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 .
Claim Status
Claims 1-20 are cancelled.
Claims 21-40 are newly added.
Claims 21-40 are currently pending and examined on the merits.
Priority
The instant application is a 371 of PCT/EP2021/055920 filed on 3/9/2021, which claims benefit under U.S.C. 119 to European Application EP20162599.3 filed on 3/12/2020. At this point in examination, the effective filing date of claims 21-40 is 3/12/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11 January 2023 is in compliance with the provisions of 37 CFR 1.97. A signed copy of the corresponding 1449 form has been included with this Office Action.
Claim Objections
Claims 21 objected to because of the following informalities:
In claim 21, line 7, the punctuation of a comma "," should be removed to ensure consistency of punctuations throughout the claim.
In claim 21, lines 17-18, “AF frequency” reads “allele frequency frequency”. This should read either “AF” or “AF value”.
In claim 21, last line, “deviates” should read “deviate”.
In claim 22, line 8, there is a space before the punctuation of a semicolon “;” that should be removed.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “sufficient” in claim 24 is a relative term which renders the claim indefinite. The term “sufficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what is considered "sufficient" intensity shown in polymorphic variants. The specification is also silent as to what is "sufficient" for polymorphic variants. One skilled in the art
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 37 and 38 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter. Claim 37 is drawn to a report. Claim 38 is drawn to a computer program product. The computer program product/computer readable media is not limited to a physical embodiment and may read on carrier waves and other nonstatutory media. See, e.g., In re Nuiten, Docket no. 2006-1371 (Fed. Cir. Sept. 20, 2007)(slip. op. at 18)(“A transitory, propagating signal like Nuijten's is not a process, machine, manufacture, or composition of matter.' … Thus, such a signal cannot be patentable subject matter.”).
Claims 21-40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); and (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion).
Eligibility Step 1: Claims 21-36 are directed to a method (process) for the analysis of genetic material in a subject and claims 39-40 are directed to a non-transitory machine-readable storage medium (machine), which are encompassed by the categories of statutory subject matter and thus satisfy the subject matter eligibility requirements under Step 1. Therefore, claims 21-36 and 39-40 have patent eligible subject matter and claims 37-38 do not. For purposes of compact prosecution, evaluation in accordance with Alice/Mayo Evaluation via MPEP 2143 continues below on all claims.
[Step 1: Claims 37-38 – NO]
[Step 1: Claims 21-36 and 39-40 – YES]
Eligibility Step 2A: First, it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception. While claims 37-38 do not fall into statutory subject matter (see above), the analysis of the claim under the remaining steps will be continued in the interest of compact prosecution.
Eligibility Step 2A, Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth described in the claim.
Claims 21-30 and 32-35 recite the following steps which fall within the mental processes and/or mathematical concepts groups of abstract ideas, as noted below.
Independent claim 21 further recites:
selecting the polymorphic variants based on one or more of the following criteria: category 1 polymorphic variants, for which the first parent and the second parent are homozygous or hemizygous for a different allele; or category 2 polymorphic variants for which the first parent is homozygous for a specific allele and the second parent is heterozygous for said specific allele; or category 3 polymorphic variants for which the second parent is homozygous for a specific allele and the first parent is heterozygous for said specific allele (i.e., mental processes);
selecting one allele per polymorphic variant and subcategorizing a corresponding AF frequency thereof in the subject into one of the following subcategories: subcategory 1A, consisting of AF values of the category 1 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the first parent; or subcategory 1B, consisting of AF values of the category 1 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the second parent; or subcategory 2A, consisting of AF values of the category 2 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the first parent; or subcategory 2B, consisting of AF values of the category 2 polymorphic variants, representing the AF values for alleles heterozygous in the second parent and absent in the first parent; or subcategory 3A, consisting of AF values of the category 3 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the second parent; or subcategory 3B, consisting of AF values of the category 3 polymorphic variants, representing the AF values for alleles heterozygous in the first parent and absent in the second parent (i.e., mental processes);
calculating mean AF values, trimmed mean AF values, or median AF values of the polymorphic variants for each subcategory, wherein the polymorphic variants are located between two genomic locations on a chromosome (i.e., mental processes, mathematical concepts);
evaluating whether a genetic anomaly is present in the genetic material of the subject based on the AF values of the polymorphic variants in one or more of the subcategories and the genomic location of said polymorphic variants (i.e., mental processes);
determining that a genetic anomaly is present in the genetic material of the subject when the AF values deviates from 0.5 (i.e., mental processes).
Dependent claim 22 further recites:
calculating a delta AF, wherein the delta AF is: a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 1A and 1B; or a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 2A and 2B; or a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 3A and 3B (i.e., mental processes, mathematical concepts);
evaluating whether a genetic anomaly is present in the genetic material of the subject based on the delta AF values observed between the genomic locations (i.e., mental processes);
determining that a genetic anomaly is present when the delta AF value deviates from 0 (i.e., mental processes).
Dependent claim 23 further recites:
removing from further analysis polymorphic variants or SNPs that are distributed less than 50 kb from each other (i.e., mental processes).
Dependent claim 24 further recites:
removing from further analysis polymorphic variants that do not show sufficient intensity (i.e., mental processes).
Dependent claim 25 further recites:
calculating a value for the parental contribution between the genomic locations from the delta AF values (i.e., mental processes, mathematical concepts);
evaluating whether a genetic anomaly is present in the genetic material of the subject based on the value for parental contribution observed between the genomic locations (i.e., mental processes).
Dependent claim 26 further recites:
wherein calculating a value for the parental contribution between the genomic locations is based on a second order generalized linear model between the delta AF values and a percentage parental contribution (%Mat or %Pat) across the genomic locations (i.e., mental processes, mathematical concepts);
wherein a deviation of the parental contribution from 50% indicates a chromosomal anomaly (i.e., mental processes, mathematical concepts).
Dependent claim 27 further recites:
wherein a percentage parental contribution from about 44.4% to about 55.6% indicates a normal disomy (i.e., mental processes);
wherein a percentage parental contribution from about 63.6% to about 72.7% indicates a trisomy (i.e., mental processes);
wherein a percentage parental contribution from about 0% to about 3.3% indicates a monosomy (i.e., mental processes).
Dependent claim 28 further recites:
visualizing the AF values, the mean AF values, the trimmed mean AF values, or the median AF values per subcategory of polymorphic variants (i.e., mental processes).
Dependent claim 29 further recites:
wherein the selected allele per polymorphic variant is an allele with a specific feature, the specific feature being selected from an A allele, a B allele, an allele with a higher allele frequency in a given population, an allele with a lower allele frequency in a given population, a reference allele in a given reference genome, an allele present in homozygous state in the first parent, the allele present in homozygous state in the second parent, the allele present in heterozygous state in the first parent and absent in the second parent, or an allele present in heterozygous state in the second parent and absent in the first parent (i.e., mental processes).
Dependent claim 30 further recites:
converting selected AF values of the polymorphic variants in the subcategories 2A, 2B, 3A, and/or 3B into discrete genotype calls (i.e., mental processes);
evaluating whether homozygous or heterozygous allele frequency values are underrepresented or overrepresented between two particular genomic locations (i.e., mental processes).
Dependent claim 32 further recites:
wherein the genetic material of the subject is genetic material isolated from a sample comprising only one or few cells of the subject or from a plasma sample obtained from a mother pregnant with the subject (i.e., mental processes).
Dependent claim 33 further recites:
wherein the genetic anomaly comprises a numerical or structural chromosomal abnormality present in all of the biopsied cells (non-mosaic) or in only a part of the biopsied cells (mosaic) (i.e., mental processes);
wherein the numerical or structural chromosomal abnormality is selected from a monosomy, a uniparental disomy, a trisomy, a tetrasomy, a duplication, a deletion, a mosaic monosomy, a mosaic disomy, a mosaic trisomy, a mosaic tetrasomy, a mosaic tandem duplication, a mosaic deletion, or combinations thereof (i.e., mental processes).
Dependent claim 34 further recites:
wherein when the delta AF value deviates from 0 by less than or equal to a first threshold value of about 0.09, the delta AF value indicates a normal disomy (i.e., mental processes, mathematical concepts);
wherein when the delta AF value deviates from 0 by greater than or equal to a second threshold value of about 0.2 and an increased copy number is observed, the delta AF value indicates a full trisomy or duplication (i.e., mental processes, mathematical concepts);
wherein when the delta AF value deviates from 0 by an amount between the first threshold value and the second threshold value and an increased copy number is observed, the delta AF value indicates mosaic trisomy/disomy or mosaic duplication (i.e., mental processes, mathematical concepts).
Dependent claim 35 further recites:
wherein when the delta AF value deviates from 0 by less than or equal to a first threshold value of about 0.09, the delta AF value indicates a normal disomy (i.e., mental processes);
wherein when the delta AF value deviates from 0 by greater than or equal to a second threshold of about 0.9 and a decreased copy number is observed, the delta AF value indicates a full monosomy or deletion (i.e., mental processes);
wherein when the delta AF value deviates from 0 by an amount between the first threshold value and the second threshold value and a decreased copy number is observed, the delta AF value indicates mosaic monosomy/disomy or mosaic deletion (i.e., mental processes).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pencil and paper, and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind.
Therefore, claims 21-30 and 32-35 recite an abstract idea.
[Step 2A, Prong One: YES]
Eligibility Step 2A, Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that, when examined as a whole, integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed 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 fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A, Prong One are not integrated into a practical application because of the reasons noted below.
Claims 21, 31, and 36-37 recite the additional non-abstract elements of data gathering:
obtaining unphased genotype information of polymorphic variants of a first parent and a second parent of the subject (claim 21);
obtaining a genomic location of the polymorphic variants (claim 21);
obtaining allele frequency (AF) values for the selected polymorphic variants in genetic material of the subject (claim 21);
wherein the genomic location is a chromosome or a chromosome segment (claim 31);
wherein the polymorphic variants are selected from single nucleotide polymorphisms (SNPs) or short tandem repeats (STRs) (claim 36);
A report displaying the AF values, the mean AF values, the trimmed mean AF values, or the median AF values (claim 37).
which are each a data gathering step, or a description of the data gathered.
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data needed to carry out the JE. The data gathering does not impose any meaningful limitation on the JE, or how the JE is performed. The additional limitation (data gathering) must have more than a nominal or insignificant relationship to the identified judicial exception. (MPEP 2106.04/.05, citing Intellectual Ventures LLC v. Symantee Corp, McRO, TLI communications, OIP Techs. Inc. v. Amason.com Inc., Electric Power Group LLC v. Alstrom S.A.).
Claims 38-40 recite the additional non-abstract element (EIA) of a general-purpose computer system or parts thereof:
a computer program product (claim 38);
a non-transitory machine-readable storage medium storing the computer program product (claim 39);
a non-transitory machine-readable storage medium storing the AF values, the mean AF values, the trimmed mean AF values, or the median AF values (claim 40).
The EIA do not provide any details of how specific structures of the computer elements are used to implement the JE. The claims require nothing more than a general-purpose computer to perform the functions that constitute the judicial exceptions. The computer elements of the claims do not provide improvements to the functioning of the computer itself (as in DDR Holdings, LLC v. Hotels.com LP); they do not provide improvements to any other technology or technical field (as in Diamond v. Diehr); nor do they utilize a particular machine (as in Eibel Process Co. v. Minn. & Ont. Paper Co.). Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not recite integrate that JE into a practical application.
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to insignificant extra-solution data gathering activity, and as such, when all limitations in claims 21-40 have been considered as a whole, the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application. Claims 21, 31, and 36-40 contain additional elements that would not integrate a judicial exception into a practical application and are further probed for inventive concept in Step 2B.
[Step 2A, Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. 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 amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
With respect to claims 21, 31, and 36-37: The limitations identified above as non-abstract elements (EIA) related to data gathering do not rise to the level of significantly more than the judicial exception. Activities such as data gathering do not improve the functioning of a computer, or comprise an improvement to any other technical field. The limitations do not require or set forth a particular machine, they do not affect a transformation of matter, nor do they provide an unconventional step (citing McRO and Trading Technologies Int’l v. IBG). Data gathering steps constitute a general link to a technological environment. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp.,).
With respect to claims 38-40: The limitations identified above as non-abstract elements (EIA) related to general-purpose computer systems do not rise to the level of significantly more than the judicial exception. These elements do not improve the functioning of the computer itself, or comprise an improvement to any other technical field (Trading Technologies Int’l v. IBG, TLI Communications). They do not require or set forth a particular machine (Ultramercial v. Hulu, LLC., Alice Corp. Pty. Ltd v. CLS Bank Int’l), they do not affect a transformation of matter, nor do they provide an unconventional step. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook, Versata Development Group v. SAP America).
[Step 2B: NO]
Therefore, claims 21-40 are patent ineligible under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 37 and 40 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Esteki et al. [US20160210402A1]; refer to as Esteki [A].
Regarding claim 37:
Regarding the recited report displaying the AF values, the mean AF values, the trimmed mean AF values, or the median AF values obtained by the computer implemented method, Esteki [A] teaches in claim 20 “A report displaying the segmented PVAF values obtainable by the method” (pg. 54, col. 2, lines 7-8). Instructions for the analysis of genetic material in a subject has no functional relationship with the values on the report. Therefore, this is rejected over any report regardless of its contents. See MPEP 2111.05 (I)(B).
Regarding claim 40:
Regarding the recited non-transitory machine-readable storage medium storing the AF values, the mean AF values, the trimmed mean AF values, or the median AF values obtained by the computer implemented method, Esteki [A] teaches in claim 25 “A non-transitory machine-readable storage medium storing the segmented PVAF values obtained by the method” (pg. 54, col. 2, lines 23-24). Instructions for the analysis of genetic material in a subject has no functional relationship with the values stored in the non-transitory machine-readable storage medium. Therefore, this is rejected over any database regardless of its contents. See MPEP 2111.05 (I)(B).
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 21-22, 24, 28-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Esteki et al. (The American Journal of Human Genetics, 2015, 96, 894-912), as provided in the IDS filed 1/11/2023, referred to as Esteki [B], in view of Germer et al. (Genome Research, 2000, 36(3), 258-266), as evidenced by Vraneković et al. (Genetic Testing and Molecular Biomarkers, 2011, 16(1), 70-73) and Mayo Clinic (Turner syndrome, Diseases & Conditions, 18 November 2017, accessed on 12 March 2026, 1-6, https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782).
With respect to claim 21:
With respect to the recited analysis of genetic material in a subject, Esteki [B] discloses “Here, we developed a method that determines haplotypes as well as the copy number and segregational origin of those haplotypes across the genome of a single cell via a process we termed haplarithmisis (Greek for haplotype numbering). This latter process deciphers SNP B-allele fractions of single cells and is integrated in a broader computational workflow for single-cell haplotyping and imputation of linked disease variants (siCHILD) containing several modules for single-cell SNP data analysis.” (pg. 895, col. 1, para. 1, lines 1-9). This describes an analysis of genetic material using a haplarithmisis process.
With respect to the recited obtaining unphased genotype information of polymorphic variants of a first parent and a second parent of the subject, Esteki [B] discloses “siCHILD is a computational workflow (Figure S1) for single-cell genome-wide haplotyping and copy-number typing of the haplotypes in a cell, allowing the determination of the inheritance of linked disease variants as well as the detection of the parental and mitotic/meiotic origin of haplotype anomalies in the cell. It consists of five modules, which are further detailed below, and uses as input discrete genotype calls (AA, AB, BB) … To identify cells with substandard WGA, we perform quality control (QC) on the single-cell discrete SNP genotypes and logR values. After hybridization of single-cell WGA products on Illumina SNP arrays, discrete SNP genotypes are determined with GenCall” (pg. 895, col. 1, para. 2-3, lines 1-14). This suggests that single-cell discrete SNP genotypes are the unphased genotype information of parents of a subject initially obtained.
With respect to the recited obtaining a genomic location of the polymorphic variants, Esteki [B] discloses “The informative SNP loci are identified.” (pg. 895, col. 2, para. 4, lines 12-13). This indicates obtaining a genomic location of polymorphic variants.
With respect to the recited selecting the polymorphic variants based on one or more of the following criteria: category 1 polymorphic variants, for which the first parent and the second parent are homozygous or hemizygous for a different allele; or category 2 polymorphic variants for which the first parent is homozygous for a specific allele and the second parent is heterozygous for said specific allele; or category 3 polymorphic variants for which the second parent is homozygous for a specific allele and the first parent is heterozygous for said specific allele, Esteki [B] discloses “The informative SNP loci are identified. A SNP locus is defined as informative when one parent is heterozygous and the other parent is homozygous for this SNP. (3) The informative SNPs are categorized as paternal or maternal. An informative SNP is defined “paternal” when the father’s genotype is heterozygous and the mother’s genotype is homozygous. Similarly, an informative SNP is defined “maternal” when the mother’s SNP genotype is heterozygous and the father’s SNP genotype is homozygous.” (pg. 895, col. 2, para. 4, lines 12-20). This suggests identifying polymorphic variants based on the category 2 or category 3 polymorphic variants criteria.
With respect to the recited obtaining allele frequency (AF) values for the selected polymorphic variants in genetic material of the subject, Esteki [B] discloses “The SNP BAF values of the single cell are distributed into a paternal or maternal category according to the informative parental SNP genotypes defined in step 3, and further into four parental subcategories (P1, P2, M1, M2) according to the informative phased parental SNP genotypes defined in step 4.” (pg. 895-896, col. 2, para. 4, lines 31-35). This suggests that BAF values, or B-allele frequency values, were obtained for the selected polymorphic variants.
With respect to the recited selecting one allele per polymorphic variant and subcategorizing a corresponding AF frequency thereof in the subject into one of the following subcategories: subcategory 1A, consisting of AF values of the category 1 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the first parent; or subcategory 1B, consisting of AF values of the category 1 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the second parent; or subcategory 2A, consisting of AF values of the category 2 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the first parent; or subcategory 2B, consisting of AF values of the category 2 polymorphic variants, representing the AF values for alleles heterozygous in the second parent and absent in the first parent; or subcategory 3A, consisting of AF values of the category 3 polymorphic variants, representing the AF values for alleles present in homozygous or hemizygous state in the second parent; or subcategory 3B, consisting of AF values of the category 3 polymorphic variants, representing the AF values for alleles heterozygous in the first parent and absent in the second parent, Esteki [B] discloses “The SNP BAF values of the single cell are distributed into a paternal or maternal category according to the informative parental SNP genotypes defined in step 3, and further into four parental subcategories (P1, P2, M1, M2) according to the informative phased parental SNP genotypes defined in step 4. Hence, paternally informative single-cell BAF values are derived from those SNPs belonging to subcategories P1 and P2, and maternally informative single-cell BAF values are derived from those SNPs belonging to subcategories M1 and M2. The phased parental genotypes that define single-cell SNP BAF values in P1 and P2 have been specified such that when the cell inherits homolog 1 (H1) of the father (and either H1 or H2 of the mother), P1 SNP BAFs have values of either 0 or 1 (corresponding to homozygous AA and BB genotypes in the cell, respectively) and P2 SNP BAFs have a value of 0.5 (corresponding to heterozygous genotypes in the cell). In contrast, when the cell inherits homolog 2 (H2) of the father (and either H1 or H2 of the mother), P1 SNP BAFs have a value of 0.5 (corresponding to heterozygous genotypes in the cell) and P2 SNP BAFs have a value of either 0 or 1 (corresponding to homozygous AA and BB genotypes in the cell, respectively).” (pg. 895-896, col. 2, para. 4, lines 31-50). This suggests subcategorizing alleles of polymorphic variants into subcategory 1A or P1, which consists of paternally informative BAF values for alleles present in homozygous state.
With respect to the recited evaluating whether a genetic anomaly is present in the genetic material of the subject based on the AF values of the polymorphic variants in one or more of the subcategories and the genomic location of said polymorphic variants, Esteki [B] discloses “Haplarithmisis can also reveal numerical chromosome anomalies that are meiotic in nature. For instance, when a cell inherited both paternal H1 and H2 (along with either maternal H1 or H2), then P1 SNP BAFs have an expected value of ~0.33 and P2 SNP BAFs have an expected value of ~0.67 across the region where both paternal and one maternal homologs are present in the cell.” (pg. 897, col. 1, para. 1, lines 32-38). This suggests that a genetic anomaly is evaluated for based on SNP BAF values in subcategories P1 and P2, and the genomic location of the polymorphic variants.
With respect to the recited determining that a genetic anomaly is present in the genetic material of the subject when the AF values deviates from 0.5, Esteki [B] discloses “Haplarithmisis can also reveal numerical chromosome anomalies that are meiotic in nature. For instance, when a cell inherited both paternal H1 and H2 (along with either maternal H1 or H2), then P1 SNP BAFs have an expected value of ~0.33 and P2 SNP BAFs have an expected value of ~0.67 across the region where both paternal and one maternal homologs are present in the cell.” (pg. 897, col. 1, para. 1, lines 32-38). This suggests that a genetic anomaly is determined to be present when P1 and P2 SNP BAF values deviate from 0.5.
Esteki [B] does not disclose calculating mean AF values, trimmed mean AF values, or median AF values of the polymorphic variants for each subcategory, wherein the polymorphic variants are located between two genomic locations on a chromosome.
However, Germer et al. discloses “Second, to show that the method works on an actual pool of individual samples, we determined the allele frequencies for three distinct SNPs (see Methods) in a pool made from 100 individual human DNA samples (Table 2). For the three polymorphisms, each of the 100 samples was individually genotyped either by
T
m
-shift genotyping (Germer and Higuchi 1999) or, for CST5, by probe strip hybridization (Saiki et al. 1988; G. Zangenberg and R. Reynolds, unpubl.). The samples were then pooled, and the allele frequency determined by kinetic PCR. Calculated allele frequencies represent the average of 12 measurements.” (pg. 261, col. 1, para. 2, lines 1-12). This suggests calculating mean AF values of SNPs from locations in human chromosomal DNA samples.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of analyzing genetic material disclosed by Esteki [B] to incorporate the calculation of mean AF values disclosed by Germer et al. One would be motivated to make this modification because the SNP experiments reported by Germer et al. have designed 22 different primer sets (2 allele-specific and 1 common primer per set) for 10 different human SNPs with an overall success rate of ~80% (pg. 263, col. 2, para. 2, lines 1-5). Therefore, the method of genetic material analysis disclosed by Esteki [B] will be able to calculate mean AF values more effectively and at a high success rate as well. There is a likelihood of success, since both teachings are techniques used to analyze genetic material, which are well known in the field of genetics.
With respect to claim 22:
With respect to the recited calculating a delta AF, wherein the delta AF is: a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 1A and 1B; or a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 2A and 2B; or a difference between the median AF values, the mean AF values, or the trimmed mean AF values of subcategories 3A and 3B, Esteki [B] discloses “reciprocity between parental profiles, i.e., the differences between P1 and P2 SNP BAF values (
d
P
a
t
) after segmentation as well as the differences between M1 and M2 SNP BAF values (
d
M
a
t
) after segmentation are in a reciprocal manner characteristic for specific copy-number anomalies of a haplotype (
d
P
a
t
=
~
0.33
and
d
M
a
t
=
~
0.67
in the example of the duplication of a paternal H1 segment).” (pg. 897, col. 1, para. 1, lines 26-32). This suggests calculating a delta AF value that is a difference between allele frequency values of subcategories 1A and 1B, or P1 and P2.
With respect to the recited evaluating whether a genetic anomaly is present in the genetic material of the subject based on the delta AF values observed between the genomic locations, Esteki [B] discloses “reciprocity between parental profiles, i.e., the differences between P1 and P2 SNP BAF values (
d
P
a
t
) after segmentation as well as the differences between M1 and M2 SNP BAF values (
d
M
a
t
) after segmentation are in a reciprocal manner characteristic for specific copy-number anomalies of a haplotype (
d
P
a
t
=
~
0.33
and
d
M
a
t
=
~
0.67
in the example of the duplication of a paternal H1 segment). Haplarithmisis can also reveal numerical chromosome anomalies that are meiotic in nature. For instance, when a cell inherited both paternal H1 and H2 (along with either maternal H1 or H2), then P1 SNP BAFs have an expected value of ~0.33 and P2 SNP BAFs have an expected value of ~0.67 across the region where both paternal and one maternal homologs are present in the cell.” (pg. 897, col. 1, para. 1, lines 26-38). This suggests that a genetic anomaly is evaluated for based on delta SNP BAF values observed between genomic locations.
With respect to the recited determining that a genetic anomaly is present when the delta AF value deviates from 0, Esteki [B] discloses “reciprocity between parental profiles, i.e., the differences between P1 and P2 SNP BAF values (
d
P
a
t
) after segmentation as well as the differences between M1 and M2 SNP BAF values (
d
M
a
t
) after segmentation are in a reciprocal manner characteristic for specific copy-number anomalies of a haplotype (
d
P
a
t
=
~
0.33
and
d
M
a
t
=
~
0.67
in the example of the duplication of a paternal H1 segment).” (pg. 897, col. 1, para. 1, lines 26-32). This suggests that a genetic anomaly is determined to be present when delta SNP BAF values deviate from 0.
With respect to claim 24:
With respect to the recited removing from further analysis polymorphic variants that do not show sufficient intensity, Esteki [B] discloses “Furthermore, for a particular SNP, the logR is the base 2 logarithm of the summed normalized SNP probe intensity values observed for each allele in the sample versus the expected summed intensity values derived from a set of normal samples (e.g., for a single cell the logR of a SNP is
l
o
g
R
=
log
2
(
R
s
i
n
g
l
e
c
e
l
l
/
R
e
x
p
e
c
t
e
d
)).” (pg. 895, col. 1, para. 3, lines 5-10). Also, further discloses “The normalized logR values were subsequently segmented by PCF (gamma = 300 for single-cell samples and gamma = 50 for multi-cell samples). To call DNA-copy-number aberrations, the segmented logR values are integrated with haplarithmisis. For nullisomic, monosomic, disomic, uniparental disomic, and trisomic loci, typical haplarithm patterns across the logR anomaly were concordant. Aberrant logR values (logR < -0.3 or logR > 0.15) not corroborated by a typical haplarithm pattern following visualization were not scored as DNA gain or loss.” (pg. 899, col. 1, para. 3, lines 1-11). This suggests that polymorphic variants with insufficient logR intensity values were not scored or removed from analysis.
With respect to claim 28:
With respect to the recited visualizing the AF values, the mean AF values, the trimmed mean AF values, or the median AF values per subcategory of polymorphic variants, Esteki [B] discloses “These segments and the underlying processed SNP BAF values are visualized into two separate “haplarithm” plots, one for each parental chromosome. In the paternal haplarithm plot, segmented P1 and P2 profiles are depicted in blue and red, respectively. Similarly, segmented M1 and M2 are shown in blue and red, respectively, in the maternal haplarithm pot. These plots, containing segmented P1, P2, M1, and M2 patterns, reveal not only the parental haplotypes and the sites of homologous recombination, but also haplotype imbalances in single cells along with their parental and mechanistic origin.” (pg. 897, col. 1, para. 1, lines 4-14). This suggests a visualization of the BAF values, which is also depicted in Figure 1.
With respect to claim 29:
With respect to the recited wherein the selected allele per polymorphic variant is an allele with a specific feature, the specific feature being selected from an A allele, a B allele, an allele with a higher allele frequency in a given population, an allele with a lower allele frequency in a given population, a reference allele in a given reference genome, an allele present in homozygous state in the first parent, the allele present in homozygous state in the second parent, the allele present in heterozygous state in the first parent and absent in the second parent, or an allele present in heterozygous state in the second parent and absent in the first parent, Esteki [B] discloses “The SNP BAF values of the single cell are distributed into a paternal or maternal category according to the informative parental SNP genotypes defined in step 3, and further into four parental subcategories (P1, P2, M1, M2) according to the informative phased parental SNP genotypes defined in step 4.” (pg. 895-896, col. 2, para. 4, lines 31-35). Also, further discloses “the analysis of SNP B-allele fractions (BAFs)—i.e., the frequency with which a SNP variant allele occurs in the dataset of a DNA sample—should enable the determination of haplotypes and their underlying copy-number state.” (pg. 894, col. 2, para. 3, lines 1-5). This suggests that the selected allele per polymorphic variant is an allele with a specific feature being from a B allele.
With respect to claim 30:
With respect to the recited converting selected AF values of the polymorphic variants in the subcategories 2A, 2B, 3A, and/or 3B into discrete genotype calls and evaluating whether homozygous or heterozygous allele frequency values are underrepresented or overrepresented between two particular genomic locations, Esteki [B] discloses “These segments and the underlying processed SNP BAF values are visualized into two separate “haplarithm” plots, one for each parental chromosome. In the paternal haplarithm plot, segmented P1 and P2 profiles are depicted in blue and red, respectively. Similarly, segmented M1 and M2 are shown in blue and red, respectively, in the maternal haplarithm pot. These plots, containing segmented P1, P2, M1, and M2 patterns, reveal not only the parental haplotypes and the sites of homologous recombination, but also haplotype imbalances in single cells along with their parental and mechanistic origin.” (pg. 897, col. 1, para. 1, lines 4-14). This suggests that SNP BAF values in the subcategories are visualized into haplarithm plots that represent genotype calls, which are used to evaluate whether homozygous or heterozygous allele frequency values are underrepresented or overrepresented between genomic locations. This is further depicted in Figure 1 along with chromosomal anomaly examples in Figure 2.
With respect to claim 31:
With respect to the recited wherein the genomic location is a chromosome or a chromosome segment, Esteki [B] discloses “The informative SNP loci are identified.” (pg. 895, col. 2, para. 4, lines 12-13). This indicates that the SNP loci is a genomic location of the SNP on a chromosome or chromosome segment, which is also depicted in Figure 1.
With respect to claim 32:
With respect to the recited wherein the genetic material of the subject is genetic material isolated from a sample comprising only one or few cells of the subject or from a plasma sample obtained from a mother pregnant with the subject, Esteki [B] discloses “We apply this method to individual lymphocytes as well as blastomeres derived from human IVF embryos and demonstrate the determination of haplotypes carrying disease alleles in single-cell genomes.” (pg. 895, col. 1, para. 1, lines 9-13). This indicates that blastomeres are isolated from human IVF embryos, which is a sample comprising cells of a subject.
With respect to claim 33:
With respect to the recited wherein the genetic anomaly comprises a numerical or structural chromosomal abnormality present in all of the biopsied cells (non-mosaic) or in only a part of the biopsied cells (mosaic), Esteki [B] discloses “We demonstrate that the method can be applied as a generic method for preimplantation genetic diagnosis on single cells biopsied from human embryos, enabling diagnosis of disease alleles genome wide as well as numerical and structural chromosomal anomalies.” (pg. 894, Section “Abstract”, lines 8-9). This suggests that the genetic anomaly comprises numerical or structural abnormalities present in biopsied cells.
With respect to the recited wherein the numerical or structural chromosomal abnormality is selected from a monosomy, a uniparental disomy, a trisomy, a tetrasomy, a duplication, a deletion, a mosaic monosomy, a mosaic disomy, a mosaic trisomy, a mosaic tetrasomy, a mosaic tandem duplication, a mosaic deletion, or combinations thereof, Esteki [B] discloses “Shown are expected haplarithm patterns for a nullisomy (A), a maternal monosomy (B), a normal disomy (C), a maternal MI UPD (D), a maternal MII UPD (E), a maternal mitotic UPD (F), a maternal MI trisomy (G), a maternal MII trisomy (H), a maternal mitotic trisomy (I), a maternal mitotic trisomy with three identical chromosomes (J), and a balanced tetrasomy (K).” (pg. 899, Figure 2, lines 5-8). This suggests that the numerical or structural chromosomal abnormality is selected from a combination of anomalies listed above.
With respect to claim 34:
With respect to the recited wherein when the delta AF value deviates from 0 by less than or equal to a first threshold value of about 0.09, the delta AF value indicates a normal disomy, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values for the segmented P1 or segmented M1 profiles that deviate from 0 by less than a threshold value of 0.09 (pg. 898, Figure 2C). Therefore, the haplarithm plots together indicate a normal disomy.
With respect to the recited wherein when the delta AF value deviates from 0 by greater than or equal to a second threshold value of about 0.2 and an increased copy number is observed, the delta AF value indicates a full trisomy or duplication, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values that deviate from 0 by greater than a threshold value of 0.2 (pg. 898, Figure 2G). A copy number plot also shows an increase in copy number from 2 to 3. Therefore, the haplarithm plots and copy number plot together suggest a maternal MI trisomy.
Vraneković et al. discloses “The majority of full trisomy 21 is caused by chromosomal nondisjunction occurring during maternal meiotic division (~90%).” (pg. 70, col. 1, para. 1, lines 2-4). This means that a chromosomal disjunction that leads to a full trisomy has a high percentage of being from maternal origin. Therefore, maternal MI trisomy is a form of chromosomal nondisjunction that occurs during maternal meiotic division, which can lead to a full trisomy.
With respect to the recited wherein when the delta AF value deviates from 0 by an amount between the first threshold value and the second threshold value and an increased copy number is observed, the delta AF value indicates mosaic trisomy/disomy or mosaic duplication, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values that deviate from 0 by an amount between a first threshold value of 0.0 and a second threshold value of 1.0 (pg. 898, Figure 2I). A copy number plot also shows an increase in copy number from 2 to 3. Therefore, the haplarithm plots and copy number plot together suggest a maternal mitotic trisomy, which is a type of mosaic trisomy.
With respect to claim 35:
With respect to the recited wherein when the delta AF value deviates from 0 by less than or equal to a first threshold value of about 0.09, the delta AF value indicates a normal disomy, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values for the segmented P1 or segmented M1 profiles that deviate from 0 by less than a threshold value of 0.09 (pg. 898, Figure 2C). Therefore, the plots with the BAF values together indicate a normal disomy.
With respect to the recited wherein when the delta AF value deviates from 0 by greater than or equal to a second threshold of about 0.9 and a decreased copy number is observed, the delta AF value indicates a full monosomy or deletion, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values that deviate from 0 by greater than a threshold value of 0.9 (pg. 898, Figure 2B). A copy number plot also shows a decrease in copy number from 2 to 1. Therefore, the haplarithm plots and copy number plot together suggest a maternal monosomy.
Mayo Clinic discloses “The genetic alterations of Turner syndrome may be one of the following: Monosomy. The complete absence of an X chromosome generally occurs because of an error in the father’s sperm or in the mother’s egg. This results in every cell in the body having only one X chromosome.” (pg. 3, Section “Causes”, lines 6-9). This suggests that a maternal monosomy is a genetic alteration of Turner syndrome, which makes it a full monosomy.
With respect to the recited wherein when the delta AF value deviates from 0 by an amount between the first threshold value and the second threshold value and a decreased copy number is observed, the delta AF value indicates mosaic monosomy/disomy or mosaic deletion, Esteki [B] discloses paternal and maternal haplarithm plots with BAF values that deviate from 0 by an amount between a first threshold value of 0.0 and a second threshold value of 1.0 (pg. 898, Figure 2B). A copy number plot also shows a decrease in copy number from 2 to 1. Therefore, the haplarithm plots and copy number plot together suggest a maternal monosomy.
Mayo Clinic discloses “The genetic alterations of Turner syndrome may be one of the following: … Mosaicism. In some cases, an error occurs in cell division during early stages of fetal development. This results in some cells in the body having two complete copies of the X chromosome. Other cells have only one copy of the X chromosome.” (pg. 3, Section “Causes”, lines 6-13). This suggests that Turner syndrome, which is a type of maternal monosomy, can also lead to mosaic monosomy.
With respect to claim 36:
With respect to the recited wherein the polymorphic variants are selected from single nucleotide polymorphisms (SNPs) or short tandem repeats (STRs), Esteki [B] discloses “siCHILD is a computational workflow (Figure S1) for single-cell genome-wide haplotyping and copy-number typing of the haplotypes in a cell, allowing the determination of the inheritance of linked disease variants as well as the detection of the parental and mitotic/meiotic origin of haplotype anomalies in the cell. It consists of five modules, which are further detailed below, and uses as input discrete genotype calls (AA, AB, BB) … To identify cells with substandard WGA, we perform quality control (QC) on the single-cell discrete SNP genotypes and logR values. After hybridization of single-cell WGA products on Illumina SNP arrays, discrete SNP genotypes are determined with GenCall” (pg. 895, col. 1, para. 2-3, lines 1-14). This suggests that the polymorphic variants are single nucleotide polymorphisms.
With respect to claims 38 and 39:
Claim 38 recites a computer program product that is capable, when executed on a processing engine, to perform the computer implemented method. Claim 39 recites a non-transitory machine-readable storage medium storing the computer program product.
Broadly claiming an automated means to replace a manual function to accomplish the same result does not distinguish over the prior art. See Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485 F .3d 1157, 1161, 82 USPQ2d 1687, 1691 (Fed. Cir. 2007) (“Accommodating a prior art mechanical device that accomplishes [a desired] goal to modern electronics would have been reasonably obvious to one of ordinary skill in designing children’s learning devices. Applying modern electronics to older mechanical devices has been commonplace in recent years.”); In re Venner, 262 F. 2d 91, 95, 120 USPQ 193, 194 (CCPA 1958); see also MPEP § 2144.04. Furthermore, implementing a known function on a computer has been deemed obvious to one of ordinary skill in the art if the automation of the known function on a general purpose computer is nothing more than the predictable use of prior art elements according to their established functions. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417, 82 USPQ2d 1385, 1396 (2007); see also MPEP § 2143, Exemplary Rationales D and F. Likewise, it has been found to be obvious to adapt an existing process to incorporate Internet and Web browser technologies for communicating and displaying information because these technologies had become commonplace for those functions. Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318, 1326-27, 87 USPQ2d 1350, 1357 (Fed. Cir. 2008).
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Esteki et al. (The American Journal of Human Genetics, 2015, 96, 894-912), referred to as Esteki [B], and Germer et al. (Genome Research, 2000, 36(3), 258-266), as evidenced by Vraneković et al. (Genetic Testing and Molecular Biomarkers, 2011, 16(1), 70-73) and Mayo Clinic (Turner syndrome, Diseases & Conditions, 18 November 2017, accessed on 12 March 2026, 1-6, https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782), as applied to claims 21-22, 24, 28-36, and 38-39 above, in view of Clevenger et al. (G3 Genes|Genomes|Genetics, 2015, 5(9), 1797-1803).
Esteki [B], Germer et al., Vraneković et al., and Mayo Clinic are applied to claims 21-22, 24, 28-36, and 38-39 above.
With respect to claim 23:
Esteki [B], Germer et al., Vraneković et al., and Mayo Clinic do not disclose removing from further analysis polymorphic variants or SNPs that are distributed less than 50 kb from each other.
However, Clevenger et al. discloses “SNPs within 35 bp of another called SNP were filtered out using a custom python script.” (pg. 1799, col. 1, para. 5, lines 5-6). This indicates removing SNPs that are distributed less than 35 bp, which equates to 0.035 kb and is less than 50 kb.
It would have been prima facie obvious to one of ordinary skill in the art to modify the teachings disclosed by Esteki [B] and Germer et al. to incorporate the removal of SNPs disclosed by Clevenger et al. One would be motivated to make this modification because the SWEEP-filtered SNPs were validated at an accuracy rate of 85% (pg. 1802, col. 1, para. 2, lines 3-4). Therefore, the method of genetic material analysis disclosed by Esteki [B] and Germer et al. can remove SNPs more efficiently. There is a likelihood of success, since both teachings are techniques used to analyze genetic material, which are well known in the field of genetics.
Claims 25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Esteki et al. (The American Journal of Human Genetics, 2015, 96, 894-912), referred to as Esteki [B], and Germer et al. (Genome Research, 2000, 36(3), 258-266), as evidenced by Vraneković et al. (Genetic Testing and Molecular Biomarkers, 2011, 16(1), 70-73) and Mayo Clinic (Turner syndrome, Diseases & Conditions, 18 November 2017, accessed on 12 March 2026, 1-6, https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782), as applied to claims 21-22, 24, 28-36, and 38-39 above, in view of Zimmermann et al. (Prenatal Diagnosis, 2012, 32(13), 1233-1241).
Esteki [B], Germer et al., Vraneković et al., and Mayo Clinic are applied to claims 21-22, 24, 28-36, and 38-39 above.
With respect to claim 25:
Esteki [B], Germer et al., Vraneković et al., and Mayo Clinic do not disclose calculating a value for the parental contribution between the genomic locations from the delta AF values.
However, Zimmermann et al. discloses “The PS algorithm uses measured parental genotypes and crossover frequency data to create, in silico, billions of possible monosomic, disomic, and trisomic fetal genotypes at measured loci, each considered as a separate hypothesis. PS then uses a data model that predicts what the sequencing data is expected to look like for a plasma sample containing different fetal cfDNA fractions for each hypothetical fetal genotype. Bayesian statistics are used to determine the relative likelihood of each hypothesis given the data, and likelihoods are summed for each copy number hypothesis family: monosomy, disomy, or trisomy. The hypothesis with the maximum likelihood is selected as the copy number and fetal fraction, and the absolute likelihood of the call is the calculated accuracy, analogous to a test-specific risk score. Briefly, different probability distributions are expected for each of the two possible alleles at a set of SNPs on the target chromosome depending on the parental genotypes, the fetal fraction, and the fetal chromosome copy number. By comparing the observed allele distributions to the expected allele distributions for each of the possible scenarios, it is possible to determine the most likely scenario and precisely how likely that scenario is.” (pg. 1234, col. 2, para. 4-5, lines 1-22). This suggests calculating parental contribution by using parental genotypes for hypothetical fetal genotypes between measured genomic locations, which is compared with allele frequency patterns.
Esteki [B], Germer et al., Vraneković et al., and Mayo Clinic do not disclose evaluating whether a genetic anomaly is present in the genetic material of the subject based on the value for parental contribution observed between the genomic locations.
However, Zimmermann et al. discloses “The data presented in this proof-of-principle study of Parental Support™ methodology demonstrate that PS enables accurate detection of fetal aneuploidy from maternal blood. The method measures cfDNA isolated from maternal plasma using targeted sequencing of 11000 SNPs and Bayesian-based maximum likelihood informatics analysis. By focusing on polymorphic loci, multiple pieces of information – the number and identity of each allele – are measured in each sequence read. The use of advanced statistical methods allows PS to incorporate parental genotypic information and enhance the predictive power of data generated from high-throughput cfDNA sequencing.” (pg. 1235, col. 2, para. 2, lines 1-11). This suggests evaluating the presence of fetal aneuploidy based on parental contribution information observed between polymorphic loci.
It would have been prima facie obvious to one of ordinary skill in the art to modify the teachings disclosed by Esteki [B] and Germer et al. to incorporate parental contribution disclosed by Zimmermann et al. One would be motivated to make this modification because chromosome copy number was determined at chromosomes 13, 18, 21, X, and Y with 100% sensitivity and 100% specificity for all samples passing the quality test (pg. 1239, col. 2, para. 6, lines 3-5). Therefore, the method of genetic material analysis disclosed by Esteki [B] and Germer et al. can determine parental contribution with high accuracy. There is a likelihood of success, since both teachings are techniques used to analyze genetic material, which are well known in the field of genetics.
With respect to claim 27:
Germer et al., Vraneković et al., Mayo Clinic, and Zimmermann et al. do not disclose wherein a percentage parental contribution from about 44.4% to about 55.6% indicates a normal disomy.
However, Esteki [B] discloses a normal disomy chromosome diagram with an allelic ratio of 1:1 paternal copy to maternal copy (pg. 898, Figure 2C). This indicates that there is a 50% percentage parental contribution from both parents, which is within the 44.4% to 55.6% range.
Germer et al., Vraneković et al., Mayo Clinic, and Zimmermann et al. do not disclose wherein a percentage parental contribution from about 63.6% to about 72.7% indicates a trisomy.
However, Esteki [B] discloses a maternal MI trisomy chromosome diagram with an allelic ratio of 1:2 paternal copy to maternal copies (pg. 898, Figure 2G). This indicates that there is a 66.7% percentage parental contribution from the mother, which is within the 63.6% to 72.7% range.
Germer et al., Vraneković et al., Mayo Clinic, and Zimmermann et al. do not disclose wherein a percentage parental contribution from about 0% to about 3.3% indicates a monosomy.
However, Esteki [B] discloses a maternal monosomy chromosome diagram with an allelic ratio of 0:1 paternal copy to maternal copy (pg. 898, Figure 2B). This indicates that there is a 0% percentage parental contribution from the father, which is within the 0% to 3.3% range.
Claim 26 which recites wherein calculating a value for the parental contribution between the genomic locations is based on a second order generalized linear model between the delta AF values and a percentage parental contribution (%Mat or %Pat) across the genomic locations; and a deviation of the parental contribution from 50% indicates a chromosomal anomaly is free of the art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jammy Luo whose telephone number is (571)272-2358. The examiner can normally be reached Monday - Friday, 9:00 AM - 5:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Larry D Riggs can be reached at (571)270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.N.L./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
Prosecution Insights