DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Invention I and the species of N6-methyladenine (6mA) in the reply filed on 16 June 2026 is acknowledged.
Claim Status
3. Claims 1-32 are pending.
Claim 32 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-31 read on the elected invention and have been examined herein.
Information Disclosure Statement
4. The information disclosure statement filed 24 September 2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein as “Cite No.” 12 and 13 (Altschul et al. 1990 and Altschul 1997) has not been considered. Note that the documents submitted for references 1 and 13 consist of 2 pages and are blank other than the following recitation:
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Claim Rejections - 35 USC § 101
5. 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 1-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of an abstract idea, and particularly mental processes and mathematical concepts.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Claims 1-17 recite the steps of “assaying the reads against one or more AMR markers to obtain read metrics; obtaining reference metrics relating to one or more of the AMR markers identified in reference nucleic acids; and identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below a threshold ratio. These steps may be accomplished mentally via critical thinking processes and thus are an abstract idea. The steps also involve mathematical concepts in which sequencing metrics and ratios are calculated / determined.
Claims 18-31 recite a method “for identifying a host of an AMR marker” and require performing the steps of “identifying one or more AMR markers from the read sequence data to obtain read metrics; obtaining reference metrics relating to any one or more of the AMR markers identified in reference sequence; and identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below a threshold ratio.” These steps may also be accomplished mentally through critical thinking processes. The steps of calculating / determining / identifying sequencing read metrics and ratios also involve the judicial exception of a mathematical concept.
The claims require performing the step of “determining” the level of expression of one or more biomarkers. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the determining step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the genes in a sample obtained from a subject. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
The claims require performing the step of “assaying” the level of expression of the REST-0003 mediated oligonucleotides. Neither the specification nor the claims set forth a limiting definition for "assaying" and the claims do not set forth how “assaying” is accomplished. The claims do not specifically require performing an active laboratory process in which expression levels are detected. The Free Dictionary (available via URL: <thefreedictionary.com/assaying>, printed on 30 January 2019) defines assaying as including “To evaluate; assess”; or “An analysis or examination.” Accordingly, the broadest reasonable interpretation of the assaying step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the oligonucleotides in a sample obtained from a subject. Such “assaying” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Claims 12-14 and 28-30 require “identifying” a host of the one or more AMRs by “comparing” methylation patterns and identifying” N6-methyladenine modifications in the reads (claim 14 and 30). The “identifying” and “comparing” steps may be accomplished mentally and are thereby an abstract idea/process.
While claims 18-31 are drawn to “computer-implemented” methods, it is noted that none of the claims specifically recites the use of a computer. To the extent that the claims require a computer or the use of an algorithm or software to calculate read metrics, the use of a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “(t)he courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “(n)or do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Further, regarding the mathematical concepts recited in the claims, see MPEP 2106.04(a)(2) which states
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.”
Also, to the extent that the claims require mathematical formulas to accomplish the steps of obtaining read metrics, such as RPKM, and ratios of the metrics, MPEP 2106.04I states “mathematical formulas are considered to be a judicial exception as they express a scientific truth, but have been labelled by the courts as both abstract ideas and laws of nature.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps in claims 1-17 of obtaining a sample; enriching nucleic acids in the sample via target enrichment and sequencing the enriched nucleic acids to obtain sequencing are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
As set forth in MPEP 2106.05(g), steps of gathering data to be used in a claimed process are pre-solution activity and do not integrate a judicial exception into a practical application.
In claims 18-31, the additional step of obtaining read sequence data is also pre-solution activity and is not a practical application of the recited judicial exceptions.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited non-patent ineligible steps in claims 1-17 of obtaining a sample, enriching nucleic acids in the sample via targeted enrichment and sequencing the enriched nucleic acids were well-known, routine and conventional in the prior art. In claims 18-31, the step of obtaining read sequence data was also well-known, routine and conventional in the prior art. This finding is supported by the teachings in the specification. For instance, see para [0095] of the specification (paragraph numbering herein is with respect to the published application) which teaches “In some embodiments, sequence reads are acquired by any methodology known in the art.” It is also disclosed that enrichment, prior to sequencing, is performed using conventional methods of PCR (e.g., para [0065]).
Further, Slizovsky (Microbiome. 2022 10:185; cited in the IDS) teaches methods of enriching for long sequencing using capture probes, prior to performing sequencing (e.g., Figure 1).
Ferreira et al (Microorganisms. 2021. 9: 1672, p. 1-13) teaches methods of enriching for target nucleic acids by hybridizing nucleic acids to capture probes and then performing sequencing of the enriched nucleic acids (e.g., Figure 1 and p. 6).
Beaudry et al (Frontiers in Microbiology. 07 April 2021. 12: 1-14) teaches methods for identifying microorganisms present in a sample wherein the methods comprise enriching for target nucleic acids by hybridizing the nucleic acids to capture probes and then performing sequencing of the enriched nucleic acids (e.g., abstract, p. 2, col. 1; and p. 4 “16S rRNA Hybridization Capture Enrichments” and “Sequencing Data Processing”). The reference (p. 12, col. 1) states “16S cap is economical and opens up the possibility of adding deep taxonomic sampling to studies that are capturing other genes of interests e.g., antibiotic resistance genes (Guitor et al., 2019; Oladeinde et al., 2019; Thomas et al., 2020).”
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015); …
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546; …
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Further, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
6. 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-31 are indefinite over the recitations of “read metrics” and “reference metrics.” These phrases are not clearly defined in the specification or the claims and there is no art recognized definition for these phrases. While the specification provides examples of what may be included by a read metrics, particularly as it relates to short read-metrics (e.g., at para [0007]) “the short-read metrics comprising quantitative metrics such as RPKM, median depth, read count, or others of any one or more of the AMR markers identified in the short-reads”), it is unclear as to what other types of attributes are encompassed by the read and reference metrics. Accordingly, the metes and bounds of the claimed subject matter are not clear. Note that while claims 15 and 29 define the read metrics, these claims do not define the reference metrics; and while claims 16 and 30 define the reference metric, these claims do not define the read metrics.
Claims 1-17 are indefinite over the recitation of “assaying the reads against one or more AMR markers to obtain read metrics.” This phrase is not clearly defined in the specification or the claims. It is unclear as to what is meant by “assaying” the reads “against” the AMR markers.
Claims 2, 15, 16, 19, 29 and 30 are indefinite over the recitation of “RPKM.” The acronym “RPKM” renders the claims indefinite because the acronym may have many different meanings in the art and it is unclear as to which particular meaning of “RPKM” is intended to be encompassed by the claims. Note that the specification recites “RPKM (Reads Per Kilobase Million)” (para [0282] and goes on to state “RPKM may be calculated as the numReads/(geneLength/1000*totalNumReads/1,000,000) with numReads being the number of reads mapped to a gene sequence, geneLength being the length of the gene sequence and totalNumReads being the total number of mapped reads of a sample.” However, it is unclear as to what alternative means for calculating RPKM are intended to be encompassed by the claims. That is, it is unclear as to RPKM herein is intended to encompass only normalizing the read counts by the “per million” scaling factor or if RPKM is also intended to take into consideration the length of the gene, as is conventional in the art.
Claims 18-31 are indefinite over the recitation of “AMR.” The acronym “AMR” renders the claims indefinite because the acronym may have many different meanings in the art, such as low density, liver disease and Lyme diseases and it is unclear as to which particular meaning of “AMR” is intended to be encompassed by the claims. This rejection may be obviated by amendment of claim 18 to recite “A computer-implemented method for identifying a host of an antimicrobial resistance (AMR) marker.”
Claim Rejections - 35 USC § 112(a) - Enablement
7. 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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-31 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims are drawn to a method for identifying a host of an antimicrobial resistance (AMR).
Claims 1-17 comprise the steps of: obtaining a sample from a source, the sample comprising a plurality of nucleic acids from a plurality of hosts; enriching the nucleic acids via target enrichment; sequencing the enriched nucleic acids to generate reads of the enriched nucleic acids; assaying the reads against one or more AMR markers to obtain read metrics; obtaining reference metrics relating to one or more of the AMR markers identified in reference nucleic acids; and identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below a threshold ratio.
Claims 18-31 comprise the steps of: obtaining read sequence data derived from one or more samples that each comprises a plurality of nucleic acids from a plurality of hosts; identifying one or more AMR markers from the read sequence data to obtain read metrics; obtaining reference metrics relating to any one or more of the AMR markers identified in reference sequence; and identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below a threshold ratio.
Thus, the claims require that a host of the one or more AMR markers is identified when average ratios between the read metrics and the reference metrics are below a threshold ratio.
However, the specification does not enable methods wherein an average ratio between the read metrics and the reference metrics below a threshold ratio identifies the host of the AMR marker, as recited in the claims.
Nor does the specification enable methods wherein the reference is any reference; wherein the read metric is any read metric; wherein the “reference metrics relating to one or more of the AMR markers identified in reference nucleic acids” is any reference metric and the threshold is any threshold.
Rather, the specification exemplifies the read metrics of RPKM, median depth, read count (para [0006]). The specification teaches using the ratio of the RPKM and median depth read metric of the sequences in the sample to that of known reference sequences of an AMR marker of a particular host organism to be detected to determine if the method can be used to identify the host of the AMR marker (e.g., Figures 1 and 2 and para [0284]). For instance, the specification (para [0284]) states:
“The method 100 moves to a decision state at block 160, where an average ratio of short-read metrics to reference metrics are compared against a threshold ratio to determine whether a host of the AMR marker can be identified based on these metrics. If the average ratio of the short-read metrics to reference metrics are above the threshold ratio, then the method 100 moves to block 170 that signifies how the host cannot be identified and the method 100 terminates at the end. If the average ratio of the short-read metrics to the reference metrics are below the threshold ratio, then the method 100 moves to block 100 for identifying the host of the AMR marker.”
The specification provides an example of using the average RPKM ratio and the average median depth ratio to determine if mecA of a Staphylococcus species is present in a sample (para [0298] and Figure 7). However, these teachings do not clearly set forth what constitutes a reference or reference metric to be used with any sample to identify a host AMR marker and do not specify how the threshold / threshold ratio is determined.
The specification (para [0283]) states:
“Without being bound by theory, these panels employ a method that uses existing sequencing metrics to infer host microorganism/AMR marker linkages. These linkages can be based on an understanding that, for endogenous AMR markers, quantitative metrics will be similar between the AMR marker and the host microorganism, as compared to other potential associated microorganisms in the sample. Moreover, for known plasmid-borne AMR markers, single-direction quantitative linkage logic may be informative for ruling out potential host microorganisms in polymicrobial samples with varying abundance.”
However, these teachings do not provide sufficient guidance to enable the broadly claimed methods which encompass using any read metrics, any reference to obtain reference metrics and any threshold ratio to identify a host of an AMR marker.
The teachings in the specification appear to indicate that when a sample contains more than one host, then sequences flanking the AMR gene are required to identify the host(s). For instance, the specification (para [0300]) states “When more than one potential host microorganism is detected in a sample, sequencing metrics such as RPKM and median depth may be useful in predicting the host, especially for chromosomally-encoded genes or genes transmitted through mobile genomic elements that insert into the host genome (e.g., mecA).” However, the claims do not require obtaining sequences flanking the AMR gene to detect a host of an AMR when multiple hosts are present in a sample.
Further, at para [0298], the specification states “Also shown in FIG. 7, the average ratios of RPKM and median depth between mecA and the predicated host were 1.5 and 1.4 respectively. In contrast, the average ratios of RPKM and median depth between mecA and the other (not predicted host) Staphylococcus species were 181 and 185, respectively.” However, it would not appear that the method would identify the host of the AMR marker (mecA) in this example if “the threshold ratio is at least 1.5” as required by claims 3 and 20 (i.e., the RPKM ratio is not below the threshold of 1.5).
In the absence of additional guidance provided in the specification or prior art, it is unpredictable as to how to practice, without undue experimentation, the broadly claimed methods for identifying the host of an AMR marker by determining a ratio of any read metric to reference metric, including an average RPKM ratio between the RPKMs of the read metrics and the reference metrics, and an average median depth ratio between the median depths of the read metrics and the reference metrics (claim 2), wherein the reference is any reference and then identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below any unidentified threshold ratio.
Case law has established that '(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.'" In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that '(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that '(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
Moreover, as set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
In view of the unpredictability in the art, and the lack of disclosure and guidance provided in the specification and in the prior art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ferreira et al (Microorganisms. 2021. 9: 1672, p. 1-13) teaches methods of identifying antimicrobial resistance (AMR) nucleic acids present in a sample, wherein the methods comprise enriching for AMR target nucleic acids by hybridizing nucleic acids to capture probes to nucleic acids present in a sample from a source, and particularly a human subject, and then performing sequencing of the enriched nucleic acids (e.g., Figure 1 and p. 6). Ferreira (p. 10) teaches “Target capture-based methods have thus been proposed as a potentially viable approach for the identification of resistomes in complex native specimens [5,33]. We have selected over 9200 targets from the AMR biomarker database ARESdb and developed a target enrichment panel and NGS workflow, suitable for the processing and sensitive AMR profiling of complex sample types.” It is reported that:
“Combining the ARESdb AMRpanel with 16S rRNA gene sequencing allowed for the culture-free detection of bacterial taxa and AMR markers directly from septic patient samples at an average sensitivity of 99%. Summarizing, the newly developed ARESdb AMR panel may serve as a valuable tool for comprehensive and sensitive AMR marker detection” (see abstract).
Ferreira (p. 7) states that “Combining the ARESdb AMRpanel with 16S rRNA gene sequencing allowed for the culture-free detection of bacterial taxa and AMR markers directly from septic patient samples at an average sensitivity of 99%. Summarizing, the newly developed ARESdb AMR panel may serve as a valuable tool for comprehensive and sensitive AMR marker detection” and used the following formula to calculate the RPKM:
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Note that the RPKM constitutes a read metric. Ferreira further states that “markers detected by whole genome sequencing (WGS) were considered the ground truth. A true positive (TP) marker was defined as a marker detected both in the reference and in the sample; a false negative (FN) marker as marker detected in the reference and not detected in the sample; and a false positive (FP) marker as marker detected in the sample being analyzed and not present in the reference” (p. 7).
The prior art of Flygare et al (US20180365375; cited in the IDS) teaches methods, including computer implemented methods for identifying a microorganism (taxa) in a sample comprising performing a sequencing assay on nucleic acids present in a sample to generate sequencing reads and “for each sequencing read: (i) performing with a computer system a sequence comparison between the sequencing read and a plurality of reference polynucleotide sequences, wherein the comparison comprises calculating k-mer weights as a measure of how likely it is that k-mers within the sequencing read are derived from a reference sequence within the plurality of reference polynucleotide sequences; and (ii) calculating a probability that the sequencing read corresponds to a particular reference sequence in a database of reference sequences based on the k-mer weights, thereby generating a sequence probability; (b) calculating a score for the presence or absence of one or more taxa based on the sequence probabilities corresponding to sequences representative of said one or more taxa; and (c) identifying the one or more taxa as present or absent in the sample based on the corresponding scores” (para [0006]; see also para [0058] and [0064]). It is stated that the methods disclosed therein can be used to identify antibiotic resistance markers, including markers from bacteria or fungi (e.g., para [0081] and [0085]). Flygare (para [0105] teaches “classifying a sequencing read is not possible on the basis of the second comparison, such as in the case where the maximum sum of k-mer weights for a sequencing read is below a threshold.” It is also stated that “The probability or a score representative of the probability may be used to determine the presence or absence of one or more taxa within a sample. For example, a probability or score above a threshold value may be indicative of presence, and/or a probability or score below a threshold value may be indicative of absence. In some embodiments, presence or absence is reported as a probability, rather than an absolute call” (para [0068]).
However, Ferreira et al and Flygare et al do not teach or suggest “identifying a host of the one or more AMR markers in the sample when average ratios between the read metrics and the reference metrics are below a threshold ratio,” particularly wherein “the average ratios comprise: an average RPKM ratio between the RPKMs of the read metrics and the reference metrics, and an average median depth ratio between the median depths of the read metrics and the reference metrics.”
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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