DETAILED ACTION
Applicant’s response, filed 11/26/2025, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
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.
Claim Status
Claims 99, 101-106, 109-116, 119-121 are pending.
Claims 100, 107-108, and 117-118 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, Election was made without traverse in the reply filed on 06/02/2025.
Claims 1-98 are canceled.
Claims 120 and 121 are newly added.
Claims 99, 101-106, 109-116, 119-121 are rejected.
Priority
Applicant's claim for the benefit of a prior-filed application, PCT/US2020/012815, filed 01/085/2020, is acknowledged.
The instant Application claims domestic benefit to US provisional application 62/871,530, filed 07/08/2019, 62/855,623, claims benefit of filed on 05/31/2019, 62/843,204, filed on 05/03/2019, claims benefit of 62/836,540, filed on 04/19/2019, claims benefit of 62/835,999, filed on 04/18/2019, and claims benefit of 62/789,929, filed on 01/08/2019.
Accordingly, each of claims 99, 101-106, 109, 110-116, and 119 are afforded the effective filing date of the 01/08/2019.
Drawings
The replacement drawing sheets submitted 07/28/2021 are accepted
Specification
The outstanding objections to the specification are withdrawn in view of the amendments submitted herein.
Claim Rejections- 35 USC § 112
The outstanding 112(b) rejections to the claims are withdrawn in view of the amendments submitted herein.
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 99, 101-106, 109, and 120 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection pertains to new matter. The rejection is newly stated based upon claim amendment .
Claims 99 and 104 recite “the system comprising: a sequencing device configured to perform sequencing of genomic DNA from the biological sample to obtain sequencing data for the biological sample” and “a sequencing device”. The specification provides support for a data processing apparatus for generating input data structure for use in training a machine learning model to predict primary origin of a biological sample, the data processing apparatus including one or more processors and one or more storage devices storing instructions [p. 5, lines 8-11]. However, there is not support within the specification, nor has Applicant provided such support, for a system coupled with a sequencing device or any other. Therefore, the limitation introduces new matter. Claims 101-106, 109, and 120 are rejected based on their dependency from claim 99.
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.
For the following rejections, underlined text indicates newly recited portions necessitated by claim amendment.
Claims 99, 101-106, 109-116, 119-121 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to method, system, and process, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claims 99, 111, and 116:
providing, the sample biological signature as an input to a machine learning model comprising a plurality of pairwise models, each pairwise model comprising a random forest classifier, wherein the machine learning model has been trained to predict a likely origin location of the biological sample from among N origin locations by performing, using training input data comprising sequencing data for genomic DNA from training samples representing each of the N origin locations, a respective pairwise model between each pair of the N origin locations
evaluating, the received output generated by each pairwise model of each pair of the N biological signatures of known origin; and based on the evaluation of the received output from each pairwise model,
predicting, that the biological sample originated in one of the N origin locations as the likely origin location.
Dependent claims 102, 114, and 118:
evaluating, the received different output generated for by each pairwise model of each pair of the N biological signatures of known origin
predicting, that the biological sample originated in a different one of the U origin locations as the likely origin location.
Dependent claim 120:
summing probabilities for the origin location from corresponding pairwise models.
Dependent claim 121:
determining, based on the prediction of the origin location of the biological sample, a proposed treatment for cancer.
Dependent claims 101, 103, 105-106, 109-110, 113, 115, and 118 recite further steps that limit the judicial exceptions in independent claims 99, 111, and 116 and, as such, also are directed to those abstract ideas. For example, claims 101, 113, and 118 further limit origin location of claims 99, 111, and 116, claims 103, 115, and 119 further limit the biological sample of claims 99, 111, and 116, claims 105-106 further limit the plurality of features of claim 99, and claims 109-110 further limit the set of one or more biomarkers of claim 106;
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually evaluate and determine. Without further detail as to the methodology involved in “evaluating the received output”, “predict a likely origin location“, “determining that the biological sample originated in one of the origin locations”, “evaluating, …, the received different output “, “determining, that the biological sample originated in a different one of the origin locations”, “summing probabilities”, and “determining, a proposed treatment for cancer.” under the BRI, one may simply, for example, use pen and paper to predict the origin of a biological sample.
Therefore, claims 99, 111, and 116 and those claims dependent therefrom recite an abstract [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claims 99, 111, and 116:
performing sequencing of genomic DNA from the biological sample to obtain sequencing data for the biological sample
obtaining, …, a sample biological signature representing the biological sample, wherein the sample biological signature includes sequencing data describing a plurality of features present in the genomic DNA of the biological sample;
receiving, … from each pairwise model, an output generated by the pairwise model that indicates a likelihood that the sample biological signature corresponds to either origin location used to train the pairwise model.
Dependent claims 102, 114, and 119:
obtaining, …, a different sample biological signature representing a different biological sample from a different subject, wherein the different sample biological signature includes data describing a plurality of features of the different biological sample;
providing, …, the different sample biological signature as an input to the machine learning model;
receiving, … and for each member of each pair of biological signatures, a different output generated by the model that represents a likelihood that the different biological sample corresponds to either member of each pair biological signatures of known origin;
Dependent claims 104 recite steps that further limit the recited additional elements in the claims. For example, claim 104 further limits the performance of the sequencing device of claim 99.
The claims also include non-abstract computing elements. For example, independent claims 99 and 116 include a system one or more processors and one or more memory units, and one or more computer-readable storage media.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “obtaining”, “providing”, and “receiving”, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
Further steps directed to additional non-abstract elements of “a system and computer-readable media” do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
With respect to claims 99 and , the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to a sequencing device do not impose any meaningful limitations on the abstract idea, or on how the abstract idea is performed. These steps are insignificant extra-solution activity to the judicial exception (MPEP 2106.05(g)(2)).
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)).
As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to claims 99 and 116 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (see MPEP 2106.06(A)). The specification as published also notes that computer processors and systems, as example, are commercially available or widely used at [0147 and 0170]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
With respect to claim 99 and those claims dependent therefrom, additional element of a sequencing device do not rise to the level of significantly more than the judicial exception. The process of using a sequencing device for next generation sequencing is well-understood, routine, and conventional in the art. Ansorge (Ansorge, Wilhelm J. "Next-generation DNA sequencing techniques." New biotechnology 25.4 (2009): 195-203, newly cited), discloses the next-generation sequencing technologies offer novel and rapid ways for genome-wide characterization and profiling of mRNAs, small RNAs, transcription factor regions, structure of chromatin and DNA methylation patterns, microbiology and metagenomics. Ansorge further discloses development of commercial sequencing devices such as the 454 GenomeSequencer FLX instrument (Roche Applied Science), The Illumina (Solexa) Genome Analyzer, The Applied Biosystems ABI SOLiD system, and Helicos single-molecule sequencing device. Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself [Step 2B: NO; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Response to Applicant Arguments
Applicant respectively submits that the claims ( e.g., machine learning aspects) are not directed to mathematical concepts but at best merely involve math [p. 23, par. 2].
It is respectfully found not persuasive. Claim 99 uses a random forest classifier, which in the specification describes as “each machine learning model of the plurality of machine learning models comprises a random forest classification algorithm” which is a mathematical concept as it is an algorithm. Further a biological signature is a vector of numbers which is a mathematical concept.
Applicant submits the claimed invention provides a technical improvement by identifying the origin of cancer through sequencing genomic DNA using a set of random forest classifiers performing pairwise classifications [p. 23, par. 6].
It is respectfully found unpersuasive. It is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. Furthermore, it is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements or by the additional element(s) in combination with the recited judicial exception. See MPEP 2106.05(a). The only additional elements are computer system and a sequencing device, which neither integrate the judicial exception into a practical application.
Applicant submits that at least the following combinations of additional limitations are unconventional [p. 25-p. 26].
It is respectfully found not persuasive. The providing steps in claims 99, 111, and 116, are judicial exceptions as they use a mathematical concept and therefore is not an additional element. The additional element of the receiving an output step with a result is data output and is found to be well understood and routine as stated in Step 2B above.
Claim Rejections - 35 USC § 102
The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein. Aharonov analyzes the expressions of nucleic acid sequences at the RNA but not DNA level of the samples.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
For the following rejections, instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims, and underlined text indicates newly recited portions necessitated by claim amendment.
A. Claims 99, 101-103, 105-108, 110-116, and 120-121 are rejected under 35 U.S.C. 103 as being unpatentable over Aharonov er al. (US 2014/315739 Al, published on 10/23/2014, cited on IDS dated 01/02/2025). The instant rejection is newly stated and is necessitated by claim amendment.
Claim 99 is directed to a system.
Aharonov discloses system and methods herein, the data processing routine can also control the data collection routine based upon the results determined [0102].
Claim 116 is directed to one or more computer-readable storage media
Aharonov discloses a “data processing routine' refers to a process that can be embodied in software that determines the biological significance of acquired data [0102].
Claim 99 are directed to for identifying an origin location of a biological sample obtained from a subject having cancer comprising: a sequencing device configured to perform sequencing of genomic DNA from the biological sample to obtain sequencing data for the biological sample; and obtaining, a sample biological signature representing the biological sample, wherein the sample biological signature includes sequencing data describing a plurality of features present in the genomic DNA of the biological sample;
Aharonov discloses identification of their tissue of origin [0002, 0078, and 0089]. Aharonov discloses nucleic acids may be single-stranded or double stranded, or may contain portions of both double-stranded and single-stranded sequences [0123]. Aharonov further discloses the nucleic acid may be DNA, both genomic and cDNA, RNA, or a hybrid, where the nucleic acid may contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, Xanthine hypoxanthine, isocytosine and isoguanine nucleic acids may be obtained by chemical synthesis methods or by recombinant methods [0123], which reads on DNA and sequencing device. Aharonov also discloses based on the abundance of the nucleic acid sequences in a biological sample [0009]. Aharonov further discloses the correlation value to the reference data generates a continuous score that can be scaled and provides diagnostic information on the likelihood that a sample belongs to a certain class of cancer origin or type. Aharonov also discloses in multivariate analysis, the microRNA signature provides a high level of prognostic information [0089]. The specification discloses “the assessment in step (b) comprises determining a presence, level, or state of a protein or nucleic acid for each biomarker, optionally wherein the nucleic acid comprises deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or a combination thereof. In some embodiments, the presence, level or state of the protein is determined using immunohistochemistry (IHC), flow cytometry, an immunoassay, an antibody or functional fragment thereof, an aptamer, or any combination thereof. In some embodiments, the presence, level or state of the nucleic acid is 30 determined using polymerase chain reaction (PCR), in situ hybridization, amplification, hybridization, microarray, nucleic acid sequencing, dye termination sequencing, pyrosequencing, next generation sequencing (NGS; high-throughput sequencing), whole exome sequencing, whole transcriptome sequencing, or any combination thereof [p. 8 lines 24-33]. It would be obvious to use either RNA or DNA for this method as mentioned in the specification. Also microRNA is a present in the genomic DNA of the biological sample and therefore reads on genomic DNA.
providing, the sample biological signature as an input to a machine learning model comprising a plurality of pairwise models, each pairwise model comprising a random forest classifier, wherein the machine learning model has been trained to predict a likely origin location of the biological sample from among N origin locations by performing using training input data comprising sequencing data for genomic DNA from training samples representing each of the N origin locations, a respective pairwise model between each pair of the N origin locations.
Aharonov discloses the expression levels of microRNA are used to infer the sample origin using analysis techniques such as but not limit to decision tree classifier, logistic regression classifier, linear regression classifier, nearest neighbor classifier (including K nearest neighbors), neural network classifier and nearest centroid classifier [0086] which reads on using a biological signature as an input to a machine learning model. Aharonov further discloses wherein said classifier algorithm is selected from the group consisting of a decision tree classifier, logistic regression classifier, nearest neighbor classifier, neural network classifier, Gaussian mixture model (GMM), Support Vector Machine (SVM) classifier, nearest centroid classifier, linear regression classifier and random forest classifier. [claim 4], ...and performing a pairwise comparison [0090]. Aharonov also discloses expression level of the nucleic acids is used to classify a test sample by comparison to a training set of samples [0090]. Aharonov further discloses the test sample is compared in turn to each one of the training set samples, where each such pairwise comparison is performed by comparing the expression levels of one or multiple nucleic acids between the test sample and the specific training sample [0090].
receiving, from each pairwise model, an output generated by the pairwise model that indicates a likelihood that the sample biological signature corresponds to either origin location used to train the pairwise model;
Aharonov discloses the threshold for assignment can be scaled to favor sensitivity or specificity, depending on the clinical scenario [0089]. Aharonov further discloses the correlation value to the reference data generates a continuous score that can be scaled and provides diagnostic information on the likelihood that a sample belongs to a certain class of cancer origin or type [0089].
evaluating, the received output generated by each pairwise model of each pair of the N biological signatures of known origin; and based on the evaluation of the received from each pairwise model, predicting that the biological sample originated in one of the N origin locations as the likely origin location.
Aharonov discloses a metric which is then compared to previously measured samples or to a threshold [0078 and 0089] which reads on an evaluation. Aharonov further discloses expression level of the nucleic acids is used to classify a test sample by comparison to a training set of samples [0090]. Aharonov also discloses the test sample is compared in turn to each one of the training set samples, where each such pairwise comparison is performed by comparing the expression levels of one or multiple nucleic acids between the test sample and the specific training sample [0090].
Claims 111 and 116 are the similar to claim 99 without a sequencing device and as such are rejected with the same arguments as claim 99 above.
Claims 101, 113, and 118 are directed to the … of claims 99, 111, and 116, wherein the origin locations comprise bladder; skin; lung; head, face or neck (NOS); esophagus; female genital tract (FGT); brain; colon; prostate; liver, gall bladder, ducts; breast; eye; stomach; kidney; and pancreas.
Aharonov discloses wherein said tissue is selected from the group consisting of liver, lung, bladder, prostate, breast, colon, ovary, testis, Stomach, thyroid, pancreas, brain, head and neck, kidney, melanocytes, thymus, biliary tract and esophagus [claim 2].
Claims 102, 114, and 119 are directed to the operations further comprising: obtaining, a different sample biological signature representing a different biological sample from a different subject, wherein the different sample biological signature includes sequencing data describing a plurality of features of the different biological sample;
providing, the different sample biological signature as an input to the machine learning model; receiving, from each pairwise model, a different output generated by the pairwise model that represents a likelihood that the different biological sample corresponds to either origin location used to train the pairwise model; evaluating, the received different output generated by each pairwise model of each pair of the N biological signatures of known origin; and based on the evaluation of the received different output, from each pairwise model, predicting, that the biological sample originated in a different one of the N origin locations as the likely origin location.
Claims 102, 114, and 119 are similar to claims 99, 111, and 116 except that it is performed on a different subject. Aharonov discloses comparing said expression profile to a reference expression profile by using a classifier algorithm whereby the expression of any of said nucleic acid sequences or combinations thereof allows the identification of the tissue of origin of said sample. [0014] which reads on a different subject.
Claims 103 and 115 are directed to wherein the biological sample comprises a metastatic tumor and wherein the predicted likely origin location comprises a primary tumor location.
Aharonov discloses a validation set of 255 new FFPE tumor samples was used to assess the performance of the assay, representing 26 different tumor origins or “classes' where about half of the samples in the set were metastatic tumors to different sites (e.g., lung, bone, brain and liver) [0194].
Claim 105 is directed to wherein the sequencing data includes (i) data identifying one or more variants and/or (ii) data identifying one or more gene copies number.
Aharonov discloses the nucleic acid may also comprise a sequence of a miRNA (including miRNA) or a variant thereof [0158].
Claim 106 discloses wherein the sequencing data comprises data corresponding to a plurality of genomic regions.
Aharonov discloses sequence listing of RNA and DNA [p. 27-68] which reads on a plurality of genomic regions.
Claim 110 is directed to wherein the sequencing data comprises data for a panel of genes.
Aharonov discloses the performance of the classifier using a small number of markers highlights the utility of microRNA as tissue-specific cancer biomarkers, and provides an effective means for facilitating diagnosis of CUP and more generally of identifying tumor origins of metastases [0079].
Claim 120 is directed to the system of claim 99, wherein evaluating the received output generated by each pairwise model including, for each origin location of the N origin locations, summing probabilities for the origin location from corresponding pairwise models.
Aharonov discloses the classifier may use a decision tree structure (including binary tree) or a voting (including weighted Voting) scheme to compare the classification of one or more classifier algorithms in order to reach a unified or majority decision [0032] which reads on summing probabilities.
Claim 121 is directed to the method of claim 111, further comprising: determining, based on the prediction of the origin location of the biological sample, a proposed treatment for cancer.
Aharonov discloses the present invention provides specific nucleic acid sequences for use in the identification, classification and diagnosis of specific cancers and tumor tissue of origin [0009]. Aharonov further discloses the nucleic acid sequences can also be used as prognostic markers for prognostic evaluation and determination of appropriate treatment of a subject based on the abundance of the nucleic acid sequences in a biological sample [0009].
B. Claim 104 is rejected under 35 U.S.C. 103 as being unpatentable over Aharonov as applied to claim 99 in the above 102 rejection, in view of Motameny et al (Motameny, Susanne, et al. "Next generation sequencing of miRNAs–strategies, resources and methods." Genes 1.1 (2010): 70-84, newly cited).
Claim 104 is directed to wherein the sequencing device performs next generation sequencing.
Aharonov discloses the use of custom microarrays for miRNA [0179], but is silent on using next generation sequencing.
However, Motameny discloses next generation sequencing of miRNAs – strategies, resources and methods [title]. Motameny further discloses that next generation sequencing technologies have enabled sequencing of the complete set of miRNAs present in an RNA sample [p. 70, par. 1].
In regards to claim(s) 104, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, Aharonov with Motameny as they both disclose the use of miRNA for data analysis. A person of ordinary skill in the art would have reasonably expected that combining teaching a microarray from Aharonov and teaching NGS from Montameny, said practitioner would have readily predicted that the combination would successfully result in an expression profile because both methods are for expression profiling and NGS can provide an unprecedented sequencing depth as disclosed by Motameny [abstract].
C. Claim 109 are rejected under 35 U.S.C. 103 as being unpatentable over Aharonov in, as applied to claim 106 in the above 103 rejection, and in further view of Asch-Kendrick (Asch-Kendrick, Rebecca, and Ashley Cimino-Mathews. "The role of GATA3 in breast carcinomas: a review." Human pathology 48 (2016), newly cited). Instantly claimed elements which are considered to be equivalent to the prior art teachings are described in bold for all claims.
Claim 109 is directed to wherein at least one of the N origin locations is breast and the plurality of genomic locations comprises locations of a set of genes comprising at least 5 of CDHI, GATA3, ELK4, KRAS, CDHl 1, CDHI, TP53, CTCF, PBXI, MYC, MECOM, CDKN2A, CAMTAI, CDX2, MAF, CBFB, EP300, FLII, MCLI, FUS, BCL9, CCNDI, YWHAE, CDK4, HMGA2, PAX8, MSI2, EXTI, CREBBP, LHFPL6, CDKN2B, ETV5, PIK3CA, RPNI, STATSB, USP6, MDM2, EWSRI, ASXLI, CACNAlD, FOXAI, APC, RMI2, COX6C, GID4, KLHL6, STAT3, MLLTl 1, SPECCI, and ZNF217
Aharonov discloses multiple miRNA sequences as biomarker [tables 5-7], but is silent on biomarkers CDH1, GATA3, ELK4, KRA3, and CDH11.
However, Asch-Kendrick discloses the role of GATA3 in breast carcinomas [title]. Asch-Kendrick further discloses GATA3 is largely used to support urothelial or breast origin in a carcinoma of unknown origin [abstract].
In regards to claim(s) 109, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, Aharonov with Asch-Kendrick as they both using biomarkers breast carcinomas identification. A person of ordinary skill in the art would have reasonably expected that combining teaching of using biomarker GATA3 of Ash-Kendrick into the methods of Aharonov, said practitioner would have readily predicted that the combination would successfully result in breast carcinomas identification because it is a known biomarker for breast cancer as disclosed by Asch-Kendrick [abstract].
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.M.B./Examiner, Art Unit 1685 /Soren Harward/Primary Examiner, TC 1600