DETAILED ACTION
Applicant's Remarks, filed 02/06/2026, have been fully considered. The following rejections and/or objections are either reiterated or newly applied in view of instant application amendments. They constitute the complete set presently being applied to the instant application. Herein, "the previous Office action" refers to the Non-Final rejection of 08/06/2025 .
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 .
Status of Claims
Claims 1-20 are currently pending and under examination herein.
Claims 1-20 are rejected.
Priority
As reviewed in the 08/06/2025 Office Action, the effective filing date (EFD) of the instant application is 10 October 2014. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Information Disclosure Statement
The Information Disclosure Statements, filed 03/06/2026, has been considered. Signed copies of the IDS are included with this Office Action.
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 1-20 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. Any newly applied rejection/portion is necessitated by instant application amendment.
The instant rejection reflects the framework as outlined in the MPEP at 2106.04:
Framework with which to Evaluate Subject Matter Eligibility:
(1) Are the claims directed to a process, machine, manufacture, or composition of matter;
(2A) Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
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
(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:
With respect to step (1): yes, the claims are directed to method, system, and non-transitory machine-readable storage medium “for identifying a presence or absence of a genetic variation”, therefore the answer is "yes".
With respect to step (2A)(1), the claims recite 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 (2A)(1) evaluation, the claims are found herein to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for obtaining, analyzing, and organizing information) and mathematical concepts (in particular mathematical relationships and formulas).
The claim steps directed to natural phenomenon are as follows:
Claims 1, 13, 18: determining the presence or absence of the genetic variation for the test sample according to raw counts or normalized counts of the mapped nucleotide sequence reads; and providing, by the computing system, a diagnosis of the human subject based on the presence or absence of the genetic variation
The claim steps to abstract ideas are as follows:
Claims 1, 13, 18: mapping the nucleotide sequence reads to the plurality of portions of the at least one re-partitioned genomic region, thereby generating mapped nucleotide sequence reads wherein the plurality of portions of the at least one re-partitioned genomic region is determined by: … determining sequencing coverage variability…selecting an initial portion length…partitioning at least two genomic regions according to the initial portion length wherein each of the at least two genomic regions is partitioned into a number of portions… comparing the sequencing coverage variability… generating a comparison… recalculating the number of portions for at least one of the genomic regions according to the comparison, thereby determining an optimized portion length… re-partitioning at least one of the genomic regions into a plurality of portions according to the optimized portion length, thereby generating at least one… … determining …raw counts or normalized counts of the mapped nucleotide sequence reads…; and providing…, a diagnosis of the human subject based on the presence or absence of the genetic variation
Claims 2, 14: “wherein determining the sequencing coverage variability comprises use of the thousands to millions of reference sequence mapped to portions of the reference genome, which and wherein the thousands to millions of reference sequence reads are reads of circulating cell-free nucleic acid from the plurality of reference samples from pregnant females bearing a fetus.”
Claims 4, 15: “selected according to an average fetal fraction for the plurality of reference samples or sequencing depth for the plurality of reference samples.”
Claim 5: “wherein the average fetal fraction is determined based on the thousands to millions of reference sequence reads…
Claim 7: “directed to a genomic region identified as having the genetic variation, and wherein the diagnosis of the human subject is further based on a result of the targeted confirmatory test”
Claim 8: “wherein the first genomic region and the second genomic region differ in size by less than a predetermined level of uncertainty.”
Claim 9: “determined from a nucleotide sequence read count…”
Claim 10: “determined from an average nucleotide sequence read count”
Claims 11, 16, 19: “determining a region-specific minority fraction for each genomic region according to a correlation between nucleotide sequence read counts per portion and a weighting factor… determining a local minimum genomic region size based on the region-specific minority fraction;… adjusting the number of portions for each of the at least two genomic regions to comprise at least two portions based on the local minimum genomic region size, thereby generating a refined re-partitioned genomic region”
Claims 11, 12, 16, 17, 19, 20: “mapping the nucleotide sequence reads to the plurality of portions of the at least one refined re-partitioned genomic region from the test sample, and wherein the minority fraction corresponds to a portion of fetal derived nucleic acid in the nucleic acid from the test sample, a portion of cancer nucleic acid in the nucleic acid from the test sample, a portion of pathogen nucleic acid in the nucleic acid from the test sample, or a portion of mutated nucleic acid in the nucleic acid from the test sample.”
Claims 12, 17, and 20: “estimating a fetal fraction for the test sample from a pregnant female bearing a fetus…determining a region-specific fetal fraction for each genomic region according to a correlation between nucleotide sequence read counts per portion and a weighting factor…determining a local minimum genomic region size based on the region-specific fetal fraction; and adjusting the number of portions for each of the at least two genomic regions to comprise at least two portions based on the local minimum genomic region size, thereby generating a refined re-partitioned genomic region…
Hence, the claims explicitly recite elements that, individually and in combination, constitute natural phenomenon and abstract ideas.
With respect to (2A), under the broadest reasonable interpretation (BRI), the instant claims recite natural phenomena (human disease diagnosis and genetic variation) with correlations (according to raw counts or normalized counts of the mapped nucleotide sequence reads; and providing, by the computing system, a diagnosis of the human subject based on the presence or absence of the genetic variation ( “determining the presence or absence of the genetic variation for the test sample according to raw counts or normalized counts of the mapped nucleotide sequence reads” (claims 1, 13, and 18) by “selecting…(re-)partitioning…” by “predetermined level” or “local minimum” sizes/lengths, correlations, weightings of sequence reads of genomic regions or portions (claims ) from average or region-specific fetal fractions (claims 2-8); and “segmenting can be performed, in full or in part, by any suitable wavelet decomposition” [p.62])”, and are therefore directed to the judicial exceptions that is an abstract idea of the type that is in the groupings of “mental processes” and “mathematical concepts”. Said operations are generating partitions estimated or calculated by size or length (kilobases) counts, or average and percentages (fetal fraction) of genomic sequence reads. The instant Specification indicates that sequencing data is used as input into mathematical calculations to determine various numerical features, such as limits of microvariant detection [p181-182], weighting factors for fetal fraction and portion-specific parameters [p. 24-25], and discretization of genomic data [p.185] using various algorithms or mathematical models, and thus, recite a judicial exception in the instant claims.
Because the claims do recite judicial exceptions, direction under (2A)(2) provides that the claims must be examined further to determine whether they integrate the abstract ideas 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 abstract idea is integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim is said to fail to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
With respect to the instant recitations, the following additional elements are considered for integration into practical applications.
Claims 1, 13, and 18: sequencing, using a high-throughput sequencer/the computing system, nucleic acid from a test sample to generate nucleotide sequence reads…
Claim 3: “wherein the sequencing the nucleic acid from the test sample generates thousands to millions of nucleotide sequence reads.”
Claim 6: “wherein the initial portion length is between about 1 kb to about 1000 kb.”
Claim 7: “further comprising performing, based on the determination of the presence of the genetic variation in the test sample, a targeted confirmatory test on the test sample or another sample obtained from the human subject, wherein the targeted confirmatory test comprises a laboratory assay selected from the group consisting of targeted PCR, Sanger sequencing, fluorescence in situ hybridization (FISH), or a molecular diagnostic assay”
Claim 8: “wherein the at least two genomic regions comprise a first genomic region and a second genomic region.”
Claims 13 and 18: “a high-throughput sequencer… processors; and a non-transitory computer readable storage medium… to sequence nucleic acid from a test sample to generate nucleotide sequence reads and to send the nucleotide sequence reads to the one or more data processor…
Said steps that are “in addition” to the recited judicial exception in the instant claims represent those of mere instructions or field of use limitations to implement in the recited judicial exception and do not impart meaning to said recited judicial exception such that is applied in a practical manner. Further with respect to the additional elements in the instant claims, these steps direct to data gathering through the routine steps of sequencing mapped genomic regions, iteratively refining or optimizing data used in the judicial exception of mathematical equations [limit of variant detection p.182-183]; GC wavelet decomposition p.64; proportionality factor equation A [p.211]), and organizing them into compartments (bins/partitions/portions/ segments) based on quantitative feature or size relationships, to carry out the abstract idea without imposing any meaningful limitation on the abstract idea, or on how the abstract idea is performed. As taught in the instant Specification citations, mapped reads are mere data gathered and organized for use in the judicial exception (mathematical and mental processes):
Mapped sequence reads that have been counted are referred to herein as raw data, since the data represents unmanipulated counts (e.g., raw counts). In some embodiments, sequence read data in a data set can be processed further (e.g., mathematically and/or statistically manipulated) and/or displayed to facilitate providing an outcome. In certain embodiments, data sets, including larger data sets, may benefit from pre-processing to facilitate further analysis [p.76]. … In some embodiments, data sets are processed based on various features (e.g., GC content, redundant mapped reads, centromere regions, telomere regions, the like and combinations thereof) and/or variables (e.g., fetal gender, maternal age, maternal ploidy, percent contribution of fetal nucleic acid, the like or combinations thereof). In certain embodiments, processing data sets as described herein can reduce the complexity and/or dimensionality of large and/or complex data sets [p.77].
Thereby, these steps are insignificant extra-solutions activity steps and are insufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g).
Further steps herein directed to additional non-abstract elements of computer components (claims 13 and 18: “a high-throughput sequencer… processors; and a non-transitory computer readable storage medium) do not describe any specific computational steps by which the “computer parts” perform or carry out the abstract idea, 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 used as a tool to perform the functions that constitute the abstract idea. Hence, these are mere instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea 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 [FIG.12] 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. (see MPEP 2106.05(f)). None of the recited dependent claims recite additional elements which would integrate a judicial exception into a practical application.
As such, the claims are lastly evaluated using the (2B) analysis, wherein it is determined that because the claims recite abstract ideas, and do not integrate that abstract ideas into a practical application, the claims also lack a specific inventive concept. Applicant is reminded that the judicial exception alone cannot provide the inventive concept or the practical application and that the identification of whether the additional elements amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
With respect to the instant claims, the additional elements of data gathering described above do not rise to the level of significantly more than the judicial exception. As directed in the Berkheimer memorandum of 19 April 2018 and set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either 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 recitations, the following additional elements are considered for inventive concepts:
Claims 1, 13, and 18: sequencing, using a high-throughput sequencer/the computing system, nucleic acid from a test sample to generate nucleotide sequence reads…
Claim 3: “wherein the sequencing the nucleic acid from the test sample generates thousands to millions of nucleotide sequence reads.”
Claim 6: “wherein the initial portion length is between about 1 kb to about 1000 kb.”
Claim 7: “further comprising performing, based on the determination of the presence of the genetic variation in the test sample, a targeted confirmatory test on the test sample or another sample obtained from the human subject, wherein the targeted confirmatory test comprises a laboratory assay selected from the group consisting of targeted PCR, Sanger sequencing, fluorescence in situ hybridization (FISH), or a molecular diagnostic assay”
Claim 8: “wherein the at least two genomic regions comprise a first genomic region and a second genomic region.”
Claims 13 and 18: “a high-throughput sequencer… processors; and a non-transitory computer readable storage medium… to sequence nucleic acid from a test sample to generate nucleotide sequence reads and to send the nucleotide sequence reads to the one or more data processor…
The instant claims recite steps in a merely generic manner (at a high level of generality, e.g. “a fetal fraction from which a weighting factor is determined can be determined by any suitable method described herein or known in the art” [p.26]; “sequences produced by any sequencing process described herein or known in the art” [p.45]; and the claim limitations are conventional techniques, according to the MPEP 2106.05(d)(II). The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts or as insignificant extra-solution activity: amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546).
As MPEP 2106.4(I) recites: the guidance set forth in the MPEP teaches instant claims are an improvement to the abstract idea itself of genomic data analysis, in which better math or a new abstract idea is still a judicial exception. Any improvement or non-routine step or nonconventional element cannot be found in the judicial exceptions alone. “An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016).” The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-20 are not patent eligible.
Response to 101 Remarks
The Applicant's remarks [p.13-21], filed 03/06/2026, have been fully considered regarding the previous 08/06/2025 Office Action. Any newly applied rejection is necessitated by instant application amendment. The Applicant asserts:
A. [Abstract ideas unable to be performed by human mind: p15-16]: Claim 1 does not recite steps that could be performed in the human mind, even with the aid of pen and paper... The sheer quantity of data (thousands to millions of sequence reads), the need for sophisticated partitioning and mapping, and the requirement to generate and analyze a sequence read profile for each portion of the re-partitioned genomic region are well beyond the capability of any person unaided by a computing system. The "mapping" step, for example, requires computational alignment of millions of sequence reads to reference genomic coordinates, a task that cannot practically be performed mentally. The computing system is not a mere tool for automating a mental process; it is an essential component for carrying out the recited steps…There is a fundamental distinction between listing four credit card transactions as in CyberSource and mapping, partitioning, and analyzing the scale and complexity of genomic data required by the present claims…The argument that there is "no numerical limit to the data processed in determination of patent eligibility" is not supported by controlling law. Both the Federal Circuit and the USPTO recognize that claims do not recite a mental process when the scale, complexity, or technical nature of the claimed data processing is such that the human mind is not equipped to perform the claimed steps. See, e.g., SRI Int'l, Inc. v. Cisco Sys., Inc., 930 F.3d 1295, 1304 (Fed. Cir. 2019) ("the human mind is not equipped to detect suspicious activity by using network monitors and analyzing network packets as recited by the claims"). Here, the claimed steps including the sequencing, mapping, and generating the sequence read profile require the operation of both a high-throughput sequencer and a computing system, as expressly recited, and cannot be "practically performed in the human mind," even theoretically. Accordingly, Applicant respectfully submits that the present claims do not recite a mental process.
However, sequencing steps are not interpreted themselves as the abstract ideas/judicial exception “to be performed in the human mind”, but are interpreted as additional elements. As they are “in addition”, sequencing with high-throughput sequencer is considered for practical integration. The claim limitations of mapping, however, are directed to an abstract idea/mental process of matching up sequences with genomic regions to provide mapped reads. Claims do recite a mental process when they contain limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions. Examples of claims that recite mental processes include: “to collecting and comparing known information (claim 1), which are steps that can be practically performed in the human mind,” Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011). Even if mapping was considered “in addition” to the recited judicial exception in the instant claims, mapping, providing, and sequencing constitute field of use limitations. The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity: amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247; using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015); detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017); analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546; (see MPEP 2106.05(d)(II)). Said claimed field of use limitations produce data to be utilized in the judicial exception, and therefore, are insufficient to integrate an abstract idea into a practical application. (MPEP 2106.05(g).
Further, the fact pattern of SRI Int'l, Inc. v. Cisco Sys., Inc., is not analogous to the instant claim steps. The broadest reasonable interpretation of mapping and repartitioning data from a high-throughput sequencer as claimed is a mental process/aligning bases to a reference sequence, and mathematically counting/dividing reads to into portions (partitions), which is a mental process a human mind is capable of performing, as was done by molecular biologists manually before sequencers. Even if aided in counting/tracking reads with machines/computer implementation, the human mind can still match a nucleotide base to a complementary base. Examiner agrees with Applicant that a digital step with computer signals (“network packets”) is not possible for a human mind to perform—and without the technology of network monitors, a human could not receive/transmit/analyze data in the format of signals in a network packet ("the human mind is not equipped to detect suspicious activity by using network monitors and analyzing network packets as recited by the claims" See, e.g., SRI Int'l, Inc. v. Cisco Sys., Inc., 930 F.3d 1295, 1304 (Fed. Cir. 2019)). This is analogous to the facts of SiRF Tech., in which the human mind cannot receive a GPS/satellite signal which is integral to the claim of a method for calculating an absolute position of a GPS receiver and an absolute time of reception of satellite signals, where the claimed GPS receiver calculated pseudoranges that estimated the distance from the GPS receiver to a plurality of satellites, SiRF Tech., 601 F.3d at 1331-33, 94 USPQ2d at 1616-17)).
A human mind is capable of performing sequence mapping of reads, and therefore, this is a mental process, even if a computer is involved as tool/calculator/data storage to handle large amounts of data. Claims can recite a mental process even if they are claimed as being performed on a computer. The Supreme Court recognized this in Benson, determining that a mathematical algorithm for converting binary coded decimal to pure binary within a computer’s shift register was an abstract idea. The Court concluded that the algorithm could be performed purely mentally even though the claimed procedures "can be carried out in existing computers long in use, no new machinery being necessary." 409 U.S at 67, 175 USPQ at 675. See also Mortgage Grader, 811 F.3d at 1324, 117 USPQ2d at 1699 (concluding that concept of "anonymous loan shopping" recited in a computer system claim is an abstract idea because it could be "performed by humans without a computer"). Another example is Berkheimer v. HP, Inc., 881 F.3d 1360, 125 USPQ2d 1649 (Fed. Cir. 2018), in which the patentee claimed methods for parsing and evaluating data using a computer processing system. The Federal Circuit determined that these claims were directed to mental processes of parsing and comparing data, because the steps were recited at a high level of generality and merely used computers as a tool to perform the processes (high-throughput sequencer).
B. Natural phenomenon practical integration [p16]: The present claims do not recite a law of nature or a natural phenomenon. Rather, as made clear by the plain language of Claim 1, the method is directed to a specific, structured technical process for acquiring, partitioning, mapping, and analyzing high-throughput sequencing data from a test sample using a computing system and a high-throughput sequencer. The steps are not the natural phenomena themselves, but are technical operations for processing and interpreting complex data. The claims do not preempt or claim ownership over the natural existence of genetic variation, the underlying sequence, or the correlations per se. Instead, they recite a practical application for sequencing nucleic acid and processing sequencing data to achieve improved detection and diagnosis. As clarified by the Federal Circuit in cases such as Illumina, Inc. v. Ariosa Diagnostics, Inc., 967 F.3d 1319 (Fed. Cir. 2020), the fact that a method may involve detection of natural phenomena (such as cell-free DNA) does not render the claim ineligible if the claim as a whole is directed to a specific, technical process for analyzing or manipulating that information. Here, the claims are not directed to the natural existence of genetic variation or the mere fact of a correlation, but to a technological solution for extracting, partitioning, and analyzing sequencing data in a way that improves the field of molecular diagnostics.
However, it is respectfully submitted that Applicant’s assertion is not persuasive regarding Applicant’s arguments of absence of a natural law in instant claim limitations (determining the presence or absence of the genetic variation for the test sample according to raw counts or normalized counts…providing, by the computing system, a diagnosis of the human subject based on the presence or absence of the genetic variation). The naturally occurring relationship between genotypes and other characteristics of an organism is a recognized, naturally occurring correlation which exists whether or not it is measured. The claims clearly obtain genetic data of the organisms in the sample, compares them to known sequences and known characteristics (GC content, fetal origin), to make the identification- a type of phenotype: strain, substrain, and genotype (variants). These correlate to at least the following examples provided in MPEP 2106.04b: “iii. a correlation between variations in non-coding regions of DNA and allele presence in coding regions of DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1375, 118 USPQ2d 1541, 1545 (Fed. Cir. 2016); iv. a correlation that is the consequence of how a certain compound is metabolized by the body, Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012); v. a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017); vii. qualities of bacteria such as their ability to create a state of inhibition or non-inhibition in other bacteria, Funk Bros., 333 U.S. at 130, 76 USPQ at 281; and xi. the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of a medication called iloperidone, Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018).”
The sequence information/genetic variation/counts of the sample are a natural phenomenon and the relationship of that information to a phenotypic trait is simply put a natural law. Nothing more than this observation is required by the claims. In Mayo, the discovery underlying the claims was that when blood levels were above a certain level harmful effects were more likely and when they were below another level the drug's beneficial effects were lost. Mayo, 566 U.S. at 74--76. The claims provided that particular levels of measured metabolite indicated a need to increase or decrease the amount of drug subsequently administered to the subject. Id. at 75. However, the claims did not require any actual action be taken based on the measured level of metabolite. Id. at 75-76. Thus, the claims which required only the observation of a natural law were deemed patent-ineligible. Similarly, here, the claim requires only the observation of the natural law, and for this reason too are properly deemed patent-ineligible.
C. Improvement to Computer and Sequencing System Function [p.17] Claim 1 recites additional elements including the sequencing, mapping, and generating the sequence read profile steps. These elements are not extra-solution activity, but are integral to the claimed method to achieve the technical result. As described in the specification, the claimed workflow improves the functioning of the entire sequencing and data analysis system by enabling dynamic, data-driven partitioning of genomic regions, thereby optimizing the analysis pipeline for each sample and each genomic context. This approach is not routine or conventional; conventional sequencing analysis methods which employ fixed-length bins and static normalization can miss or misclassify genetic variations due to regional variability and noise. By contrast, the claimed method dynamically adjusts partition sizes and mapping strategies based on observed coverage variability, and generates a sequence read profile that is tailored for improved sensitivity and specificity. This is precisely the type of technological improvement recognized as patent-eligible in Enfish, LLC v. Microsoft Corp., 822 F.3d 1327 (Fed. Cir. 2016) and McRo.
However, it is respectfully submitted that Applicant’s assertion is not persuasive. As claimed, there is no improvement to the high-throughput sequencer/computer technology, as any high-throughput sequencer hardware can perform the claimed steps of providing sequencing data and generating a sequence profile to be used in diagnosis. The high-throughput sequencer is generically linked to the JE as a source of data for input
According to updated July 2024 guidance on computer-implemented AI models, an improvement in the judicial exception (a dynamic binning mathematical machine learning model determining partitions and iteratively repartitioning based on sequence coverage variability, GC partitioning and fetal fraction) itself is not an improvement in computer technology (a computing system/high-throughput sequencer/data processors/non-transitory computer readable storage medium, computer program product). For example, in MPEP 2106.05(a), subsection II), in In re Board of Trustees of Leland Stanford Junior University, 989 F.3d 1367, 1370, 1373 (Fed. Cir. 2021) ( Stanford I ), the applicant claimed methods of resolving a haplotype phase involving steps of determining an inheritance state based on received allele data using a Hidden Markov Model. The applicant further claimed determining a haplotype phase based on the pedigree data, the earlier-calculated inheritance state, transition probability data, and population linkage disequilibrium data using a computer system (i.e. processor/system). The applicant argued that the claimed process was an improvement over prior processes because it “yields a greater number of haplotype phase predictions,” (i.e. “the dynamic, optimized partitioning and mapping pipeline allows for detection of smaller copy number variations and more reliable quantitation of genetic differences than could be achieved with static methods. The sequence read profile is not a generic data output, but a technical artifact reflecting the improved analytical process and enabling more accurate diagnosis”…) but the court found it was not “an improved technological process” and instead was an improved “mathematical process.” The court explained that such claims were directed to an abstract idea because they describe “mathematically calculating alleles' haplotype phase,” like the “mathematical algorithms for performing calculations” (neural network implemented machine learning model) in prior cases. Notably, the Federal Circuit found that the claims did not reflect an improvement to a technological process, which would render the claims eligible.
D. Improvement to Genetic Variation Detection Using Nucleic Acid & Transformation of Data and Practical Application [p18] The dynamic, optimized partitioning and mapping pipeline allows for detection of smaller copy number variations and more reliable quantitation of genetic differences than could be achieved with static methods. The sequence read profile is not a generic data output, but a technical artifact reflecting the improved analytical process and enabling more accurate diagnosis…The method as claimed is not a drafting effort to monopolize a judicial exception, but a practical application of sequencing technology to solve a concrete problem in genomics and diagnostics. The integration of sequencing, dynamic computational analysis, generation of a sequence read profile, and use of the profile for diagnosis, ensures that any alleged judicial exception is meaningfully limited to the particular technological context and is not preempted in the abstract.
However, it is respectfully submitted that Applicant’s assertion is not persuasive. As claimed, there is no improvement or practical integration through transformation of data. While there may be to increased genetic variation detection, the steps do not enact a transformation of the JE, as the sequence read profile is “but a technical artifact reflecting the improved analytical process” (data manipulation) which is generated for diagnosis (data for input into another abstract idea/JE of diagnosing). An assertion of improvement to technology for practical application can be supported with evidence of a particular transformation of the high-throughput sequencer (“the specificity of the claim limitations is relevant to the evaluation of several considerations including the use of a particular machine, particular transformation and whether the limitations are mere instructions to apply an exception”, see MPEP §§ 2106.05(b), 2106.05(c), and 2106.05(f)).
An example for particular transformation is claiming steps bounded by the specification which clearly recite the high-throughput sequencer is reconfigured as a result of the dynamically optimizing data partitioning (the JE/analysis), e.g. the JE/analysis is performed, then the high-throughput sequencer is reconfigured to sequence the data with lower depth or higher depth/less or more sequence coverage, and thereby, tangibly performs fewer or more runs (“focus on high-priority genomic regions directly because of the repartitioning”). In this way or the equivalent, the high-throughput sequencer would not be generically linked or merely providing data input/output within in the JE, but the high-throughput sequencer itself is altered by the use of the JE as in the claims in Diamond v. Diehr, 450 U.S. 175 (1981). In Diehr, the mathematical calculation (the JE) reconfigured the forces of the rubber molder (the machine) and so, reduced the likelihood of “overcuring” or “undercuring,” (the improvement) to achieve practical integration. The instant claims do not generate anything except data/a “sequence read profile” (raw/normalized counts of the mapped sequences in claims 1, 13, and 18), without any structure or active steps to use in diagnosis determination (such as equivalents of providing a new genotype/haplotype or variant as compared to a healthy reference library; determining there is a variant associated with a genetic diagnosis X when compared to a genetic variants reference library and their corresponding disease diagnosis; determining said subject’s sample variant is consistent with diagnosis X genetic variants; and finally, treating said sample subject with therapy Z, wherein therapy Z is the first line treatment for diagnosis X).
E. Practical Integration/Nonconventionality by Dependent Claims [p.19]: Claims 7, 11-12 explicitly recite additional technical feature that further integrate into a practical application and in Step 2B represent nonconventional data-driven genomic analysis based on observed variability/sample mix with generation of a sequence read profile.
a. Claim 7: a physical, laboratory-based confirmatory test that is targeted and conditional upon the computational detection of a genetic variation. This step effects a transformation of a physical article and ties the computational analysis to a concrete laboratory workflow, thereby integrating any alleged judicial exception into a practical, real- world application.
b. Claim 11: further limits the analysis by reciting a non-conventional, technical refinement to the partitioning and mapping process, further defining the data-driven, sample-specific adjustment that transforms the analytical workflow and the resulting technical output (sequence read profile) to improve detection of clinically relevant minority fractions (e.g., fetal or cancer DNA) in a heterogeneous sample. This is a meaningful limitation that integrates any alleged exception into a practical, technical application in molecular diagnostics.
c. Claim 12: analogous steps for estimating fetal fraction and using region-specific fetal fraction for further refining partitioning and mapping. The steps cannot be performed in the human mind and are not abstract; they are technical solutions to the concrete problem of detecting rare genetic variation in mixed DNA samples.
However, it is respectfully submitted that Applicant’s assertion is not persuasive, analogously as noted above in the response to arguments and rejection above regarding intended improvements to Genetic Variation Detection Using Nucleic Acid & Transformation of Data. Regarding the claim limitations of genomic data analysis from a high throughput sequencer/utilizing region-specific mapped fetal sequence reads/ performing confirmatory laboratory assays (targeted PCR, Sanger sequencing), these are elements “in addition” to the recited judicial exception in the instant claims, and unfortunately, they constitute field of use limitations (claim 7: confirmatory tests) producing more data to be utilized in the judicial exception, and therefore, insufficient to integrate an abstract idea into a practical application or provide an inventive concept, when considered individually or as an ordered combination (MPEP 2106.05(g). Claims 11 (determining/adjusting/mapping with fractions/sizes/portions) and 12 (estimating/ determining/adjusting/mapping with fractions/sizes/portions) are mental with mathematical steps, which are judicial exceptions themselves and cannot provide integration or novelty. Any improvement or non-routine step or nonconventional element cannot be found in the judicial exceptions alone. “An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016).” As MPEP 2106.4(I) recites: The Federal Circuit has also applied this principle, for example, when holding a concept of using advertising as an exchange or currency to be an abstract idea, despite the patentee’s arguments that the concept was "new". Ultramercial, Inc. v. Hulu, LLC, 772 F.3d 709, 714-15, 112 USPQ2d 1750, 1753-54 (Fed. Cir. 2014). Cf. Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016) ("a new abstract idea is still an abstract idea") (emphasis in original).
Further, Applicant asserts nonconventionality/nonroutine steps in instant data-driven genomic analysis based on observed variability/sample mix with generation of a sequence read profile. The prior art to Kim 2013 teaches fetal fraction analysis of cffDNA with training sets, utilizing portion or region-specific mapped fetal sequence reads (Claim 1; [0048, 0215] in USPUB 20150005176A1, priority to 06/21/2013; previously cited, herein Kim 2013) with training sets [Kim 2013 claim 7] against weighting factors to determine portion-specific fetal fractions [Kim 2013 claim 6], variable bin sizes, raw counts normalized based on GC bias [Kim 2013 claims 1, 4, 5, 16]. Applicant’s arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections.
Therefore, with respect to the instant claims, the steps (repartitioning genotype data from a high throughput sequencer) and additional elements (computer system/sequencer hardware elements for obtaining data, laboratory assay, targeted PCR, Sanger sequencing, fluorescence in situ hybridization (FISH), or a molecular diagnostic assay) requiring applied mathematical concepts and automated mental steps do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. The guidance set forth in the MPEP teaches instant claims are an improvement to the abstract idea itself of genomic data analysis, in which better math (abstract idea) even with better findings, is still a judicial exception. Because the instant claims do not amount to significantly more than the judicial exception itself, the claimed invention is directed to an abstract idea without significantly more.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
A. Claims 1-10, 13-15, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-12, and 15-19 of U.S. Patent No 10,892,035. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the patent claims overlap in scope. The conflicting patented claims are a species set of the instant claims.
B. Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Application No. 19/026,416. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the patent claims overlap in scope.
C. Claims 1-10, 13-15, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No 10,482,994. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the reference patent claims (reference “sections” = instant partitions) overlap in scope. The conflicting patented claims are a species set of the instant claims. This newly applied rejection is necessitated by instant application amendment.
Response to DP Remarks
The Applicant's remarks [p.20], filed 03/06/2026, have been fully considered regarding the previous 08/06/2025 Office Action. They are not persuasive because they do not provide any arguments against the merits of the NSDP rejection. Any newly applied rejection is necessitated by instant application amendment, as discussed above.
No prior art has been applied to the following claims
As previously discussed, no prior art is applied to claims 1, 13, and 18. Close art for limitations on partitioning in for classifying aneuploidy in cell-free fetal DNA/cffDNA, for example Kim et al. 2012 (US10,504,613 USPUB 20140180594A1, priority to 12/20/2012; IDS reference), while addressing partitioning based on read length based calculation [Kim 2012 reference claims 1-3], normalizing counts for guanine and cytosine content [Kim 2012 reference claim 8], varying sequence coverage levels [Kim 2012 reference claim 9-10], thresholds to classify aneuploidy [Kim 2012 reference claims 4-5] and partitioning (with lengths <1kb) to classify fetal aneuploidy, however, Kim does not address refining the partitions based on iterations of sequence coverage optimized with refined portion lengths criteria (1-1000kb, average fetal fraction and sequencing depth of a training set), local minimum genome regions, and region-specific fetal fractions. Close art for limitation of normalized counts used in determining presence or absence of a chromosome trisomy in cffDNA, for example Deciu 2011 (US 9,367,663, USPUB 20130085681, priority to 10/06/2011; IDS reference) applies guanine and cytosine based count and bias normalization to filter fetal sequence reads [Deciu 2011 claims 1, 17]. Close art for limitation of fetal fractions with training sets/reference samples in cffDNA, Kim et al 2013 (US Patent 10,622,094, USPUB 20150005176A1, priority to 06/21/2013) utilizing reference mapped fetal sequence reads (>1kb) with training sets [Kim 2013 claim 7] against weighting factors to determine portion-specific fetal fractions [Kim 2013 claim 6], variable bin sizes, raw counts normalized based on GC bias [Kim 2013 claims 1, 4, 5, 16. However, Kim 2013 uses sequence depth of test samples [Kim 2013 claim 20] , but not to filter training set, using bins, however not based on iteratively optimized sequence coverage variability or optimized lengths. It is not clear that any combination of art would have rendered the claims obvious or to fairly suggest the instant claims.
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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/VR/
Examiner
Art Unit 1685
/MARY K ZEMAN/Primary Examiner, Art Unit 1686
Prosecution Insights