DETAILED ACTION
Applicant’s response, filed 14 April 2025, has been fully considered. 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 14 April 2025 has been entered.
Claim Status
Claims 2, 3, 14, 20, 24, 49, 50, 98-101 are pending and examined herein.
Claims 2, 3, 14, 20, 24, 49, 50, 98-101 are rejected.
Priority
Claims 2, 3, 14, 20, 24, 49, 50, 98-101 are not granted the claim to the benefit of priority to U.S. Provisional application 62/877755 filed 23 July 2019 because there is no disclosure of when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents selected from hormones, immune therapies, radiography, or cancer drugs. Thus, the effective filling date of claims 2, 3, 14, 20, 24, 49, 50, 98-101 is 23 July 2020.
Information Disclosure Statement
The information disclosure statement (IDS) was received on 14 April 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings received 23 July 2020 are objected to for reasons stated below.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: 132 and 134 (1 or N). Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
Claim 98 recites “when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises…” which is a contingent limitation. The MPEP states that the BRI of a method claim having contingent limitations only requires those steps that must be performed and does not include steps that are not required to be performed because the condition precedent is not met (see MPEP 2111.04(II)). Therefore, there exists an embodiment of the claim where the plurality of tumor fractions of the subject across the epoch does not exceed a threshold amount and the step of changing a treatment for the subject is not performed.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112a new matter of claims 2, 3, 14, 20, 24, 49, 50, 98-101 in Office action mailed 17 October 2024 is withdrawn in view of the amendment of “each bin value represents a count of cell-free nucleic acids from the reference genome that maps to the corresponding bin; and determining, based on the plurality of bin values, a plurality of copy numbers” received 14 April 2025.
112/b
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 14, 20, and 100 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 14 recites “The method of claim 98, further comprising copy numbers and the allele counts to generate a plurality of features with reduced dimensionality” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear what the relationship between copy numbers and the allele counts with a plurality of features with reduced dimensionality (i.e., are the copy numbers and allele counts used to generate a plurality of features with reduced dimensionality or are the copy numbers and allele counts themselves features with reduced dimensionality since they describe the over all data in a condensed manner). For the sake of furthering examination, this limitation will be interpreted as copy numbers and allele counts are features with reduced dimensionality.
Claim 20 recites the limitation "the genomic loci having copy number instability” and “the allele loci” in lines 2-3 and line 5 of the claim. There is insufficient antecedent basis for this limitation in the claim. The indefiniteness arises because the claim does not make clear what “the genomic loci having copy number instability” that are being sequenced are. For the sake of furthering examination, this limitation will be interpreted as the first sequencing provides an average coverage of between 20x and 70,000x across a set of genes in a targeted panel.
Claim 100 recites “the DNA fragments” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if “the DNA fragments” is referring to the first plurality of DNA fragments, the second plurality of DNA fragments, or both. The specification does not provide a clear and precise definition of the limitation, nor would one skilled in the art recognize the metes and bounds of said limitation. For the sake of furthering examination, this limitation will be interpreted as referring to both plurality of DNA fragments.
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 2, 3, 14, 20, 24, 49-50, and 98-101 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 2-3, 14, 20, 24, 49, 50, and 98-101 are found to be directed to a statutory category of a process.
(Step 2A prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations. The instant claims further recite judicial exceptions that fall in the grouping of a “law of nature”.
Independent claim 98 recites mental processes of “aligning sequence reads of the at least one million cell-free DNA fragments to a refence genome to obtain a plurality of bin values…”, “determining, based on the plurality of bin values, a plurality of copy numbers”, “aligning a sequence read of each DNA fragment of the second plurality to a corresponding allele locus in the reference genome”, “determining, for each sequenced DNA fragment aligned to an allele locus, an allele type…”, “counting the number of sequenced DNA fragments aligned to each allele locus, for each allele type…”, “inputting the plurality of copy numbers and the allele counts with a trained reference model to generate the tumor fraction estimating the proportion of DNA fragments originated from tumor cells among all DNA fragments in the DNA sample”, and repeating the judicial exceptions above across an epoch to obtain a plurality of tumor fractions of the subject across the epoch.
Independent claim 98 mathematical concepts of “counting the number of sequenced DNA fragments aligned to each allele locus, for each allele type…” and “inputting the plurality of copy numbers and the allele counts with a trained reference model to generate the tumor fraction estimating the proportion of DNA fragments originated from tumor cells among all DNA fragments in the DNA sample”, and repeating the judicial exceptions above across an epoch to obtain a plurality of tumor fractions of the subject across the epoch.
The claims recite analyzing/evaluating sequencing data through alignment (to obtain bin values and to align reads to a corresponding allele locus), determining copy numbers based on bin the plurality of bin values, determining an allele type, counting reads for allele types to get an allele count, and inputting copy number and allele counts into a model to generate a tumor fraction. The human mind is capable of performing these analyses on data. The claims recite mathematical concepts of mathematical calculations as counting the number of sequence DNA fragments and inputting the plurality of copy numbers and allele counts into a trained reference model (this reference model encompasses models such as multivariate logistic regression and a regression algorithm which are mathematical models that input numeric data into a mathematical function to produce a numerical output of the estimated tumor fraction see claim 49). Dependent claims 14, 49 (except for the neural network and convolutional neural network which are additional elements addressed below), 50, and 99 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept.
(Step 2A prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claim 98 sequencing a first plurality of DNA fragments in a DNA sample obtained from the DNA sample, wherein the first plurality of DNA fragments comprises at least one million cell -free DNA fragments for the analysis, the additional element in claim 2 of the first and the second sequencing are the same sequencing, the additional element in claim 3 of the sequencing is targeted panel sequencing using probes, the additional element in claim 20 of the first sequencing provides an average coverage of between 20x and 70,000x and the second sequencing provides an average coverage of between 1,000x and 70,000x, the additional element in claim 24 of wherein the DNA sample comprises one or a combination selected from the group of blood, whole blood, plasma, serum, urine, cerebrospinal fluid, fecal, saliva, tears, pleural fluid, pericardial fluid, and peritoneal fluid of the subject do not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of data gathering. These additional elements are insignificant extra solution activity because they only interact with the judicial exceptions by providing the judicial exceptions data to process.
The additional element in claim 98 of when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents for cancer to the subject, wherein the agents for cancer are selected from hormones, immune therapies, radiography, or one or more cancer drugs does not integrate the judicial exceptions into a practical application. This additional element does not integrate the judicial exceptions into a practical application because changing a treatment is a contingent limitation and is not required to be performed by the claim. Since changing a treatment is not required, it does not constitute as a particular treatment. Further, changing a treatment for the subject based on the plurality of tumor fractions does not integrate the judicial exception into a practical application because this step is mere instructions to apply the exception. The step of changing a treatment for the subject based on the plurality of tumor fractions is mere instructions to apply the exception because this is a general application of the judicial exception (i.e., the claim does not set out how one is changing the treatment). Further, this step of changing a treatment is mere instructions to apply the exception because of the generality of the limitation of “cancer drugs”. See MPEP 2106.04(d)(2) for a discussion on particular treatments and MPEP 2106.05(f) for a discussion on mere instructions to apply an exception. The additional element in claim 101 of further limiting the one or more cancer drug does not integrate the judicial exceptions into a practical application because changing a treatment is not required and changing a treatment for the subject based on the plurality of tumor fractions is mere instructions to apply the exception (i.e., the claim does not set out how one is changing the treatment). It is noted that the list of drugs recited in claim 101 does fix the issue of changing the treatment being mere instructions to apply due to the generality of “cancer drugs”.
The additional elements in claim 49 of using a neural network and a convolutional neural network are not required by the claims because they are listed as alternative embodiments. Thus, under the BRI the model can be a regression model which is a judicial exception (i.e., a mathematical concept). These additional elements do not integrate the judicial exceptions into a practical application because they are not required by the claim. Further, the additional elements of using a neural network and a convolutional neural network amounts to using a computer to perform abstract ideas and is generally linking the abstract idea to the technological environment of neural networks see MPEP 2106.05(h) and do not integrate the judicial exceptions into a practical application because this is applying the judicial exceptions to a generic computer without an improvement to computer technology. These additional elements only interact with the judicial exceptions by using a generic computer as a tool to perform the judicial exceptions and generally links the abstract idea to the technological environment of neural networks.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 2, 3, 14, 20, 24, 49-50, and 98-101 are directed to the abstract idea.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claim 98 sequencing a first plurality of DNA fragments in a DNA sample obtained from the DNA sample, wherein the first plurality of DNA fragments comprises at least one million cell -free DNA fragments for the analysis and sequencing a second plurality of DNA fragments in the DNA sample, the additional element in claim 2 of the first and the second sequencing are the same sequencing, the additional element in claim 3 of the sequencing is targeted panel sequencing using probes, the additional element in claim 20 of the first sequencing provides an average coverage of between 20x and 70,000x and the second sequencing provides an average coverage of between 1,000x and 70,000x, the additional element in claim 24 of wherein the DNA sample comprises one or a combination selected from the group of blood, whole blood, plasma, serum, urine, cerebrospinal fluid, fecal, saliva, tears, pleural fluid, pericardial fluid, and peritoneal fluid of the subject are conventional shown by Venn et al. (WO 2019204360 A1; newly cited) in [0010], [0115], and [0132]-[0135] which shows sequencing at least one million cell-free DNA fragments, a targeted panel using probes, average coverages within the range of 20x and 70,000x and within the range of 1,000x and 70,000x and shows the DNA samples are selected from the same group, Labgaa et al. (Oncogene 37, 3740–3752 (2018); newly cited) which shows targeted deep sequencing of cell-free DNA using probes with coverages within the range of 20x and 70,000x and within the range of 1,000x and 70,000x and utilizing blood samples on page 3742, the instant disclosure which shows that sequence reads are produced by sequencing such as Illumina parallel sequencing which is a commercially available sequencer (see [0140] and [0387] of instant disclosure), and the instant disclosure further shows that a number of targeted cancer assay panels are known in the art (see [0352] of instant disclosure).
The additional element in claim 98 of when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents for cancer to the subject, wherein the agents for cancer are selected from hormones, immune therapies, radiography, or one or more cancer drugs does not amount to significantly more because it is not required by the claim. Therefore, there exists an embodiment of the claim where the change in the plurality of tumor fractions of the subject across the epoch does not exceed a threshold amount and therefore the treatment is not changed.
The additional elements in claim 49 of a neural network and a convolutional neural network are not required by the claims because they are listed as alternative embodiments. Thus, under the BRI the model can be a regression model which is a judicial exception (i.e., a mathematical concept). These additional elements do not amount to significantly more because they are not required by the claim. Further, the additional elements of using a neural network and a convolutional neural network (which amounts to using a computer to perform abstract ideas) is conventional as shown by MPEP 2106.05(b) and MPEP 2106.05(d)(II).
Thus, the additional elements do not amount to significantly more than the judicial exceptions because they are conventional.
Response to Arguments
Applicant's arguments filed 26 February 2025 have been fully considered but they are not persuasive.
Applicant argues the claim amendment of when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents for cancer to the subject, wherein the agents for cancer are selected from hormones, immune therapies, radiography, or one or more cancer drugs integrates the judicial exception into a practical application due to being previously identified in the last office action as integrating the judicial exception into a practical application (Reply p. 7).
It is noted after further consideration that the amendment of “when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents for cancer to the subject, wherein the agents for cancer are selected from hormones, immune therapies, radiography, or one or more cancer drugs” does not integrate the judicial exception into a practical application because it is a contingent limitation which depends on a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount. It is noted that positively reciting language of an active step of determining that the plurality of tumor fractions exceeds a threshold amount before this step will limit the method to embodiments that perform the change in treatment. Further, as described above (under Step 2A Prong 2) the step of changing a treatment for the subject based on the plurality of tumor fractions is mere instructions to apply the exception because this is a general application of the judicial exception (i.e., the claim does not set out how one is changing the treatment) and the step of changing a treatment is mere instructions to apply the exception because of the generality of the limitation of “cancer drugs”. It is further noted that claim 101 that lists several cancer drugs alleviates the issue of changing the treatment being mere instructions to apply due to the generality of the limitations of “cancer drugs”.
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 2, 3, 14, 20, 24, 49, 50, and 98-101 are rejected under 35 U.S.C. 103 as being unpatentable over Venn et al. (WO 2019204360 A1; newly cited) in view of Adalsteinsson et al. (Nat Commun 8, 1324 (2017)., newly cited).
Claim 98 is directed to a method for determining, in a DNA sample obtained from a subject, a tumor fraction estimating a proportion of DNA fragments originated from tumor cells, comprising: (a) sequencing a first plurality of DNA fragments in the DNA sample or derived from the DNA sample, wherein the first plurality of DNA fragments comprises at least one million cell-free DNA fragments;
Venn et al. shows sequencing cell-free nucleic acids in a DNA sample obtained from the patient to obtain sequence reads (Venn et al. [0114]). Venn et al. shows millions of cell-free nucleic acid fragments are sequenced (Venn et al. [0115]). Venn et al. shows different sequencing methods are used when deriving certain data from the reads and shows that a whole genome assay plasma looks for copy number variation in the genome and target plasma assay looks for somatic copy number alterations in a targeted panel of genes (Venn et al. [0130]-[0132] and [0135]).
(b) sequencing a second plurality of DNA fragments in the DNA sample; aligning a sequence read of each sequenced DNA fragment of the second plurality to a corresponding allele locus in the reference genome; determining, for each sequenced DNA fragment aligned to an allele locus, an allele type and using the allele type to determine whether the sequenced DNA fragment is originated from a tumor cell or a non-tumor cell;
Venn et al. shows different sequencing methods are used when deriving certain data from the reads and shows that a targeted plasma assay looks for single nucleotide variants, insertions, and deletions (Venn et al. [0135]).Venn et al. shows using sequence reads to identify support for each variant in a variant set by aligning a sequence read in the plurality of sequence reads to a region in a reference genome in order to determine whether the sequence read contains a first variant (Venn et al. [0018]).
and counting the number of sequenced DNA fragments aligned to each allele locus, for each allele type, as an allele count at the allele locus for the allele type; and
Venn et al. shows that a plurality of sequence reads is used to identify support for each variant in a variant set thereby determining an observed frequency of each variant in the variant set (Venn et al. [0009]).
(c) inputting the plurality of copy numbers and the allele counts into a trained reference model to generate the tumor fraction estimating the proportion of DNA fragments originated from tumor cells among all DNA fragments in the DNA sample;
Venn et al. shows determining tumor fraction in cell-free nucleic acids of a liquid biological sample of a subject by evaluating an observed frequency of each respective variant in a first variant set against observed frequency of the respective reference set (Venn et al. [0009]). Venn et al. shows that each variant in the variant set is for a different genetic variation in the genome of the subject (Venn et al. [0047]). Venn et al. shows that the ctDNA fraction (or tumor fraction in cell-free DNA) is estimated by adding the probabilities provided by each variant in the set of variants in logarithmic space which is a regression algorithm (Venn et al. [0173]). Venn et al. shows that observed sequence reads are corrected for background copy number such as sequence reads that support variants that arise from chromosomes or portions of chromosomes that are duplicated in the subject are corrected for this duplication (Venn et al. [0179]). Venn et al. shows that this may be done by normalization of reads based on copy number or allowing for more than one value of ctDNA fraction which enables assessment of heterogeneity within/across tumors (Venn et al. [0179]).
repeating steps (a)-(c) at a plurality of time points across an epoch to obtain a plurality of tumor fractions of the subject across the epoch; and
Venn et al. shows repeating the steps at a plurality of time points across an epoch to obtain a plurality of tumor fractions across an epoch (Venn et al. [0031]).
when a change in the plurality of tumor fractions of the subject across the epoch exceeds a threshold amount, changing a treatment for the subject based on the plurality of tumor fractions, wherein the treatment comprises applying agents for cancer to the subject, wherein the agents for cancer are selected from hormones, immune therapies, radiography, or one or more cancer drugs.
As noted above in the claim interpretation section this limitation is a contingent limitation. Thus, the BRI of the claimed method does not require this step to be performed.
Venn et al. does not show aligning sequence reads to a reference genome to obtain a plurality of bin values respectively corresponding to a plurality of regions of the reference genome, and each bin value represents a count of cell-free nucleic acids from the reference genome that maps to the corresponding bin; and determining, based on the plurality of bin values, a plurality of copy numbers
Like Venn et al., Adalsteinsson et al. shows utilizing cell-free DNA to predict tumor fraction. Adalsteinsson et al. shows aligning cell-free DNA to a reference genome to obtain a plurality of bin values which corresponds to a plurality of regions of the reference genome with each bin value representing a count of cell-free nucleic acids from the reference genome that corresponds to the bin (Adalsteinsson et al. page 7 right col. – page 8 left col.). Adalsteinsson et al. further shows determining a plurality of copy numbers based on the plurality of bin values (Adalsteinsson et al. page 8 left col.).
Claim 2 is directed to wherein the first and the second sequencing are the same sequencing. Claim 3 is directed to wherein: the sequencing is targeted panel sequencing, the targeted panel sequencing uses a plurality of probes, and each probe in the plurality of probes includes a nucleic acid sequence that corresponds to the sequence, or a complementary sequence thereof, of a portion of the reference genome.
Venn et al. shows a targeted plasma assay that looks for somatic copy number alterations in the targeted panel of genes and SNVs in targeted panel of genes, insertions in targeted panel of genes, and deletions in targeted panel of genes with a coverage of at least 50,000x (Venn et al. [0135]). Venn et al. shows that target DNA sequences are enriched using hybridization probes (Venn et al. [0314]).
Claim 14 is directed to further comprising copy numbers and allele counts are features with reduced dimensionality.
Venn et al. shows copy numbers and allele counts which are determined which produces features from the sequence reads with reduced dimensionality (i.e., sequencing data which is reduced to a numeric feature) (Venn et al. [0009]-[0010]).
Claim 20 is directed to wherein: the first sequencing provides an average coverage of between 20x and 70,000x across a set of genes in a targeted panel, and the second sequencing provides an average coverage of between 1,000x and 70,000x across a set of genes in a targeted panel.
Venn et al. shows a targeted plasma assay that looks for somatic copy number alterations in the targeted panel of genes and SNVs in targeted panel of genes, insertions in targeted panel of genes, and deletions in targeted panel of genes with a coverage of at least 50,000x (Venn et al. [0135]).
Claim 24 is directed to wherein the DNA sample comprises one or a combination selected from the group consisting of blood, whole blood, plasma, serum, urine, cerebrospinal fluid, fecal, saliva, tears, pleural fluid, pericardial fluid, and peritoneal fluid of the subject.
Venn et al. shows that the DNA sample may be blood, whole blood, plasma, serum, urine, cerebrospinal fluid, fecal, saliva, sweat, tears, pleural fluid, pericardial fluid, or peritoneal fluid of the subject (Venn et al. [0110]).
Claim 49 is directed to wherein the reference model is a multivariate logistic regression, a neural network, a convolutional neural network, a support vector machine, a decision tree, a regression algorithm, or a supervised clustering model.
Venn et al. shows that the ctDNA fraction (or tumor fraction in cell-free DNA) is estimated by adding the probabilities provided by each variant in the set of variants in logarithmic space which is a regression algorithm (Venn et al. [0173]).
Claim 50 is directed to wherein each allele type is a single nucleotide variant associated with a predetermined genomic location, an insertion mutation associated with a predetermined genomic location, a deletion mutation associated with a predetermined genomic location, a somatic copy number alteration, a nucleic acid rearrangement associated with a predetermined genomic locus, or an aberrant methylation pattern associated with a predetermined genomic location.
Venn et al. shows a variant in the first variant set is a single nucleotide variant associated with a predetermined genomic location, an insertion mutation associated with a predetermined genomic location, a deletion mutation associated with a predetermined genomic location, a somatic copy number alteration, a nucleic acid rearrangement associated with a predetermined genomic locus, or any aberrant methylation pattern associated with a predetermined genomic location (Venn et al. [0010]).
Claim 99 is directed to wherein an allele count at each allele locus represents an allele frequency.
Venn et al. shows that a plurality of sequence reads is used to identify support for each variant in a variant set thereby determining an observed frequency of each variant in the variant set (Venn et al. [0009]).
Claim 100 is directed to wherein the DNA fragments are cell free DNA fragments.
Venn et al. shows sequencing cell-free nucleic acids in a DNA sample obtained from the patient to obtain sequence reads (Venn et al. [0114]).
Claim 101 is directed to wherein the one or more cancer drugs include Lenalidomid, Pembrolizumab, Trastuzumab, Bevacizumab, Rituximab, Ibrutinib, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Pertuzumab, Pemetrexed, Nilotinib, Nilotinib, Denosumab, Abiraterone acetate, Promacta, Imatinib, Everolimus, Palbociclib, Erlotinib, Bortezomib, or Bortezomib.
This limitation further limits the step of changing a treatment for the subject based on the plurality of tumor fractions which is a contingent limitation. The BRI of the claimed method does not require the changing a treatment for the subject based on the plurality of tumor fractions or the particular cancer drugs that the treatment is changed to.
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date to have modified the process of estimating tumor fraction of a cell-free DNA sample with sequence read correction for background copy number of Venn et al. to incorporate the process of aligning cell-free DNA to a reference genome to obtain bin values to assign copy number states for each bin of Adalsteinsson et al. because this will allow for a process that can compute and utilize bin specific copy number states for correcting sequence read counts that support a variant used for calculating tumor fraction in a sample which will give context to varying allele counts caused by deletions and duplications in differing regions of the genome (Adalsteinsson et al. page 8 left col.). One would have a reasonable expectation of success because Venn et al. shows obtaining cell-free DNA for estimating tumor fraction utilizing a process for accounting for copy number while Adalsteinsson et al. shows a specific process of analyzing cell-free DNA data to produce copy number states for regions of a genome.
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685