DETAILED ACTION
Applicant’s response, filed 21 March 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 21 March 2025 has been entered.
Claim Status
Claims 1-12, 23, 25-30, 47, and 48 are pending and examined herein.
Claims 1-12, 23, 25-30, 47, and 48 are rejected.
Priority
Claims 1-12, 23, 25-30, 47, and 48 are granted the claim to the benefit of priority to U.S. Provisional application 62/958676 filed 08 January 2020. Thus, the effective filling date of claims 1-12, 23, 25-30, 47, and 48 is 08 January 2020.
Information Disclosure Statement
The information disclosure statements (IDS) were received on 07 April 2025, 30 June 2025, and 21 October 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
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 1-12, 23, 25-30, 32, 47, and 48 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claims 1-12, 23, 25-30, 32 and 47 falls under the statutory category of a process and claim 48 falls under the statutory category of a machine.
(Step 2A Prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations. The instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “law of nature”.
Independent claims 1 and 48 recite a mental process of “for each of the at least 10,000 cell free DMA fragments, determining a pair of sequence motifs for the ending sequences of the cell-free DNA fragment”, “determining one or more relative frequencies of a set of one or more sequence motif pairs corresponding to the ending sequences of the at least 10,000 cell-free fragments…”, “generating, using a machine learning model, an aggregate value of the one or more relative frequencies of the set of one or more sequence motif pairs”, “determining a classification of a level of the pathology for the subject based on comparison of the aggregate value to a reference value”.
Independent claims 1 and 48 recite mathematical concepts of “determining one or more relative frequencies of a set of one or more sequence motif pairs corresponding to the ending sequences of the at least 10,000 cell-free fragments…”, “generating, using a machine learning model, an aggregate value of the one or more relative frequencies of the set of one or more sequence motif pairs”.
Independent claim 12 recites a mental process of “for each of the at least 10,000 cell free DMA fragments, determining a pair of sequence motifs…”, “determining one or more relative frequencies of a set of one or more sequence motif pairs corresponding to the ending sequences of the at least 10,000 cell-free fragments…”, “generating, using a machine learning model, an aggregate value of the one or more relative frequencies of the set of one or more sequence motif pairs”, “determining a classification of a the fractional concentration of clinically-relevant DNA in the biological sample by comparing the aggregate value to one or more calibration values…”.
Independent claim 12 recites mathematical concepts of “determining one or more relative frequencies of a set of one or more sequence motif pairs corresponding to the ending sequences of the at least 10,000 cell-free fragments…” and “generating, using a machine learning model, an aggregate value of the one or more relative frequencies of the set of one or more sequence motif pairs...”.
Dependent claim 2 recites a mental process of filtering the cell-free DNA using one or more criteria to identify the plurality of cell-free DNA fragments. Dependent claim 9 recites a mental process of determining one or more additional relative frequencies of a set of one or more additional sequence motif pairs corresponding to the ending sequences of the plurality of cell-free DNA fragments, determining an additional aggregate value of the one or more additional relative frequencies of the set of one or more additional sequence motif pairs, determining a stage of the cancer for the subject based on a comparison of the additional aggregate value to an additional reference value. Dependent Claim 9 further recites mathematical concepts of determining one or more additional relative frequencies of a set of one or more additional sequence motif pairs corresponding to the ending sequences of the plurality of cell-free DNA fragments, determining an additional aggregate value of the one or more additional relative frequencies of the set of one or more additional sequence motif pairs. Dependent claim 10 further recites a mental process and a mathematical concept by further limiting the one or more relative frequencies includes a plurality of relative frequencies, and wherein determining the aggregate value of the plurality of relative frequencies and a reference frequency of a reference pattern, and wherein the aggregate value includes a sum of the differences. Dependent claim 29 further recites a mental process of determining one or more additional classifications for one or more additional sets of sequence motif pairs, and determining a final classification using the first classification and the one or more additional classifications.
The claims recite a process of identifying a pair of sequence motifs for the ending sequences of the cell-free DNA fragment, determining one or more relative frequencies, generating an aggregate value of the one or more relative frequencies of the set of sequence motifs, determining a classification of a level of the pathology for the subject based on a comparison of the aggregate value to a reference value. The human mind is capable of make observations, evaluating data based on the observations, and making a judgment based on the evaluated data. Though the claim requires 10,000 cell-free fragments to be analyzed, the action of determining a pair of sequence motifs for the ending sequences of the cell-free DNA fragment is a mental process of making an observation about data. The amount of data requires multiple instances of performing the mental process but does not change the nature of the step in a manner that excludes a human observing particular aspects of data. The claims recite a mathematical calculation of determining a relative frequency because as shown by the specification at [063] a relative frequency may refer to a proportion (a percentage or fraction) which encompasses calculating a proportion of a motif by dividing a count of one motif over a different motif count. The claims recite another mathematical calculation of generating, using a machine learning model, and aggregate value of the one or more relative frequencies because the machine learning model in the instant case encompasses a logistic regression model (instant disclosure [0214]). Therefore, the claims encompass calculating an aggregate numerical value by inputting numerical relative frequency values into a mathematical equation (i.e. logistic regression model) which is a mathematical calculation. Dependent claims 3-8, 11, 23, 25-28, 30, and 47 further limit the mental process/mathematical concept recited in the independent claim but do not change their nature as a mental process/mathematical concept.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element of claims 1, 12, and 48 of 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 sequence to obtain the sequence reads does not integrate the judicial exceptions into a practical application because this is adding insignificant extra solution activity of data gathering.
The additional element in claims 1, 12, and 48 of using a generic computer to perform judicial exceptions does not integrate the judicial exception into a practical application because this is applying the exception to a generic computer without an improvement to a computer technology.
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claims 1-12, 23, 25-30, 32, 47, and 48 are directed to the abstract idea.
(Step 2B)
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). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claims 1, 12, and 48 of using a generic computer to perform judicial exceptions is conventional see MPEP 2106.05(b) and MPEP 2106.05(d)(II).
The additional element of claims 1, 12, and 48 of performing an assay on a plurality of cell free DNA fragments form the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads is conventional as shown on pages 904-905 of Volik et al. (Mol Cancer Res. 2016 Oct;14(10):898-908; previously cited) and online methods of Cristiano et al. (Nature 570, 385–389 (2019); previously cited).
Thus, the additional elements are not sufficient to amount to significantly more than the judicial exception because they are conventional.
Response to Arguments
Applicant's arguments filed 21 March 2025 have been fully considered but they are not persuasive.
Argument 1:
Applicant argues the Office is reading out “practically” from the guidelines for a step to be practically performed in the mind. Applicant argues that the number (10,000) of cell-free DNA fragments is too large for someone to practically analyze mentally Similarly, the determining of the sequence motif pairs for the at least 10,000 cell-free DNA fragments also cannot be practically performed mentally (Reply p. 10).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.04(a(2)(III) “the “mental processes” abstract idea grouping is defined as concepts performed in the human mind, and examples of mental processes include observation, evaluations, judgments, and opinions”. The step of determining a pair of sequence motifs for the ending sequences of the cell-free DNA fragment recites an active step of an observation/evaluation on the cell-free DNA fragment data. The amount of data requires multiple instances of performing the mental process of an observation/evaluation but does not change the nature of the observation/evaluation in a manner that excludes a human mind from performing the action.
Argument 2:
Applicant argues determining a pair of sequence motifs for an ending sequence and determining relative frequencies of sequence motif pairs at best merely involves a mathematical concept. Applicant further argues determination of a relative frequency may involve counting of sequence motif pairs, but at best a mathematical concept is merely involved, as the limitation is directed to a measurement of a physical property of a sample and a modification of the measurements into a more useable form (Reply p. 10-11).
This argument has been fully considered but found to be not persuasive. It is noted that the limitation of “determining a pair of sequence motifs for an ending sequence” was identified in the rejection as reciting a mathematical concept. The MPEP states at 2106.04(a)(2)(I)(C) that “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 determination a of a relative frequency is a mathematical calculation, because as shown by the specification at [063] a relative frequency may refer to a proportion (a percentage or fraction). Determining a relative frequency does not merely involve math because the BRI encompasses calculating a proportion of a motif by dividing a count of one motif over a different motif count. Thus, this limitation recites a mathematical calculation.
Argument 3:
Applicant points to example 39 which does not recite an abstract idea and argues that claims 1 and 12, which similarly recite steps for using and training machine learning models, similarly do not recite judicial exceptions and accordingly are eligible under Prong One of Step 2A” (Reply p. 11).
This argument has been fully considered but found to be not persuasive. Example 39 has a different fact pattern than the instant case. Example 39 recites a particular method for training a neural network using data augmentation techniques. The instant claims do not recite any active step of training a neural network model (or even a machine learning model). Further, the machine learning model in the instant case encompasses a logistic regression model (instant disclosure [0214]). The claims recite using a machine leaning model which encompasses a logistic regression model (i.e. a mathematical equation) to produce an aggregate value (i.e. a numerical value) from a relative frequency (i.e. a numerical value). Therefore, the claims encompass calculating an aggregate numerical value by inputting numerical relative frequency values into a mathematical equation which falls under a mathematical concept of a mathematical calculation. Thus, the claim limitation of “generating, using a machine learning model, an aggregate value of the one or more relative frequencies of the set of one or more sequence motif pairs” is a mathematical calculation.
Argument 4:
Applicant argues that the newly added feature of “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” is an additional element that integrates any judicial exception into a practical application. Applicant further argues by limiting claim 1 to performing an assay by sequencing, the newly added feature imposes meaningful limits on the claim and is not nominally or tangentially related to the invention and all uses of the recited judicial exception do not require sequencing and cannot be considered an insignificant extra-solution activity.
This argument has been fully considered but found to be not persuasive. As stated above in the rejection, the additional element of “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” does not integrate the judicial exceptions into a practical application because this step is insignificant extra solution activity of data gathering. This additional element is insignificant extra solution activity of data gathering because this additional element only interacts with the judicial exceptions by collecting and providing data to the judicial exceptions to analyze. The MPEP provides examples of activities that the courts have found to be insignificant extra solution activity of data gathering (MPEP 2106.05(g)) such as “Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989)” and “Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)”. These examples show additional elements that collect data with the only interaction between the additional element and the judicial exceptions being providing data to be analyzed by the judicial exceptions were found to be insignificant extra solution activity. Further, the MPEP provides examples of cases that were found to provide meaningful limitations (MPEP 2106.05(e)) such as Diamond v. Diehr and Classen Immunotherapies Inc. v. Biogen IDEC. The MPEP states at 2106.05(e) that “In Diehr, the claim was directed to the use of the Arrhenius equation (an abstract idea or law of nature) in an automated process for operating a rubber-molding press. 450 U.S. at 177-78, 209 USPQ at 4. The Court evaluated additional elements such as the steps of installing rubber in a press, closing the mold, constantly measuring the temperature in the mold, and automatically opening the press at the proper time, and found them to be meaningful because they sufficiently limited the use of the mathematical equation to the practical application of molding rubber products” and “In Classen, the claims recited methods that gathered and analyzed the effects of particular immunization schedules on the later development of chronic immune-mediated disorders in mammals in order to identify a lower risk immunization schedule, and then immunized mammalian subjects in accordance with the identified lower risk schedule (thereby lowering the risk that the immunized subject would later develop chronic immune-mediated diseases). 659 F.3d at 1060-61; 100 USPQ2d at 1495-96. Although the analysis step was an abstract mental process that collected and compared known information, the immunization step was meaningful because it integrated the results of the analysis into a specific and tangible method that resulted in the method "moving from abstract scientific principle to specific application." 659 F.3d at 1066-68; 100 USPQ2d at 1500-01”. These examples provide interactions between additional elements and judicial exceptions that go beyond collecting and providing data to be analyzed by the judicial exceptions. Since the additional element of performing an assay of sequencing to produce sequence reads only interacts with the judicial exception by providing data to be processed by the judicial exception, performing an assay of sequencing constitutes as insignificant extra solution activity of data gathering.
Argument 5
Applicant argues the claimed invention provides an improvement in technology and therefore the claims are not directed to a judicial exception. Applicant points to CardioNet v. Infobionic, 2019-1149 (Fed. Cir. 2020) (hereinafter, “CardioNet”) which the Federal Circuit held that an improved cardiac monitoring device was not directed to an abstract idea, specifically the device in CardioNet resulted in “few false negatives and false positives when used to detect atrial fibrillation or atrial flutter”. Applicant argues that the instant claimed invention provides improved detection through more accurate detection of a pathology. Applicant argues the similarities between claim 48 and the device claim in CardioNet (Reply. p. 12-13).
This argument has been fully considered but found to be not persuasive. The determination of an improvement to technology has two steps, the identification of additional elements (i.e. the technology) and an evaluation of the interaction between the judicial exceptions with these additional elements (or the evaluation of the additional elements themselves) to determine if the improvement is realized in the additional elements. CardioNet provides that the improvement is realized in the additional elements of the cardiac monitoring device (i.e. a beat detector to identify a beat-to-beat timing of cardiac activity and a ventricular beat detector to identify ventricular beats in the cardiac activity) through the interaction between the judicial exceptions and the additional element. Instant claim 48 recites two additional elements as a sequencing device and a logic system (i.e. computer system). When evaluating the interaction between these additional elements and the judicial exceptions the interaction is a sequencer that gathers data to be processed by the judicial exceptions and a computer that performs judicial exceptions. The sequencer does not interact with the judicial exceptions in a manner that provides an improvement which is realized in the sequencer device/technology (i.e. such as the sequencer’s ability to detect, measure, or sequence genetic material). The sequencer interacts with the judicial exceptions by only providing data to be processed by the judicial exceptions. The improvement is not realized in the sequencing device/technology because the sequencing device/technology itself is not affected by the judicial exceptions that allows the device to function in an improved manner. Although the judicial exceptions process the data in a manner that may be improved, the improvement is not realized in the sequencing device/technology itself and therefore does not constitute as an improvement to technology. This is unlike CardioNet in which the judicial exceptions interact with the additional elements (i.e. the cardiac monitoring device) in a manner which provides an improvement realized in the devices ability to detect atrial fibrillation or atrial flutter. Therefore, the instant claims do not provide an improvement which is realized in the additional elements and thus the additional elements do not integrate the judicial exceptions into a practical application.
Argument 6:
Applicant argues that the claimed invention can use fewer nucleic acids and achieve a same accuracy (e.g., a particular AUC or a particular specificity/sensitivity) as other methods. Applicant argues the claimed invention provides an improvement in technology by enabling smaller sample sizes without any loss of accuracy (Reply p. 14).
This argument has been fully considered but found to be not persuasive. It is noted that the specific size of the sample is not limited in the claim to being fewer nucleic acids compared to other methods. Therefore, the improvement is not commensurate in scope with the claims because there exist embodiments of the claim where the size of the sample is not small. However, if applicant amends the process of sequencing to be limited to samples of small sizes then the claims could provide an improvement which is realized in the additional elements of sequencing due to the ability of utilizing smaller biological samples while retaining accuracy through the interaction of the additional element and the judicial exceptions.
Argument 7:
Applicant points to Trading Technologies Int’l (which was cited in the previous office action) and argues that there was no special or new rule for how to analyze eligibility by determining where the improvement was. Instead, the holding was the that the presentation of economic data does not improve a computer or other technology since the entire context was economic data. Applicant states that the instant claimed invention does not relate to economic data, but instead to measurements of a biological sample and how to physically determine whether cancer is present and this problem is decidedly technical as it takes a deep knowledge of biology to provide the present solution. Applicant argues the Office miscites the Federal Circuit precedent and does not perform the proper analysis of determining whether the improvement is in a technical field. Applicant further argues to read Trading Technologies Int’l as indicated in the Office action would mean that any improvement from a combination of additional limitations and the abstract idea is necessarily not an improvement since it involves the abstract idea (Reply p. 14-15).
This argument has been fully considered but found to be not persuasive. It is noted that Trading Technologies Int’l was previously cited to capture that improving an abstract idea itself does not constitute as an improvement to a technology. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception…”. The determination of an improvement to technology has two steps, the identification of additional elements (i.e. the technology) and an evaluation of the interaction between the judicial exceptions with these additional elements (or the evaluation of the additional elements themselves) to determine if the improvement is realized in the additional elements. In the instant case, the additional elements are sequencing to produce sequence reads and utilizing a computer system. The interaction between the additional element of sequencing to produce sequence reads and the judicial exceptions is a step which gathers data and provides this data to be processed by the abstract ideas (this constitutes as insignificant extra solution activity of data gathering). The interaction between the additional element of a computer system and the judicial exceptions is the utilization of a computer system to perform abstract ideas. Thus, an improvement is not provided by the additional elements of sequencing and a computer system or sequencing and a computer in combination with the recited judicial exceptions. These additional elements do not integrate the judicial exceptions into a practical application because the improvement is not provided by the additional elements in the claim.
Argument 8:
Applicant argues that the combination of the following limitations, which Applicant argue above are additional limitations, are unconventional: “for each of the at least 10,000 cell- free DNA fragments, determining…a pair of sequence motifs for the ending sequences of the cell-free DNA fragment” and “determining…one or more relative frequencies of a set of one or more sequence motif pairs corresponding to the ending sequences of the at least 10,000 cell-free DNA fragments, wherein a relative frequency of a sequence motif pair provides a proportion of the plurality of cell-free DNA fragments that have a pair of ending sequences corresponding to the sequence motif pair” (reply p. 15).
This argument has been fully considered but found to be not persuasive. As described above these limitations fall under the judicial exception. The MPEP states at 2106.05 “Another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry” which shows the analysis for conventionality is reserved for additional elements. Therefore, these limitations do not amount to significantly more than the judicial exceptions because these limitations are judicial exceptions (i.e. not additional elements).
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/J.E.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685