DETAILED ACTION
Applicant’s response, filed 01 Oct. 2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01 Oct. 2025 has been entered.
Status of Claims
Claims 22-27 and 39-53 are canceled.
Claims 54 is newly added.
Claims 1-21, 28-38, and 54-55 are pending.
Claims 8-9, 15-17, 28, 30, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 Dec. 2022.
Claims 1-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-55 are rejected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 27 June 2025, 09 Sept. 2025, and 14 Nov. 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, cited references were considered by the examiner.
Claim Interpretation
Claims 1, 11, and 21 recite “…at least a portion of the plurality of cell-free DNA fragments are blunt-ended”, which is interpreted to mean that both sides of each DNA fragment of the portion is blunt-ended.
Claims 1, 11, and 21 recite a “sequence motif”, which is defined at Applicant’s specification at para. [0062] to mean a recurring pattern of bases in DNA fragments that occurs at an end of a fragment and thus be part of or include an ending sequence.
Claims 1 ,11, and 21 recite an “end motif”, which is defined at Applicant’s specification to refer to a sequence motif for an ending sequence which can occur just before or just after ends of a fragment.
Claims 1, 11, and 21 recite “to determine… a collective property of the end motif pattern…”. Applicant’s specification at para. [0059] defines an aggregate value to refer to a collective property of a set of end motifs, such as a mean, median, etc. Applicants specification does not mention a collective property elsewhere in the specification, and thus the “collective property” is considered synonymous to an aggregate value as defined.
Claim 2 recites “…filtering the cell-free DNA to identify the plurality of cell-free DNA fragments.”. In light of Applicant’s specification at para. [0228]-[0232], which describes various ways the DNA fragments can be filtered based on information determined after sequencing (e.g. read location, methylation metrics, sequence variations), the filtering step is interpreted to be an in-silico filtering of the cell-free DNA fragments.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-55 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1, 11, and 21 being representative) is directed to a method. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claims 1, 11, and 21 recite the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
for each of the plurality of cell-free DNA fragments, determining…. a sequence motif for each of one or more ending sequences of the cell-free DNA fragment;
determining….an end motif pattern of a set of one or more sequence motifs corresponding to the ending sequences of the ends of the plurality of cell-free DNA fragments, wherein the end motif pattern is determined using a respective plurality of cell-free DNA fragments that have an ending sequence corresponding to each sequence motif of the set;
training a machine learning model using reference end motif patterns of reference samples having known classifications of the level of the pathology;
processing, using the machine learning model, the end motif pattern to determine a collective property of the end motif pattern of the set of one or more sequence motifs; and
determining a classification of the level of the pathology for the subject based on a comparison of the collective property to a reference value (claim 1 only); and
determining a classification of the clinically-relevant DNA in the biological sample by comparing the collective property of the end motif pattern to one or more calibration values determined from one or more calibration samples whose fractional concentration of clinically-relevant DNA are known (claim 11);
Claim 21 further recites the following steps which fall under the mental processes groupings of abstract ideas:
obtaining one or more calibration data points, wherein each calibration data point specifies a calibration gestational age corresponding to a calibration collective property, and wherein the one or more calibration data points are determined from a plurality of calibration samples with known gestational ages and including cell-free DNA molecules;
comparing the collective property of the end motif pattern to the calibration value of at least one calibration data point; and estimating the gestational age of the fetus based on the comparing.
The identified claim limitations falls into the group of abstract ideas mental processes for the following reasons. In this case, the steps of determining a sequence motif for each of 1,000 cell-free DNA fragments encompasses reading each fragment read to determine the last N number of bases of each read, which is a mental process. Furthermore, determining an end motif pattern of a set of one or more sequence motifs can be practically performed in the mind by summing a number of reads with the respective motif by the total number of reads. Determining a collective property of the end motif pattern can be performed mentally by summing relative frequencies of the one or more sequence motifs. With respect to claim 21, obtaining calibration data points for calibration samples, encompasses repeating the above operations of determining an end sequence motif pattern and collective property for samples with known gestational ages, which can be performed mentally as discussed above. Last, determining a classification by comparing a collective property to a calibration, or reference value, encompasses merely performing data comparisons which can be practically performed in the mind. That is, other than reciting the limitations are performed by a computer system, nothing in the claims precludes the steps from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
The steps of training a machine learning model using reference end motif patterns of reference samples having known classifications of the level of the pathology or known gestational ages and determining a collective property using the machine learning model further recite a mathematical concept. Training a machine learning model using end motif patterns (e.g. numerical values) encompasses training a logistic regression model, which amounts to a textual equivalent to inputting numbers into a regression model, performing mathematical calculations (e.g. multiplication, division, addition) to calculate a model output, calculating a loss function, adjusting model parameters and repeating the process. Similarly, applying a trained machine learning model encompasses simply inputting numerical values of the end motif pattern into the regression model and performing mathematical calculations to determine the output of a collective property, which encompasses a mathematical aggregate value of a probability as disclosed in the specification (see Applicant’s specification at para. [0066] and [0233]). Therefore, these limitations further recite a mathematical concept. See MPEP 2106.04(a)(2) I.
Last, claims 1 and 11 further recite a law of nature of a natural correlation between frequencies of end sequence motifs and a level of pathology or clinically-relevant DNA (i.e. an amount of disease). Similarly, claim 21 recites the law of nature of a natural correlation between a frequency of end motifs and gestational age. See MPEP 2106.04(b).
Dependent claims 2-7, 10, 12-14, 18-20, 29, 31-35, 37-38, and 54-55 further recite an abstract idea and/or are part of the judicial exception. Dependent claim 2 further recites the mental process of filtering fragments. Dependent claim 3 further recites the mental process of filtering based on a size of, or a region from which the DNA fragment is derived. Dependent claim 4 further recites the mental process of filtering the DNA fragments for open chromatin regions of a particular tissue. Dependent claims 5-6 further limit the classification of the pathology to be for a cancer from the group of cancers in claim 6. Dependent claim 7 further limits the classification to be determined from a plurality of levels of cancer. Dependent claim 10 further limits the classification to be for a fractional concentration of clinically-relevant DNA. Dependent claim 12 further limits the classification to be for a fractional concentration of fetal DNA, tumor DNA, DNA from a transplanted organ, or a tissue type. Dependent claims 13-14 further limit the classification to be for clinically relevant DNA of a particular tissue type of liver or hematopoietic. Dependent claim 18 further limits the comparison to be with one or more aggregative values of relative frequencies from one or more calibration samples. Dependent claim 19 further recites the abstract idea of measuring fractional concentrations of clinically relevant DNA in the calibration sample and determining an aggregate value of relative frequencies by analyzing cell-free DNA fragments from the calibration sample. Dependent claim 20 further limits the mental process of claim 19 to determine the fractional concentration using an allele specific to the clinically relevant DNA. Dependent claims 29 and 31 further limit the step of determining relative frequencies to be for a set of one a top M sequence motifs with a largest difference between two reference samples having different classifications for the level of pathology. Dependent claim 32 further limits the step of determining relative frequencies to be a top M most frequent sequence motifs. Dependent claims 33-34 further limit the step of determining relative frequencies to be for a plurality of sequence motifs and the aggregative value to be a weighted sum of the relative frequencies of the set, and thus additionally recite a mathematical concept of determining a weighted sum. Dependent claim 35 further limits the aggregate value to include an entropy term which includes a sum of terms multiplied by a logarithm of the relative frequency, and thus also further recites a mathematical concept. Dependent claims 37-38 further limit the abstract idea of determining the aggregate value to be from a machine learning model of clustering, support vector machines, or logistic regression, which also recites a mathematical concept. Dependent claim 54 further limits the set of one or more sequence motifs to be 7 bases or less, and thus is part of the mental process of claim 1. Dependent claim 55 further limits the mental process of performing classification to indicate a presence of cancer. Therefore, claims 1-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-55 recite an abstract idea and/or law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 2-7, 10, 12-14, 18-20, 29, 31-35, 37-38, and 54 do not recite any elements in addition to the judicial exception and thus are part of the judicial exception.
The additional elements of claims 1, 11, and 21 include:
a computer system;
performing an assay on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended;
and wherein the plurality of cell-free DNA fragments include at least 1,000 cell free DNA fragments.
The additional element of claim 55 includes:
performing imaging of the subject to detect a presence of a tumor.
Regarding the computer system, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Regarding the step of performing an assay on cell-free DNA fragments, including blunt-ended fragments, to obtain sequence reads (i.e. performing sequencing), this step only serves to collect read information for use by the abstract idea, and thus amounts to insignificant extra-solution activity, which does not integrate the recited judicial exception into a practical application.
Last, performing imaging of the subject to detect the presence of a tumor amounts to insignificant extra-solution activity and mere instructions to apply the exception. First, merely imaging the subject to detect the presence of a tumor after the judicial exception indicates the presence of cancer only serves to confirm the determination already made by the abstract idea, which amounts to an insignificant application that is nominally related to the invention, similar to printing or downloading generated menus in Ameranth, 842 F.3d at 1241-42, 120 USPQ2d at 1854-55. See MPEP 2106.05(g). Furthermore, MPEP 2106.05(f) explains the recitation of claim limitations that attempt to cover any solution to an identified problem with no restriction on how the result is accomplished and no description of the mechanism for accomplishing the result, does not integrate a judicial exception into a practical application or provide significantly more because this type of recitation is equivalent to the words "apply it". See Electric Power Group, LLC v. Alstom, S.A., 830 F.3d 1350, 1356, 119 USPQ2d 1739, 1743-44 (Fed. Cir. 2016). See MPEP 2106.05(f). Here, claim 55 merely states the classification “indicates the presence of cancer” and then requires detecting the presence of the tumor. However, claim 55 does not provide any details regarding how the classification indicates the presence of cancer, and instead merely states the classification indicates cancer and then detects cancer by imaging. Therefore, the additional element amounts to mere instructions to apply the exception.
Therefore, the additionally recited elements amount to mere instructions to apply the exception and/or amount to insignificant extra-solution activity and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-55 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception.
Dependent claims 2-7, 10, 12-14, 18-20, 29, 31-35, 37-38, and 54 do not recite any elements in addition to the judicial exception and thus are part of the judicial exception.
The additional elements of claims 1, 11, and 21 include:
a computer system;
performing an assay on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended;
and wherein the plurality of cell-free DNA fragments include at least 1,000 cell free DNA fragments.
The additional element of claim 55 includes:
performing imaging of the subject to detect a presence of a tumor.
Regarding the computer system used to implement the abstract idea, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Regarding the additional element of sequencing cell-free DNA fragments including blunt-ended fragments, Grace et al. (Cell-free DNA Screening: Complexities and Challenges of Clinical Implementation, 2016, Obstet Gynecol Surv., 71(8), pg. 477-487; previously cited). Grace reviews screening using cell-free DNA (Abstract), and discloses commercial laboratories utilize whole genome sequencing of cell-free DNA in plasma samples (Abstract; pg. 11, para. 2; pg. 12, para. 3). Applicant’s specification at para. [0158] further discloses the sequencing of cell-free DNA fragments, which may include blunt-end fragments, can be performed in a variety of ways and that skilled person will appreciate the variety of sequencing techniques that may be used, demonstrating the conventionality of the additional element. Therefore, the additional element is not sufficient to amount to significantly more than the judicial exception.
The additional element of imaging the subject to detect a presence of a tumor is well-understood, routine, and conventional. This position is supported by Zhang et al. (Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes, 2017, 41, pg. 755-768; newly cited), Cheng et al. (Circulating cell-free DNA and circulating tumor cells, the “liquid biopsies” in ovarian cancer, 2017, Journal of Ovarian Research, 10:75, pg. 1-10; newly cited), Gorgannezhad et al. (Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies, March 2018, Lab Chip, 18, pg. 1174-1196; newly cited), and Heitzer et al. (Circulating tumor DNA as a liquid biopsy for cancer, 2015, Clinical Chemistry, pg. 112-123; newly cited), and
First, Zhang reviews liquid biopsies for analyzing cell-free DNA in cancer (Abstract) and discloses traditional biomarkers and imaging techniques play important roles in tumor diagnosis (pg. 755, para. 1), and that imaging, including ultrasound, CT, or MRI, remains the gold standard in solid tumor screening and monitoring (pg. 759, para. 3). Zhang further discloses a combination of circulating tumor cell detection with imaging is a better choice than either alone (pg. 759, para. 3). Cheng reviews the use of serial monitoring of tumor genotypes with circulating cell-free (cf) DNA (Abstract), and that for ovarian cancer, cf-DNA may be used as an adjuvant diagnostic method for ovarian cancer, and the use of cf-DNA as a combination application tool along with ultrasound imaging to diagnose ovarian cancer. Gorgannezhad reviews detection technologies of circulating tumor DNA and liquid biopsies in diagnosis of cancer patients (Abstract), and discloses analysis of cell-free DNA allows for early diagnosis of cancer 5 months before being confirmed by imaging (Table 2). Gorgannezhad further discloses imaging studies are required to analyze clinical progression and/or therapeutic resistance in better detail (pg. 1193, col. 2, para. 2). Last, Heitzer similarly reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses sequencing analysis of plasma DNA and biopsies in combination with imaging studies are needed to assess clinical progression (pg. 121, col. 1, para. 2). Therefore, the use of imaging to detect a tumor is well-understood, routine, and conventional, even considered in combination with performing an assay on cell-free DNA.
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 02 April 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Step 2A, Prong 1:
Applicant remarks, regarding the “…determining…a sequence motif….”, “determining…one or more relative frequencies…”, “determining an aggregate value…”, and “determining a classification…”, that whether some of the claimed steps can be performed in the human mind is not determinative, and the question is whether the claimed invention “could not, as a practical matter, be entirely performed in the human mind” (Applicant’s remarks at pg. 10, para. 4 to pg. 11, para. 3).
This argument is not persuasive. An explanation regarding why each of the above limitations can be practically performed in the mind is provided in the above rejection.
Applicant remarks that determining relative frequencies of sequence motifs and determining an aggregate value at best merely involve a mathematical concept, but does not recite the mathematical concept itself in the claim, and that the Examiner’s position removes the guideline that merely involving a mathematical concept is insufficient, and further remarks the claims have been amended to remove this language regardless (Applicant’s remarks at pg. 11, para. 4 to pg. 12, para. 3).
This argument is not persuasive. First, the claims no longer recite “determining relative frequencies” so this is not classified as reciting a mathematical concept in the above rejection. Furthermore, while Applicant has amended the “aggregate value” to instead recite a “collective property”, MPEP 2106.04(a)(2) I. C. explains there is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.
In the instant case, the singular mention of “collective property” in Applicant’s specification is within a definition of the “aggregate value” at para. [0066], stating “An ‘aggregate value’ may refer to a collective property…Examples include a mean, a median, a sum of relative frequencies, a variation…”. Applicant is merely using a different set of words to describe the previously recited aggregate value, but the claimed “collective property” still clearly encompasses a mathematical concept for the same reasons previously discussed regarding the “aggregate value” and for the reasons discussed above. It is not persuasive that determining a “collective property” encompassing a mean, median, etc., with no other non-mathematical embodiments described in the specification, does not recite a mathematical concept. Determining a mean or median does not merely “involve” math, but is math. Applicant is merely using words as a replacement for a mathematical calculation, and thus the claim recites a mathematical concept.
Applicant remarks the steps of “determining…an end motif pattern”, “processing, using the machine learning model…”, “determining a classification of the level…” do not recite a mathematical concept, and then points to the “training the neural network…” from example 39, and that the limitations of the claims are analogous to the limitations from example 39 because they do not require specific mathematical calculations (Applicant’s remarks at pg. 12, para. 4 to pg. 14, para. 1).
This argument is not persuasive. As explained above, MPEP 2106.04(a)(2) I. C. explains there is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation. The instant claims merely recite “processing, using the machine learning model the end motif pattern to determine a collective property…”, which encompasses inputting numbers into a linear regression model to determine the collective property (i.e. aggregate value, as defined above). This is not analogous to training a neural network on digital facial images as in example 39.
Applicant remarks that claim 1 has been amended to recite “…training a machine learning model”, which cannot be performed in the mind and is not directed to math (Applicant’s remarks at pg. 14, para. 2).
This argument is not persuasive. As explained above, training a machine learning model using end motif patterns (e.g. numerical values) encompasses training a logistic regression model, which amounts to a textual equivalent to inputting numbers into a regression model, performing mathematical calculations (e.g. multiplication, division, addition) to calculate a model output, calculating a loss function, adjusting model parameters and repeating the process.
Applicant remarks that claim 55 recites “performing imaging of the subject…” which does not recite an abstract idea (Applicant’s remarks at pg. 14, para. 3).
It is agreed performing imaging is an additional element, rather than part of the abstract idea, as addressed in the above rejection.
Step 2A, Prong 2:
Applicant remarks that training a machine learning model is an additional element that integrates the judicial exception into a practical application by improving a technology, because the machine learning model is improved and can more accurately detect a pathology as in Cardio Net I (Applicant’s remarks at pg. 14, para. 5 to pg. 15, para. 2).
This argument is not persuasive. It is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. Furthermore, it is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements. See MPEP 2106.05(a). The alleged improvement in detecting a pathology amounts to an improved abstract idea, which is not a technology.
In addition, the step of training a machine learning model is part of the abstract idea, and thus cannot provide the improvement. It is noted that even if the “training” was considered an additional element, at best, this would serve to generally link the abstract idea of determining a collective property from the set of end motifs to the technological environments of neural network, which is not a practical application. See MPEP 2106.05(h) and also claim 2 of Example 47, which explains ““using a trained ANN” in limitations (d) and (e) also merely indicates a field of use or technological environment in which the judicial exception is performed”. The instant claims provide no details regarding how the training is performed and instead, just generally train any machine learning model to perform the abstract idea of classifying as claimed.
Last, the instant claims are not analogous to those in CardioNet, because the instant claims do not serve to improve an cardiac monitoring device, or any other device. Instead, the instant claims amount to an improved abstract idea.
Applicant remarks claim 11 trains a machine learning model with improved accuracy because conventional techniques to determine a fractional concentration from a particular tissue type entail obtaining a biopsy of that tissue, genotyping the tissue, identifying a tissue-specific allele, and then analyzing a sample mixture that includes from DNA from tissue, and in contrast the claimed invention of claim 11 can simply analyze the biological sample, which results in more usable DNA fragments for a given ml of sample compared to only analyzing certain loci (Applicant’s remarks at pg. 15, para. 1). Applicant remarks that CardioNet II did not hold that the improvement in accuracy is not sufficient (Applicant’s remarks at pg. 16, para. 2-3).
This argument is not persuasive. Applicant’s alleged improvement in simply analyzing a biological sample instead of taking a biopsy is a result of performing a sequencing assay on cell-free DNA to obtain sequence reads, rather than taking a biopsy of a sample. However, non-invasive methods for diagnosis by sequencing cell-free DNA are conventional in the art, as demonstrated by Grace (cited in the above rejection). Grace reviews screening using cell-free DNA (Abstract), and discloses commercial laboratories utilize whole genome sequencing of cell-free DNA (Abstract; pg. 11, para. 2; pg. 12, para. 3), including for diagnosis (pg. 9, para. 1; pg. 12, para. 3). Thus, simply sequencing cell-free DNA rather than performing a biopsy does not clearly reflect an improvement to technology.
Regarding claim 11, the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Applicant has not provided any evidence that the claimed invention improves the sensitivity and/or specificity of determining a fractional concentration of relevant DNA such that less input DNA is required; while it is possible utilizing all loci in a sample, rather than specific loci, could improve the sensitivity of detection, this is not necessarily the case. For example, Applicant’s own specification at para. [0228] discusses filtering cell-free DNA fragments to originate from specific regions of a particular tissue to improve discrimination.
Regarding CardioNet II, the court explicitly states “’To qualify as a patent-eligible improvement’, the invention must be directed to a specific improvement in the computers functionality, not simply to use of the computer ‘as a tool’ to improvement the abstract idea”, and noted this case falls into the latter category and is not a patent-eligible improvement.
Applicant remarks that the claimed invention can use fewer nucleic acids and achieve a same accuracy as other methods, since the claimed invention has a higher AUC, it is better at capturing subtle patterns in the sequence reads data, especially when the sample size (i.e. smaller volume of cell-free DNA fragments) is limited, and further remarks the claimed invention provides an improvement in technology of enabling smaller sample sizes without any loss of accuracy (Applicant’s remarks at pg. 16, para. 4 to pg. 17, para. 1).
This argument is not persuasive. First, arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Applicant has not provided any evidence that the claimed invention improves the sensitivity and/or specificity of determining a fractional concentration of relevant DNA such that less input DNA is required; while it is possible utilizing all loci in a sample, rather than specific loci, could improve the sensitivity of detection, this is not necessarily the case. For example, Applicant’s own specification at para. [0228] discusses filtering cell-free DNA fragments to originate from specific regions of a particular tissue to improve discrimination.
Second, Applicant’s arguments are not commensurate with the scope of the claims. The claim must be evaluated to ensure the claim itself reflects the disclosed improvement in technology. Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1316, 120 USPQ2d 1353, 1359 (Fed. Cir. 2016). The full scope of the claim under the BRI should be considered to determine if the claim reflects an improvement in technology. See MPEP 2106.05(a). Applicant argues the alleged improvement is provided by using a particular sample size or sample with a concentration of DNA. However, the claims encompass using a sample with any amount of DNA, and thus the alleged improvement is not reflected in the claims.
Last, applicant’s explanation provides purported benefits of the abstract idea, but does not provide an explanation regarding how the additional element(s), contribute to the improvement in using less input DNA. See MPEP 2106.05(a) regarding improvements, cited above.
Applicant remarks, regarding the citation of MPEP 2106.05(a) “it is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. For example, in Trading Technologies Int’l v. IBG, 921 F.3d 1084, 1093-94, 2019 USPQ2d 138290 (Fed. Cir. 2019)”, that the court case does not use such language and is distinguishable, and further remarks the instant claims do not relate to economic data but instead to measurements of a biological sample and how to physically determine whether cancer is present, which is decidedly technical as it takes a deep knowledge of biology (Applicant’s remarks at pg. 17, para. 2-3). Applicant remarks that accordingly, the Office does not perform the proper analysis and it is incumbent on the Examiner to provide a reasoned explanation instead of summarily stating the improvement is in the abstract idea, which is not the rule, and further remarks reading MPEP 2106.05(a)(II) as indicated would mean any improvement from a combination of additional elements and the abstract idea is not necessarily an improvement since it involves the abstract idea (Applicant’s remarks at pg. 18, para. 1-2).
This argument is not persuasive. Regardless of whether Trading Technologies states the exact same phrase as in MPEP 2106.05(a), the court concluded the claims were directed to an improvement in an abstract idea, specifically certain methods of organizing human activity. MPEP 2106.05(a) clearly states it is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology, but does not limit the statement to certain methods of organizing human activity. Therefore, simply because the instant claims do not relate to economic data is not persuasive.
Applicant is also directed to the July 2024 Updated Subject Matter eligibility guidance, specifically claim 1 of Example 49, which was found ineligible and states “At best, the claimed combination amounts to an improvement to the abstract idea of determining patient risk rather than to any technology. See MPEP 2106.05(a)”. Applicant is further directed to the discussion of In re Board of Trustees of Leland Stanford Junior University, 989 F.3d 1367, 1370, 1373, in the 2024 Updated Subject Matter eligibility guidance, which explains that an improvement in the judicial exception is not an improvement to technology.
A reasoned explanation regarding why the claims do not reflect an improvement to technology has been provided in previous Office actions and again above.
Last, it was never stated that simply because an improvement is provided in part by the abstract idea, this is cannot be improvement to technology. MPEP 2106.05(a) states the improvement can be provided by one or more additional elements. See the discussion of Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)) in subsection II, below. In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception. However, it is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. Therefore, the rule is not arbitrary: the improvement cannot be an improvement to the abstract idea, and furthermore, the improvement must be provided by an additional element(s), alone or in combination with the judicial exception.
Step 2B:
Applicant remarks that the steps of “determining… an end motif pattern…; training a machine learning model…; processing, using the machine learning model, the end motif pattern…; determining a classification..” are additional elements, and using end motif patterns of blunt-ended DNA fragments to classify a pathology represents an inventive concept, and that Applicant’s claimed invention produces biological measurements in am manner that is unconventional (Applicant’s remarks at pg. 18, para. 3 to pg. 19, para. 2). Applicant remarks this is similar to the techniques in Exergen Corp. v. Kaz USA, Inc, where the federal circuit concluded that the claimed invention was patent eligible, even though the claim was directed to measuring a natural phenomenon, because the prior art detectors did not involve scanning across a target surface, taking multiple samples per round, or using a lateral scan (Applicant’s remarks at pg. 18, para. 3 to pg. 19 para. 2).
This argument is not persuasive. Under Step 2B, the additional elements are evaluated to determine whether they provide an inventive concept. See MPEP 2106.05. The above limitations identified by Applicant are part of the abstract idea, and thus cannot provide the inventive concept. This is not analogous to those claims in Exergen Corp., which involved additional elements of scanning across a surface, taking multiple samples per round, and using a lateral scan, as noted by Applicant.
Double Patenting
The provisional rejection of claims 1-3, 5-7, 10-14, and 18-19, on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, 20, and 26 of copending Application No. 18/227,831 (reference application) in the Office action mailed 02 May 2025 has been withdrawn in view of claim amendments filed 01 Oct. 2025.
The provisional rejection of claims 4, 38, and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, 20, and 26 of copending Application No. 18/227,831 (reference application) in view of Kincaid (2018) in the Office action mailed 02 May 2025 has been withdrawn in view of claim amendments filed 01 Oct. 2025.
A 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 1-2, 5-7, 10-14, 18-19, 29, 31-35, and 37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 23, 25-30, and 47 of copending Application No. 17/144,021 (reference application). This rejection is previously recited. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 1, reference claim 1 discloses the limitations of instant claim 1, except for that a portion of the DNA fragments are blunt ended, and further differs in scope due to the using motifs corresponding to both ending sequences of a fragment.
However, reference claim 1 discloses sequencing a plurality of cell-free DNA fragments in a biological sample to obtain sequence reads, and then determining end sequence motifs of the plurality of DNA fragments in the sample, regardless of whether the fragments are blunt ended or not. Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have determined the end motifs of blunt ended fragments in the sample according to the method of reference claim 1, and such a modification would have been obvious to try, given the biological sample finitely includes blunt ended DNA and/or non-blunt ended DNA, and reference claim 1 determines end sequence motifs of any DNA fragments of the sample.
Reference claim 2 discloses the limitations of instant claim 2.
Reference claim 6 discloses the limitations of instant claim 5.
Reference claim 7 discloses the limitations of instant claim 6.
Reference claim 8 discloses the limitation of instant claim 7.
Reference claim 12 discloses the limitation of instant claim 10.
Regarding instant claim 11, reference claim 12 discloses the limitations of instant claim 12 except for the cell-free DNA fragments including blunt ended DNA fragments, and differs in scope for the same reason discussed for instant claim 1. However, instant claim 11 is obvious over reference claim 12 for the same reasons discussed above for instant claim 1 with respect to the blunt ended fragments.
Reference claims 6-7 disclose the limitations of instant claims 12-14.
Reference claims 6 and 11-12 disclose the limitation of instant claim 18.
Reference claims 10-12 disclose the limitations of instant claim 19.
Reference claim 23 discloses the limitations of instant claim 29.
Reference claims 25-29 discloses the limitations of instant claims 31-35.
Reference claim 30 discloses the limitations of instant claim 37.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3-4, 38, and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 23, 25-30, 32, and 47 of copending Application No. 17/144,021 (reference application) in view of Kincaid (2018). This rejection is previously recited.
Cited reference: Kincaid (US 2021/0054366 A1; effectively filed 20 Nov. 2018; previously cited).
The reference claims disclose the limitations of instant claims 1-2 as applied above.
Further regarding instant claims 3-4, the reference claims do not disclose the filtering is based on a size or a region from which the DNA fragment is derived, wherein the cell-free DNA is filtered from open chromatin regions of a particular tissue.
Further regarding instant claim 38, the reference claims do not disclose the machine learning model uses clustering, supporting vector machines, or logistic regression.
Further regarding instant claim 54, the reference claims do not disclose each of the set of one or more end sequence motifs is 7 bases or less.
However, Kincaid discloses a method of classifying a level of a medical condition (pathology) in a subject (Abstract; [0021]), which comprises determining percentages (i.e. relative frequencies) dinucleotides (motifs each less than 7 bases, as recited in instant claim 54) in overhang (i.e. ending) sequences of cell-free DNA fragments ([0374]; FIG. 21), wherein a percentage is a proportion/percentage of the cell-free DNA fragments that have an ending sequence including (i.e. corresponding to) the overhang sequence (FIG. 21; [0374]). Kincaid further discloses the cell-free DNA is filtered for overhangs contained in open chromatin regions of healthy or cancer tissues (i.e. the cell-free DNA is filtered for DNA fragments of an open chromatin region) (Table 7; [0374]; [0050]), as recited in instant claims 3-4. Kincaid further discloses using the overhang features in a support vector machine to classify a subject with cancer ([0213]; [0379]), as recited in instant claim 38.
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Kincaid, thus arriving at the inventions of instant claims 3-4, 38, and 54. One of ordinary skill in the art would have be