DETAILED ACTION
Applicant’s response, filed 02/03/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. 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 .
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 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.
Claim Status
Claims 1-4, 6-7, 9-10, and 12-14 are pending.
Claims 5, 8, 11, and 15-17 are canceled.
Claims 1-4, 6-7, 9-10, and 12-14 are rejected.
Applicant's claim for the benefit of a prior-filed application, PCT/EP2021/052880, filed 02/05/2021, is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to App. No. (EPO) 20156032.3, filed 02/07/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Accordingly, each of claims 1-17 are afforded the effective filing date of 02/07/2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01 November 2024 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The replacement drawing sheets submitted 09/16/2025 are accepted and the outstanding objections from the previous Office Action are withdrawn.
Specification
The disclosure is objected to for the following informalities. It is noted that for purposes of the instant Office Action, any reference to the specification pertains to the clean copy of the substitute specification as originally filed on 09/12/2021.
Hyperlinks
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Non-limiting examples include paragraphs [0036, 0045, and 0111]. Applicant will note that this is exemplary and other instances may exist. It is requested that all instances be corrected.
Claim Rejections- 35 USC § 112
The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein.
35 U.S.C. 112(b)
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 1-4, 6-7, 9-10, and 12-14 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.
Claim 1 recites “ligating DNA adaptors to the DNA fragments to produce a library of DNA adaptor products, wherein the DNA adaptors comprise a barcode for use in the identification of sample of origin in a downstream bioinformatic analysis”. As described in claim 1, the “downstream bioinformatic analysis” is an intended use that limits the barcode, not claim 1 as a wholeHowever claim 1 has detailed steps of the “downstream bioinformatics analysis”. It is unclear if the applicant intends for the claimed method to include the bioinformatic analysis steps or not. Claims 2-4, 6-7, 9-10, and 12-14 is/are rejected for the same reason because they depend from claim 1, and does not resolve the indefiniteness issue in those claims.
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.
For the following rejections, underlined text indicates newly recited portions necessitated by claim amendment.
Claims 1-4, 6-7, 9-10, and 12-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portions are necessitated by claim amendment.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to method, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) are as follows:
Independent claim 1:
aligning the sequencing reads to a reference genome DNA sequence comprising a predefined set of N microsatellite genomic loci;
determining the patient sample repeat length distribution DMs of the nucleotide repeat lengths from the set of aligned sequencing reads mapped to the reference genome DNA sequence at the microsatellite locus i; characterized in that the method further comprises
estimating using a curve-fitting method, at least two independent scalar parameters pi, p2 of a multi-parametric function F(DMss, pi, p2) wherein DMss is the reference nucleotide repeat length distribution at the microsatellite genomic locus i; wherein the multi-parametric function F(DMss, p1, p2) is defined for each possible length value lat the microsatellite locus i, O< l < lm as: F(DMss, p1, p2) (l) = (1 - p1)* DMss (l) + p1* DMss (l + p1. * lr) if 0 < l + p2. * lr < lm
F(DMss ,p1• p2 )(l) = (1 - p1) * DMss (l) if l + p2. * lr < 0 or if l + p2. * lr > lm where lr is the length of the repeat at this locus in the reference genome DNA sequence and lm is a maximum repeat length at this locus; and
the independent scalar parameters p=( pi, p2) at locus i are inferred by minimizing the difference between the measured patient repeat length distribution DMsr and the predicted patient repeat length distribution F(DMss, p) at locus i,
estimating a local MSI score s, as a function of the at least two independent scalar parameters pi, p2 at the microsatellite genomic locus I as Si= p1 * p2;
determining a global MSI score S to characterize the MSI status of the patient sample as a function of all estimated local MSI scores s,i=1 to N;
determining the microsatellite instability (MSI) status of the patient as positive if the global MSI score S over the N loci is above a predefined cutoff value.
Dependent claim 2:
calculated as a function of at least three independent scalar parameters p1,p2,p3of a multi- parametric function F(Dmss, p1,p2,p3) of the reference repeat length distribution Dmss, wherein the parameters p1,p2,p3 at locus i are inferred by minimizing the difference between the measured patient sample repeat length distribution DMSI and F(DMss, p1,p2,p3).
Dependent claim 9:
minimizing the difference between the measured patient distribution DMsr and the predicted patient repeat length distribution F(DMss, p) comprises minimizing the a sum of the absolute differences (SAD) or a least square error (LSE) between the measured and the predicted distributions.
Dependent claim 10:
assuming a constant value for at least one of the parameters p={p1, p2}
or p={p1, p2, p3} and brute force searching among all possible values for the other variable parameters for those that minimize the difference between DMSR= and F(Dmss, p).
searching for all possible values for the other variable parameters such that such that DMSI=F(DMSS, p)
Dependent claim 12:
determining the global MSI score as a raw MSI score S calculated as a sum of the local MSI scores over si the N loci, or a normalized MSI score calculated as the sum of the local MSI scores si normalized to the highest local MSI score over the N loci, and/or an MSI score count calculated as a number of loci in the set of N loci where the local MSI score is over a predefined threshold
Dependent claims 4, 6-7, and 13-14 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 4 further limits the independent scalar parameters of claim 1, claim 6 further limits the independent scalar parameters of claim 2, claim 7 further limits the multi-parametric function of claim 2, and claims 13 and 14 further limits the microsatellite genomic locus of claim 1.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance in the mind because the method only requires a user to manually align, determine, and search. Without further detail as to the methodology involved in “aligning the data reads”, “determining a patient sample repeat length distribution”, “determining the microsatellite instability (MSI) status”, and “searching for all possible values”, under the BRI, one may simply, for example, use pen and paper to determine a patients MSI status.
Some of these steps and those recited in the dependent claims require mathematical techniques such as “estimating, with a curve-fitting method”, “estimating a local MSI score”, “determining a global MSI score S”, “calculated as a function of at least three independent scalar parameters”, “minimizing the difference”, “minimizing the sum”, “assuming a constant value”, “estimating the local MSI score” and “determining the global MSI score”.
Therefore, claim 1 and those claims dependent therefrom recite an abstract idea and a law [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, the claims recite the following additional elements:
Independent claim 1:
obtaining DNA fragments from a biological DNA sample from the patient, the sample comprising material from a solid tissue or a bodily fluid;
ligating DNA adaptors to the DNA fragments to produce a library of DNA adaptor products, wherein the DNA adaptors comprise a barcode for use in the identification of sample of origin in a downstream bioinformatic analysis;
amplifying the library of DNA adaptor products via polymerase chain reaction (PCR) to generate PCR duplicates;
sequencing the DNA fragments with a high throughput sequencing technology to obtain a plurality of sequencing reads for each DNA fragment
obtaining a reference repeat length distribution DMss of the nucleotide repeat length at the microsatellite genomic locus i
reporting, the microsatellite instability (MSI) status of the patient.
Dependent claims 3 recites steps that further limit the recited additional elements in the claims. For example, claim 3 further limits the DNA sample of claim 1.
Considerations under Step 2A, Prong Two
With respect to Step 2A, Prong Two, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to data gathering, such as “obtaining”, and to data outputting, such as “reporting”, perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering and outputting do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into a practical application (MPEP 2106.05(g)).
With respect to claim 1, the additional elements of the claims do not integrate the judicial exceptions into a practical application for the following reasons. Those steps directed to sequencing the DNA fragments with a high throughput sequencing technology do not impose any meaningful limitations on the abstract idea, or on how the abstract idea is performed. These steps are insignificant extra-solution activity to the judicial exception (MPEP 2106.05(g)(2))
Thus, none of the claims recite additional elements which would integrate a judicial exception into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represents other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims, the courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)).
As such, the claims simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception (MPEP2106.05(d)). The data gathering steps as recited in the instant claims constitute a general link to a technological environment which is insufficient to constitute an inventive concept which would render the claims significantly more than the judicial exception (MPEP2106.05(g)&(h)).
With respect to sequencing the DNA fragments with a high throughput sequencing technology is well-understood, routine, and conventional in the art. The specification as published discloses the microsatellite loci may be analyzed from a tumor sample such as a with whole genome sequencing data (WGS), whole exome sequencing data (WES), amplicon-based targeted enrichment probes sequencing data, capture-based targeted enrichment sequencing data with various barcoding and molecular identification tagging technologies, such as single strand sequencing, double strand sequencing, duplex sequencing, circular sequencing, variable length tagging sequencing, and other methods known by those skilled in the art of NGS wet lab practice. Various high throughput sequencing technologies may be used, including those from Illumina, Ion Torrent Systems, Oxford Nanopore Technologies, Complete Genomics, Pacific Biosciences, and others, to produce a plurality of NGS reads of a predefined size [0111].
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; See MPEP § 2106.05].
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
Response to Applicant Arguments
Applicant submits the ligating and amplifying steps must be performed physically, in a laboratory environment, and cannot practically be performed in the human mind, nor with any kind of computer, generic or otherwise [p. 9, par. 1].
It is respectfully found that those steps are directed to additional elements that are well known and conventional as stated in the above 101 rejection not a mental process.
Applicant submits that the ligation of DNA adaptors to the DNA fragments to produce a library of DNA adaptor produces is integral to the downstream bioinformatic analysis of the sequencing reads and do not merely recite extra solution activities [p. 9, par. 2].
It is respectively found not persuasive. The specification states that the sequencing and sequencing device can be any of whole genome sequencing data (WGS), whole exome sequencing data (WES), amplicon-based targeted enrichment probes sequencing data, capture-based targeted enrichment sequencing data with various barcoding and molecular identification tagging technologies, such as single strand sequencing, double strand sequencing, duplex sequencing, circular sequencing, variable length tagging sequencing, and other methods known by those skilled in the art of NGS wet lab practice. Various high throughput sequencing technologies may be used, including those from Illumina, Ion Torrent Systems, Oxford Nanopore Technologies, Complete Genomics, Pacific Biosciences, and others, to produce a plurality of NGS reads of a predefined size [0111] which is not a specific device. As these methods are well known in the art and the claims do not improve these methods, they are extra solution activities.
Applicant submits the method recited in the instant claims provides an improvement to currently available methods in determining MSI [p. 10, par. 1].
It is respectfully found unpersuasive. 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 or by the additional element(s) in combination with the recited judicial exception. See MPEP 2106.05(a). The instant claims do not recite any additional elements other than general data gathering and extra solution activity such as sequencing and obtaining data which do not provide the improvement and/or that the improvement is in the abstract idea, which is not a technology.
Applicant submits that instantly amended claim 1 is not directed to an abstract idea without significantly more, as the instantly amended claims comprise active method steps that must be performed physically [p. 10, par. 2].
It is respectfully found not persuasive. As noted above claim 1 recites particular algorithm such as F(DMss, p1, p2) (l) = (1 - p1)* DMss (l) + p1* DMss (l + p1. * lr) if 0 < l + p2. * lr < lm F(DMss ,p1• p2 )(l) = (1 - p1) * DMss (l) if l + p2. * lr < 0 or if l + p2. * lr > lm, and Si= p1 * p2, which is a algorithm, estimating and determining a local MSI score are mathematical concepts, and least square error (LSE) as examples are abstract mathematical concepts.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dawn Bickham whose telephone number (703)756-1817. The examiner can normally be reached on Monday - Friday 8-4.
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/D.M.B./Examiner, Art Unit 1685 /Soren Harward/Primary Examiner, TC 1600