DETAILED ACTION
Applicant’s response, filed 04 April 2025 and entered 30 April 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 30 April 2025 has been entered.
Status of Claims
Claims 5, 8-9, 19, 22-23, and 25 are cancelled.
Claims 38-39 are newly added.
Claims 1-4, 6-7, 10-18, 20-21, 24, and 26-39 are pending.
Claims 2, 4, 20-21, 24, and 26-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 16 Feb. 2024.
Claims 1, 3, 6-7, 10-18, and 35-39 are rejected.
Priority
The effective filing date of the claimed invention is 27 Feb. 2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 30 April 2025 and 04 June 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references were considered by the Examiner.
Drawings
The replacement drawings received on 24 Jan. 2025 and 04 April 2025 are accepted.
Specification
The replacement abstract filed 04 April 2025 is accepted.
Claim Objections
The objection to claim 3 in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments received 04 April 2025.
Claim Interpretation
Claims 1 and 3 recite “detecting/detect a residual disease in responsive to the statistical significance framework…exceeding an empirical threshold”. The limitation of detecting residual disease is interpreted as a contingent limitation that is only required to occur if the statistical significance framework exceeds the empirical threshold. Therefore, the method of claim 1 does not require detecting residual disease under the broadest reasonable interpretation of the claim, while claim 3 requires the processor is configured to detect residual disease as claimed. See MPEP 2111.04 II.
Claims 1 and 3, recite “..a first filtered read set based on and spanning the first genome-wide compendium of reads and a second filtered read set based on and spanning the second genome-wide compendium of reads”. The filtered read sets spanning a genome-wide compendium of reads is interpreted to mean the first and second filtered read sets are genome-wide read sets with errors filtered from the reads according to the at least one error suppression protocol, in light of Applicant’s specification and Applicant’s remarks filed 04 April 2025 at pg. 21, para. 2.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1, 3, 6-7, 10-18, and 35-39 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendment.
Claims 1 and 3, and claims dependent therefrom, recite “…computing/compute a statistical significance framework of the first and second biological sample using the first and second filtered read sets by applying a background noise model and one or more integrative mathematical models”.
Under certain circumstances, omission of a limitation can raise an issue regarding whether the inventor had possession of a broader, more generic invention. See, e.g., Gentry Gallery, Inc. v. Berkline Corp., 134 F.3d 1473, 45 USPQ2d 1498 (Fed. Cir. 1998). See MPEP 2163.05 I. A. In the instant case, Applicant broadened the claims to no longer compute “an estimated tumor fraction (eTF)” and no longer use the estimated tumor fraction to detect residual disease. Instead, the claims broadly require computing “a statistical significance framework”, which is used for the detection.
Applicant’s specification at para. [00158] and [00175] discloses tumor detection and estimation is performed only for samples that show tumor fraction that is significantly higher than the PON noise TF values using a statistical significance framework (z-score). The statistical significance framework or z-score is not mentioned elsewhere in the specification or in the originally filed claims. Furthermore, throughout the specification, computing an estimated tumor fraction and then using the estimated tumor fraction to detect residual disease is described (see [0008]; [0011]; [0013]; FIG. 1D-1E, FIG. 2B, etc.). Therefore, Applicant’s specification discloses computing an estimated tumor fraction and then determining whether the tumor fraction is statistically significant using a z-score to detect residual disease.
However, Applicant’s specification does not appear to disclose any other values/parameters that can be used with the statistical significance framework (e.g. z-score) to detect residual disease in the subject.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the above limitations to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Claims 1 and 3, and claims dependent therefrom, recite “adjusting/adjust a therapy administered to the subject according to a stratification of adjuvant therapy based on the statistical significant framework”.
Applicant remarks filed 04 April 2025 cites various paragraphs, including [0047], [0159], [0176], and [0233] as providing support for the claim amendments.
The closest description cited by Applicant is at para. [0233]-[0236] of the specification. Applicant’s specification at para. [0236] discloses the model can be useful in a physician’s decision regarding adjuvant therapy, and the disclosed methods provide a tool for physicians and clinicians to predict an outcome. Applicant’s specification at para. [0236] discloses the prediction tool can be an effective decision add and can be useful as a benchmark for judging the predictive ability of any new therapy, such as chemotherapy, immunotherapy, or targeted therapy. Applicant’s specification at para. [0235] discloses an estimated tumor fraction above a threshold indicates that adjuvant therapy is needed and that a patient with low risk may wish to avoid the toxicity associated with therapy. Applicant’s specification at para. [0047] and FIG. 8 discloses classifying subjects as candidate for adjuvant therapy using the invention; however stratifying patients does not disclose adjusting an administered therapy as claimed.
Therefore, while Applicant’s specification does appear to generally disclose determining to administer adjuvant therapy and/or “continued non-administration”, by describing the determination of a therapy and avoiding therapy, the specification does not disclose altering an administered therapy as claimed, particularly according to “a stratification of adjuvant therapy”, or any administration step.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the above limitations to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Claim Rejections - 35 USC § 112(b)
The rejection of claims 17-18 and 37 under 35 U.S.C. 112(b) in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments received 04 April 2025.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 3 and 39 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 3, and dependent claim 39, recites “a processor configure and arranged to:…adjust a therapy administered to the subject according to a stratification of adjuvant therapy…”. Given claim 3 recites the adjusting step as being performed by a processor, it is unclear if the limitation intends to require physically adjusting a therapy administered to a subject, which is outside the scope of what a processor can perform, or if the limitation intends to only require determining an adjusted therapy to be administered to the subject. If Applicant intends to require physically adjusting the therapy, then the metes and bounds of structures including processors “configured…to adjust a therapy administered to the subject” are unclear. For purpose of examination, the limitation is interpreted to mean an adjusted therapy is determined, given this is within the scope of what a processor can perform.
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, 3, 6-7, 10-18, and 35-39 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 and 3 being representative) is directed to a method and system for detecting residual disease. 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 and 3 recite the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
filtering/filter artefactual sites from the first compendium of reads, wherein the filtering comprises removing, from the first compendium of genetic markers, recurring sites generated over a cohort of reference healthy samples, and/or identifying germ line mutations in peripheral blood mononuclear cells of the normal cell sample and removing said germ line mutations from the first compendium of genetic markers;
detecting/detect reads from a second subject-specific genome wide compendium of genetic markers in a second biological sample of the subject to generate a tumor-associated genome-wide representation of genetic markers in the second sample (claim 1 only)
filtering/filter noise from the first and second genome-wide compendium of reads using at least one error suppression protocol to produce a first filtered read set based on and spanning the first genome-wide compendium of reads and a second filtered read set based on and spanning the second genome-wide compendium of reads, wherein the at least one error suppression protocol comprises (a) calculating a probability that any single nucleotide variation in the first and second compendium is an artefactual mutation, and removing said mutation, wherein the probability is calculated as a function of features selected from the group consisting of mapping-quality (MQ), variant base-quality (MBQ), position-in-read (PIR), mean read base quality (MRBQ), and combinations thereof; and/or (b) removing artefactual mutations using discordance testing between independent replicates of the same DNA fragment generated from polymerase chain reaction or sequencing processing, and/or duplication consensus testing, wherein artefactual mutations are identified and removed when lacking concordance across a majority of a given duplication family;
computing/compute a statistical significance framework of the first and second biological sample using the first and second filtered read sets by applying a background noise model and one or more integrative mathematical models;
detecting/detect a residual disease in the subject in response to the statistical significance framework in the second biological sample exceeding an empirical threshold; and
adjust…according to a stratification of adjuvant therapy based on the statistical significance framework;
The identified claim limitations falls into one of the groups of abstract ideas of mental processes, for the following reasons. In this case, filtering artefactual sites encompasses identifying markers present in a cohort of reference healthy samples and removing these markers from the first compendium of reads, which amounts to a mere analysis of data. Furthermore, detecting reads from a second-subject-specific genome wide compendium of genetic markers in a second biological sample to generate a tumor-associated genome-wide representation of genetic markers encompasses analyzing and collecting read information corresponding to marker locations of sequencing information generated from a tumor sample of the subject, which is a mental process. Filtering noise from the first and second compendium of reads using an error suppression protocol of calculating a probability that a variant is artefactual and removing the variant can be practically performed in the mind, for example, by inputting quality features into al linear regression model to calculate a probability, and removing variants with a probability above a certain threshold. The other alternative embodiments for filtering noise also amount to a mere analysis of data to identify variants that involve performing data comparisons to identify discordance. Computing an statistical significance framework by using one or more integrative mathematical models and a background noise model can be practically performed in the mind by performing addition and multiplication to perform the calculation, as discussed in Applicant’s specification (see FIG. 1D). Detecting a residual disease involves simply comparing the estimated statistical significance framework to a threshold, which is a mental process. Providing a diagnosis of residual disease involves analyzing if the framework is greater than a threshold, which amounts to mental data comparisons. Last, determining an adjustment of a therapy to be administered to a subject is a mental evaluation that can be performed by analyzing which adjuvant therapy the subject is stratified into using the statistical significance framework and adjust the therapy accordingly. That is other, than reciting the limitations are performed by a processor in claim 3, nothing in the claims precludes the step from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
The steps of calculating the probability that any single nucleotide variation is an artefactual mutation as a function of features and computing a statistical significance framework using models further recite a mathematical concept. The claim limitations amount to a textual equivalent to performing mathematical calculations. For example, the step of calculating a probability encompasses inputting numerical values of the features into a linear regression model and performing weighted addition to calculate the probability. Similarly, for estimating a statistical significance framework in light of Applicant’s specification (see FIG. 1D), the framework can be estimated by performing addition and multiplication to perform the calculation. Therefore, these limitations recite a mathematical concept.
Last, the claims recite the law of nature of a natural correlation between the presence of genetic markers and residual disease. See MPEP 2106.04(b).
Dependent claims 6-7, 10-17, and 35-39 further recite an abstract idea and/or are part of the abstract idea of claims 1 and 3 above. Dependent claims 6-7 further recites the mental process of generating a panel of normal (PON) blacklist or mask and filtering germ line mutations in PBMC, respectively. Dependent claim 10 further recites the mental process and mathematical concept of employing a machine learning algorithm to filter artefactual noise. Dependent claims 11-13 further limit the filtering noise in claim 1, and thus are part of the judicial exception of filtering noise. Dependent claim 14 further limits the mathematical concept and mental process of using the one or more integrative mathematical models to calculate eTF. Dependent claims 15-16 further limit the mathematical concept and mental process of filtering noise using the background noise model to calculate expected noise distributions and provide an estimated mean and standard-deviation of artefactual mutation detection rate, respectively. Dependent claim 17 further recites the mental process and mathematical concept of integrating fragment size shift into the one or more mathematical model. Dependent claim 18 further recites the mental process and mathematical concept of analyzing intra-subject fragment size shifts in a list of tumor-specific markers and random markers using statistical methods. Dependent claims 35-36 further limit the mental process and mathematical concept of employing a machine learning algorithm to employ one or more support vector machine (SVM). Dependent claim 37 further limits the mental process and mathematical concept of using statistical methods to use one or more tests of significance or a Gaussian mixture model. Dependent claims 38-39 further limit the mental process and mathematical concept of computing the statistical significance framework to compute a z-score. Therefore, claims 1, 3, 6-7, 10-18, and 35-39 recite an abstract idea. [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.
Claims 6-7, 10-18, and 35-39 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 and 3 include:
an analyzing unit comprising a processor and a computing unit comprising a processor (claim 3);
receiving/receive a first subject-specific genome wide compendium of reads associated with genetic markers from a first biological sample of a subject, the first biological sample comprising a baseline sample and a normal sample, wherein the baseline sample comprises a tumor sample or a plasma sample (claims 1 and 3) (i.e. receiving data); and
receive reads from a second subject-specific genome wide compendium of genetic markers in a second biological sample of the subject to generate a tumor-associated genome-wide representation of genetic markers in the second sample (claim 3) (i.e. receiving data).
The additional elements of claim 1 further includes:
adjusting a therapy administered to the subject.
The additional elements of a processor and receiving data are generic computer components and/or functions. 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).
Furthermore, the steps of receiving reads only serve to collect data for use by the abstract idea, which amounts to insignificant extra-solution that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Last, the step of adjusting a therapy administered to the subject is not sufficient to integrate the recited judicial exception for the following reasons. The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). Consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2). In this case, the step of adjusting a therapy is not a particular treatment and instead is analogous to the example of “administering a suitable medication to the patient” in MPEP 2106.04(d)(2). Instead, the limitation amounts to mere instructions to apply an exception because the claim does not recite any details regarding what administration is to be administered “according to a stratification of adjuvant therapy based on the statistical significance framework”, nor how the therapy is actually adjusted. See MPEP 2106.05(f), stating 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.
Therefore, the additionally recited elements amount to insignificant extra-solution activity and/more merely uses a computer as a tool, and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1, 3, 6-7, 10-18, and 35-39 are directed to an abstract idea. [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.
Claims 6-7, 10-18, and 35-39 do not recite any elements in addition to the judicial exception and thus are part of the judicial exception.
Claims 6-7, 10-18, and 35-37 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 and 3 include:
an analyzing unit comprising a processor and a computing unit comprising a processor (claim 3);
receiving/receive a first subject-specific genome wide compendium of reads associated with genetic markers from a first biological sample of a subject, the first biological sample comprising a baseline sample and a normal sample, wherein the baseline sample comprises a tumor sample or a plasma sample (claims 1 and 3) (i.e. receiving data); and
receive reads from a second subject-specific genome wide compendium of genetic markers in a second biological sample of the subject to generate a tumor-associated genome-wide representation of genetic markers in the second sample (claim 3) (i.e. receiving data).
The additional elements of claim 1 further includes:
adjusting a therapy administered to the subject.
The additional elements of a processor and receiving data are conventional computer components and/or functions. 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 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).
The Furthermore, the additional element of adjusting a therapy administered is well-understood, routine, and conventional. This position is supported by Penault-Llorca et al. (Biomarkers of residual disease after neoadjuvant therapy for breast cancer, 2016, Nature Reviews Clinical Oncology, 13, pg. 487-503; newly cited). Penault-Llorca reviews monitoring residual disease after neoadjuvant therapy for breast cancer (Abstract), and discloses neoadjuvant therapy has become a part of the standard-of-care treatment of patients with breast cancer (pg. 487, col. 1, para. 2). Penault-Llorca discloses that nowadays, the decision of which adjuvant therapy to give to patients is based on molecular subtype and the estimated residual tumor burden after neoadjuvant therapy (Abstract; pg. 488, col. 1, para. 2), demonstrating the conventionality of adjusting treatments after residual disease detection. Furthermore, 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); Intellectual Ventures I v. Symantec, 838 F.3d 1307, 1327, 120 USPQ2d 1353, 1366 (Fed. Cir. 2016); Internet Patents Corp. v. Active Network, Inc., 790 F.3d 1343, 1348, 115 USPQ2d 1414, 1417 (Fed. Cir. 2015).
Therefore, taken alone, the additional elements do not provide significantly more. 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 04 April 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Step 2A, Prong 1:
Applicant remarks the claims do not recite a mental process because the MPEP 2106.04(a)(2) makes clear “a claim with limitation(s) that cannot practically be performed in the human mind does not recite a mental process”, states all of the claim limitations of claims 1 and 3 cannot be practically performed in the mind, and then states it is impractical for a human mind to perform the claimed steps with high efficiency, if at all, because filtering sites and noise from a genome-wide compendium of reads associated with markers will necessarily involve a large volume of sequencing data, and it is impractical for the human mind to adjust a therapy administered to the subject (Applicant’s remarks at pg. 17, para. 1-4).
This argument is not persuasive. First, it is noted that the step adjusting an administered therapy is not identified as reciting a judicial exception, and instead is treated as an additional element in the above rejection.
Regarding, the amount of data relating to a “genome wide compendium of reads”, the amount of data, in and of itself is not a limitation which takes a process out of the realm of the human mind. it is the process performed on that data which is the mental step, and mental steps identified in the claims do not have to be fastest, most efficient, or require specialized computing elements. Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also SiRF Tech., Inc. v. Int’l Trade Comm ’n, (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
Therefore, whether performing the limitations mentally is “efficient” is not considered in determining whether the claims recite a mental process, nor has Applicant provided particular reasoning the limitations cannot be performed mentally other than stating there is a large amount of data. For the reasons discussed in the above rejection, each of the limitations can be practically performed in the mind.
Applicant remarks that the Action asserts that the complexity and length of time in performing a step does not mean the claimed step cannot be practically performed in the mind, and Applicant disagrees with this position as it would amount to all inventions in computer technology amounting to a mental process (Applicant’s remarks at pg. 17, para. 17, para. 5-6).
This argument is not persuasive. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also SiRF Tech., Inc. v. Int’l Trade Comm ’n, (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
Therefore inventions in computer technology, a machine or additional element that plays a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, may be patent eligible. MPEP 2106.05(a) I. provides various examples in which the courts have indicated show an improvement to computer technology.
Step 2A, Prong 2:
Applicant remarks the claims integrate any alleged abstract idea into a practical application of an improvement to gene sequencing technology as it relates to genetic screening a subject for residual disease, providing a diagnosis, and medical treatment, and optimizing therapy (Applicant’s remarks at pg. 18, para. 3-4).
This argument is not persuasive. An indication that the claimed invention provides an improvement can include a discussion in the specification that identifies a technical problem and explains the details of an unconventional technical solution expressed in the claim, or identifies technical improvements realized by the claim over the prior art. 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).
In the instant case, Applicant has not provided a technical explanation regarding how the claims improve sequencing technology. The claims do not even require performing any steps of sequencing, and therefore it is unclear how any sequencing technology is being performed. Furthermore, any improvements in the analysis of sequencing data would be an improved abstract idea, which is not an improvement to technology.
Applicant remarks that claims 1 and 3 have been amended to recite “…detect a residual disease…; and adjust a therapy administered to the subject according to a stratification of adjuvant therapy…”, and therefore it is clear there is a practical application for the claimed method and system, namely the provision of medical treatment for optimizing therapy, which goes beyond the mere correlation of genetic markers with residual disease (Applicant’s remarks at pg. 16, para. 1-4). Applicant further remarks claim 1 is amended to render the medical treatment as an active step and provide specificity to the medical treatment, and thus the claims go beyond the abstract idea to adjust a therapy administered to the subject according to a stratification of adjuvant therapy, which is a practical application (Applicant’s remarks at pg. 18, para. 4 to pg. 19, para. 2).
This argument is not persuasive. First, with respect to claim 3, the step of adjusting a therapy by a processor is interpreted to be a step of determining an adjustment of a therapy, as discussed in the 35 U.S.C. 112(b) rejection of the claim, which is part of the abstract idea and thus cannot provide integration. Regarding the administration step in claim 1, the administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2). In this case, the step of adjusting a therapy is not a particular treatment and instead is analogous to the example of “administering a suitable medication to the patient” in MPEP 2106.04(d)(2). The limitation amounts to mere instructions to apply an exception because the claim does not recite any details regarding what administration is to be administered “according to a stratification of adjuvant therapy based on the statistical significance framework”, nor how the therapy is actually adjusted. See MPEP 2106.05(f), stating 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.
Step 2B:
Applicant remarks the combination of the aforementioned claimed features is also novel and nonobvious (Applicant’s remarks at pg. 19, para. 3-4).
This argument is not persuasive. Lack of novelty under 35 U.S.C. 102 or obviousness under 35 U.S.C. 103 of a claimed invention does not necessarily indicate that additional elements are well-understood, routine, conventional elements. Because they are separate and distinct requirements from eligibility, patentability of the claimed invention under 35 U.S.C. 102 and 103 with respect to the prior art is neither required for, nor a guarantee of, patent eligibility under 35 U.S.C. 101. See MPEP 2106.05 I.
Applicant remarks the dependent claims are patent eligible for the same reasons as claims 1 and 3 (Applicant’s remarks at pg. 19, para. 5).
This argument is not persuasive for the same reasons discussed above for claims 1 and 3.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 6-7, and 10-16 under 35 U.S.C. 102(a)(1) as being anticipated by Newman 2016 in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments 04 April 2025.
Claim Rejections - 35 USC § 103
The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Newman (2016) in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments 04 April 2025.
The rejection of claims 35-36 under 35 U.S.C. 103 as being unpatentable over Newman (2016) in view of O’Fallon (2013) in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments 04 April 2025.
The rejection of claims 17-18 and 37 under 35 U.S.C. 103 as being unpatentable over Newman (2016) in view of Soo (2017) in the Office action mailed 04 Feb. 2025 has been withdrawn in view of claim amendments 04 April 2025.
However, after further consideration, new grounds of rejection are set forth below in view of the claim amendments.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1, 3, 6-7, 10-16, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Newman (2016) in view of Diehn (2014), as evidenced by Bratman (2014). This rejection is newly recited and necessitated by claim amendment.
Cited reference:
Newman et al., Integrated digital error suppression for improved detection of circulating tumor DNA, 2016, nature biotechnology, 34(5), pg. 547-555 and supplementary (previously cited);
Diehn et al., US 2018/0251848 A1, effectively filed 12 Sept. 2014 (newly cited); and
Newman et al. ( hereinafter Bratman), An ultrasensitive method for quantifying circulating tumor DNA with broad patient coverage, 2014, Nature Medicine, 20(5), pg. 548-554 and Suppl.) (newly cited).
Regarding claim 1, Newman discloses a method for detecting circulating tumor DNA (ctDNA) in a subject (Abstract) comprising the following steps.
Newman discloses (A) performing exome sequencing DNA of a blood sample (i.e. a baseline sample comprising a plasma sample) and paired germline (i.e. normal) sample (i.e. a first biological sample comprising a baseline and normal cell sample) from a patient (i.e. the subject) (pg. 547, col. 1, para. 1, e.g. sequencing of tumor biopsies; FIG. 1, e.g. cell-free DNA first blood draw pg. 548, col. 1, para. 4 to col. 1, para. 1;pg. 551, col. 2, para. 4, e.g. exome sequencing; pg. 554, col. 1, para. 4), to generate (i.e. receive) genome-wide reads associated with a selector of genetic variants (i.e. marker) (pg. 551, col. 2, para. 4). Newman further discloses the reads are generated using 2x150 paired end sequencing (pg. 556, col. 1, para. 5), such that the reads are of a single base pair length.
Newman discloses (B) excluding (i.e. filtering) germline SNPs from the sequencing data of the subject if they were present in any patient or control (ONLINE methods: ctDNA monitoring analysis, para. 1, e.g. positions with a germline SNP in any patient or control removed from variant list of patient), wherein the controls are healthy samples (ONLINE METHODS: Background polishing).
Newman discloses (C) sequencing a second blood sample of the subject (Figure 1, e.g. later blood draw) to identify genome-wide tumor markers in the second sample (pg. 551, col. 2, para. 4; Figure 4c; pg. 553, col. 2, para. 3, e.g. selector-wide genotyping from exome sequencing of plasma for ctDNA monitoring).
Newman discloses (D) removing errors (i.e. filtering noise) from the sequencing data of the first and second reads (Fig. 2, e.g. error suppression; Fig. 1, e.g. reads from first and later blood draws) by analyzing reads of a given barcode family (i.e. independent replicates of the same DNA template) and removing the less abundant mutations from consideration, thereby producing a first and second filtered read set (Fig. 2, e.g. barcodes label reads originating from same DNA template; ONLINE methods, Analysis of molecular barcodes, para. 1-2, step 1, e.g. the frequency of the most abundant nonreference allele is used). Newman discloses the source of the removed errors is library preparation and sequencing (pg. 547, col. 1, para. 2).
Newman discloses (E) computing a circulating tumor DNA (ctDNA) percentage at time 0 (i.e. of the first biological sample) and after one month (i.e. for the second biological sample), using the reads from the corresponding blood draws (Fig. 1, e.g. reads analyzed from blood draws at different time points; FIG. 5(c)-(d), e.g. estimated %ctDNA; eONLINE methods, statistical methods for ctDNA detection). Newman discloses the ctDNA percent is calculated by a mathematical model integrating information on the number of reporters and an expected number of mutant copies (i.e. an integrative mathematical model) (ONLINE methods, statistical methods for ctDNA detection, para. 1-2), and applying a model of the selector-wide background noise (i.e. a background noise model) to the ctDNA level of the mathematical model to determine if the level is statistically significant (i.e. computing a statistical significance framework using the noise and mathematical models) (ONLINE METOHDS, statistical methods for ctDNA detection, para. 3, e.g. tested the null hypothesis that the mean and s are not jointly above selector-wide background).
Newman discloses (F) detecting the ctDNA (i.e. residual disease) if the ctDNA level is above the detection limit at an empirical confidence level of 90% confidence (i.e. the statistical significance framework exceeds an empirical threshold) (ONLINE METOHDS, statistical methods for ctDNA detection, para. 2-3, e.g. detection limit = 0.12% at 90% confidence, statistical significance of ctDNA determined at a given confidence level, e.g. only levels with p value < 0.05 considered detectable). Newman discloses providing a determination of residual disease when the ctDNA level is above the threshold (i.e. when residual is detected) (ONLINE METOHDS, statistical methods for ctDNA detection, para. 2-3; suppl. Figure 14, e.g. providing graph indicating statistically significant ctDNA detection).
Regarding claims 1 and 3¸ Newman does not disclose the following:
First, regarding claim 3¸ Newman does not explicitly disclose a system comprising a processor (i.e. the claimed unit/engines). However, the court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04.
Regarding claims 1 and 3, Newman does not disclose the filtered first and second read sets span the first genome-wide compendium of reads and span the second genome-wide compendium of reads, respectively, which is interpreted to mean the first and second filtered read sets are also genome-wide after removing errors.
Instead, Newman identifies the genetic markers and tumor-associated genetic markers from whole-exome sequencing data (pg. 551, col. 2, para. 4), but then filtering out regions from the reads less likely to have tumor markers to generate a targeted panel of regions (referred to as a selector) (pg. 550, col. 2, para. 2, e.g. regions that are highly recurrent in NSCLC; FIG. 1, e.g. CAPP-Seq). Newman discloses estimating the percentage of ctDNA and residual disease using tumor markers from the targeted read data (Figure 1), rather than from genome-wide read data..
However, Diehn also discloses the CAPP-Seq selector method of Newman for detecting residual disease (Abstract; Figure 4; FIG. 15A-E) and expands this method to other cancers, stating genomic regions recurrently mutated in a particular cancer can be used in a selector ([0128]; [0129]). Diehn further discloses that the number of genomic regions in a selector may vary depending on the nature of the cancer, and the inclusion of a larger number of regions may increase the likelihood a unique somatic mutation will be identified, but with a cost ([0128]). Diehn further discloses at the extreme, the entire genome of a tumor sample and genomic sample could be sequenced, and resulting sequences could be compared to not any differences with the non-tumor tissue (i.e. genome-wide read sets) ([0128]).
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 modified the method of Newman to have utilized reads across the entire genome in predicting tumor fraction, as shown by Diehn ([0128]; FIG. 15A-E), such that the filtered read sets (i.e. after removing artefactual mutations/noise) are genome-wide. One of ordinary skill in the art would have been motivated to combine the methods of Newman and Diehn in order to increase the likelihood of unique somatic mutations being identified and thus the detection limit of residual disease, as shown by Diehn ([0034]; [0128]). This modification would have had a reasonable expectation of success given both Newman and Diehn disclose the generation and application of a selector for detecting residual disease, and Diehn discloses the number of regions in a selector may vary up to including all regions in a genome ([0128]). Diehn discloses the ctDNA detection limit (i.e. detection of residual disease) increases as the number of available tumor reporters increase ([0034]; FIG. 15A-F).
Furthermore, 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 used all regions in a genome in the selector (i.e. providing genome-wide filtered read sets) through routine experimentation of the number of regions in the selector, as shown by Diehn ([0128]) within the prior art conditions of increasing the number of regions to improve the likelihood of identifying somatic mutations and thus improve residual disease detection, as shown by Diehn ([0034]; [0128]) and decreasing the number of regions to reduce sequencing costs, as shown by Newman (pg. 548, col. 1, para. 4). See MPEP 2144.05 II. A.
Regarding claims 1 and 3, Newman further does not explicitly disclose adjusting a therapy administered to the subject according to a stratification of adjuvant therapy based on a statistical significance framework.
However, Newman does disclose that the analysis of ctDNA is likely to play a major role in personalized cancer therapy by detecting minimal residual disease that is radiologically occult during disease surveillance (pg. 554, col. 1, para. 1), suggesting that the detection of residual disease should be used to determine and provide a cancer therapy for a person in which residual disease is detected (i.e. provide an adjuvant therapy based on a stratification of whether residual disease is detected or not).
Furthermore, Diehn discloses the method accurately quantifies cell-free tumor DNA from early and advanced tumor stages, and because tumor-derived DNA levels often parallel clinical responses to diverse therapies, the method may be used to detect tumor and facilitate personalized cancer therapy ([0080]). Diehn discloses the method includes recommending or not recommending a therapy based on the presence or absence of tumor cells ([0046]), and that the results of diagnosing can be used t