DETAILED ACTION
Applicant’s response, filed Nov 24 2025, 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 Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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, 3-4, 6-7, 9-13, 15-22, 24-26, 28-29, 31-32, 34-38, 40-47, 49, and 51 are pending.
Claims 2, 5, 8, 14, 23, 27, 30, 33, 39, 48, and 50 are canceled.
Claim 51 is newly added.
Claims 1, 3-4, 6-7, 9-13, 15-22, 24-26, 28-29, 31-32, 34-38, 40-47, 49, and 51 are rejected.
Priority
The instant Application claims domestic benefit to US provisional applications 62/612,048, filed Dec 29 2017, and 62/699,685, filed Jul 17 2018.
However, the provisional applications do not disclose at least the limitations of claims 1 and 26 which recite “identifying any mismatched nodes… between the first directed graph aligned to the reference genome”.
Accordingly, each of claims 1, 3-4, 6-7, 9-13, 15-22, 24-26, 28-29, 31-32, 34-38, 40-47, 49, and 51 are afforded the effective filing date of the Dec 28 2018.
Claim Rejections- 35 USC § 112
Unless otherwise noted, the outstanding rejections to the claims are withdrawn in view of the amendments submitted herein.
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, 3-4, 6-7, 9-13, 15-22, 24-26, 28-29, 31-32, 34-38, 40-47, 49, and 51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant rejection is maintained from the previous Office Action.
Claim 1, 8th and 9th limitations recite “calling, by the computer processor, a plurality of test reads from the first directed graph as variants by identifying any mismatched nodes or edges between the first directed graph aligned to the reference genome” and “calling, by the computer processor, a plurality of control reads from the second directed graph as normals by identifying any mismatched nodes or edges between the second directed graph aligned to the reference genome”.
The specification as published provides support for comparing a directed graph to a reference sequence by aligning edges of the directed graph to the reference sequence, and recording the genomic positions of mismatched edges and mismatched nucleotide bases adjacent to the edges as the locations of candidate variants [0060].
However, there is not support within the specification, nor has Applicant provided such support, for identifying mismatched nodes to call as variants or normal. Therefore, the limitations introduce new matter.
Claims 26 and 51 are similarly rejected. Claims 3-4, 6-7, 9-13, 15-22, 24-25, 28-29, 31-32, 34-38, 40-47, and 49-50 are rejected based on their dependency from claims 1 and 26.
35 USC § 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 25, 46, and 49 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. The instant rejection is maintained from the previous Office Action.
Claim 25 recites “wherein the plurality of control reads is obtained from a secondary sample previously known not to include microsatellite instability”. However, claim 1 recites that the test reads and control reads originate from different portions of the same sample, the plasma and the buffy coat fractions of a blood sample. It is therefore not clear whether claim 25 intends to require producing more control reads from a different secondary sample, if claim 25 intends to replace the control reads of claim 1, and would therefore be an improper dependent claim, or if claim 25 should have been deleted when the sample for the control reads was limited in the independent claim. For compact examination, it is assumed that claim 25 does not intend to replace the sample of claim 1 and should have been deleted. The rejection may be overcome by clarifying the relationship between claims 1 and 25.
Claim 46 recites “wherein filtering the plurality of markers”. The limitation is unclear because claim 26 does not recite a step of filtering. Therefore, it is unclear what step of claim 26 is intended to be further limited by claim 46. The rejection may be overcome by clarifying which step of claim 26 the limitation actually limits.
Claim 49 recites “wherein the plurality of test reads and the plurality of control reads are obtained from a sample previously known not to include cancer cells”. It is unclear whether the wherein clause is intended to require obtaining the samples in each claim within the metes and bounds of the claimed invention, or if it is only further limiting the type of samples analyzed in the invention such that obtaining the samples are not required within the metes and bounds of the invention. As set forth in MPEP 2111.04.I, “wherein” clauses raise the question as to the limiting effect of the language in a claim. As neither of the claims nor the claim from which they depend recite an active obtaining step, the metes and bounds of the claims are unclear. Because the claims are directed to a system, it is assumed that obtaining the samples is not required and that the claims only further limit the type of sample and data analyzed. The rejection may be overcome by clarifying that the steps are not required to be performed by amending claim 49 to recite “were obtained”.
Response to Applicant Arguments
Applicant has provided no amendments, remarks, or arguments pertaining to the rejections maintained from the previous Office Action. Therefore, the rejections are maintained.
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, 3-4, 6-7, 9-13, 15-22, 24-26, 28-29, 31-32, 34-38, 40-47, 49, and 51 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 a method and systems, 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).
The claims also recite a law of nature or a natural phenomenon. The MPEP at 2106.04(b) further explains that laws of nature and natural phenomena include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
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) as well as a law of nature or a natural phenomenon are as follows:
Independent claims 1 and 26: generating… a first directed graph for the cell-free nucleic acid fragments by forming nodes of the first directed graph from k-mers extracted from the first plurality of reads and connecting the nodes of the first directed graph with one or more edges representing overlapping nucleotide sequences between the nodes;
generating… a second directed graph for the white blood cell nucleic acid fragments by forming nodes of the second directed graph from k-mers extracted from the second plurality of reads and connecting the nodes of the first directed graph with one or more edges representing overlapping nucleotide sequences between the nodes;
aligning… the first directed graph and the second directed graph to a reference genome ;
calling… a plurality of test reads from the first directed graph as variants and to identify a plurality of control reads from the second directed graph as normal by identifying any mismatched nodes or edges between the first directed graph aligned to the reference genome;
calling… a plurality of control reads from the second directed graph as normals by identifying any mismatched nodes or edges between the second directed graph aligned to the reference genome;
selecting… a plurality of markers from the plurality of test reads and the plurality of control reads, each marker identifying a set of nucleotides present in both the plurality of test reads and the plurality of control reads, and the plurality of markers known to be associated with MSI in cancer;
for each marker, determining… whether the marker is significant or insignificant by calculating a marker significance based on an entropy score, a divergence score, a statistical significance score, and a viability score, the marker significance indicating the significance and viability for the marker in detecting MSI, and wherein:
the entropy score, representing an entropy of the marker, is calculated by quantifying a difference in entropy between test reads and control reads for the marker,
the divergence score, representing a relative entropy for the marker, is calculated by quantifying a relative difference in an expected length variation between the test reads and control reads for the marker,
the statistical significance score is calculated by quantifying a statistical significance of the marker,
the viability score is calculated by quantifying similarities between the marker and other markers in the filtered plurality of markers;
determining… an instability score for the sample based on the calculated marker significances scores for the selected plurality of markers, the instability score a ratio of significant to insignificant markers representing a likelihood that the sample contains MSI; and
determining… that the individual likely has MSI based on the instability score (claim 1);
informing treatment in the individual based on the instability score for the sample (claim 26).
Independent claim 51: aligning the first directed graph and the second directed graph to a reference genome;
calling a plurality of test reads from the first directed graph as variants by identifying any mismatched nodes or edges between the first directed graph aligned to the reference genome;
calling a plurality of control reads from the second directed graph as normals by identifying any mismatched nodes or edges between the second directed graph aligned to the reference genome;
selecting a plurality of markers from the plurality of test reads and the plurality of control reads, each marker identifying a set of nucleotides present in both the plurality of test reads and the plurality of control reads, and the plurality of markers known to be associated with MSI in cancer;
for each marker, determining whether the marker is significant or insignificant by calculating a marker significance based on an entropy score, a divergence score, a statistical significance score, and a viability score, the marker significance indicating significance and viability for the marker in detecting MSI, and wherein:
the entropy score, representing an entropy of the marker, is calculated by quantifying a difference in entropy between test reads and control reads for the marker,
the divergence score, representing a relative entropy for the marker, is calculated by quantifying a relative difference in an expected length variation between the test reads and control reads for the marker,
the statistical significance score is calculated by quantifying a statistical significance of the marker, and
the viability score is calculated by quantifying similarities between the marker and other markers in the plurality of markers;
determining the instability score for the sample based on the calculated marker significances for the selected plurality of markers, the instability score a ratio of significant to insignificant markers representing a likelihood that the sample contains MSI; and
determining that the individual likely has MSI based on the instability score.
Dependent claims 3-4, 6-7, 9-13, 15-22, 28-29, 31-32, 34-38, and 40-47 recite further steps that limit the judicial exceptions in independent claims 1 and 26 and, as such, also are directed to those abstract ideas. For example, claims 3-4 and 28-29 further limit the entropy score and its role in determining marker significance; claims 6-7 and 31-32 further limit the divergence score and its role in determining marker significance; claims 9-13 and 34-38 further limit the statistical significance score and its role in determining marker significance; claims 15-16, 18, 40-41, and 43 further limit the viability score and its role in determining marker significance; claims 17, 19-20, 42, and 44-45 further limit calculating the marker significance by applying an error correction model; claims 21 and 46 further limit selecting or filtering the markers; and claims 22 and 47 further limit the read depth of the markers.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually determine the likelihood that a sample contains MSI. Without further detail as to the methodology involved in “generating”, “aligning”, “calling”, “identifying”, “selecting”, “determining”, “calculating”, “quantifying”, “comparing”, and “informing” under the BRI, one may simply, for example, use pen and paper to draw nodes and edges between k-mers of sequences to generate directed graphs, align those directed graphs to a reference sequence, call variants and normal by identifying mismatched sequences in the directed graph alignments, select markers , determine whether the markers are significant by calculating one or more of an entropy score, a divergence score, a statistical significance score, and a viability score, determine a ratio of significant to insignificant markers, and use that ratio to determine that the individual has MSI. It is noted that no active step of treating the individual is recited, and a step of informing treatment is considered to be a mental process. Some of these steps, such as calculating an entropy score, a divergence score, a statistical significance score, and a viability score and determining an instability score, and those recited in the dependent claims require mathematical techniques as the only supported embodiments, as is supported in the Specification at least at: [0111-0112], [0114], [0116], [0118-0120]. The claims also include the limitations “determining… that the individual likely has MSI based on the instability score” in claim 1 and “informing treatment in the individual based on the instability score for the sample” in claim 26, which are considered to recite a relationship between the individual’s genotype and MSI status and the individual’s MSI status and their response to a treatment. Therefore, the claims recite a law of nature.
Therefore, claims 1 and 26 and those claims dependent therefrom recite an abstract idea and a law of nature [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:
Claim 1: obtaining a blood sample collected from an individual and comprising cell-free nucleic acid fragments and white blood cell nucleic acid fragments;
separating the cell-free nucleic acid fragments suspended in plasma from the white blood cell nucleic acid fragments in a buffy coat fraction;
sequencing the cell-free nucleic acid fragments to obtain a first plurality of reads; and
sequencing the white blood cell nucleic acid fragments to obtain a second plurality of reads.
Claim 26: accessing a first plurality of reads and a second plurality of reads sequenced from a blood sample collected from an individual, wherein the first plurality of reads was obtained from sequencing cell-free nucleic acid fragments isolated in plasma of the blood sample and the second plurality of reads was obtained from sequencing white blood cell nucleic fragments isolated in a buffy coat fraction separated from the plasma.
Claim 51: storing: a first directed graph representing sequence reads of cell-free nucleic acid fragments obtained from a biological sample, the first directed graph comprising edges representing sequences of k nucleotide bases from a first plurality of sequence reads derived from sequencing the cell-free nucleic acid fragments and nodes connecting the edges in the first directed graph; a second directed graph representing sequence reads of white blood cell nucleic acid fragments obtained from the biological sample, the second directed graph comprising edges representing sequences of k nucleotide bases from a second plurality of sequence reads derived from sequencing the white blood cell nucleic acid fragments and nodes connecting the edges in the second directed graph.
Dependent claims 24-25 and 49 recite steps that further limit the recited additional elements in the claims. For example, claims 24-25 and 49 further limit the samples from which the reads were obtained.
Independent claims 1, 26, and 51 includes the additional non-abstract elements of a computer process, a system comprising one or more processors and one or more memories storing computer instructions, and a system comprising a computer-process and a non-transitory computer-readable storage medium directed graphs and instructions.
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” samples, “separating” cell-free and white blood cell nucleic acid fragments, and “sequencing” and “accessing” test and control reads, in claims 1 and 26, and “storing” directed graphs” perform functions of collecting the data needed to carry out the judicial exceptions. Data gathering does 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)).
Further steps directed to additional non-abstract elements of the systems do not describe any specific computational steps by which the “computer parts” perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer, such as the computer-readable recording media, are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, and therefore the claim does not integrate that judicial exceptions into a practical application. The courts have weighed in and consistently maintained that when, for example, a memory, display, processor, machine, etc.… are recited so generically (i.e., no details are provided) that they represent no more than mere instructions to apply the judicial exception on a computer, and these limitations may be viewed as nothing more than generally linking the use of the judicial exception to the technological environment of a computer (MPEP 2106.05(f)).
The Specification discloses that the detection method improves sensitivity of MSI detection over the prior art method at [0126-0130], but does not provide a clear explanation for how the additional elements provide these improvements. Therefore, the additional elements do not clearly improve the functioning of a computer, or comprise an improvement to any other technical field. Further, the additional elements do not clearly effect a particular treatment; they do not clearly require or set forth a particular machine; they do not clearly effect a transformation of matter; nor do they clearly provide a nonconventional or unconventional step (MPEP2106.04(d)).
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 prior art to Mohamadkhani et al. (Middle East Journal of Digestive Diseases, 2015 7(2), p.61-68; previously cited) reviews the importance of collecting and storing the buffy coat of blood samples, which includes white blood cells as a source for cellular/germline nucleic acids, and serum and plasma samples, which are the source of cell free DNA or RNA, for use in genomic sequencing and copy-number variation analysis (see the abstract and (p. 62, col. 1, p.ar 2; p. 63, col. 1 through col. 2, par. 2; p. 64, col. 1, par. 4 through col. 2, par. 1; Tables 1-2). Further, the prior art to Siravegna et al. (Clinical Oncology, 2017, 14(9), pp.531-548; previously cited) reviews the comparison of circulating tumor DNA sequences generated via next-generation sequencing to germ line DNA from nonmalignant tissue like peripheral blood mononuclear cells obtained from the same patient (p. 537, col. 2, par. 2) and the use of cell free DNA to detect microsatellite instability (p. 534, col. 2, par. 3). The prior art references to Matsuguchi et al. (US 2018/0119137; cited on the 5 Jul 2023 PTO-892; previously cited; see the abstract, FIG. 2, and [0014; 0042; 0045; 0088-0089; 0100; 0143; 0163; 0172]), Devogelaere et al. (US 2018/0211002; previously cited; see the abstract and [0021; 0367; 0494-0500]), and Allemeersch et al. (EP 3118324; previously cited; see the abstract and [0010; 0054; 0086-0087; 0095; 0121; 0183-0186]) disclose methods for sequencing cell-free DNA from the plasma and genomic DNA from the buffy coat to detect MSI. Therefore, the steps directed to “obtaining a blood sample collected from an individual and comprising cell-free nucleic acid fragments and white blood cell nucleic acid fragments”, “separating the cell-free nucleic acid fragments suspended in plasma from the white blood cell nucleic fragments in a buff coat fraction”, “sequencing the cell-free nucleic acid fragments to obtain a plurality of test reads”, and “sequencing the white blood cell nucleic acid fragments to obtain a plurality of control reads” in claim 1 and “accessing a plurality of test reads and a plurality of control reads sequenced from a blood sample collected from an individual, wherein the plurality of test reads are obtained from sequencing cell-free nucleic acid fragments isolated in plasma of the blood sample and the plurality of control reads are obtained from sequencing white blood cell nucleic fragments isolated in a buff coat fraction separated from the plasma” in claim 26 are routine, well-understood and conventional in the art, both separately and in combination with one another. Further, the courts have found that storing and receiving data, as recited in at least claim 51, is a well-understood, routine, and conventional function 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) and 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) as discussed in MPEP 2106.05(d)(II)(i)). “Data per se” is not directed to a statutory category (see MPEP 2106.03(I), and therefore data stored by a computer cannot provide significantly to the claim when merely stored on a computer system and employed in data gathering purposes. It is further noted that the prior art review to Paten et al. (Genome Research, Mar 30 2017, 27(5):665-676; newly cited) discloses that directed graphs are the simplest common graph representation of genomes, where each node represent a k-mer and each directed edge represents an overlap of k – 1 bases between the suffix of the “from” node and the prefix of the “to” node, and that one of the most important use cases for a genomic reference is as a target for read mapping to discover variants (p. 666, col. 2, par. 3; p. 669, col. 1, par. 3 through p. 673, col. 2, par. 1; entire document is relevant). 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 claims 26 and 51 and those claims dependent therefrom, the computer-related elements or the general purpose computer do not rise to the level of significantly more than the judicial exception. The claims state nothing more than a generic computer which performs the functions that constitute the judicial exceptions. Hence, these are mere instructions to apply the judicial exceptions using a computer, which the courts have found to not provide significantly more when recited in a claim with a judicial exception (see Voter Verified, Inc. v. Election Systems & Software, LLC, 887 F.3d 1376, 1385, 126 USPQ2d 1498, 1504 (Fed. Cir. 2018), MPEP 2106.06(A)). The specification also notes that computer processors and systems, as example, are commercially available or widely used at least at [0133-0135]. The additional elements are set forth at such a high level of generality that they can be met by a general purpose computer. Therefore, the computer components constitute no more than a general link to a technological environment, which is insufficient to constitute an inventive concept that would render the claims significantly more than the judicial exceptions (see MPEP 2106.05(b)I-III).
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
At p. 20-24, Applicant submits that Step 2A, Prong 1, the limitations directed to “generating” a first and second directed graph, “aligning” the directed graphs to a reference genome”, and “calling” variants in test and control reads based on the aligned graphs cannot be considered as directed to an abstract idea because they do not recite mathematical concepts and mental processes. Applicant submits that the claims cannot be practically performed in the human mind because the directed graphs are a complex data structure that cannot be input or output by the human mind. Applicant submits that the claims are similar to SiRF in that the computer processor is essential to the generation of the structure and their use in variant calling.
It is respectfully submitted that this is not persuasive. As set forth in the above rejection, these limitations are considered to recite abstract ideas because they can be practically performed in the mind, not because they recite mathematical concepts. Applicant’s arguments regarding these limitations reciting mathematical concepts are acknowledged but are not pertinent to the rejection.
Regarding SiRF, it is submitted that the instant claims are not analogous those in SiRF because the instant claims do not require the use of a GPS receiver. As discussed next, the computer in the instant claims does not perform a similar function to the GPS receiver in SiRF because the computer in the instant claims serves only to apply the recited judicial exception to a computer. As discussed in the previous Office Action response to arguments, the claims require only extracting k-mers from the plurality of reads to form nodes and edges of the directed graphs. The claims do not require using all of the reads or any amount of reads that a human mind could not feasibly process. There are no limitations of the dataset herein to preclude such an interpretation. The formation of the nodes could also be performed using pen and paper. An abstract idea performed with the aid of a pen and paper or a tool remains an abstract idea. Aligning k-mers of a directed graph of unspecified size to a reference genome is similarly not considered to be beyond the mental capacity of a human mind. An example of a directed graph of k-mers which could be produced by hand and used for variant calling is illustrated by Figure 1 of Cameron et al. (Genome Research, 2017, 27:2050-2060; newly cited), reproduced below.
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Although the claims require performing the actions using a computer processor, the use of a physical aid, such as a computer, does not negate the mental and mathematical nature of said limitations at Step 2A, Prong 1. The MPEP at 2106.05(f) states that claims which merely include instructions to implement an abstract idea on a computer, or merely use a computer as a tool to perform an abstract idea, effectively add words that “apply” the judicial exception in a computer, while claims that purport to improve computer capabilities or to improve an existing technology may integrate a judicial exception into a practical application or provide significantly more. The computer as claimed herein is not specifically implemented or changed by operation of said steps. Rather, the computer functions as a tool to perform said steps and any computer is considered capable of performing said tasks.
At p. 24-25, Applicant submits that the above pointed to limitations integrate any potential judicial exceptions into a practical application at Step 2A, Prong 2 because the directed graph improves the functioning of a computer by minimizing file-storage size of the read data to increase computational speed. Applicant submits that performing MSI detection from variants and normal identified from the partitioned nucleic acid fragments provides for a more robust detection in comparison to prior art methods which rely only on genomic DNA from a separate biological sample.
It is respectfully submitted that this is not persuasive. Applicant alleges that directed graphs represent a practical application. However, steps directed to generating and using the directed graphs that provide the supposed improvement (i.e., to the functioning of a computer) in the instant claims are steps that are, themselves, the judicial exceptions and cannot therefore be a practical application of the judicial exception. The courts have made clear that a judicial exception is not eligible subject matter (Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)) if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, it is the additional elements (if any) in the claim that must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B. If there are no additional elements in the claim, then it cannot be eligible. It is submitted here that the instant claims do not include any additional elements that provide for a practical application. Rather, the “additional element” in the instant claims (see exemplary claim 1) includes only the step of directed to sample preparation and sequencing. As set forth above, said steps operate in the claim as data gathering steps and do not integrate any of the recited judicial exceptions into a practical application, nor do the claims as a whole include any inventive concept beyond well-understood, routine and conventional steps.
Further, even if these steps were considered to recite additional elements rather that judicial exceptions, they would not provide for a practical application at Step 2A Prong 2, because they merely provide the data for use by the judicial exceptions in the claim. Specifically, the limitations pointed to by Applicant function to identify the variants in the test data as in comparison to the control data. Those variants are then used to identify markers, which are mathematically evaluated to determine whether the sample has a likelihood of microsatellite instability. Therefore, the variants must first be identified to be used by the judicial exceptions, and those steps indicated by Applicant would merely serve to gather such data.
The improvement as submitted by Applicant that the use of control reads from the partitioned nucleic acid sample, rather than an unmatched DNA sample, provides for more robust detection is not convincing because such an improvement flows from the use of the data by the judicial exceptions, not from sample collection or variant calling steps as submitted by Applicant. As discussed above, a judicial exception cannot provide a practical application for itself or other judicial exceptions.
At p. 25-26, Applicant submits that the above identified steps are not WURC at Step 2B, as is evidenced by the lack of a prior art rejection.
It is respectfully submitted that this is not persuasive. MPEP 2106.05(d) sets forth that, at Step 2B, it is the additional elements which are examined to determine whether they are well-understood, routine, conventional activities previously known to the industry. The limitations pointed to be Applicant are considered to recite a judicial exception as described above and are therefore not considered at Step 2B. Those additional elements in the claims are considered in the above rejection and are found to recite well-understood, routine, and conventional activity in the field.
It is noted that even if those limitations directed to generating and using the directed graphs to detect variants were considered to recite additional elements, they would be found to be well-understood, routine, and conventional elements in the field, as discussed about in the rejection regarding the graphs stored on the databased in claim 51.
Applicant is reminded that the standard for assessing the conventionality of the additional elements at Step 2B of the 35 USC 101 analysis is separate and distinct from the standard for applying prior art under 35 USC 102 or 103 (see MPEP 2106.05(I)). 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. It is further noted that the prior art rejection was withdrawn in the Office Action mailed Jul 5 2023 for the limitations directed to calculating the various scores, which recite judicial exceptions and are not evaluated at Step 2B.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.N.S./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685