have a non-favorable response with said radiotherapy in combination with anakinra; thereby treating a solid cancer in a subject in need thereof.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL EZEWOKO whose telephone number is 571 272 7850. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Marc Jimenez can be reached on 571 272 4530. The fax phone number for the organization where this application or proceeding is assigned is 571-273-7850.
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/MICHAEL I EZEWOKO/Primary Examiner, Art Unit 3681
1 See Form 892: Non-Patent Literature
2 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
3 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
4 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
5 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
6 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
7 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
8 PTEN is a tumor suppressor protein where loss or reduced expression is strongly correlated with therapeutic resistance in cancer, reduced PTEN levels impairing tumor suppression, promoting drug resistance, immunotherapy resistance, and disease progression
9 Please see Form 892 for complete listing