DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
As detailed on the Filing Receipt filed 10/7/2024, the instant application claims priority to as early as 10/8/2020. At this point in prosecution, all claims are accorded the earliest claimed priority date.
Information Disclosure Statement
The Information Disclosure Statements filed on 5/26/2023 and 3/13/2026 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. Signed copies of the IDS are included with this Office Action.
Claim Status
Claims 12-13, 17, 22-42 and 44 are canceled.
Claims 1-11, 14-16, 18-21 and 43 are pending, and under examination.
Claim Objections
Claims 1 and 43 are objected to because of the following minor informalities:
The recited term “gnomic” (claim 1, line 22; claim 43, line 22) should read “genomic”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 USC § 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 1-11, 14-16, 18-21 and 43 are rejected under 35 USC § 101 because the claimed invention is directed to judicial exceptions without significantly more (i.e., non-statutory subject matter).
"Claims directed to nothing more than abstract ideas, natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I).
Abstract ideas include mathematical concepts (including formulas, equations and calculations), and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
Natural phenomena and laws of nature and include principles, relations, and products that are naturally occurring or do not have markedly different characteristics compared to what occurs in nature (MPEP 2106.04(b)).
The claims as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than an abstract idea and a natural phenomenon.
Step 1: The Four Categories of Statutory Subject Matter (MPEP 2106.03)
The claims are directed to a method (claims 1-11, 14-16 and 18-21) and system (claim 43), which fall under categories of statutory subject matter.
Step 2A, Prong One: Whether the Claims Set Forth or Describe a Judicial Exception (MPEP 2106.04 § II.A.1)
‘Mathematical concepts’ are relationships between variables and numbers, numerical formulas or equations, or acts of calculation, which need not be expressed in mathematical symbols (MPEP 2106.04(a)(2) § I). The claims recite elements which encompass mathematical concepts, at least under their broadest reasonable interpretation, including:
estimat[ing] a fraction of nucleic acid from the first subject in the mixture (claim 1), i.e., calculating a value based on input data, using:
an expectation maximization (EM) algorithm (claim 4),
a Dirichlet process (claim 5);
generat[ing] a plurality of genotype likelihoods for the pluralities of genomic loci given the fraction estimated and according to the plurality of allele quantifications (claims 1 and 43), i.e., calculating probability values based on calculated count values;
generat[ing] a plurality of genotype likelihoods for a target reference allele and a target alternative allele at each of the plurality of target genomic locus based on the plurality of linked genomic locus genotype likelihoods and the plurality of target genomic locus genotype likelihoods generated (claims 1 and 43), i.e., calculating probability values based on calculated probability values;
generating a probability that the first subject is homozygous reference, heterozygous, or homozygous alternative at a target genomic locus (claim 14), comprising summing probabilities of haplotypes that are compatible with one or more genotypes at the target genomic locus (claim 15) i.e., calculating a probability value by summing calculated probability values; and
generating a combined likelihood for a linked genomic locus based on the estimated fraction of nucleic acid from the first subject (claim 16); i.e., calculating a probability value based on a calculated value.
The recited acts of calculation constitute mathematical concepts.
‘Mental processes’ are processes that can be performed in the human mind at least with use of a physical aid, e.g., a slide rule or pen and paper (MPEP 2106.04(a)(2) § III). The claims recite elements that encompass processes that are practicably performable in the human mind, at least under their broadest reasonable interpretation, including:
from the sequence reads for the first test sample, quantify[ing] pluralities of alleles, thereby generating pluralities of allele quantifications for pluralities of genomic loci (claims 1 and 43), i.e., tallying character occurrences at certain string positions;
generat[ing] a plurality of genotypes each corresponding to a respective genomic locus based on each set of genotype likelihoods (claims 1 and 43), i.e., determining a set of labels based on calculated label probabilities;
obtaining genotypes for the plurality of genomic loci for the second subject (claim 3); and
identifying the first subject based on the results of the database query (claim 21).
The recited steps of evaluating and determining information, which are practicably performable in the human mind, constitute mental processes.
Mathematical concepts and mental processes constitute enumerated groupings of abstract ideas (MPEP 2106.04(a)(2) §§ I and III). Hence, the claims recite elements that, individually and in combination, constitute an abstract idea.
The claims further recite the following claim elements, which require that analyzed data embodies particular natural phenomena and/or laws of nature:
processed sequence reads are derived from a first test sample comprising a mixture of nucleic acid from a first subject and a second subject (claims 1 and 43);
the sequence reads comprise subsequences representing various types of alleles (linked reference, linked alternative, target reference and target alternative) and sequence positions representing genomic loci (claims 1 and 43);
the plurality of linked genomic loci comprises loci within about 10 kilobases upstream and about 10 kilobases downstream of a target genomic locus (claims 1 and 43);
a plurality of target genomic loci comprises at least 100,000 loci (claims 1 and 43);
calculated values represents fractions of nucleic acid in the mixture, genotype likelihoods, etc. for the first subject or second subject (claims 1-5, 14-16 and 43);
processed sequence reads are derived from a second test sample comprising nucleic acid from the second subject and comprising no nucleic acid from the first subject (claim 2);
a genotype likelihood of the set of genotype likelihoods is for a locus where the second subject has an alternative allele (claim 6);
the second subject is homozygous for a linked alternative allele at the locus (claim 7);
the second subject is heterozygous for a linked alternative allele and a linked reference allele at the locus (claim 8);
a genotype of the plurality of genotypes is a single nucleotide polymorphism (SNP). (claim 9);
a genotype of the plurality of genotypes is an unphased genotype (claim 10);
the first subject is an unknown subject and the second subject is a known subject (claim 18);
the first subject is an unknown subject and the second subject is an unknown subject (claim 19); and
the first subject and the second subject are members of the same species (claim 20).
The above elements specify that analyzed data represents naturally occurring genetic attributes, i.e., natural phenomena, having naturally occurring probabilistic relationships, i.e., laws of nature, that the claimed invention allows a user of the claimed method and/or system to observe.
The claims must therefore be examined further to determine whether they integrate these judicial exceptions into a practical application (MPEP 2106.04(d)).
Step 2A, Prong Two: Whether the Claims Contain Additional Elements that Integrate the Judicial Exception(s) into a Practical Application (MPEP 2106.04 § II.A.2)
The claims recite additional elements that gather data necessary for performance of claimed method steps, including:
obtain[ing], for a first test sample comprising a mixture of nucleic acid from a first subject and a second subject, sequence reads aligned to a reference genome (claims 1 and 43);
obtaining, for a second test sample comprising nucleic acid from the second subject and comprising no nucleic acid from the first subject, sequence reads aligned to the reference genome (claim 2); and
sequencing nucleic acid in the first test sample using a sequencing process, thereby generating the sequence reads (claim 11).
Necessary data gathering is considered to be insignificant pre-solution activity, and as such insufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
The claims further recite additional elements that require performance of claimed functions on a computer, or constitute computer hardware for performing claimed functions, including:
querying a database using the plurality of genotypes (claim 21); and
a processor configured to perform functions of the claimed method (claim 43).
The claims do not describe any specific computational steps by which a computer performs or carries out functions drawn to the judicial exceptions, nor do they provide any details of how specific structures of a computer are used to implement these functions. The claims state nothing more than that a generic computer performs functions drawn to the judicial exceptions, and are therefore mere instructions to apply the judicial exceptions using a computer. As such, the claims do not integrate the judicial exceptions into a practical application (see MPEP 2106.04(d) § I and 2106.05(f)).
No further additional elements are recited.
When the claims are considered as a whole: they do not improve the functioning of a computer, other technology, or technical field (MPEP 2106.04(d)(1) and 2106.05(a)); they do not apply the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition (MPEP 2106.04(d)(2)); they do not implement the judicial exceptions with, or in conjunction with, a particular machine (MPEP 2106.05(b)); they do not effect a transformation or reduction of a particular article to a different state or thing (MPEP 2106.05(c)); and they do not apply or use the judicial exceptions in some other meaningful way beyond linking the use of the judicial exceptions to a particular technological environment and/or field of use (e.g., forensic analysis; MPEP 2106.05(e) and 2106.05(h)).
Hence, the recited judicial exceptions are not integrated into a practical application. See MPEP 2106.04(d) § I.
Because the claims recite an abstract idea and a natural phenomenon, and do not integrate those judicial exceptions into a practical application, the claims are directed to those judicial exceptions. Claims that are directed to judicial exceptions must be examined further to determine whether the additional elements besides the judicial exceptions render the claims significantly more than the judicial exceptions. Additional elements besides the judicial exceptions may constitute inventive concepts that are sufficient to render the claims significantly more (MPEP 2106.05).
Step 2B: Whether the Claims Contain Additional Elements that Amount to an Inventive Concept (MPEP 2106.05)
As noted above, several recited additional elements amount to insignificant extra-solution activity. Mere addition of insignificant extra-solution activity does not amount to an inventive concept that would render the claims significantly more than the recited judicial exceptions, particularly when the activities are well-understood or conventional (MPEP 2106.05(g)). The conventionality of recited additional elements that amount to insignificant extra-solution activity must be further considered.
Recited additional elements amounting to insignificant extra-solution activity encompass the following processes, which are indicated as activities that may be performed with commercially-available products by the instant specification (see MPEP 2106.07(a) § III):
obtaining sequence reads from a test sample, sequencing nucleic acid (para. 00196: “Nucleic acid may be sequenced using any suitable sequencing platform… such as, for example, a sequencing platform provided by Illumina® (e.g., HiSeq™, MiSeq™ and/or Genome Analyzer™ sequencing systems); Oxford Nanopore® Technologies (e.g., MINION sequencing system)…”).
Additionally, recited additional elements amounting to insignificant extra-solution activity encompass the following computer-implemented functions, which the courts have held as coextensive with a general-purpose computer and/or well-understood, routine and conventional:
Receiving, storing, and processing data (In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1316 (Fed. Cir. 2011); EON Corp. IP Holdings LLC v. AT&T Mobility LLC, 785 F.3d 616, 622 (Fed. Cir. 2015)), including:
Sending messages (e.g., queries) over a network (buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355 (Fed. Cir. 2014); OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363 (Fed. Cir. 2015)).
Hence, the encompassed extra-solution activity is considered well-understood, routine and conventional. Well-understood, routine and conventional activity is insufficient to constitute an inventive concept that would render the claims significantly more than judicial exceptions (MPEP 2106.05(d)).
Mere instructions to implement judicial exceptions using a computer are, when considered individually, similarly insufficient to constitute an inventive concept that would render the claims significantly more than said judicial exceptions (see MPEP 2106.05(f)).
When the claims are considered as a whole, they do not integrate the judicial exceptions into a practical application; they do not confine the use of the judicial exceptions to a particular technology; they do not solve a problem rooted in or arising from the use of a
particular technology; they do not improve a technology by allowing the technology to
perform a function that it previously was not capable of performing; and they do not
provide any limitations beyond generally linking the use of the judicial exceptions to a particular technological environment and/or field of use (e.g., forensic analysis; MPEP 2106.05(e) and 2106.05(h)).2106.05(h).
Hence, the claims do not include additional elements that are sufficient to amount to significantly more than the recited judicial exceptions. See MPEP 2106.05.
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole, are directed to judicial exceptions and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the judicial exceptions, so the claims are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 USC §§ 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 USC § 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 USC § 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 USC § 102(b)(2)(C) for any potential 35 USC § 102(a)(2) prior art against the later invention.
Claims 1-3, 6-11, 14-16, 18-21 and 43 are rejected under 35 USC § 103 as being unpatentable over Scheffler (WO 2018/236827; effectively filed 6/20/2017; on IDS filed 5/26/2023), in view of Zimmermann (WO 2014/018080; effectively filed 7/24/2012; on IDS filed 5/26/2023) and Ehrich (US 2010/0105049; effectively filed 9/16/2008; on IDS filed 5/26/2023).
Claim 1 recites a method for generating a plurality of genotypes for a plurality of target
genomic loci for an unknown subject, comprising:
obtaining, for a first test sample comprising a mixture of nucleic acid from a first subject and a second subject, sequence reads aligned to a reference genome;
from the sequence reads for the first test sample, quantifying a plurality of linked reference alleles, quantifying a plurality of linked alternative alleles, quantifying a plurality of target reference alleles, and quantifying a plurality of target alternative alleles, thereby generating a plurality of allele quantifications for a plurality of linked genomic loci and a plurality of allele quantifications for the plurality of target genomic loci, wherein:
the plurality of linked genomic loci comprises loci within about 10 kilobases upstream and about 10 kilobases downstream of a target genomic locus, and
a plurality of target genomic loci comprises at least 100,000 loci;
estimating a fraction of nucleic acid from the first subject in the mixture;
for the first subject, generating a plurality of genotype likelihoods for the plurality of linked genomic loci and the plurality of target genomic loci given the fraction estimated in (c) and according to the plurality of allele quantifications in (b);
for the first subject, generating a plurality of genotype likelihoods for a target reference allele and a target alternative allele at each of the plurality of target genomic locus based on the plurality of linked genomic locus genotype likelihoods and the plurality of target genomic locus genotype likelihoods generated in (d); and
for the first subject, generating a plurality of genotypes each corresponding to a respective target genomic locus of the plurality of target genomic loci based on each set of genotype likelihoods generated in (e).
With respect to claim 1, Scheffler discloses methods and systems for quantifying a nucleic acid sample (Abstract), comprising:
receiving nucleic acid sequence reads obtained from a nucleic acid mixture sample including nucleic acid of two or more contributors (paras. 0004, 0007);
mapping reads to a plurality of unbiased target sequences each encompassing a polymorphic locus, said target sequences comprising reference alleles and alternative alleles, thereby determining allele counts for each of the alleles at the polymorphic loci (paras. 0007, 0079, 0149);
quantifying one or more fractions of nucleic acid of the one or more contributors in the nucleic acid sample (para. 0007);
generating a probability of allele counts as a function of the fraction of the nucleic acid of a contributor (paras. 00116-20), estimating a probability of an allele configuration (comprising status of two or more alleles) at each of the one or more polymorphism loci for each of the contributors (paras. 00164-65);
calculating a plurality of genotype likelihood values using a plurality of potential fraction values and a likelihood function of the allele counts (para. 00122); and
determining a posterior probability that a specific contributor has a specific multiple-locus genotype, based on the posterior genotype probabilities at each locus (paras. 0012, 00164-65).
Scheffler does not disclose particular application to linked loci, e.g., loci within about 10 kilobases upstream and about 10 kilobases downstream of a target genomic locus; or analysis of at least 100,000 loci.
Zimmermann discusses methods for amplifying multiple nucleic acid regions of interest (Abstract), and teaches embodiments wherein the methods are applied to samples containing mixtures of DNA from multiple distinct individuals, to determine relative ratios of alleles at a set of at least 100,000 different polymorphic loci and genotype proportions therefrom (pg. 3, para. 1; pg. 62, para. 4; pg. 76, para. 1, pg. 83, para. 2).
Zimmermann also teaches application of their methods to determine presence or absence of different haplotypes in a sample, i.e., combinations of alleles at a set of loci that are typically inherited together on the same chromosome (para 80, para. 3, see discussion of haplotypes at pg. 32, para. 7). Zimmerman further discusses incorporation of information regarding recombination rates, and physical distance between loci, by the allele frequency model to more accurately estimate allele frequencies at genetically and physically linked loci (pg. 110, para. 2).
Zimmermann thus teaches application of their methods to analysis of linked loci and linked alleles. However, Zimmerman does not particularly discuss analysis of linked loci within about 10 kb upstream or downstream of a target locus.
Ehrich discusses compositions and processes to separate, isolate or enrich fetal nucleic acid from a maternal sample (Abstract), and teaches sequencing and analysis of DNA regions no more than 10kb upstream and/or downstream from a selected locus (paras. 0008 and 0067).
Ehrich teaches that differential methylation can occur next to or within known genes, including in promotor regions, coding regions and downstream (para. 0188). In other words, areas upstream and downstream of a given locus of interest can contain differentiating polymorphisms.
With respect to claim 2, Scheffler discloses embodiments where the analyzed sample is an amniotic fluid sample obtained from a pregnant female, i.e., a mixed sample containing DNA from both a pregnant female and a fetus (paras. 00352-54). Scheffler describes embodiments wherein a sample consists of an isolated polynucleotide, and discloses performing additional analysis on additional samples taken from the subject from whom a maternal test sample was taken (paras. 00352-354 and 00398). In other words, a sample comprising only nucleic acid from one contributor.
With respect to claim 3, Scheffler discloses determining a posterior probability that a specific contributor has a specific multiple-locus genotype, based on the posterior genotype probabilities at each locus (paras. 0012, 00164-65). ().
With respect to claim 6-8 and 14, Scheffler discloses calculation of per-contributor prior probabilities of homozygous and heterozygous genotypes, based on reference and alternative allele frequencies, according to a Hardy-Weinberg equations (paras. 0007, 0079, 0149 and 00345).
With respect to claim 9, Scheffler discloses embodiments wherein the alleles at the one or more polymorphism loci include single nucleotide polymorphism (SNP) alleles (para. 0028).
With respect to claim 10, there is nothing in Scheffler that requires genotypes to be phased. Additionally, Zimmermann specifically discusses analysis of unphased genotypic information (pg. 177, para. 4).
With respect to claim 11, Scheffler discloses extracting nucleic acid molecules from the sample, amplifying the extracted nucleic acid molecules, and sequencing the amplified nucleic acid molecules to produce nucleic acid sequence reads (paras. 00110-12).
With respect to claims 15-16, Scheffler discloses obtaining the posterior probability that a specific contributor among the one or more contributors has a specific genotype, comprising: multiplying prior probabilities of genotype configurations by likelihoods of the genotype configurations, and summing over genotype configurations containing (i.e., haplotypes compatible with) the specific genotype (para. 0011).
With respect to claim 18, Scheffler discloses embodiments wherein one contributor genome is unknown (para. 0010).
With respect to claim 19, Scheffler discloses application to deconvolution of mixture samples including nucleic acid of two or more contributors of unknown genotypes (e.g., para. 0087).
With respect to claim 20, Scheffler discloses analysis of sequence reads obtained from a nucleic acid mixture sample including nucleic acid of two or more contributors (paras. 0004 and 0007), wherein ‘contributor’ refers to a human contributor (para. 0083). In this way, Scheffler discloses embodiments wherein the contributors are members of the human species.
With respect to claim 21, Scheffler discloses determining a probability that a specific contributor has a specific genotype (e.g., para. 0007), and discusses application to identifying human individuals from a forensic sample (paras. 0002 and 0079). Scheffler also discusses alignment of reads to a database of reference and alternative sequences, and assigning a read to a reference genome, e.g., taken from a particular individual (paras. 0074-5, 0078, 0093 and 00177-78).
Claim 43 recites a system comprising a processor configured to perform functional limitations of substantive similarity to the process limitations of claim 1. The teachings of Scheffler, in view of Zimmermann and Ehrich, are considered to apply to the substantively similar limitations of the claim in the same manner as detailed above regarding the process limitations of claim 1.
With respect to the unique limitations of claim 43, Scheffler discloses implementation of the methods at a computer system that includes one or more processors configured to deconvolve a nucleic acid mixture sample (para. 0006), i.e., perform functions of the method.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented analysis of linked loci and alleles, as taught by Zimmermann, with the analytical techniques of Scheffler, because Zimmermann teaches that physical distance and genetic linkage affect inheritance patterns while incorporating linkage information allows for accurate estimation of allele frequencies (pg. 110, para. 2). Thus, Zimmermann indicates that analysis of linked loci and alleles is an enabled extension of the analytical techniques of Scheffler. Said practitioner would have had a reasonable expectation of success because Scheffler and Zimmermann both concern analysis of mixed samples containing nucleic acid from multiple distinct individuals to determine relative ratios of alleles at a set of polymorphic loci and genotypes therefrom.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented consideration of bases no more than 10kb upstream and downstream of a particular locus of interest, as taught by Ehrich, with the analytical techniques of Scheffler, because Ehrich exemplifies consideration of bases no more than 10kb upstream and downstream of a locus of interest and teaches that regions upstream and downstream of a given locus of interest can contain differentiating polymorphisms (paras. 0008, 0067 and 0188). Said practitioner would have had a reasonable expectation of success because Scheffler and Ehrich both concern analysis of mixed samples containing nucleic acid from multiple distinct individuals to determine relative ratios of alleles at a set of polymorphic loci and genotypes therefrom.
In this way the disclosure of Scheffler, in view of Zimmermann and Ehrich, makes obvious the limitations of claims 1-3, 6-11, 14-16, 18-21 and 43. Thus, the claimed invention is prima facie obvious.
Claim 4 is rejected under 35 USC § 103 as being unpatentable over Scheffler, in view of Zimmermann and Ehrich, as applied to claim 1 above, and further in view of Lucas-Lledó (BMC Bioinformatics 15: 163, 13 pages; published 5/29/2014; on IDS filed 5/26/2023).
With respect to claim 4, Scheffler discloses iteratively estimating contributor DNA fractions via maximum likelihood estimation (paras. 00291-92). Scheffler does not disclose using an expectation maximization algorithm.
Zimmermann teaches estimation of nucleic acid fractions via maximum likelihood or maximum a posteriori techniques (pg. 15, para. 2). Zimmermann does not teach using an expectation maximization algorithm.
Ehrich teaches implementation of various statistical algorithms to analyze the data (para. 0100). Ehrich does not teach using an expectation maximization algorithm.
Lucas-Lledó presents svgem, an expectation-maximization approach implementation, to estimate allele and genotype frequencies, calculate genotype posterior probabilities, and test for Hardy-Weinberg equilibrium and population differences, from allelic count data, that does not require accurate prior genotype information (pg. 1, Abstract). In other words, constituent genotypes can be unknown prior to analysis.
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented an expectation-maximization approach, as taught by Lucas-Lledó, to estimate allele frequencies in combination with the analytical techniques of Scheffler, because Lucas-Lledó teaches that their expectation-maximization approach can robustly estimate allele and genotype frequencies and probabilities from allelic count data in the absence of prior genotype information (pg. 1, Abstract). In this way, Lucas-Lledó indicates that expectation-maximization is an enabled statistical means of estimating these parameters given the application to deconvolution of unknown genomes disclosed by Scheffler. Said practitioner would have had a reasonable expectation of success because Scheffler and Lucas-Lledó both concern analysis of mixed samples containing nucleic acid from multiple distinct individuals (see Lucas-Lledó at pg. 3, l. column) to determine relative frequencies and probabilities of alleles and genotypes therefrom.
In this way the Scheffler, in view of Zimmermann, Ehrich and Lucas-Lledó, makes obvious the limitations of claim 4. Thus, the claimed invention is prima facie obvious.
Claim 5 is rejected under 35 USC § 103 as being unpatentable over Scheffler, in view of Zimmermann and Ehrich, as applied to claim 1 above, and further in view of Liu (US 2003/0059808; effectively filed 6/8/2001).
With respect to claim 5, Scheffler discloses modeling contributor DNA fraction using a beta distribution (para. 0092). Scheffler does not disclose using a Dirichlet process.
Zimmermann teaches modeling allelic frequencies using beta-binomial distributions (pg. 114, para. 2). Zimmermann does not teach using a Dirichlet process.
Ehrich teaches modeling probabilities using a Poisson distribution (para. 0170). Ehrich does not teach using a Dirichlet process.
Liu discusses determination of haplotypes from unphased genomic information for a plurality of individuals (Abstract), and teaches modeling of haplotype frequencies for contributing individuals based on a Dirichlet prior probability distribution (e.g., paras. 0023-4).
An invention would have been obvious to one of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, said practitioner would have implemented a Dirichlet process, as taught by Liu, to model frequencies and probabilities in combination with the analytical techniques of Scheffler, because Liu presents this as an enabled statistical means for modeling haplotype probabilities given the application to deconvolution of unknown genomes disclosed by Scheffler. Said practitioner would have had a reasonable expectation of success because Scheffler and Liu both deconvolution of individual haplotypes based on allelic marker information (see Liu at para. 0014).In this way the Scheffler, in view of Zimmermann, Ehrich and Liu, makes obvious the limitations of claim 5. Thus, the claimed invention is prima facie obvious.
Conclusion
At this point in prosecution, no claim is allowed.
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/T.C.S./Examiner, Art Unit 1685
/JESSE P FRUMKIN/Primary Examiner, Art Unit 1685 July 15, 2026
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