DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application filed 10/05/2022 is a National Stage entry of PCT/NL2021/050220, with an International Filing Date of 04/06/2021, and claims foreign priority to 20168150.9, filed 04/06/2020. The claims are therefore examined as filed on 04/06/2020, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Claim Status
Claims 1-16 are pending.
Claims 1-16 are examined.
Claims 1-16 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pg 23-24). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 is unclear with respect to the phrase “wherein the survival difference (SurvDiff) for each individual genetic marker and/or gene is calculated for >0 and >1.” Specifically, it is unclear what >0 and >1 are referring to. Therefore, the claim is indefinite due to lack of clarity.
Claim 9 is unclear as it recites an equation without defining the variables in the equation (survAL, survBL, survAR, survBR, nAL, nBL, nAR, and nBR ). Therefore, the claim is indefinite due to lack of clarity.
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 1-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental processes and mathematical concepts, without significantly more.
The MPEP at MPEP 2106 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of matter?
(2A)(1) Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
(2A)(2) Do the claims recite additional elements that integrate the judicial exception into a practical application?
(2B) If the claims recite a judicial exception and do not integrate the judicial exception, do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?
With regard to step (1) (Are the claims directed to a process, machine, manufacture or composition of matter?): Yes. The claims are directed to one of the statutory classes. Claims 1-16 are directed to a process (machine-implemented method).
With regard to step (2A)(1) (Do the claims recite a judicially recognized exception?): Yes. Claims 1-16 recite the abstract ideas of processing data using mental steps and mathematical concepts, and observing the processed data. Claims that recite nothing more than abstract ideas, natural phenomena, or laws of nature are not eligible for patent protection (see MPEP 2106.04).
Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include but are not limited to:
Calculating a survival difference for each genetic marker and/or gene (mental process/mathematical concept; the human mind is capable of calculating survival difference from survival data, and doing to is a mathematical concept of performing a calculation; claim 1)
Using a random forest model to train multiple tree classifiers (mathematical concept; training a classifier is equivalent to implementing an algorithm/performing a calculation; claim 1)
Calculating a hazard ratio (mental process/mathematical concept; the human mind is capable of calculating a ratio, doing so is equivalent to performing a calculation; claim 10
Dependent claims 3, and 7-9 further limit the abstract ideas recited in the independent claims, and do not change their characterization as abstract ideas.
Therefore, the claims recite elements that constitute one or more judicial exceptions.
With regard to step (2A)(2) (Do the claims recite additional elements that integrate the judicial exception into a practical application?): No. The claims recite the additional element of the method being “machine-implemented” (which refers to computer-implemented, as stated on pg 5 of the specification). Claim 1 also recites the additional element of providing data from a group of individuals for use in the methods’ analysis, and using a trained random forest model for the analysis. Claims 2, 4-6, 11- 16 further describe the provided data.
While the claims recite the additional element of providing data for analysis, such steps that only amount to necessary data gathering , without any technical details of how the data is obtained that integrate the judicial exception, are insignificant extrasolution activities that do not add a meaningful limitation to the claims (see MPEP 2106.05(g)). As a result, the judicial exception is not integrated into a practical application. In addition, while the claims recite additional elements related to the use of computers, they do not provide any specific details by which the machine/computer performs or carries out the judicial exception listed in step (2A)(1), nor do they provide any details of how specific structures of the computer are used to implement these functions. This also applies to the use of a trained model to process and output data, as a machine learning model, without recited physical structure outside of general computer components, is also analogous to implementing an abstract idea of data analysis on a computer. The judicial exception is therefore not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea, as they amount to simply implementing the abstract idea on a computer (see MPEP 2106.05(f)). Because the claims do not recite any additional elements that integrate the judicial exception into a practical application, the claims as a whole are directed to an abstract idea.
With regard to step (2B) (Do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?): No. The claims recite an abstract idea with additional elements; however, these additional elements are general computer elements added to abstract ideas, and non-particular instructions to apply the abstract idea by linking it to a field of use or extrasolution activity (see MPEP 2106.05(f-h)). General computer elements used to perform an abstract idea do not provide an inventive concept, and similarly, non-particular instructions to gather or provide data do not provide an inventive concept. Non-particular instructions to gather or provide data using computer elements are also considered well-understood, routine and conventional activities (see MPEP 2106.05(d), which indicates that limitations such as “Receiving or transmitting data over a network” from Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362, and “Storing and retrieving information in memory” from Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, are recognized as conventional activities). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As a result, the claims as a whole do not provide an inventive concept.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim Rejection
Claims 1-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over KESHAMOUNI 2015 (US 20150153346 A1, as cited on the IDS filed 10/20/2022) in view of GOLDSTEIN 2011 “Random Forests for Genetic Association Studies.”
Claim Interpretation and Scope and Contents of Prior Art
Claim 1 recites a machine-implemented method for identifying a signature that identifies subgroups of individuals which have a better survival outcome with a treatment of interest, relative to an alternative therapy, said method comprising - providing data from a group of individuals, said data comprising for each individual (i) a plurality of genetic marker data and/or expression data for a plurality of genes, (ii) treatment arm data, and (iii) survival data.
With respect to these limitations, KESHAMOUNI teaches a computer-based method [0079] of identifying lung cancer markers indicative of survival [0008], where raw data from individual patients is received [0080] consisting of gene marker data, treatment data and survival data [0012, 35, 85-86, 101-102, Table 2].
Claim 1 also recites the limitation of calculating a survival difference (SurvDiff) for each genetic marker and/or for each gene, and using a random forest model to train multiple tree classifiers, wherein each individual decision tree is trained on a different subset of the genetic markers and/or genes, and wherein for each node in the tree a calculation of the SurvDiff is used as splitting criterion; whereby the trained random forest model identifies a signature that can distinguish subgroups of individuals which have a better survival outcome with the therapy of interest, relative to an alternative treatment.
With respect to these limitations, KESHAMOUNI teaches calculating and comparing patient survival differences based on a randomly selected subset of variables at each node in a random forest tree, where trees are trained on genetic markers [0101-104], and where the model identifies individual patients as belonging to different risk groups based on the gene signatures, and further identifies high risk early stage patients that may benefit the most from adjuvant therapy [0101-104, 116].
KESHAMOUNI also teaches using a training set of lung adenocarcinoma associated genes [101, 111, Table 1] but does not specifically teach the limitation wherein each individual decision tree is trained on a different subset of the genetic markers and/or genes.
However, GOLDSTEIN teaches that changes in the training data in a random forest model will lead to different tree structures, resulting in multiple trees each with low bias and high variance (pg 9 par 1), and that using a combination of multiple training sets can be used to reduce variance (pg 9-10) so one of ordinary skill would be motivated to use different subsets of genetic markers/genes in training the trees.
Claim 2 recites the limitation wherein each genetic marker or gene expression is coded as a ternary value. KESHAMOUNI does not teach this limitation, however GOLDSTEIN teaches that SNPs can be coded as an ordinal 0/1/2 value (ternary value) for use in the random forest algorithm (pg 4).
Claim 3 recites the limitation wherein the survival difference (SurvDiff) for each individual genetic marker and/or gene is calculated for >0 and >1. With respect to this limitation, KESHAMOUNI teaches calculating patient survival differences for each gene marker [0101-104].
Claim 4 recites the limitation wherein the genetic marker data and/or expression data is germline data or tumor cell genetic data. With respect to this limitation, KESHAMOUNI teaches that the data is tumor cell genetic data [0034-37].
Claim 5 recites the limitation wherein the genetic markers are SNPs (single nucleotide polymorphisms). With respect to this limitation, KESHAMOUNI teaches that the genetic markers can be SNPs [0056], and GOLDSTEIN also teaches applying random forest models to SNPS (pg 3-4).
Claim 6 recites the limitation wherein for each individual the survival data is known or imputed. With respect to this limitation, KESHAMOUNI teaches that the survival data is known [102].
Claim 7 recites the limitation wherein the calculation of the survival difference score is based on the survival data, treatment arm data and the number of individuals included. With respect to this limitation, KESHAMOUNI teaches that the survival difference score is based on survival data, treatment data and number of individuals included [12, 81, 112, 116].
Claim 8 recites the limitation wherein the survival difference score represents the absolute difference between the survival data in the left node of the split and the right node of the split. With respect to this limitation, KESHAMOUNI teaches splitting patients by comparing survival differences via log-rank test based on a randomly selected subset of variables at each node [0102].
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Claim 9 recites the limitation wherein the survival difference score is calculated by the equation:
This equation is the calculation of the absolute difference between Welch’s t-test statistics. With respect to this limitation, KESHAMOUNI teaches that the t-test was used to assess the difference of mean expression of gene signatures in clinical and pathological groups, but not specifically the survival difference score [0104]. However, it would be obvious to one of ordinary skill in the art to use t-test statistics to determine differences between groups for survival as well as gene expression.
Claim 10 recites the limitation wherein a hazard ratio is calculated, whereby a hazard ratio below 1 indicates benefit from receiving the treatment. With respect to this limitation, KESHAMOUNI teaches calculating a hazard ratio, wherein a hazard ratio at 1 or below indicates a low risk group [0111] and that results of the analysis can be used to determine treatment [012]; one of ordinary skill would deduce that a lower risk group would benefit from receiving treatment.
Claim 11 recites the limitation wherein the data was obtained from clinical trials. With respect to this limitation, KESHAMOUNI teaches receiving information that includes clinical data [0101].
Claim 12 recites the limitation wherein the data from individuals does not have classification labels. With respect to this limitation, KESHAMOUNI teaches that the data from individuals does not have classification labels [0102].
Claim 13 recites the limitation wherein the data is obtained from individuals having cancer. With respect to this limitation, KESHAMOUNI teaches that the data is from individuals with lung cancer [0102].
Claim 15 recites the limitation wherein the ternary value is 0, 1 or 2. KESHAMOUNI does not teach this limitation, however GOLDSTEIN teaches that SNPs can be coded as an ordinal 0/1/2 value for use in the random forest algorithm (pg 4).
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in using random forest models to analyze genetic data would have been motivated to combine the teachings of KESHAMOUNI with the teachings of GOLDSTEIN, in order to achieve the claimed invention, because using a combination of multiple training sets can be used to reduce variance (pg 9-10), and because coding SNPs are ternary values allows data on the number of minor alleles to be included (pg 4). A person of ordinary skill would reasonably expect success from combining these teachings, as both KESHAMOUNI and GOLDSTEIN teach methods of analyzing genetic data using random forest models, such that the random forest models of KESHAMOUNI can contain many of the same characteristics of GOLDSTEIN. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Claim Rejection
Claim 14 is also rejected under 35 U.S.C. 103 as being unpatentable over KESHAMOUNI in view of GOLDSTEIN as applied to claims 1-13 and 15 above, and further in view of QUAN 2011 “Most Lung and Colon Cancer Susceptibility Genes Are Pair-Wise Linked in Mice, Humans and Rats.”
Claim Interpretation and Scope and Contents of Prior Art
KESHAMOUNI in view of GOLDSTEIN teaches the limitations of claims 1-13 and 15 above.
Claim 14 recites the limitation wherein the data is obtained from individuals having colorectal cancer. KESHAMOUNI does not teach this limitation (teaching lung cancer instead), however QUAN teaches that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related (Abstract) so it would be obvious to one of ordinary skill that the methods of KESHAMOUNI can be performed for colorectal cancer as well as lung cancer.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in cancer analysis would have been motivated to combine the teachings of KESHAMOUNI in view of GOLDSTEIN with the teachings of QUAN, in order to achieve the claimed invention, because the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related (Abstract), such that analysis applied to lung cancer genes can be applied to the same genes in colorectal cancer. A person of ordinary skill would therefore reasonably expect success from combining these teachings, as the lung cancer of KESHAMOUNI in view of GOLDSTEIN can be substituted for the colorectal cancer of QUAN. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Claim Rejection
Claim 16 is also rejected under 35 U.S.C. 103 as being unpatentable over KESHAMOUNI in view of GOLDSTEIN as applied to claims 1-13 and 15 above, and further in view of LIM 2019 “Randomization in clinical studies.”
Claim Interpretation and Scope and Contents of Prior Art
KESHAMOUNI in view of GOLDSTEIN teaches the limitations of claims 1-13 and 15 above.
Claim 16 recites the limitation wherein individuals are randomly assigned to one or more treatment arms. KESHAMOUNI teaches that the data can come from clinical studies, but does not explicitly teach random assignment of treatment. However, LIM teaches that randomization of treatment in clinical studies is well known, and necessary to minimize selection bias (Abstract, pg 221) and one of ordinary skill would be motivated to randomly assign treatment before collecting data and proceeding with survival analysis to reduce bias as well.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in clinical trials would have been motivated to combine the teachings of KESHAMOUNI in view of GOLDSTEIN with the teachings of LIM, in order to achieve the claimed invention, because randomized clinical trials are widely accepted as the best design for evaluating the efficacy of a treatment, and reducing bias (Abstract). A person of ordinary skill would reasonably expect success from combining these teachings, as randomized clinical trials as described in LIM can be included as part of the clinical data used for the random forest models of KESHAMOUNI. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz R. Skowronek can be reached at (571) 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARY C LEVERETT/Examiner, Art Unit 1687
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