DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response
Applicant’s response, filed 06/01/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claims Status
Claim 7 is canceled.
Claims 1-3, 6, 8, 10, 12, 15-18, 20, 21, 23, 25, 28, and 31-33 are pending.
Claims 1-3, 6, 8, 10, 12, 15-18, 20, 21, 23, 25, 28, and 31-33 are examined.
Withdrawn Objections/Rejections
The objection to claims 1, 2, 6, 16-18, 20, 21, 23, 25, and 28 is withdrawn in view of the amendments submitted.
The rejection of claims 1-3, 6, and 15 under 35 USC 102(a)(1) and 102(a)(2) over Wong et al. is withdrawn in view of the amendments submitted.
Information Disclosure Statement
The Information Disclosure Statement filed 08/19/2026 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is 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 1-3, 6, 8, 10, 12, 15-18, 20, 21, 23, 25, 28, and 31-33 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to an abstract idea of mental steps, mathematic concepts, or a natural law without significantly more. Any newly recited portion is necessitated by claim amendments.
The MPEP at MPEP 2106.03 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of
matter?
(2A)(1) Are the claims directed to a judicially recognized exception, i.e. a law of nature,
a natural phenomenon, or an abstract idea?
(2A)(2) If the claims are directed to a judicial exception under Prong One, then is the
judicial exception integrated into a practical application?
(2B) If the claims are directed to a judicial exception and do not integrate the judicial
exception, do the claims provide an inventive concept?
With respect to step (1): Yes, the claims recite methods.
With respect to step (2A)(1): The claims recite abstract ideas of mental processes.
“Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection” (MPEP 2106.04). Abstract ideas include mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (procedures for observing, evaluating, analyzing/judging and organizing information (MPEP 2106.04(a)(2)). Laws of nature or natural phenomena include naturally occurring principles/relations that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature (MPEP 2106(b)).
Mental processes recited in claim 1:
(b) from the sequence reads, quantifying a plurality of linked reference alleles and quantifying a plurality of linked alternative alleles, thereby generating a plurality of allele quantifications for a plurality of linked genomic loci
(c) generating a set of genotype likelihoods for a target reference allele and a target alternative allele at the target genomic locus according to (1) a probability of the allele quantifications in (b), given a particular genotype at the target genomic locus, and (2) a probability of a genotype at the target genomic locus based on prior probabilities of the target reference allele and the target alternative allele
(d) generating a genotype at the target genomic locus based on the set of genotype likelihoods
(e) generating a report of the genotype generated in (d)
Mental processes recited in claim 16:
(b) for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group according to the sequence reads generated in a), thereby generating allele quantifications for each linked genomic locus in the haplotype group
(c) generating a haplotype pair likelihood set for the haplotype group according to (i) the allele quantifications in (b), and (ii) a probability of each haplotype pair
(d) generating a genotype at the target genomic locus based on the haplotype pair likelihood set in (c)
(e) generating a report of the genotype generated in (d)
Dependent claims 2, 3, 6, 8, 10, 12, 15, 17, 18, 20, 21, 23, 25, 28, and 31-33 recite additional steps that either are directed to abstract ideas or further limit the judicial exceptions in independent claim 1, and as such, are further directed to abstract ideas. Hence, the claims explicitly recite numerous elements that individually and in combination constitute abstract ideas. The relevant recitations are:
Claim 2: “the probability in (c)(1) is generated according to (i) a probability of observing the linked reference allele at the linked genomic locus, given a target reference allele at the target genomic locus, and/or (ii) a probability of observing the linked reference allele at the linked genomic locus, given a target alternative allele at the target genomic locus”
Claim 3: “the probability in (i) is based, in part, on a measure of linkage disequilibrium for the linked reference allele and the target reference allele, and the probability in (ii) is based, in part, on a measure of linkage disequilibrium for the linked reference allele and the target alternative allele, wherein the measure of disequilibrium is based on a haplotype frequency”
Claim 6: “the probability in (c)(2) is based, in part, on haplotype frequencies for (i) the target reference allele and the linked reference allele, (ii) the target reference allele and the linked alternative allele, (iii) the target alternative allele and the linked reference allele, and (iv) the target alternative allele and the linked alternative allele”
Claim 7: “(b) comprises quantifying a plurality of linked reference alleles and quantifying a plurality of linked alternative alleles, thereby generating a plurality of allele quantifications for a plurality of linked genomic loci”
Claim 8: “wherein (i) a plurality of genotype likelihood sets for the target genomic locus is generated according to the plurality of allele quantifications for the plurality of linked genomic loci, wherein the genotype at the target genomic locus is generated based on the plurality of genotype likelihood sets”
Claim 10: “a composite genotype likelihood is generated for each genotype from the plurality of genotype likelihood sets, wherein the genotype at the target genomic locus is generated based on the composite genotype likelihoods”
Claim 12: “generating a plurality of genotypes at a plurality of target genomic loci for the test sample, wherein each genotype in the plurality of genotypes is generated independently from the other genotypes in the plurality of genotypes, and identifying a subject based on the plurality of genotypes generated for the test sample”
Claim 15: “generating the genotype at the target genomic locus does not comprise generating a haplotype for two or more target genomic loci”
Claim 17: “the haplotype pair likelihood set for the haplotype group is generated in (c) according to a Bayesian probability”
Claim 18: “the haplotype group is generated in (c), given the allele quantifications in (b), according to i) a probability of the allele quantifications in (b) given each haplotype pair, and ii) a probability of each haplotype pair, wherein the probability in (i) is determined according to which genotype is most likely observed at each genomic locus across the haplotype group, given a particular haplotype pair”
Claim 20: “calculating the probability of the allele quantifications in (b) at each genomic locus and generating a product across all genomic loci in the haplotype group”
Claim 21: “the probability of each haplotype pair in (c)(ii) is determined, in part, according to haplotype frequencies, wherein the probability of each haplotype pair in (c)(ii) is determined, in part, according to haplotype frequencies for (i) a target reference allele and the linked reference allele, and (ii) a target reference allele and the linked alternative allele, (iii) a target alternative allele and the linked reference allele, and (iv) a target alternative allele and the linked alternative allele”
Claim 23: “identifying the most probable haplotype pair from the haplotype pair likelihood set, wherein the genotype at the target genomic locus is generated in (d) according to the most probable haplotype pair”
Claim 25: “aggregating the haplotype pair likelihoods across all haplotype pairs for the haplotype group, thereby generating aggregate likelihoods, wherein the genotype at the target genomic locus is generated in (d) according to the highest aggregate likelihood”
Claim 28: “wherein (b) comprises, for a plurality of haplotype groups each comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in each group according to the sequence reads generated in (a), thereby generating allele quantifications for each linked genomic locus for each group in the plurality of haplotype groups, wherein a plurality of haplotype pair likelihood sets are generated in (c) according to the allele quantifications for each linked genomic locus for each group in the plurality of haplotype groups, wherein a plurality of genotypes at a plurality of target genomic loci are generated in (d) based on the plurality of haplotype pair likelihood sets”
Claim 31: “wherein each genotype in the plurality of genotypes is generated independently from the other genotypes in the plurality of genotypes”
Claim 32: “identifying a subject based on the plurality of genotypes generated for the test sample”
Claim 33: “wherein generating the genotype at the target genomic locus does not comprise generating a haplotype group comprising two or more target genomic loci”
The abstract ideas in the claims are evaluated under Broadest Reasonable Interpretation (BRI) and determined herein to each cover mental processes because the claims recite no more than performing a statistical analysis of sequence information in order to identify a genotype.
With respect to step (2A)(2): The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone or in combination to determine if the judicial exception 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 judicial exception, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d).III).
Claims 1 and 16 recite the following additional elements that are not abstract ideas:
for a test sample comprising nucleic acid, sequencing the nucleic acid, thereby generating sequence reads, and aligning the sequence reads to a reference genome, thereby obtaining sequence reads aligned to a reference genome
The step of obtaining sequence reads is directed to data gathering as it gathers the data on which the judicial exceptions are performed. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
None of the dependent claims recite additional elements.
Lastly, the claims have been evaluated with respect to step (2B): Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims lack a specific inventive concept. Under said analysis, Applicant is reminded that the judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea 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 described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP at 2106.05(d)(I), 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 claims 1 and 16: The additional element of for a test sample comprising nucleic acid, sequencing the nucleic acid, thereby generating sequence reads, and aligning the sequence reads to a reference genome, thereby obtaining sequence reads aligned to a reference genome does not rise to the level of significantly more than the judicial exception. As referenced in the MPEP at 2106.05(d).II. with respect to Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546, analyzing DNA to provide sequence information or detect allelic variants is a well-understood, routine, and conventional activity. As such, it is recognized that these additional limitations are routine, well understood, and conventional in the art. These limitations do not improve the functioning of a computer, or comprise an improvement to any other technical field, they do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide a non-conventional or unconventional step. As such, these limitations fail to rise to the level of significantly more.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. Individually, the limitations of the claims and the claims as a whole have been found lacking.
Response to Arguments
Applicant states that “none of the elements of independent claim 1 or independent claim 16 recite a mental process, as each of the claimed methods cannot practically be performed in one’s mind. The claims are directed to methods for generating a genotype for a target genomic locus for a test sample. Claims 1 and 16 specify in part (a) sequencing nucleic acid, thereby generating sequence reads, and aligning the sequence reads to a reference genome, thereby obtaining sequence reads aligned to a reference genome. Sequencing nucleic acid from a test sample typically generates a massive amount of sequence reads, often in the thousands to millions. The sequence reads generated in part (a) are aligned to a reference genome. A human reference genome, for example, is about three billion bases in length. […] aligning even one sequence read to the human reference genome cannot practically be performed in the mind, let alone aligning the multiple sequence reads that would be required to provide a meaningful amount of data for genotype analysis. The further processes of parts (b), (c), (d), and (e) are based on the massive amount of sequence reads generated and aligned to a reference genome in part (a). Given the massive amount of data involved, a person could not practically perform the further claim elements in the mind.”
It is respectfully submitted that this is not persuasive. The step of sequencing and aligning the sequence reads to a reference genome is not interpreted as a mental processes and is considered an additional element, but the other claimed steps are under broadest reasonable interpretation able to be performed mentally. The claims require a plurality of alleles, which could comprise two or three. Furthermore, the steps following the generation of the sequence reads and aligning of the sequence reads is performed from the sequence reads, not the aligned reads. Furthermore, even if it was performed on aligned reads, that does not mean the claimed step requires one to mentally process the entire reference genome. One of ordinary skill can mentally quantify three alleles and calculate probabilities. Furthermore, under broadest reasonable interpretation, a report can be mentally performed or with a pencil and paper (see MPEP 2106.04(a)(2).III.B). Therefore, the rejection under 35 USC 101 is maintained.
Applicant states that “the claims herein are patent eligible under Step 2A, prong (2), of the eligibility analysis, by way of demonstrating an improvement to a technology. For example, the claimed method provides specific benefits over conventional genotyping methods. […] Additionally, the claims include additional elements outside the alleged judicial exception that integrate the alleged judicial exception into a practical application. For example, independent claims 1 and 16 recite nucleic acid sequencing in part (a) and recite generating a report in part (e).” Furthermore, Applicant cites the PTAB decision, Ex parte EVAN MAXWELL, LUKAS HABEGGER, and JEFFREY REID. Applicant states that “like the claimed method in Maxwell, claims 1 and 16 herein include a reporting step which is an additional element outside any judicial exception that sufficiently integrates the recited judicial exception into a practical application of the alleged exception(s), as demonstrated by an improvement to genotyping technology”.
It is respectfully submitted that this is not persuasive. The step of reporting, under broadest reasonable interpretation, is interpreted as a mental process. It is the additional elements of the claims that are analyzed to determine whether the claims are integrated into a practical application (MPEP 2106.04(d).I; MPEP 2106.05(a-h)). Thus, the improvement that applicant is arguing is within the judicial exceptions, and thus the judicial exceptions are not integrated into a practical application, as the improvement must be implemented or reflected within the additional elements. The step of sequencing is a data gathering step that gathers data for the judicial exceptions. Data gathering steps are not abstract ideas but represent extra-solution activity, as said steps collect the data needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract idea, or how the abstract idea is performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)). Furthermore, it is respectfully submitted that Maxwell is a non-precedential decision, and Maxwell reports a result in regard to a specific issue and thus the claims more so reflect an improvement to detecting abnormal karyotypes, whereas the instant claims only generally report a genotype. Therefore, the rejection under 35 USC 101 is maintained.
Furthermore, Applicant states that “the claims recite additional claim elements, or a combination of additional claim elements, that were not well-understood, routine, and convention at the time the application was filed. As noted above under the Step 2A, prong (2), analysis, sequencing nucleic acid from a test sample recited in part (a) of claims 1 and 16, and generating a report for a genotype recited in part (e) of claims 1 and 16, are additional elements outside the alleged judicial exception. Applicant respectfully submits the combination of part (a), sequencing the nucleic acid, and part (e), generating a report for a genotype, especially a genotype based on a set of genotype likelihoods (claim 1) or a genotype based on a haplotype pair likelihood set (claim 16), was not well-understood, routine, or conventional at the time the application was filed. The combination of parts (a) and (e) in view of claim 1 as a whole therefor amounts to an inventive concept; and the combination of parts (a) and (e) in view of claim 16 as a whole therefore amounts to an inventive concept.”
It is respectfully submitted that this is not persuasive. As discussed above, the generation of a report is determined to be a mental process. It is the additional elements that are examined to determine if there is an inventive concept (MPEP 2106.05.A i-vi). Furthermore the additional element of sequencing and aligning does not provide an inventive concept for the claims. As referenced in the MPEP at 2106.05(d).II. with respect to Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546, analyzing DNA to provide sequence information or detect allelic variants is a well-understood, routine, and conventional activity. Therefore, the rejection under 35 USC 101 is maintained.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 6, 8, 10, 15-18, 20, 21, 23, 25, 28, 31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. (US 8,428,886 B2, patented April 2013, IDS reference) in view of Howie et al. (“A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies”, IDS reference). This is a new ground of rejections.
Regarding claim 1, Wong et al. teaches a method for generating a genotype for a target genomic locus for a test sample, comprising:
(a) for a test sample comprising nucleic acid, sequencing the nucleic acid, thereby generating sequence reads (column 10, line 10; column 10, line 27), and aligning the sequence reads to a reference genome, thereby obtaining sequence reads aligned to a reference genome (column 7, line 11);
(b) from the sequence reads, quantifying a linked reference allele and quantifying a linked alternative allele, thereby generating allele quantifications for a linked genomic locus (column 14, line 25);
(c) generating a set of genotype likelihoods for a target reference allele and a target alternative allele at the target genomic locus according to (1) a probability of the allele quantifications in (b), given a particular genotype at the target genomic locus, and (2) a probability of a genotype at the target genomic locus based on prior probabilities of the target reference allele and the target alternative allele (column 14, line 35); and
(d) generating a genotype at the target genomic locus based on the set of genotype likelihoods (column 13, line 26); and
(e) generating a report of the genotype generated in (d) (column 4, line 5; column 8, line 66).
Wong et al. does not teach the claim elements of quantifying a plurality of linked reference alleles and quantifying a plurality of linked alternative alleles.
However, Howie et al. teaches genotype imputation methods integrating information from larger reference panels (Abstract). Howie et al. teaches that most imputation analyses to date have used HapMap as a reference dataset and teaches a method that is flexible with increased accuracy that combines information across multiple reference panels while remaining computationally feasible (Abstract). Howie et al. teaches imputing a genotype based on a plurality of linked alternative alleles and a plurality of reference alleles (page 5, Scenario B).
Regarding claim 16, Wong et al. teaches a method for generating a genotype for a target genomic locus for a test sample, comprising:
(a) for a test sample comprising nucleic acid, sequencing the nucleic acid, thereby generating sequence reads (column 10, line 10; column 10, line 27), and aligning the sequence reads to a reference genome, thereby obtaining sequence reads aligned to a reference genome (column 7, line 11);
(b) for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group according to the sequence reads generated in (a), thereby generating allele quantifications for each linked genomic locus in the haplotype group (column 14, line 25);
(c) generating a haplotype pair likelihood set for the haplotype group according to (i) the allele quantifications in (b), and (ii) a probability of each haplotype pair; and
(d) generating a genotype at the target genomic locus based on the haplotype pair likelihood set in (c) (column 13, line 26); and
(e) generating a report of the genotype generated in (d) (column 4, line 5; column 8, line 66).
Wong et al. does not teach the claim elements of a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, c) generating a haplotype pair likelihood set for the haplotype group according to i) the allele quantifications in (b), and ii) a probability of each haplotype pair, and d) generating a genotype based on the haplotype pair likelihood set in (c).
However, Howie et al. teaches genotype imputation methods integrating information from larger reference panels (Abstract). Howie et al. teaches estimating information for each haplotype pair and then performing haploid imputation (page 3, column 2, paragraph 3). Howie et al. teaches for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group (page 5, Section Scenario B).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the imputation of a plurality of linked alleles and haplotype pairs of Howie et al. to the method of Wong et al., because Wong et al. is directed to determining a genetic sequence for a particular site (Abstract), and Howie et al. is directed to genotype imputation methods (Abstract). Howie et al. teaches a method that is flexible with increased accuracy that combines information across multiple reference panels while remaining computationally feasible (Abstract). Thus, one of ordinary skill in the art would have a reasonable expectation of success of calling genotypes within a haplotype group and would be motivated to do so in order to increase accuracy of the genotype imputation.
Regarding claim 2, the claim is directed to the probability in (c)(1) being generated according to (i) a probability of observing the linked reference allele at the linked genomic locus, given a target reference allele at the target genomic locus, and/or (ii) a probability of observing the linked reference allele at the linked genomic locus, given a target alternative allele at the target genomic locus. Wong et al. teaches the method of claim 1 in view of Howie et al. Wong et al. also teaches generating genotype likelihoods according to the probability of observing the linked reference allele given a target alternative allele at the target genomic locus (column 14, line 35).
Regarding claim 3, the claim is directed to the probability in (i) being based, in part, on a measure of linkage disequilibrium for the reference allele and the target reference allele, and the probability in (ii) being based, in part, on a measure of linkage disequilibrium for the linked reference allele and the target alternative allele, wherein the measure of disequilibrium is based on a haplotype frequency. Wong et al. teaches the method of claim 2 in view of Howie et al. Wong et al. teaches a measure of linkage disequilibrium for the reference and target alleles (column 14, line 55) and the measure of disequilibrium being based on a haplotype frequency (column 14, line 57).
Regarding claim 6, the claim is directed to the probability in (c)(2) being based, in part, on haplotype frequencies for (i) the target reference allele and the linked reference allele, (ii) the target reference allele and the linked alternative allele, (iii) the target alternative allele and the linked reference allele, and (iv) the target alternative allele and the linked alternative allele. Wong et al. teaches the method of claim 1 in view of Howie et al. Wong et al. also teaches the probability of a genotype based on prior probabilities being based in part on haplotype frequencies for the target, reference and linked alleles (column 14, line 57).
Regarding claim 8, the claim is directed to (i) a plurality of genotype likelihood sets for the target genomic locus being generated according to the plurality of allele quantifications for the plurality of linked genomic loci, wherein the genotype at the target genomic locus is generated based on the plurality of genotype likelihood sets. Wong et al. teaches the method of claim 1 in view of Howie et al. Wong et al. teaches generating a genotype likelihood according to allele quantifications for the linked loci (column 14, line 35), wherein the genotype is generated according to the quantifications (column 13, line 26).
Wong et al. does not teach the claim element of generating a plurality of genotype likelihood sets according to the plurality of allele quantification for the plurality of linked genomic loci, wherein the genotype at the target genomic locus is generated based on the plurality of genotype likelihood sets.
However, Howie et al. teaches generating a plurality of genotype likelihood sets according to a plurality of allele quantifications for a plurality of linked genomic loci, and calling the genotype based on this likelihood set (page 5, Section Scenario B).
Regarding claim 10, the claim is directed to a composite genotype likelihood being generated for each genotype from the plurality of genotype likelihood sets, wherein the genotype at the target genomic locus is generated based on the composite genotype likelihoods. Wong et al. teaches the method of claim 8 in view of Howie et al. Wong et al. also teaches composite genotype likelihoods and generating a genotype at the target locus based on the composite genotype likelihoods (column 13).
Regarding claim 15, the claim is directed to generating the genotype at the target genomic locus not comprising generating a haplotype for two or more target genomic loci. Wong et al. teaches the method of claim 1 in view of Howie et al. Wong et al. teaches generating a genotype for one target genomic loci (column 13, line 26), and thus not two or more target genomic loci.
Regarding claim 17, the claim is directed to the haplotype pair likelihood set for the haplotype group being generated in (c) according to a Bayesian probability. Wong et al. teaches the method of claim 16 in view of Howie et al. Wong et al. also teaches an allele likelihood being generated according to a Bayesian probability (column 12, line 40).
Furthermore, Howie et al. teaches calculating haplotype pair likelihood sets according to Bayesian probability (page 5, Section Scenario B).
Regarding claim 18, the claim is directed to the haplotype pair likelihood set for the haplotype group being generated in (c), given the allele quantifications in (b), according to i) a probability of the allele quantifications in (b) given each haplotype pair, and ii) a probability of each haplotype pair, wherein the probability in (i) is determined according to which genotype is most likely observed at each genomic locus across the haplotype group, given a particular haplotype pair. Wong et al. teaches the method of claim 16 in view of Howie et al. Wong et al. teaches allele likelihoods being generated according to 1) a probability of the allele quantifications in (b), given a particular genotype at the target genomic locus, and 2) a probability of a genotype at the target genomic locus based on prior probabilities of the target reference allele and the target alternative allele (column 14, line 35).
Wong et al. does not teach the claim element of generating a haplotype pair likelihood.
However, Howie et al. teaches estimating information for each haplotype pair and then performing haploid imputation (page 3, column 2, paragraph 3). Howie et al. teaches for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group (page 5, Section Scenario B).
Regarding claim 20, the claim is directed to calculating the probability of the allele quantifications in (b) at each genomic locus and generating a product across all genomic loci in the haplotype group. Wong et al. teaches the method of claim 18 in view of Howie et al. Wong et al. teaches quantifying a linked reference allele and quantifying a linked alternative allele, thereby generating allele quantifications for a linked genomic locus (column 14, line 25).
Wong et al. does not teach the claim element of a haplotype group.
However, Howie et al. teaches calculating probabilities of allele quantification across the loci in the haplotype group (page 5, Section Scenario B).
Regarding claim 21, the claim is directed to the probability of each haplotype pair in (c)(ii) is determined, in part, according to haplotype frequencies, wherein the probability of each haplotype pair in (c)(ii) is determined, in part, according to haplotype frequencies for (i) a target reference allele and the linked reference allele, (ii) a target reference allele and the linked alternative allele, (iii) a target alternative allele and the linked reference allele, and (iv) a target alternative allele and the linked alternative allele. Wong et al. teaches the method of claim 16 in view of Howie et al. Wong et al. teaches quantifying a linked reference allele and quantifying a linked alternative allele, thereby generating allele quantifications for a linked genomic locus (column 14, line 25).
Wong et al. does not teach the claim element of a probability of specifically a haplotype pair.
However, Howie et al. teaches estimating information for each haplotype pair and then performing haploid imputation (page 3, column 2, paragraph 3). Howie et al. teaches for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group (page 5, Section Scenario B).
Regarding claim 23, the claim is directed to (c) further comprising identifying the most probable haplotype pair from the haplotype pair likelihood set, wherein the genotype at the target genomic locus is generated in (d) according to the most probably haplotype pair. Wong et al. teaches the method of claim 16 in view of Howie et al.
Wong et al. does not teach the claim element of identifying the most probably haplotype pair.
However, Howie et al. teaches calculating haplotype pair likelihoods and teaches calling a genotype based on the haplotype pair likelihood (page 5, column 1, Section Scenario B, last paragraph).
Regarding claim 25, the claim is directed to (c) further comprising aggregating the haplotype pair likelihoods across all haplotype pairs for the haplotype group, thereby generating aggregate likelihoods, wherein the genotype at the target genomic locus is generated in (d) according to the highest aggregate likelihood. Wong et al. teaches the method of claim 16 in view of Howie et al.
Wong et al. does not teach the claim element of generating or aggregating haplotype pair likelihoods.
However, Howie et al. teaches calculating haplotype pair likelihoods and aggregating the likelihoods and imputing new alleles based on the condition of aggregated likelihoods (page 5, column 1, Section Scenario B).
Regarding claim 28, the claim is directed to (b) comprising, for a plurality of haplotype groups each comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in each group according to the sequence reads generated in (a), thereby generating allele quantifications for each linked genomic locus for each group in the plurality of haplotype groups, wherein a plurality of haplotype pair likelihood sets are generated in (c) according to the allele quantifications for each linked genomic locus for each group in the plurality of haplotype groups, wherein a plurality of genotypes at a plurality of target genomic loci are generated in (d) based on the plurality of haplotype pair likelihood sets. Wong et al. teaches the method of claim 16 in view of Howie et al. Wong et al. teaches quantifying a linked reference allele and quantifying a linked alternative allele, thereby generating allele quantifications for a linked genomic locus (column 14, line 25), generating a set of genotype likelihoods for a target reference allele and a target alternative allele at the target genomic locus according to 1) a probability of the allele quantifications in (b), given a particular genotype at the target genomic locus, and 2) a probability of a genotype at the target genomic locus based on prior probabilities of the target reference allele and the target alternative allele (column 14, line 35), and generating a genotype at the target genomic locus based on the set of genotype likelihoods (column 13, line 26).
Wong et al. does not teach the claim element of applying this method to a haplotype group.
However, Howie et al. teaches estimating information for each haplotype pair and then performing haploid imputation (page 3, column 2, paragraph 3). Howie et al. teaches for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group (page 5, Section Scenario B).
Regarding claim 31, the claim is directed to each genotype in the plurality of genotypes being generated independently from the other genotypes in the plurality of genotypes. Wong et al. teaches the method of claim 28 in view of Howie et al. Wong et al. also teaches generating genotypes for multiple samples independently (column 9, line 47).
Regarding claim 33, the claim is directed to generating the genotype at the target genomic locus not comprising generating a haplotype group comprising two or more target genomic loci. Wong et al. teaches the method of claim 16 in view of Howie et al. Wong et al. teaches generating a genotype without generating a haplotype group (column 13, line 26).
Furthermore, Howie et al. teaches generating a genotype at a target genomic locus comprising a haplotype group comprising one target genomic locus (page 4, column 1, Section Scenario A).
Claims 12 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wong et al. in view of Howie et al., as applied to claims 1-3, 6, 8, 10, 15-18, 20, 21, 23, 25, 28, 31, and 33 above, and further in view of Hiroaki et al. (“Approaches for identifying multiple-SNP haplotype blocks for use in human identification”, Legal Medicine, published 2015). This is a new ground of rejection.
Regarding claim 12, the claim is directed to generating a plurality of genotypes at a plurality of target genomic loci for the test sample, wherein each genotype in the plurality of genotypes is generated independently from the other genotypes in the plurality of genotypes, and identifying a subject based on the plurality of genotypes generated for the test sample. Wong et al. teaches the method of claim 1 in view of Howie et al. Wong et al. teaches the test sample comprising genetic material from multiple individuals and the genotypes for each individual are generated independently (column 9, line 47).
Wong et al. does not teach the claim element of a plurality of genotypes at a plurality of target genomic loci, and identifying a subject based on the plurality of genotypes generated.
However, Howie et al. teaches estimating information for each haplotype pair and then performing haploid imputation (page 3, column 2, paragraph 3). Howie et al. teaches for a haplotype group comprising a target genomic locus and a plurality of linked genomic loci, quantifying a linked reference allele and quantifying a linked alternative allele for each linked genomic locus in the group (page 5, Section Scenario B).
Howie et al. does not teach the claim element of -- identifying a subject based on the plurality of genotypes generated for the test sample.
However, Hiroaki et al. teaches genomic regions containing 3 SNP loci with more than 2 haplotypes and observing via direct sequencing of more than 100 individuals the frequencies of the haplotypes for each region (Abstract). Hiroaki et al. teaches independently genotyping each individual (Table 2). Hiroaki et al. teaches that this increases the effectiveness of individual identification (Abstract).
Regarding claim 32, the claim is directed to identifying a subject based on the plurality of genotypes generated for the test sample. Wong et al. teaches the method of claim 28 in view of Howie et al.
Neither Wong et al. nor Howie et al. teach the claim element of identifying a subject based on the plurality of genotypes generated for the test sample.
However, Hiroaki et al. teaches genomic regions containing 3 SNP loci with more than 2 haplotypes and observing via direct sequencing of more than 100 individuals the frequencies of the haplotypes for each region (Abstract). Hiroaki et al. teaches independently genotyping each individual (Table 2). Hiroaki et al. teaches that this increases the effectiveness of individual identification (Abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to have incorporated the application of identifying an individual to the method of Wong et al. in view of Howie et al., because Wong et al. is directed to determining a genetic sequence for a particular site (Abstract), Howie et al. is directed to genotype imputation methods based on haplotypes (Abstract), and Hiroaki et al. observing via direct sequencing of more than 100 individuals the frequencies of the haplotypes for each region (Abstract) and independently genotyping each individual (Table 2). Hiroaki et al. teaches that using haplotypes increases the effectiveness of individual identification (Abstract). Thus, one of ordinary skill in the art would have a reasonable expectation of success of using haplotypes to genotype a sample to identify an individual and would be motivated to do so to increase the accuracy of the identification.
Response to Arguments
Applicant submits that claim 1 includes subject matter of formerly pending claim 7 and states that “Wong discusses a method to determine genotypes by considering data from a genotyping assay (e.g., genotyping array) and contextual information. Additionally, Wong discussed types of contextual information that may be available such as the genotype calls at linked sites and the genotype calls from a close relative, and uses a Bayesian framework to incorporate this information. Wong describes how this contextual information might be incorporated into making a call. Accordingly, Wong uses ‘contextual’ information to adjust a Bayesian prior for the genotype call. In contrast, the claimed methods are integrated frameworks for incorporating all contextual information instead of just a prior. Regarding the use of linkage information (the non-random assortment of alleles), Wong uses pairwise linkage between the site to be called and a nearby linked site. In contrast, the claimed methods use all linked sites in a haplotype summary. The claimed methods avoid over or undercounting the linkage information when there are multiple linked sites. In an example, A is correlated with B and A is correlated C. Further, B is correlated with C. To properly account for the correlation of A with B and C, an adjustment for the correlation between B and C is useful. Wong does not describe doing this or how to do it. The claimed methods do.”
It is respectfully submitted that this is not persuasive. The independent claim 1 does not reflect the analysis of linkage information that Applicant is describing herein. However, Wong et al. teaches accounting for linkage information when performing a genotype call (column 14, line 25). Furthermore, in view of the amended claims, Wong et al. does not teach the claim limitations of quantifying a plurality of linked alleles and a plurality of haplotype pairs, a new rejection has been set forth. Furthermore, Wong et al. incorporates the contextual information into the calculation of the prior probabilities, and it is interpreted that then Wong et al. teaches the claim limitations of generating the likelihood based on the contextual information and the probability based on prior probabilities, because the contextual information is accounted for in the calculation of the probability.
Furthermore, Applicant states that “Ball discusses a method of genotype phasing, which is not a method for genotype calling. While Ball deals with genotypes and haplotypes (aka phased genotype calls), the method in Ball is a very different method aimed at a different problem. Specifically, Ball describes how to make and use a data structure of phased haplotypes to phase new haplotypes. Thus, Ball is a method for taking genotypes and phasing them. The claims herein are directed to methods for taking sequence data and calling genotypes”.
It is acknowledged that Ball et al. teaches a different framework than the claimed methods and a new ground of rejection has been set forth.
Conclusion
No claims are allowed.
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/E.A.S./Examiner, Art Unit 1686
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
