Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Claims
Claims 45-63 are currently pending. Claims 45, 51-53, 55, 61 and 62 have been amended by Applicants’ amendment filed 01-07-2026. No claims have been added or canceled by Applicants’ amendment filed 01-07-2026.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 45-63 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed August 5, 2022 is CON of US Patent Application 16169458, filed October 24, 2018 (now US Patent 11441185); which is a DIV of US Patent Application 13720273, filed December 19, 2012 (now US Patent 10131947), which is a CIP of US Patent Application 13338963, filed December 28, 2011 (now US Patent 8700338), which is a CIP of US Patent Application 13316154, filed December 9, 2011 (now abandoned), which claims the benefit of US Provisional Patent Application 61436135, filed January 25, 2011.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, the as-filed Specification of US Application 13/316,154, filed December 9, 2011, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claims 45 and 55 do not have support for; “identifying the presence or absence of a fetal aneuploidy in a sample from a female with an egg donor pregnancy”. Therefore, the priority date for the presently claimed invention is December 28, 2011, the filing date of US Patent Application 13/720,273.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claims 45 and 55 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed January 7, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112, 2nd paragraph
The rejection of claims 45-63 is maintained under 35 U.S.C. 112, 2nd paragraph as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The rejection of claims 45, 54 and 63 is maintained, and claim 51 is newly rejected, as being indefinite for the recitation of the terms “low frequency” and “high and low frequency” such as recited in claim 45, line 5 because the terms “low” and “high” are relative terms that render the claim indefinite. The terms “low” and “high” are not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of allele frequency as compared to some other value that qualifies as a “low frequency” alleles and/or as “high and low frequency” alleles, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claims 45, 51, 54 and 63 are indefinite for the recitation of the term “the high and low frequency alleles” such as recited in claim 45, lines 5-6. There is insufficient antecedent basis for the term “the high and low frequency alleles” in the claim. The Examiner suggests that Applicant amend claim 45 to recite, for example, “a relative frequency of a total of all high and low frequency alleles.”
Claims 45, 51 and 55 are indefinite for the recitation of the term “the nucleic acid regions” such as recited in claim 45, line 16. There is insufficient antecedent basis for the term “the nucleic acid regions” in the claim because claim 45, line 13 recites the term “two or more nucleic acid regions;” and claim 55, line 3 recites the term “two or more polymorphic nucleic acid regions” such that it is unclear whether these terms refer to the same regions or different regions and, thus, the metes and bounds of claim cannot be determined.
Claims 45 and 55 are indefinite for the recitation of the term “the first and at least the second chromosome” such as recited in claim 45, line 16. There is insufficient antecedent basis for the term “the first and at least the second chromosome” in the claim because claim 45, lines 9 and 11 recites the term “a first chromosome” and “at least a second chromosome”.
Claim 51 is indefinite for the recitation of the term “calculating…from a pregnant female with an egg donor pregnancy” such as recited in amended claim 51, lines 1-2 because claim 51 depends from instant claim 45, wherein claim 45 does not recite ‘calculating a percent of fetal cfDNA in a maternal sample from a pregnant female with an egg donor pregnancy’. Moreover, claim 45 does not recite an egg donor or an egg donor pregnancy in the body of instant claim 45, such that the term “egg donor pregnancy” is not given patentable weight and, thus, the metes and bounds of claim cannot be determined.
Claim 51 is indefinite for the recitation of the term “relative frequency of alleles” such as recited in claim 51, lines 5, 6, 8 and 10 because instant claim 51 depends from instant claim 45, wherein claim 45, lines 5-6 and 13 recites the terms “relative frequency of low frequency alleles,” “a relative frequency of both the high and low frequency alleles,” and “a relative frequency of the interrogated two or more nucleic acid regions,” such that it is unclear which alleles are being referred to and, thus, the metes and bounds of claim cannot be determined.
Claim 51 is indefinite for the recitation of the term “the alleles” such as recited in claim 51, line 12. There is insufficient antecedent basis for the term “the alleles” in the claim.
Claim 51 is indefinite for the recitation of the terms “a second chromosome” and “the second chromosome” such as recited in claim 51, lines 7-9, 11 and 13 because instant claim 51 depends from instant claim 45, wherein claim 45, line 11 recites the term “at least a second chromosome.”
The rejection of claims 52 and 53 is maintained as being indefinite for the recitation of the term “the egg donor” such as recited in claim 52, line 1. There is insufficient antecedent basis for the term “the egg donor in the claim. Moreover, claims 52 and 53 depend from claims 45 and 51, wherein claims 45 and 51 do not recite the presence of an “egg donor” and, thus, the metes and bounds of the claim cannot be determined.
Claim 52 is indefinite for the recitation of the term “egg donor informative loci comprise loci in which maternal DNA and the fetal cfDNA differ in at least one allele” in claim 52, lines 1-2 because the egg donor and the maternal sample are from two different people such that the loci will inherently differ in at least one allele and, thus, the metes and bounds of the claim cannot be determined.
The rejection of claims 52, 53, 61 and 62 is maintained as being indefinite for the recitation of the term “maternal DNA,” such as recited in claim 52, line 2 because claims 52 and 53 depend from instant claim 45, and claims 61 and 62 depend from claim 55, wherein claims 45 and 55 do not recite the term “maternal DNA.” Additionally, the Examiner proposes that if a percent fetal cell-free DNA is calculated from a maternal sample, the maternal sample should also comprise “cell-free maternal DNA” and, thus, the metes and bounds of the claim cannot be determined.
The rejection of claims 52, 53, 61 and 62 is maintained as being indefinite for the recitation of the terms “at least one allele” and “both alleles” such as recited in claims 52, line 2 and claim 53, line 2. There is insufficient antecedent basis for the terms “at least one allele” and “both alleles” in the claim because claim 45, lines 5-6 recite the terms “low frequency alleles” and “low and high frequency alleles”.
Claim 53 is indefinite for the recitation of the term “egg donor informative loci comprise loci in which maternal DNA and the fetal cfDNA differ in both alleles” in claim 53, lines 1-2 because the egg donor and the maternal sample are from two different people, such that the loci will inherently differ in “both alleles” and, thus, the metes and bounds of the claim cannot be determined.
Claim 54 is indefinite for the recitation of the term “wherein calculating…and low frequency alleles” such as recited in claim 54, lines 1-3 because claim 54 depends from claim 45, wherein claim 45 already recites “calculating a percent fetal DNA…and low frequency alleles” and, thus, the metes and bounds of the claim cannot be determined.
Claims 46-50 are indefinite insofar as they ultimately depend from instant claim 45. Claims 56-60 are indefinite insofar as they ultimately depend from instant claim 55.
Response to Arguments
Applicant’s arguments filed January 7, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) regarding the use of relative terms with respect to “low frequency” and “high and low frequency,” Applicants contend that one skilled in the art would find these claims along with the supporting specification (such as in paragraph [0072] of the instant application) to define the metes and bounds of the claims and therefore be appraised of the scope of the invention (Applicant Remarks, pg. 8, last full paragraph).
Regarding (a), it is noted that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). The terms “low frequency” and “high and low frequency” are indefinite because the terms “low” and “high” are relative terms that render the claim indefinite. The instant as-filed Specification teaches that “high frequency alleles” are maternal alleles, whether or not those alleles are present in the fetal genome, since maternal alleles are naturally in greater abundance in the maternal sample; and that “low frequency alleles” are fetal alleles where at least one copy of the allele is absent from the maternal genome (See; paragraph [0071]). In the instant case, all maternal alleles are high frequency alleles, and all fetal alleles are low frequency alleles given that the mother and the fetus do not share any alleles. The fetal alleles, therefore, do not contain any copies of a maternal allele. Thus, it is completely unclear how calculating a relative frequency would identify the presence or absence of fetal aneuploidy using this method.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 51-53 is maintained under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 51 recites (in part): “wherein calculating a percent fetal cell-free DNA in the maternal sample from a pregnant female with an egg donor pregnancy…the egg donor informative loci” in claim 51, lines 1-15 because claim 51 depends from claim 45, wherein claim 45 does not recite calculating a percent fetal cell-free DNA in the maternal sample, an egg donor, an egg donor pregnancy, egg donor informative loci, etc. Thus, claim 51 is improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 52 recites (in part): “wherein the egg donor informative loci comprise loci in which maternal DNA and the fetal cell-free DNA differ in at least one allele” in claim 52, lines 1-3 because claim 52 depends from claims 45 and 51, wherein claims 45 and 51 do not recite the presence of an egg donor, maternal DNA, and/or at least one allele. Thus, claim 52 is improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 53 recites (in part): “wherein the egg donor informative loci comprise loci in which maternal DNA and the fetal cell-free DNA differ in both alleles” in claim 53, lines 1-2 because claim 52 depends from claims 45 and 51, wherein claims 45 and 51 do not recite the presence of an egg donor, maternal DNA, and/or both alleles. Thus, claim 53 is improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
The rejection of claims 45-63 is maintained under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See; Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at: http://www.uspto.gov/patents/law/exam/mdc_examples_ nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In the instant case, the claims are directed to a natural phenomenon, which is the natural presence of maternal cfDNA and fetal cfDNA in the body of a pregnant woman, wherein the relative frequencies of nucleic acid regions from more than one chromosome is indicative of the presence or absence of fetal aneuploidy; and an abstract idea in the form of calculating a percent fetal cfDNA in a sample; comparing relative frequencies; interrogating nucleic acid regions from more than one chromosome; and identifying the presence or absence of fetal aneuploidy. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claims as a whole, claims 45-63 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
In the instant case, claims 45 and 55 are broadly directed to a method for predicting an outcome for a patient, for claim 45, the method comprising: providing a maternal sample; calculating a percent fetal cfDNA in the sample; demonstrating the sample comprises cfDNA relative to a threshold value; interrogating two or more nucleic acid regions from a first chromosome; interrogating two or more nucleic acid regions from a second chromosome from the maternal sample; determining a frequency of the interrogated nucleic acid region; and identifying the presence of absence of fetal aneuploidy. For claim 55, the method comprising: providing a maternal sample; interrogating two or more polymorphic nucleic acid regions from a first chromosome; quantifying a relative frequency of alleles for the first chromosome; interrogating two or more nucleic acid regions from a second chromosome; quantifying a relative frequency of alleles for the second chromosome; comparing the relative frequencies; identifying egg donor informative loci; calculating a percent fetal cfDNA in the maternal sample; demonstrating the sample comprises fetal cfDNA relative to a threshold value; interrogating two or more regions from a first chromosome; interrogating two of more nucleic acid regions from a least a second chromosome from the maternal sample; determining a frequency of the interrogated nucleic acid region; and identifying the presence or absence of a fetal aneuploidy.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process, thus, the instant claims are directed to a statutory category. Step I [YES].
Proceeding to Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 45 and 55 are drawn to a natural phenomenon, and an abstract idea including: a natural phenomenon in the form of a natural correlation between the frequency of interrogated nucleic acids regions on a first chromosome and at least a second chromosome in a maternal sample comprising fetal cfDNA and the presence or absence of aneuploidy; and to an abstract idea in the form of mathematical relationships, formulas or equations, and/or calculations; as well as, mental process (e.g., in the form of calculating, demonstrating; interrogating; determining a frequency; quantifying; comparing; identifying, etc.).
Thus, the claims recite a natural phenomenon, and an abstract idea, which falls within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, equations, and calculations that can be carried out in the human mind, and/or by using a general computer that performs routine and conventional functions, as well as, mental process performed in the human mind including concepts such as observation, evaluation, judgement, and/or opinion. Thus, under the revised Step IIA analysis, the claims are directed to a natural phenomenon, and to an abstract idea. Step IIA – Prong One [YES].
Step IIA - Prong Two asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Claim 45 recites: “calculating a percent fetal cell-free DNA in the sample using a comparison of a relative frequency of low frequency alleles to a relative frequency of both the high and low frequency alleles” in lines 4-6; “demonstrating the sample comprises fetal cell-free DNA relative to a threshold value” in line 7; “interrogating two or more nucleic acid regions from a first chromosome” in line 8; “interrogating two or more nucleic acid regions from at least a second chromosome determining a frequency of the interrogated nucleic acid regions from the first and at least second chromosome” in lines 10-11; and “identifying the presence or absence of a fetal aneuploidy based on the determined relative frequencies of the nucleic acid regions from the first and at least second chromosome” in lines 12-13. Claim 55 recites: “interrogating two or more polymorphic nucleic acid regions from a first chromosome” in line 4; “quantifying a relative frequency of alleles from the nucleic acid regions from the first chromosome” in lines 5-6; “interrogating two or more selected nucleic acid regions from a second chromosome” in line 7; “quantifying a relative frequency of alleles from the nucleic acid regions from the second chromosome” in lines 8-9; “comparing the relative frequency of the nucleic acid regions from the first chromosome to the relative frequency of the nucleic acid regions form the second chromosome” in lines 10-11; “identifying egg donor informative loci based on the frequency of the alleles from the first and second chromosome” in lines 12-13; “calculating a percent fetal cell-free DNA in the sample based on the egg donor informative loci” in lines 14-15; “demonstrating the sample comprises fetal cell-free DNA relative to a threshold value” in line 16; “interrogating two or more nucleic acid regions from a first chromosome” in line 17; “interrogating two or more nucleic acid regions from at least a second chromosome” in line 18; “determining a frequency of the interrogated nucleic acid regions from the first and at least second chromosome” in lines 19-20; and “identifying the presence or absence of a fetal aneuploidy based on the determined relative frequencies of the nucleic acid regions from the first and at least second chromosome” in lines 21-22. These limitations simply describe a process of collecting and analyzing information, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); as well as, “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)). Moreover, many of Applicant’s process steps can be practiced as a mental process performed in the human mind, by pen and paper, or through the use of a generic computer, for example, “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Hence, these limitations are akin to an “abstract idea itself” which was at issue in Alice Corp. and has been identified among non-limiting examples to be an abstract idea. Additionally, the dependent limitations of claims 46-54 and 56-63 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 51 recites, “interrogating two or more polymorphic nucleic acid regions from a first chromosome; quantifying a relative frequency of alleles from the nucleic acid regions from the first chromosome; interrogating two or more selected nucleic acid regions from a second chromosome; quantifying a relative frequency of alleles from the nucleic acid regions from the second chromosome; comparing the relative frequency of the nucleic acid regions from the first chromosome to the relative frequency of the nucleic acid regions form the second chromosome; identifying egg donor informative loci based on the frequency of the alleles from the first and second chromosome; and calculating a percent fetal cell-free DNA in the sample based on the egg donor informative loci”, while claim 63 recites “wherein calculating the percent fetal cell free DNA comprises comparing a relative frequency of low frequency alleles and a relative frequency of both high and low frequency alleles”; which clearly resembles “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). The claims do not provide other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment, e.g., an immunization step that integrates an abstract idea of data comparison into a specific process of immunizing that lowers the risk that immunized patients will later develop chronic immune-mediated diseases, as discussed in Classen Immunotherapies Inc. v. Biogen IDEC, 659 F.3d 1057, 1066-68, 100 USPQ2d 1492, 1499-1502 (Fed. Cir. 2011) (see MPEP § 2106.05(e)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea?
The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception are covered. For instance, claims 45 and 55 are recited without any specificity as to the identity of the maternal sample (who is considered the “mother”); the type of maternal sample; the method of providing; the method of calculating; the method of quantifying; the methods of calculating; the percent fetal cfDNA; the relative frequencies of alleles; what constitutes a low frequence and/or high frequency allele; the method of demonstrating; the method of interrogating; the nucleic acid regions; the threshold values; the chromosomes; whether the maternal or fetal cfDNA are interrogated; the method of identifying; how the presence or absence of aneuploidy is determined; the type of aneuploidy, wherein the steps of the method are well-known in the art.
For example, methods and genotyping panels for detecting alleles, genomes, and transcriptomes in admixtures of two individuals were known in the art, wherein a mixture of maternal and fetal cells is obtained as mixed maternal and fetal cell-free nucleic acids, and enriched to generate a sample concentrated for fetal cells relative to maternal cells; and aliquots are individually screened for a non-maternal allele at least one locus that was previously identified as homozygous in the maternal sample or genotyped at least one locus that was previously identified as heterozygous in the maternal sample, with detection of a heterozygous or homozygous genotype, respectively; and that the ratio of alleles from the third SNP on Chromosome 21 is then analyzed to detect the presence of aneuploidy as evidenced by Oliphant (WO2010075459; Abstract; paragraph [0014]; [0021]; and [0103]). Moreover, compositions and methods for simultaneously determining the presence or absence of fetal aneuploidy and the relative amount of fetal nucleic acids in a sample obtained from a pregnant female was known in the art including the use of sequencing technologies and exploits the occurrence of polymorphisms to provide a streamlined noninvasive process applicable to the practice of prenatal diagnostics; and that the method enables the determination of fetal fraction and the determination of the presence or absence of fetal aneuploidy from a single diagnostic sequencing process, wherein the method allows for determining fetal fraction in a gender independent manner, which relies on quantification of alleles on multiple chromosomes, such that the noninvasive diagnostic method encompasses the use of next generation sequencing (NGS) technology that can be implemented in a streamlined and cost-effective process to provide noninvasive prenatal diagnoses of fetal aneuploidies with greater confidence as evidenced by Quake (US2011224087Abstract; and paragraph [0008]). Moreover, methods for differentiating or detecting fetal DNA in a maternal sample, or to differentiate DNA of an organ donor from DNA of an organ recipient are known in the art including methods of detecting genetic abnormalities in a fetus by detecting fetal DNA in a biological sample obtained from a mother; and methods for differentiating DNA species originating from an organ donor from those of an organ recipient; and that differentiation between maternal and fetal DNA can be performed, wherein when the fetal DNA is quantified in maternal plasma or serum, the measured concentration can be used to predict, monitor or diagnose or prognosticate a pregnancy-associated disorder including a chromosomal aneuploidy as evidenced by Lo Yuk-Ming (US20050282185; Abstract; paragraphs [0007]-[0008]). A method comprising obtaining genotypic data from one or both parents of the fetus; processing the first sample by purifying the DNA so as to obtain a second sample; measuring the DNA in the second sample at a set of polymorphic alleles; calculating, on a computer, allele ratios at the set of polymorphic alleles from the DNA measurements made on the second sample; creating, on a computer, a plurality of ploidy hypotheses concerning expected allele ratios at the set of polymorphic alleles on the chromosome for different possible ploidy states of the chromosome; and using a set of DNA probes designed to target loci where the loci have maximal minor allele frequencies including loci having the maximum likelihood of the fetus having a highly informative SNP at that loci; and calculating the fraction of fetal DNA using population frequencies to adjust the model on the probability on particular allele measurements was known in the art as evidenced by Rabinowitz (US20110288780; paragraphs [0009]; [0280]; and [0322]). Moreover, it was known that presence or absence of an outcome can be expressed in any suitable form, and in conjunction with any suitable variable, collectively including, without limitation, ratio, deviation in ratio, frequency, distribution, probability (e.g., odds ratio, p-value), likelihood, percentage, value over a threshold, or risk factor, associated with the presence of a outcome for a subject or sample, wherein an outcome may be provided with one or more variables, including, but not limited to, sensitivity, specificity, standard deviation, probability, ratio, coefficient of variation (CV), threshold, score, probability, confidence level, or combination of the foregoing; and a method for identifying the presence or absence of an outcome, which comprises (a) detecting signal information indicating the presence, absence or amount of enriched nucleic acid; (b) receiving, by the logic processing module, the signal information; (c) calling the presence or absence of an outcome by the logic processing module, wherein a ratio of alleles different than a normal ratio is indicative of a chromosomal disorder; and (d) organizing, by the data display organization model in response to being called by the logic processing module, a data display indicating the presence or absence of the outcome including chromosomal aneuploidy as evidenced by Wisneiwski (WO20110115016; pg. 8, lines 13-22; pg. 62, lines 33-34; pg. 63, lines 1-5; and pg. 70, lines 1-7). Moreover, a method for the detection of specific polymorphic alleles in a mixed DNA populati0n was known in the art, comprising enriching the relative percentage of a given polymorphic allele that is exponentially amplifiable by PCR; and methods for selectively enriching target nucleic acid, for example, fetal nucleic acid in a maternal sample including for detecting fetal nucleic acid in a maternal sample; and that the relative enrichment of the target allele in the sample allows accurate detection of allele frequencies using practically any method of nucleic acid detection known including in transplant nucleic acid detection evidenced by Ehrich (US20120115737; Abstract; and paragraphs [0024]; and [0043]). Furthermore, comparing screening efficacy for aneuploidy detection in ovum donor pregnancies were known in the art including performing aneuploidy risk calculations on the ovum donor as evidenced by Donnenfeld (Am J Obstet Gynecol, 2002, 187(5), 1-4; Abstract). Thus, the claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, wherein the steps are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). Step IIA [YES].
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 47 DOES NOT qualify as eligible subject matter.
Dependent claims 46-54 and 56-63 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the natural phenomenon in claim 45, significantly different. For example, claim 46 encompasses the method of claim 45, wherein the threshold value is between 1.0 and 5.0 percent, but it does not add anything that makes the natural phenomenon and abstract idea in claim 45 significantly different. Moreover, claim 56 encompasses the method of claim 55, wherein the threshold value is between 1.0 and 5.0 percent, but it does not add anything that makes the natural phenomenon and abstract idea in claim 55 significantly different.
In light of the above consideration and the new guidance, claims 45-63 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
Response to Arguments
Applicant’s arguments filed January 7, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant asserts that claim 45 is not directed to an abstract idea, but that it is directed to a non-invasive technology for determining the presence or absence of fetal aneuploidy in a maternal sample from a pregnant female with an egg donor pregnancy (Applicant Remarks, pg. 13, last partial paragraph, lines 1-2); (b) the process of claim 45 amounts to significantly more than a mathematical concept or a mental process and, instead, provides an ability to more safely, efficiently, and accurately determine and deliver important and time sensitive healthcare information to a patient, wherein the method of claim 45 can provide safe, efficient, and more accurate determinations of the presence or absence of a fetal aneuploidy in a maternal sample, which includes maternal and fetal cell-free DNA, from a pregnant female with an egg donor pregnancy and thus integrates the process of claim 45 into a practical application of improving the technological field of fetal aneuploidy determinations (Applicant Remarks, pg. 13, last partial paragraph through pg. 14, first partial paragraph); (c) the MPEP directs: "some improvements to technology or to computer functionality are not abstract when appropriately claimed, and thus claims to such improvements do not always need to undergo the full eligibility analysis." MPEP § 2106.06(b). The subject matter of Claim 45 pertains to improvements in determining the presence or absence of a fetal aneuploidy in a maternal sample from a pregnant female with an egg donor pregnancy, and the maternal sample includes maternal and fetal cell-free DNA (Applicant Remarks, pg. 14, first full paragraph); (d) the process of claim 45 determines fetal aneuploidy based on a maternal sample comprising maternal and fetal cell-free DNA, which does not require an invasive and potentially harmful procedure to the patient (e.g., pregnant female and/or unborn fetus), wherein existing processes and methods for determining fetal aneuploidy have various limitations, including lower accuracy and/or increased risk for harm to the patient (Applicant Remarks, pg. 15, entire page); (e) the Applicant's Specification clearly provides, and the claims definitively recite, an improvement to a technological implementation rooted in computing technology, which provides a practical solution to a known problem-obtaining results safely, efficiently, with improved accuracy--by practically applying specific complex computational analysis that cannot be performed as a mental step (Applicant Remarks, pg. 16, first and second full paragraphs); and (f) the pending claim elements are not well-understood, routine or conventional because claim 45 recites significantly more than the alleged abstract idea of a mental process or mathematical concept (Applicant Remarks, pg. 16, last partial paragraph through pg. 18, first full paragraph).
Regarding (a), the Office asserts that the claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Applicant has provided no evidence or argument to support the contention that claim 45 is not directed to an abstract idea. Additionally, Applicant has failed to address any arguments with regard to independent claim 55; as well as, arguments regarding the rejection of instant claims 45 and 55 as being directed to a natural phenomenon. Thus, the claim remain rejected for the reasons of record.
Regarding (b) and (d), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. It is noted that MPEP 2112.01(II) indicates:
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty") (underline added).
MPEP 716.02(b) states:
the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (See also; In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
MPEP 716.02(c) indicates:
unexpected results must be weighed against evidence supporting a prima facie obviousness. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978); and where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Moreover, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) and In re Baxter TravenoILabs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). See MPEP § 716.02 - § 716.02(g). Applicant’s assertion that the process of claim 45 amounts to significantly more than a mathematical concept or a mental process including improvements in a technological field, is not found persuasive. As an initial matter, Applicant has failed to address any arguments with regard to independent claim 55 and/or provided arguments regarding the rejection of instant claims 45 and 55 as being directed to a natural phenomenon.
Moreover, instant claims 45 and 55 do not amount to significantly more than the judicial exception because the claims do not recite any specific methods of providing; specific maternal sample, specific egg donor; an egg donor pregnancy; methods of calculating; algorithms; reference values; low frequency alleles; a relative frequency of both low and high frequency alleles; any alleles shared between the egg donor and mother; method of interrogating; methods of calculating; chromosomes; relative frequencies of two or more nucleic acid regions; methods of determining; methods of identifying; determined relative frequencies; specific fetal aneuploidies that can be present or absent; what relative frequencies establish the presence or absence of a particular fetal aneuploidy; what threshold value is indicative of the presence or absence of a specific aneuploidy, etc. One of ordinary skill in the art could not use the method to identify the presence or absence of a single fetal aneuploidy based on the vague and broad limitations as recited. Moreover, as indicated by the cited references including Quake, Oliphant, Lo Yuk-Ming, Rabinowitz, Wisneiwski, Ehrich, and Donnenfeld, the process as recited in claims 45 and 55 are well known, purely conventional, and routine in the art.
Regarding improvements in a technological field, it is unclear what technology Applicant is asserting has been improved. Additionally, instant claims 45 and 55 do not recite any measurements of safely, efficiency, and/or accuracy; and/or the claims do not recite any safely, efficiency, and/or accuracy data of the instant method as compared to any other method for identifying fetal aneuploidies in a maternal sample. In fact, there is nothing inventive about the instant processes as recited because the instant as-filed Specification teaches that “numerous analytical methods can be used to reduce variation and, thus, improve the sensitivity of the method to detect aneuploidy” (See; paragraph [000144]). Furthermore, regarding the delivery of time-sensitive healthcare data, it is noted that the claims do not recite an amount of time that it takes to carry out the method (e.g., within 4 hours, 6 hours, 24 hours, etc.); any reduction in the amount of time as compared to any other method; and the claims do not recite delivering results and/or healthcare information to a patient. Clearly, instant claims do not even recite a patient, maternal DNA, an egg donor, and/or an egg donor pregnancy. Moreover:
Evidence has not been provided that the asserted "improvements in a technological field" were unknown in the prior art.
Applicant has not shown that there is a nexus and/or a co-extensiveness between what is recited in instant claims 45 and 55, and the improvements asserted by Applicant.
Applicant has not pointed to where the asserted improvements in a technological field are identified and discussed in the as-filed Specification.
The working examples provided in the as-filed Specification lack specificity as to the oligonucleotides synthesized and used, the allele frequencies detected, the informative loci identified, etc. and there are no working examples that appear to identify of the presence or absence of a fetal aneuploidy in a maternal sample.
Thus, the claims remain rejected.
Regarding (c) and (e), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Once again, Applicant has failed to address any arguments with regard to independent claim 55 and/or provided arguments regarding the rejection of instant claims 45 and 55 as being directed to a natural phenomenon. Applicant’s assertion that the subject matter of claim 45 pertains to improvements in determining the presence or absence of a fetal aneuploidy in a maternal sample from a pregnant female with an egg donor pregnancy; as well as, improvement to a technological implementation rooted in computing technology, is not found persuasive. Applicant has not provided any evidence and/or arguments regarding how the instant claims illustrate the asserted improvements in computer technology, healthcare, efficiency, sensitivity, safety, etc. The Examiner fails to understand how the processes as recited in claims 45 and 55, which are well-known, purely conventional, and routine in the art, are an improvement in any technology and/or are an improvement in computer functionality. The instant claims do not recite any specific improvements including improved healthcare; an unborn fetus, an egg donors, an egg donor pregnancy, medical procedures avoided, the use of a computer, computer components, methods of calculating, methods of analyzing, methods of determining, methods of identifying, specific algorithms, processors, memory, processing chips, computer codes, etc. and/or the implementation of any combination of technology and/or computer techniques. Thus, the claims remain rejected.
Regarding (f), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments including what is not recited in the instant claims, that Applicant has not provided any evidence or arguments regarding the asserted improvements, shown that the improvements are unknown in the prior art, indicated how the claims recite significantly more than the judicial exception, etc. The Examiner again notes that Applicant has failed to address any arguments with regard to independent claim 55 and/or provided arguments regarding the rejection of instant claims 45 and 55 as being directed to a natural phenomenon. Applicant’s assertion that the pending claim elements are not well-understood, routine or conventional because claim 45 recites significantly more than the alleged abstract idea of a mental process or mathematical concept, is not found persuasive. It is noted that:
Wisneiwski teaches that the presence or absence of an outcome can be expressed in any suitable form, and in conjunction with any suitable variable, collectively including, without limitation, ratio, deviation in ratio, frequency, distribution, probability (e.g., odds ratio, p-value), likelihood, percentage, value over a threshold, or risk factor, associated with the presence of a outcome for a subject or sample, wherein an outcome may be provided with one or more variables, including, but not limited to, sensitivity, specificity, standard deviation, probability, ratio, coefficient of variation (CV), threshold, score, probability, confidence level, or combination of the foregoing; and a method for identifying the presence or absence of an outcome, which comprises (a) detecting signal information indicating the presence, absence or amount of enriched nucleic acid; (b) receiving, by the logic processing module, the signal information; (c) calling the presence or absence of an outcome by the logic processing module, wherein a ratio of alleles different than a normal ratio is indicative of a chromosomal disorder; and (d) organizing, by the data display organization model in response to being called by the logic processing module, a data display indicating the presence or absence of the outcome including chromosomal aneuploidy.
Oliphant teaches methods and genotyping panels for detecting alleles, genomes, and transcriptomes in admixtures of two individuals were known in the art, wherein a mixture of maternal and fetal cells is obtained as mixed maternal and fetal cell-free nucleic acids, and enriched to generate a sample concentrated for fetal cells relative to maternal cells; and aliquots are individually screened for a non-maternal allele at least one locus that was previously identified as homozygous in the maternal sample or genotyped at least one locus that was previously identified as heterozygous in the maternal sample, with detection of a heterozygous or homozygous genotype, respectively; and that the ratio of alleles from the third SNP on Chromosome 21 is then analyzed to detect the presence of aneuploidy.
Quake teaches compositions and methods for simultaneously determining the presence or absence of fetal aneuploidy and the relative amount of fetal nucleic acids in a sample obtained from a pregnant female was known in the art including the use of sequencing technologies and exploits the occurrence of polymorphisms to provide a streamlined noninvasive process applicable to the practice of prenatal diagnostics; and that the method enables the determination of fetal fraction and the determination of the presence or absence of fetal aneuploidy from a single diagnostic sequencing process, wherein the method allows for determining fetal fraction in a gender independent manner, which relies on quantification of alleles on multiple chromosomes, such that the noninvasive diagnostic method encompasses the use of next generation sequencing (NGS) technology that can be implemented in a streamlined and cost-effective process to provide noninvasive prenatal diagnoses of fetal aneuploidies with greater confidence.
Rabinowitz teaches methods comprising obtaining genotypic data from one or both parents of the fetus; processing the first sample by purifying the DNA so as to obtain a second sample; measuring the DNA in the second sample at a set of polymorphic alleles; calculating, on a computer, allele ratios at the set of polymorphic alleles from the DNA measurements made on the second sample; creating, on a computer, a plurality of ploidy hypotheses concerning expected allele ratios at the set of polymorphic alleles on the chromosome for different possible ploidy states of the chromosome; and using a set of DNA probes designed to target loci where the loci have maximal minor allele frequencies including loci having the maximum likelihood of the fetus having a highly informative SNP at that loci; and calculating the fraction of fetal DNA using population frequencies to adjust the model on the probability on particular allele measurements.
Lo Yuk-Ming teaches methods for differentiating or detecting fetal DNA in a maternal sample, or to differentiate DNA of an organ donor from DNA of an organ recipient are known in the art including methods of detecting genetic abnormalities in a fetus by detecting fetal DNA in a biological sample obtained from a mother; and methods for differentiating DNA species originating from an organ donor from those of an organ recipient; and that differentiation between maternal and fetal DNA can be performed, wherein when the fetal DNA is quantified in maternal plasma or serum, the measured concentration can be used to predict, monitor or diagnose or prognosticate a pregnancy-associated disorder including a chromosomal aneuploidy.
Ehrich teaches method for the detection of specific polymorphic alleles in a mixed DNA populati0n was known in the art, comprising enriching the relative percentage of a given polymorphic allele that is exponentially amplifiable by PCR; and methods for selectively enriching target nucleic acid, for example, fetal nucleic acid in a maternal sample including for detecting fetal nucleic acid in a maternal sample; and that the relative enrichment of the target allele in the sample allows accurate detection of allele frequencies using practically any method of nucleic acid detection known including in transplant nucleic acid detection.
Donnenfeld teaches comparing screening efficacy for aneuploidy detection in ovum donor pregnancies were known in the art including performing aneuploidy risk calculations on the ovum donor.
Based on the discussion supra, the Examiner contends that the instant claim recite processes that are well-known, purely conventional, and routine in the art. Thus, the claims remain rejected.
Claim Rejections - 35 USC § 103
The rejection of claims 45-63 is maintained under 35 U.S.C. 103 as being unpatentable over Quake et al. (hereinafter “Quake”) (US Patent Application Publication No. 20110224087, published September 15, 2011; effective filing date October 26, 2010) in view of Wisneiwski et al. (hereinafter “Wisneiwski”) (International patent publication WO2010115016, published October 7, 2010).
Regarding claims 45, 51-54, 55 (in part), 61 (in part), 62 (in part) and 63, Quake teaches compositions and methods for simultaneously determining the presence or absence of fetal aneuploidy and the relative amount of fetal nucleic acids in a sample obtained from a pregnant female including the use of sequencing technologies and exploits the occurrence of polymorphisms to provide a streamlined noninvasive process applicable to the practice of prenatal diagnostics (Abstract). Quake teaches that the method enables the determination of fetal fraction and the determination of the presence or absence of fetal aneuploidy from a single diagnostic sequencing process, wherein the method allows for determining fetal fraction in a gender independent manner, which relies on quantification of alleles on multiple chromosomes, such that the noninvasive diagnostic method encompasses the use of next generation sequencing (NGS) technology that can be implemented in a streamlined and cost-effective process to provide noninvasive prenatal diagnoses of fetal aneuploidies with greater confidence (interpreted as encompassing identifying the presence of absence of fetal aneuploidy; fetal cfDNA; a first chromosome and at least a second chromosome; quantifying alleles including low and high frequency alleles; and interpreting NGS as interrogating, claims 45 and 55) (paragraph [0008]). Quake teaches that a method is provided for simultaneously determining aneuploidy and fetal fraction in a maternal sample comprising a mixture of fetal and maternal nucleic acid molecules, the method comprising: (a) enriching said mixture for a plurality of polymorphic target nucleic acids; (b) sequencing at least a portion of the enriched mixture obtained in step (a), wherein sequencing comprises providing a plurality of sequence tags; and (c) based on the sequencing, simultaneously determining the fetal fraction and the presence or absence of the fetal aneuploidy (interpreted as a maternal sample; interrogating by sequencing; and identifying the presence or absence of fetal aneuploidy, claims 45 and 55) (paragraph [0010]). Quake teaches that aneuploidy is a chromosomal aneuploidy that is selected from trisomy 8, trisomy 13, trisomy 15, trisomy 16, trisomy 18, trisomy 21, trisomy 22, monosomy X, and XXX, wherein determining the aneuploidy comprises calculating a chromosome dose based on the number of said sequence tags for a chromosome of interest and for a normalizing chromosome, and comparing said dose to a threshold value, while determining the fetal fraction comprises identifying at least one informative polymorphic site in the enriched mixture, and calculating the fetal fraction from that amount of fetal and maternal polymorphic sites in the enriched sample (interpreted as determining; comparing; threshold value; identifying and informative loci comprising maternal and fetal DNA, claims 45, 52, 53, 55, 61 and 62) (paragraph [0023]). Quake teaches that the fraction of fetal nucleic acids in the mixture of fetal and maternal nucleic acids is calculated for each of the informative allele (allelex) as follows:
(2 x ∑Feta! sequence tags for allelex)
% fetal fraction allelex = -------------------------------------------------------------------------------------- x 100
(∑Maternal sequence tags for allelex)
and the percent fetal fraction is calculated for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 30, at least 35, at least 40 or more informative allele, wherein the fetal fraction is the average fetal fraction determined for at least 3 informative alleles interpreted as identifying informative loci based on the frequence of alleles; comprising maternal and fetal DNA that differ in one or more alleles; calculating percent fetal cfDNA relative to both high and low frequency alleles, claim 51-55 and 61-63) (paragraph [0148]-[0149]). Quake teaches that the qualified chromosome doses serve as a basis for determining threshold values when identifying aneuploidies in test samples as described in Tables 2-4 (interpreted as encompassing threshold values, claims 45 and 55) (paragraph [0180]; and Tables 2-4). Quake illustrates in Figure 5 a flow chart that shows the process 500 whereby normalizing sequences e.g. normalizing chromosomes, are identified, and the presence or absence of an aneuploidy is determined, where (1) in step 510, a set of qualified maternal samples is obtained to identify qualified normalizing sequences e.g. normalizing chromosomes, and to provide variance values for use in determining statistically meaningful identification of an aneuploidy in test samples, such that a plurality of biological qualified samples are obtained from a plurality of subjects known to comprise cells having a normal copy number for any one sequence of interest e.g. a chromosome of interest such as a chromosome associated with an aneuploidy including where the qualified samples are obtained from mothers pregnant with a fetus that has been confirmed using cytogenetic means to have a normal copy number of chromosomes relative to the chromosome of interest; such that the biological qualified maternal samples can be biological fluid samples e.g. plasma samples, or any suitable sample as described above that contains a mixture of fetal and maternal cfDNA molecules (interpreted as comprising cell-free nucleic acids); (2) in step 520, at least a portion of each of all the qualified nucleic acids contained in the qualified maternal samples are sequenced to generate sequence reads of between 20 and 40 bp e.g. 36 bp, which are aligned to a reference genome, e.g. hg18, wherein the sequence reads comprise about 20 bp, about 25 bp, about 30 bp, about 35 bp to about 500 bp, wherein sequence reads are aligned to a human reference genome, and the reads that are uniquely mapped to the human reference genome are counted as sequence tags including at least about 3x 106 qualified sequence tags to at least about 50xl06 qualified sequence tags comprising between 20 and 40 bp reads are obtained from reads that map uniquely to a reference genome; (3) in step 530, all the tags obtained from sequencing the nucleic acids in the qualified maternal samples are counted to determine a qualified sequence tag density, wherein the sequence tag density is determined as the number of qualified sequence tags mapped to the sequence of interest on the reference genome; (4) in step 540, based on the calculated qualified tag densities, a qualified sequence dose for a sequence of interest is determined as the ratio of the sequence tag density for the sequence of interest and the qualified sequence tag density for additional sequences from which normalizing sequences are identified subsequently, such as doses for the chromosome of interest e.g. chromosome 21 , is determined as a ratio of the sequence tag density of chromosome 21 and the sequence tag density for each of all the remaining chromosomes i.e. chromosomes 1-20, chromosome 22, chromosome X, and chromosome Y (interpreted as a first chromosome and at least one second chromosome; calculating a percent fetal cfDNA in a sample; quantifying a relative frequency of alleles; and determining a frequency); (5) in step 545, a normalizing sequence e.g. a normalizing chromosome, is identified for a sequence of interest e.g. chromosome 21, in a qualified sample based on the calculated sequence doses (paragraphs [0126]-[0130]). Quake teaches that (1) in step 515, a test sample e.g. plasma sample, comprising fetal and maternal nucleic acids e.g. cfDNA, is obtained from a pregnant subject e.g. a pregnant woman, for which the presence or absence of a fetal aneuploidy needs to be determined (interpreted as providing a sample of fetal cfDNA in a maternal sample, claims 45 and 55); (2) in step 525, at least a portion of the test nucleic acids in the test sample is sequenced to generate millions of sequence reads comprising between 20 and 500 bp e.g. 36 bp., and as in step 520, the reads generated from sequencing the nucleic acids in the test sample are uniquely mapped to a human reference genome and are counted (interpreted as interrogating; and quantifying, claims 45 and 55); (3) in step 535, all the tags obtained from sequencing the nucleic acids in the test samples are counted to determine a test sequence tag density, wherein the number of test sequence tags mapped to a sequence of interest is normalized to the known length of a sequence of interest to which they are mapped to provide a test sequence tag density; (4) in step 550, based on the identity of at least one normalizing sequence in the qualified samples, a test sequence dose is determined for a sequence of interest in the test sample, wherein the sequence dose e.g. chromosome dose, for a sequence of interest in a test sample is a ratio of the sequence tag density determined for the sequence of interest in the test sample and the sequence tag density of at least one normalizing sequence determined in the test sample, wherein the normalizing sequence in the test sample corresponds to the normalizing sequence identified in the qualified samples for the particular sequence of interest (interpreted as comparing the relative frequency of nucleic acid regions in a first chromosome, to the relative frequency of nucleic acid regions of a second chromosome, claims 45 and 55); (5) in step 555, threshold values are derived from standard deviation values established for a plurality of qualified sequence doses, wherein accurate classification depends on the differences between probability distributions for the different classes i.e. type of aneuploidy, such that thresholds are chosen from empirical distribution for each type of aneuploidy e.g. trisomy 21 (interpreted as a sample comprising fetal cfDNA relative to a threshold value, claims 45 and 55); (6) in step 560, the copy number variation of the sequence of interest e.g. chromosomal or partial aneuploidy, is determined in the test sample by comparing the test sequence dose for the sequence of interest to at least one threshold value established from the qualified sequence doses (interpreted as comparing the relative frequency, claim 55); (7) in step 560, the calculated dose for a test sequence of interest is compared to that set as the threshold values that are chosen according to a user-defined threshold of reliability to classify the sample as a "normal" an "affected" or a "no call" in step 565 (interpreted as identifying the presence or absence of aneuploidy based on the relative differences in nucleic acid regions from a first and second chromosome, claims 45 and 55) (paragraphs [0138]-[0144]). Figure 5 is shown below:
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602
552
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Quake teaches that the diagnosis is made based on receiving the data from sequencing at least a portion of the mixture of the fetal and maternal nucleic acid molecules derived from a biological test sample e.g. a maternal plasma sample, computing from the sequencing data a normalizing chromosome dose for one or more chromosomes of interest, determining a statistically significant difference between the normalizing chromosome dose for the chromosome of interest in the test sample and a threshold value established in a plurality of qualified (normal) samples, and providing the prenatal diagnosis based on the statistical difference (interpreted as donor informative loci comprise maternal and fetal DNA that different in at least one or both alleles, claims 52, 53, 61 and 62) (paragraph [0145]). Quake teaches that the determination of the fetal fraction is based on the total number of tags that map to the first allele and the total number of tags that map to second allele at an informative polymorphic site e.g. a SNP, contained in a reference genome, wherein the reference genome is the human reference genome NCBI36/hg18 sequence, or the reference genome comprises the human reference genome NCBI36/hg18 sequence and an artificial target sequences genome, which includes the target polymorphic sequences, such as comprising SNPs rs560681 (SEQ ID NOS 1 & 2), rs1109037 (SEQ ID NOS 3 & 4), etc. (interpreted as interrogating two or more polymorphic nucleic acid regions, claims 51 and 55) (paragraph [0147]). Quake teaches that thresholds were calculated to be 2 standard deviations above and below the mean determined in the qualified samples (interpreted as encompassing threshold values between 1 to 5 percent, claims 45-50 and 55-60) (paragraph [0188]).
Regarding claims 46-50 and 56-60, Quake teaches that thresholds were calculated to be 2 standard deviations above and below the mean determined in the qualified samples (interpreted as encompassing threshold values between 1 to 5 percent, claims 45-50 and 55-60) (paragraph [0188]).
Quake does not specifically exemplify an egg donor (claim 55, 61, and 62, all in part); and specific threshold values (claims 46-50 and 56-60, all in part).
Regarding claims 46-50 (all in part) and 56-60 (all in part), Wisneiwski teaches methods and compositions to extract and enrich by, physical separation or amplification, relatively short nucleic acids from a nucleic acid composition containing a high background of longer nucleic acids (e.g., host or maternal nucleic acids; genomic nucleic acid and the like) (Abstract). Wisneiwski teaches an improved nucleic acid preparation compositions and methods suitable for enrichment, isolation and analysis of relatively short nucleic acid species targets, sometimes found in cell free or substantially cell free biological compositions containing mixed compositions (e.g., viral nucleic acid in host background, fetal nucleic acid in maternal background, mixed nucleic acid populations from environmental samples, and the like), and often associated with various disease conditions or apoptotic cellular events (e.g., cancers and cell proliferative disorders, prenatal or neonatal diseases, genetic abnormalities, and programmed cell death events), wherein the relatively short nucleic acid species targets, which can represent degraded or fractionated nucleic acids, can also be used for haplotyping and genotyping analysis, such as fetal genotyping for example (pg. 2, lines 13-22). Wisneiwski teaches that the term "amount" as used herein with respect to amplified nucleic acid species refers to any suitable measurement, including, but not limited to, copy number, weight (e.g., grams) and concentration (e.g., grams per unit volume (e.g., milliliter; molar units), wherein the ratio of fetal nucleic acid to maternal nucleic acid (or conversely maternal nucleic acid to fetal nucleic acid) can be used in conjunction with measurements of the ratios of mismatch sequences for determination of chromosomal abnormalities possibly associated with sex chromosomes; that is, the percentage of fetal nucleic acid detected in a maternal nucleic acid background or the ratio of fetal to maternal nucleic acid in a sample, can be used to detect chromosomal aneuploidies (pg. 38, lines 17-25). Wisneiwski teaches that amounts of amplified nucleic acid species within a set can vary up to a threshold level at which a chromosome abnormality can be detected with a confidence level of about 95% (e.g., about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or greater than 99%); or the amounts of the amplified nucleic acid species in a set vary by about 50% or less (e.g., about 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2 or 1%, or less than 1%) (interpreted as threshold values of 1 to 5 percent, claims 46-50 and 56-60) (pg. 38, lines 30-34). Wisneiwski teaches presence or absence of an outcome can be expressed in any suitable form, and in conjunction with any suitable variable, collectively including, without limitation, ratio, deviation in ratio,
that frequency, distribution, probability (e.g., odds ratio, p-value), likelihood, percentage, value over a threshold, or risk factor, associated with the presence of a outcome for a subject or sample, such that an outcome can be provided with one or more variables, including, but not limited to, sensitivity, specificity, standard deviation, probability, ratio, coefficient of variation (CV), threshold, score, probability, confidence level, or combination of the foregoing, in certain embodiments including a coefficient of variation (CV) in some embodiments is expressed as a percentage, and sometimes the percentage is about 10% or less (interpreted as threshold values of 1 to 5 percent, claims 46-50 and 56-60) (pg. 62, lines 33-34 and pg. 63, lines 1-5).
Regarding claims 55 (in part), 61(in part) and 62 (in part), Wisneiwski teaches that cell-free nucleic acid can originate from several sources, it has been demonstrated that one source of circulating extracellular nucleic acid originates from programmed cell death, also known as apoptosis, where the source of nucleic acid that arise as a result of apoptosis can be found in many body fluids and originate from several sources, including, but not limited to, normal programmed cell death in the host, induced programmed cell death in the case of an autoimmune disease, septic shock, neoplasms (malignant or non-malignant), or non-host sources such as an allograft (transplanted tissue), or the fetus or placenta of a pregnant woman, such that the applications for the detection, extraction and relative enrichment of extracellular nucleic acid from peripheral blood or other body fluids are widespread and can include inter alia, non-invasive prenatal diagnosis, cancer diagnostics, pathogen detection, auto-immune response and allograft rejection (interpreting transplanted tissue allograft, and the fetus or placenta of a pregnant woman to encompass a donated egg and an egg donor pregnancy, claims 55, 61 and 62) (pg. 7, lines 2-13).
“It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of an improved method of enriching cell-free nucleic acids containing mixed compositions of nucleic acids as exemplified by Wisneiwski, it would have been prima facie obvious at the time the invention was made to modify the method of simultaneously determining the presence or absence of fetal aneuploidy and the relative amounts of nucleic acids in a sample obtained from a pregnant female as disclosed by Quake to include the method of enriching cell-free nucleic acids that can originate from several sources for the detection of chromosome abnormalities such as fetal aneuploidy such as by selectively dissociating nucleic acids smaller than 300 nucleotides or base pairs, which can contain target nucleic acids as taught by Wisneiwski with a reasonable expectation of success in detecting fetal nucleic acids in maternal background and/or transplanted tissue; and/or in diagnosing the presence or absence of a fetal aneuploidy in the fetus of a pregnant female including aneuploidies such as trisomy 8, trisomy 13, trisomy 15, trisomy 16, trisomy 18, trisomy 21, trisomy 22, monosomy X, and XXX.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103 as obvious over the art.
Response to Arguments
Applicant’s arguments filed January 7, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) the combined references of Quake and Wisneiwski fail to teach all of the features recited in claims 45 and 55; accordingly, Applicant requests withdrawal of the rejections (Applicant Remarks, pg. 19, last partial paragraph through pg. 21, second full paragraph).
Regarding (a), Applicant pointed to the entirety of claims 45 and 55 as not being taught by the combined references of Quake and Wisneiwski. Thus, Applicant did not distinctly and specifically point out the supposed errors in the Examiner’s action as required by 37 CFR 1.111(b). The claims remain rejected for the reasons already of record.
Conclusion
Claims 45-63 are rejected.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684