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 .
Status of the Claims
Claims 1-3 and 5-14 are pending.
Claim 3 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 16 February 2023.
Claim 4 is canceled.
Claims 1-2 and 5-14 are examined herein.
Priority
As detailed on the date filing receipt, the application claims priority as early as 19 June 2015. At this point in examination, all claims have been interpreted as being accorded the priority date of the effective filing date: 19 June 2015.
Withdrawn Rejections
The rejection under 35 USC 102 is withdrawn in view of amendment requiring an aneuploidy risk assessment when the fetal fraction is 0.037 or less.
The following rejections constitute the complete sets of rejections for the application.
35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3 and 5-14 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of determining an aneuploidy risk score.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to a method, which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Mathematical concepts recited in claim 1 include “to determine an aneuploidy risk score,” where determining a score is interpreted as application of mathematical concepts to generate a numerical value. A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation (MPEP 2106.04(a)(2)). The claims are also interpreted as reading on a mental process, where determining a score may be data evaluation or judgment.
Claim 5 recites additional information about the risk score.
Claim 6 recites “transforming the determined fetal fraction distribution to logarithm space” where it is assumed to have a Gaussian distribution with a mean and standard deviation based on the data, which are mathematical concepts.
Claim 7 recites determining likelihood and an integral of a probability, which are both mathematical concepts.
Claims 8-10 recite additional information about the model.
Claim 11 recites grouping data and generating a distribution of parameters, which are interpreted as a step performed by the human mind and a mathematical step, respectively.
Claim 12 recites mathematical steps related to treatment of the average fetal fraction
Claim 13 recites additional information about the fetal fraction.
Claim 14 recites determining a fetal fraction distribution, which is interpreted as a mental process or mathematical concept. Claim 14 recites generating a model, determining a fetal fraction, and applying a Bayesian probability distribution, which are interpreted as a mathematical concept. Claim 14 recites outputting a score, which is interpreted as the result of a mathematical concept.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Claim 1 recites additional elements that are not abstract ideas: "extracting cell-free DNA,” “preparing a non-naturally occurring composition of amplified DNA” by amplifying targeted SNPs, and “analyzing… by performing high-throughput sequencing or a microarray assay.” Claim 2 recites “measuring genetic data” that was sequenced. Claim 14 recites receiving data and processors.
These claims are interpreted as required data collecting steps necessary to perform the mathematical steps of determining a risk score. Therefore, they are considered to be insignificant extra-solution activity (MPEP 2106.05(g)), which do not integrate the abstract ideas into a practical application. The use of processors are interpreted as use of a general purpose computer to perform the abstract ideas. Instructions to implement an abstract idea on a computer do not integrate the abstract ideas into a practical application (MPEP 2106.05(f)). [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Claim 1 recites additional elements that are not abstract ideas: "extracting cell-free DNA,” “preparing a non-naturally occurring composition of amplified DNA” by amplifying targeted SNPs, and “analyzing… by performing high-throughput sequencing or a microarray assay.” Claim 2 recites “measuring genetic data” that was sequenced. Claim 14 recites receiving data.
The specification states that “noninvasive prenatal testing [using cell-free DNA] is rapidly becoming part of clinical care for pregnant women" (pg. 1, paragraph [4]), that "methods are known in the art for obtaining genetic data from a sample" (pg. 4, paragraph [52]), and describes several commercially-available systems for high-throughput sequencing (pg. 10, paragraph [53]). Furthermore, the review by Canick (Prenatal Diagnosis 33: 667-674, 2013; previously cited on the 11 February 2022 IDS form) teaches sequencing SNPs to determine fetal fraction (pg. 668, col. 2, second paragraph). Canick teaches analyzing data from Infanet (pg. 668, col. 1, “Methods”), which is interpreted as receiving data on a computer. These elements were therefore well-understood, routine and conventional practices in the art prior to the time of invention. Further, the step of receiving information using a computer network is a conventional computer function (buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (MPEP 2106.05(d)).
Hence, these elements, when considered individually and in combination, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(d)). [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Response to the 22 December 2025 Applicant Remarks
Applicant remarks assert the instant claims represent an improvement to a technology at Step 2A Prong Two and an unconventional arrangement of additional elements at Step 2B. Neither argument is persuasive.
At Step 2A Prong Two, it is determined whether the judicial exception integrated into a practical application by additional elements (MPEP 2106.04(d)). Here, the elements in addition to the abstract ideas are "extracting cell-free DNA,” “preparing a non-naturally occurring composition of amplified DNA” by amplifying targeted SNPs, and “analyzing… by performing high-throughput sequencing or a microarray assay” (claim 1), “measuring genetic data” that was sequenced (claim 2), receiving data (claim 14), and processors (claim 14). As explained above, these elements are interpreted as insignificant extra-solution activity for data collecting (MPEP 2106.05(g)) and a general purpose computer to perform the tasks (MPEP 2106.05(f)) , neither of which integrate the abstract ideas into a practical application.
Applicant remarks state an analogy to Illumina v. Ariosa Diagnostics, 967 F.3d 1319 (Fed. Cir. 2020), where the instant claims are also directed to methods of DNA preparation by wet lab steps (pg. 6, first paragraph). This argument is not persuasive because, unlike the claims recites in Illumina v. Ariosa
Diagnostics, 967 F.3d 1319 (Fed. Cir. 2020), the instant claims do not modify the DNA based on a threshold to capitalize on a natural phenomenon. The wet lab steps are performed in the same way no matter the fetal fraction. The wet lab steps are extracting cfDNA, amplifying cfDNA, and sequencing cfDNA, which is not changed based on the fetal fraction. Furthermore, the fetal fraction is not known until after the sequencing step. Therefore, it is not clear that the elements in addition to the abstract ideas provide an improvement.
Applicant remarks state only mental processes described a high level with no limits on their performance are patent ineligible (pg. 7, second paragraph). However, the “tangible, biochemical steps” are not abstract ideas but the mathematical step of determining a score is. Determining the score is based at least on explicitly mathematical concepts, such as determining a likelihood based on Bayesian probability as found in claim 14 and evidenced by a numerical value representing the score (Fig. 8). Even if mental steps are claimed, the presence of elements in addition to the abstract ideas do not preclude them from being mental. The elements in addition to the abstract ideas are more specifically analyzed at Steps 2A Prong Two and 2B.
Applicant remarks state alleged improvements by the instant invention in the forms of determining an aneuploidy risk score for cell-free DNA having a fetal fraction of 0.037 or less. By doing so, the presently claimed invention successfully provides an unconventional method for determining genetic data for DNA in a mixed sample that does not require invasive biopsy, has higher sensitivity and accuracy than conventional histology-based diagnostics, and is performed non-invasively allowing mass screening and regular follow up, and results in lower cost and faster turnaround time than conventional genetic testing technology (pg. 9, first paragraph). However, all of these improvements are not provided by the elements in addition to the abstract ideas. As explained above, the additional elements appear to be used in the same way regardless of the fetal fraction, and the fetal fraction is not known until after the steps are completed. The fetal fraction is not determined prior to performing the extraction step, so it cannot be a distinguishing characteristic from conventional cfDNA processing.
At Step 2B, it is determined whether the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05). Applicant remarks state the additional elements are not routinely or conventionally used (pg. 6, second paragraph). Again, the elements in addition to the abstract ideas are "extracting cell-free DNA,” “preparing a non-naturally occurring composition of amplified DNA” by amplifying targeted SNPs, and “analyzing… by performing high-throughput sequencing or a microarray assay” (claim 1), “measuring genetic data” that was sequenced (claim 2), receiving data (claim 14), and processors (claim 14). As taught by at least Canick, amplifying and sequencing cfDNA are conventional in fetal fraction analysis in combination, or as a whole, as explained in the previous and above office action, not only individually as asserted (pg. 7, last paragraph). These steps are the same regardless of fetal fraction being greater than or less than 0.037, and therefore do not provide significantly more than the judicial exception. The recited steps of extracting cell-free DNA from a biological sample, amplifying a plurality of target loci from the extracted cell-free DNA, and sequencing the amplification products to produce genetic data for the target loci, and determining "an aneuploidy risk score for the cell-free DNA having a fetal fraction of 0.037 or less" (pg. 10, first paragraph) are interpreted as conventional as these steps are together taught by at least Canick. The fetal fraction of at most 0.037 would not be known until after the sequencing step; the prior additional elements are considered to be conducted conventionally as, at that point in the analysis, the fetal fraction would not be known. Therefore, it remains unclear why these elements are not conventional alone or in combination.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann (Prenatal Diagnosis 2012; on IDS of 11 February 2022) in view of Benn (Prenatal Diagnosis 34: 778-783, 2014; newly cited).
Claim 1 recites “extracting cell-free DNA having a fetal fraction of 0.037 or less from the target sample of maternal blood or plasma comprising both maternal and fetal cell-free DNA.” Zimmermann teaches obtaining a maternal blood sample from patients with aneuploid pregnancies (p. 1234, bot. of col. 1), and isolating cfDNA from those samples (abstract); at least one of the samples has a fetal fraction less than 0.037 (pg. 1235, Figs. 1 and 2).
Claim 1 recites “preparing a non-naturally occurring composition of amplified DNA” comprising “amplifying a plurality of targeted single nucleotide polymorphism (SNP) loci from the DNA extracted… to obtain amplified DNA derived from said targeted SNP loci, and performing a barcoding PCR to append a sample barcode onto the amplified DNA.” Zimmermann teaches “targeting sequencing of of 11,000 SNPs” (pg. 1234, col. 2, second paragraph), amplifying regions of the cfDNA that contain SNPs (abstract), thereby obtaining amplicons (i.e. "amplified DNA") and "samples were prepared for sequencing by adding barcoded tags in a third 12-cycle round of PCR" (Supplementary Information, pg. 1, second paragraph).
Claim 1 recites “analyzing the non-naturally occurring composition of amplified cell-free DNA by performing high-throughput sequencing or a microarray assay on the amplified DNA obtained… to determine an aneuploidy risk score for the cell-free DNA having a fetal fraction of 0.037 or less.” Zimmermann teaches “massively parallel shotgun sequencing” (pg. 1233, col. 2, last paragraph) and “an individualized risk score for each patient” (pg. 1234, col. 1, fourth paragraph) but not a score for individuals with a fetal fraction below said threshold.
Benn teaches non-invasive prenatal testing for aneuploidies, including a reported detection rate percentage for Down syndrome where the fetal fraction is 3%.
Claim 2 recites “measuring genetic data of the target sample from the non-naturally occurring composition of amplified DNA by high throughput sequencing.” Zimmermann teaches “data generated from high-throughput cfDNA sequencing” (pg. 1235, col. 2, second paragraph).
Claim 13 recites “the fetal fraction of cell-free DNA is between 0.013 and 0.037.” Zimmermann teaches at least one of the samples has a fetal fraction between 0.013 and 0.037 (p. 3, Fig. 1). However, as the fetal fraction is an inherent characteristic of the extracted cfDNA, and does not represent a patentable difference.
Combining Zimmermann and Benn
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Zimmermann, which teaches cfDNA amplification and sequencing to determine a risk score, with the work of Benn, which teaches determining a risk of Down Syndrome at a fetal fraction of 3%, because Benn teaches a sufficient depth of sequencing allows conclusions to be drawn from fetal fractions below 4%, which was previously considered to be a test failure (pg. 781, col. 1, last paragraph). Therefore, performing risk assessment where the fetal fraction is below 0.037 would be expected to succeed. Zimmermann and Benn are both directed to the common field of endeavor of non-invasive prenatal aneuploidy screening, and their combination is prima facie obvious.
Claims 5-6, 8–12 and 14
Claims 5-6, 8–12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann in view of Benn as applied to claims 1-2 and 13 above, and further in view of Kim (Prenatal Diagnosis 35: 810-815, 2015; previously cited on the 26 August 2025 PTO-892 form), Ashoor (Ultrasound in Obstetrics and Gynecology 2013; previously cited), and Quinn (Experimental Design and Data Analysis for Biologists 2002; previously cited).
Claim 5 recites “the previously determined risk score is a SNP based risk score.” Zimmermann teaches “targeted sequencing of 11,000 SNPs” (pg. 1235, col. 2, second paragraph).
Claim 6 recites “transforming the determined fetal fraction distribution to logarithm space, wherein a logarithm of the fetal fraction is assumed Gaussian distributed with a mean and standard deviation that are a function of gestational age and maternal weight for the known prenatal testing samples.” Zimmermann does not teach such a transformation.
Quinn teaches log-transforming the fetal fraction data, and that both square root and log transformations make right-skewed data more normal. Ashoor teaches that the transformed data are normally distributed (p. 28, Fig. 1). The maternal weight and gestational age coefficients in the model describe the effect that these factors have on the mean and standard deviation of the fetal fraction distribution; e.g. each kg of maternal weight subtracts 0.015 from the mean of the fetal fraction distribution.
Claim 8 recites “the generated model is associated with trisomy 13.” Zimmermann teaches application to trisomy 13 (pg. 1235, col. 2, last paragraph).
Claim 9 recites “the generated model is associated with trisomy 18.” Zimmermann teaches application to trisomy 18 (pg. 1235, col. 2, last paragraph).
Claim 10 recites “the generated model is associated with maternal triploidy.” Zimmermann teaches application to maternal triploidy (pg. 1235, col. 2, last paragraph).
Claim 11 recites “determining a fetal fraction distribution for the received known genetic data comprises: grouping the genetic data for the at least 50 known prenatal testing samples into sets according to gestational age and maternal weight; and generating a grid of distribution parameters corresponding to each set, wherein the distribution parameters include average fetal fraction and standard deviation.”
Ashoor teaches that the maternal and fetal characteristics can be binned (i.e. "grouping … into sets"), and corresponding fetal fraction distribution characteristics created for each bin (e.g. p. 30, Tables 3 and 4), which in the case of normal or log-normal distributions would be the mean and standard deviation.
Claim 12 recites “the fixed rate reduction in the average fetal fraction correspond to a constant subtracted offset as determined by analysis of empirical data.”
Ashoor teaches that some of the model coefficients (e.g. maternal weight) are negative; i.e. they are a "subtracted offset … determined by analysis of empirical data". When the fetal fraction distribution characteristics are binned (see above), their effects are turned into constants; i.e. they become "a constant subtracted offset…determined by analysis of empirical data". In Table 3, the median estimated fetal fraction decreases as weight increases, suggesting that, for a particular maternal weight, some empirically-derived constant should be subtracted from the expected fetal fraction.
Claim 14 recites “receiving, by one or more processors, known genetic data from at least 50 known noninvasive prenatal testing samples, wherein gestational age and maternal weight are known for the 50 known noninvasive prenatal testing samples.” Zimmermann teaches 145 samples with gestational age (Table 1) but does not teach weight.
Claim 14 recites “receiving, by the one or more processors, the genetic data for the target sample measured by high throughput sequencing or the microarray assay, and a gestational age, a maternal weight, and a fetal fraction associated with the target sample.” Zimmermann teaches sequencing of sample data (pg. 1234, col. 2, third paragraph) and gestational age (Table 1) but not maternal weight.
Claim 14 recites “determining, by the one or more processors, a fetal fraction distribution for the received known genetic data based on the gestational age and the maternal weight associated with the target sample.” Zimmermann teaches a fetal fraction distribution (Figure 2) and gestational age (Table 1) but does not take weight into account.
Claim 14 recites “generating, by the one or more processors, a model for a plurality of ploidy states based on a fixed rate reduction of the determined fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight associated with the target sample.”
Claim 14 recites “determining, by the one or more processors, a fetal fraction based data likelihood for the target sample for each of the plurality of ploidy states using the generated model and the fetal fraction associated with the target sample.” Zimmermann does not teach generating a likelihood based model.
Claim 14 recites “applying, by the one or more processors, a Bayesian probability determination to combine each fetal fraction based data likelihood with a previously determined risk score as a conditional value.” Zimmermann teaches “a Bayesian-based maximum likelihood statistical method” (abstract) and a “prior age-specific aneuploidy risk” (pg. 1237, col. 2, first paragraph).
Claim 14 recites “outputting, by the one or more processors, the aneuploidy risk score for the target sample based on the applying.” Zimmermann teaches “an individualized risk score for each patient” (pg. 1234, col. 1, fourth paragraph).
Kim teaches training a model based on data from 25,312 pregnant women (abstract).
Ashoor teaches that various maternal and fetal characteristics affect the fraction of fetal nucleic acid in a maternal blood sample. Among these characteristics are maternal weight, gestational age, and the fetal karyotype (p. 29, Table 2); i.e., presence of aneuploidies.
In the model of Ashoor, "the measured fetal fraction was square root (√) transformed to make the distribution Gaussian" (p. 27 § "Statistical analysis"). Hence, the terms in the linear model do not constitute "fixed ratio reduction of the fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight".
Quinn teaches that log transformation of data is a straightforward substitute for the square root transformation (p. 64 § 4.3), and has the added benefit of easy interpretation of the coefficients of a linear model: additive effects in a model with log-transformed responses are equivalent to multiplicative effects in the untransformed responses (p. 67 § 4.3.3).
Combining Zimmermann, Benn, Kim, Ashoor, and Quinn
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention.
Zimmermann teaches a statistical model using an algorithm incorporating data quality (pg. 1234) and modeled a relationship between at least fetal fraction and gestational age (Figure 1). Benn teaches weight having a correlation with fetal faction (pg. 781, col. 1, first paragraph). Together, these are taken to teach that early gestational age or heavier patients may affect quality of the Parental Support algorithm’s output. Therefore, it is considered to be prima facie obvious for a model aiming to produce accurate results, as that of Zimmermann, to use maternal age and weight in fetal fraction distributions, where subjects’ ages and weights are taught by Zimmermann and Ashpoor.
One would have been motivated to combine Ashoor and Quinn because Quinn teaches that the linear modeling method of Ashoor can be improved by replacing the √-transformed fetal fraction measurements with log-transformed fetal fraction measurements. Both transformations mitigate right skew, but a linear model based on log-transformed data is much more readily interpretable: the additive effects in log-space are equal to multiplicative effects in untransformed space, or in other words, "a fixed ratio reduction of the determined fetal fraction distribution compared to [the] expected average fetal fraction" for effects including gestational age and maternal weight (cf. Specification ¶ 0046: "In an embodiment for a log-normal distribution of fetal fraction, a fixed rat[io] reduction in the average fetal fraction corresponds to a constant subtracted offset").
Zimmermann teaches that the data model needs an accurate estimate of expected fetal fraction. The model of Ashoor and Quinn teaches how to estimate an expected fetal fraction for a specific woman, based on characteristics including her weight and gestational age. Zimmermann teaches that the ploidy hypotheses are calculated from the data "using standard Bayesian statistical techniques" (p. 3, ll. 15–16), and adapting Bayesian models to include additional evidentiary parameters (e.g. maternal weight and gestational age) is within the ordinary skill in the art. Modifying the fetal aneuploidy testing method of Zimmermann to include the improvements taught by Ashoor and Quinn with necessarily result in steps including "determining a fetal fraction distribution for the received known genetic data based on the gestational age and the maternal weight" using the linear model of log-fetal fraction, and "generating a model for a plurality of ploidy states based on a fixed ratio reduction of the determined fetal fraction distribution compared to an expected average fetal fraction for the gestational age and the maternal weight associated with the target sample" by including these characteristics in the Bayesian calculation.
Further combination with Kim would be motivated by the significantly larger training set taught by Kim in comparison to Zimmermann, where the former uses samples from pregnant women for its training. Kim teaches such training is straightforward (pg. 810, col. 2, last paragraph) and it can be reasonably expected that more training data improves the resulting model. Kim and Zimmermann are both drawn to estimating fetal fraction.
Therefore, the invention is prima facie obvious.
Claim 7
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zimmermann, Benn, Kim, Ashoor, and Quinn as applied to claims 1 and 5-14 above, as evidenced by Dodge (Concise Encyclopedia of Statistics 2008; cited previously).
Claim 7 recites “determining a fetal fraction based data likelihood for the target sample comprises determining an integral of a probability density function of the generated model.”
The combination of Zimmermann, Kim, Ashoor and Quinn teaches a method of calculating the likelihood of fetal aneuploidy using a Bayesian model, but does not explicitly teach that this procedure "comprises computing an integral of the probability density of the generated model". But Dodge teaches that calculating Bayes theorem with variables having continuous density function — which is the case with the model of Zimmermann, Ashoor and Quinn, in which expected fetal fraction is a continuous variable with log-normal distribution — requires calculating the integral of the density function of the variable (p. 31 § "Mathematical Aspects"). So the step of "computing an integral" is inherent in the combined method of Zimmermann, Benn, Ashoor and Quinn.
Response to the 22 December 2025 Applicant Remarks
Applicant remarks state aneuploidy risk score is determined "for the cell-free DNA having a fetal fraction of 0.037 or less" and this differs from Zimmerman where the risk score is not determined for fetal fraction levels below 4%. Zimmerman teaches determining a fetal fraction in the 2-4% range (pg. 1234, Fig. 2) but not generating a score. Benn teaches generating a percent risk of Down Syndrome, which is an aneuploid condition, based on 3% fetal fraction, and thus the combination of Zimmermann and Benn teaches the requirements of claim 1.
Regarding claim 14, applicant remarks state although Ashoor reports gestational age and maternal weight as sample characteristics and observes correlations between these variables and fetal DNA fraction, Ashoor does not teach or suggest using gestational age or maternal weight to generate fetal-fraction distributions, nor does it incorporate these covariates into any modeling workflow. Ashoor merely provides observational correlations, not an algorithm or modeling approach (pg. 13, second paragraph). This argument is not persuasive because Zimmermann teaches a statistical model using an algorithm incorporating data quality (pg. 1234, col. 2, second paragrah) and modeled a relationship between at least fetal fraction and gestational age (Figure 1). Benn teaches weight having a correlation with fetal faction (pg. 781, col. 1, first paragraph), where weight may cause test failure by upsetting the expected fetal fraction, and thus is an quality issue. Together, these are taken to teach that early gestational age or heavier patients may affect quality of the Parental Support algorithm’s output. Therefore, it is considered to be prima facie obvious for a model aiming to produce accurate results, as that of Zimmermann, to use maternal age and weight in fetal fraction distributions, where subjects’ ages and weights are taught by Zimmermann, Benn, and Ashpoor.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/243593 (reference application) in view of Zimmermann and Benn.
The reference application teaches extracting cf-DNA from multiple individuals and amplifying loci. Zimmermann also teaches extracting cell-free DNA from multiple individuals in form of cell-free DNA isolation from maternal blood, which includes maternal and fetal DNA (abstract). Zimmermann teaches targeted amplification of more than 50 loci (pg. 1234, col. 2, second paragraph).
The reference application teaches sequencing the amplicons at claim 2.
The reference application does not teach determining a risk score where a fetal fraction value is at most 0.037. Zimmermann teaches determining a risk score where the fetal fraction is greater than 4%, and Benn teaches determining a risk for an aneuploidy condition where the fetal fraction is 3%.
Claims 1 and 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 23 of copending Application No. 17/413464 (reference application in view of Zimmermann and Benn.
Instant claim 1 recites extracting cell-free DNA, which is taught by reference claim 23.
Instant claim 1 recites amplifying SNP data, which is taught by reference claim 16 as amplifying SNVs.
Instant claim 1 recites sequencing the amplicons, which is taught by reference claim 16.
The reference application does not teach determining a risk score where a fetal fraction value is at most 0.037. Zimmermann teaches determining a risk score where the fetal fraction is greater than 4%, and Benn teaches determining a risk for an aneuploidy condition where the fetal fraction is 3%.
Claims 1 and 2 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/747138 (reference application).
Instant claim 1 recites extracting cell-free DNA from a maternal blood sample comprising fetal and maternal DNA; this is taught by reference claim 1.
Instant claim 1 recites amplifying and sequencing said cfDNA; these are taught by reference claim 1.
The reference application does not teach determining a risk score where a fetal fraction value is at most 0.037. Zimmermann teaches determining a risk score where the fetal fraction is greater than 4%, and Benn teaches determining a risk for an aneuploidy condition where the fetal fraction is 3%.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented. The above provisional applications teach the data generating wet lab steps of the instant application. As has been previously put forth, the fetal fraction percent is not a distinguishing characteristic as it is does not materially affect the performance of the wet lab steps and is unknown until after the method is initiated. Further applying sequencing depth to determining aneuploidy risk for low fetal fraction, as taught by Benn, and determining a risk score, as taught by Zimmermann, would be obvious to combine with the reference applications, which generate cell-free DNA from multiple individuals, who may be mother and fetus, as the ratio of genotypes of the individuals in the form of a fetal fraction is informative for non-invasive aneuploidy screening.
Response to the 22 December 2025 Applicant Remarks
Applicant remarks state none of the claims of the cited applications teach determining an aneuploidy risk score for cell-free DNA having a fetal fraction of 0.037 or less from the target sample of maternal blood or plasma comprising both maternal and fetal cell-free DNA and thus the claims are non-obvious over the cited references (pg. 14, second paragraph). However, previously cited art by Zimmermann and Benn together teach cfDNA amplification and sequencing to determine aneuploidy risk at a fetal fraction of 3%, and such a combination with the reference application would be obvious because the reference applications teach generating cell-free DNA from multiple individuals, who may be mother and fetus, as the ratio of genotypes of the individuals in the form of a fetal fraction is informative for non-invasive aneuploidy screening. Therefore, the non-statutory double patenting rejections are maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/R.J.K./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685