DETAILED ACTION
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 .
Claim Status
Claims 1-26 are pending and under examination.
No claims are allowed, amended, canceled, new, or withdrawn.
Claims 1-26 are rejected.
Claims 1 and 14 are independent.
Claims 1, 5, 11, 14, 18, and 24 are objected to.
Office Action Outline
Rejections applied
Abbreviations
x
112/b Indefiniteness
PHOSITA
"a Person Having Ordinary Skill In The Art before the effective filing date of the claimed invention"
112/b "Means for"
BRI
Broadest Reasonable Interpretation
x
112/a Enablement,
Written description
CRM
"Computer-Readable Media" and equivalent language
112 Other
IDS
Information Disclosure Statement
x
102, 103
JE
Judicial Exception
x
101 JE(s)
112/a
35 USC 112(a) and similarly for 112/b, etc.
101 Other
N:N
page:line
Double Patenting
MM/DD/YYYY
date format
Priority
As detailed in the 06/15/2023 filing receipt, this application claims priority to U.S. Provisional Applications 63/431,957, filed 12/12/2022, and 63/314,734, filed 02/28/2022.
Claim Objections
Claims 1, 5, 11, 14, 18, and 24 are objected to because of the following informalities:
Claims 1 and 14 recite the term "sequence genetic variants." It is suggested to amend the term to "genetic sequence variants," if appropriate.
Claims 1 and 14 recite the phrase "already annotated in a targeted disease;" which appears grammatically awkward. It is suggested to amend the phrase to "already annotated [[in]]for a targeted disease;" this amendment would reflect a similar phrase in Specification paragraphs [0003] and [0057].
Claims 5 and 18 recite "the control genetic sequence samples and the experimental genetic sequence samples of the dataset," which should be corrected to "the one or more control genetic sequence samples and the one or more experimental genetic sequence samples of the dataset."
Claim 11 recites "wherein server" which should be corrected to "wherein the server."
Claim 24 recites "wherein server" which should be corrected to "wherein a server."
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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 9 and 22 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.
Claims 9 and 22 recite the phrase "...as compensated by their neighbor k-mer sequences." Specification paragraph [0041-0042], [0047-0048], and [0050] mention "compensated" or "compensating", while [0047] discloses "the pair (original and neighbor) k-mer sequences pass the Density Compensation Filter module 220 if psi is smaller than a threshold." However, "...as compensated by their neighbor k-mer sequences" is not described in the Specification. As appropriate, this rejection may be overcome, for example, (i) by narrowing to clearly supported embodiments and/or (ii) by clarifying on the record where support can be found and how that support relates to the recitations. (See associated 112(a) rejection for this element.)
Claim Rejections - 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.
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 1-26 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 depending from rejected claims are rejected similarly, unless otherwise noted, and any amendments in response to the following rejections should be applied throughout the claims, as appropriate.
Claim 1 is rejected as directly reciting a machine and a process in the same claim. A claim to a machine, e.g. here a "system," cannot directly recite a process step such as "receives" as well as the subsequent steps. MPEP 2173.05(p).II pertains. Possibly such a step may be claimed indirectly via the structure of stored computer instructions, claiming also structure that stores the instructions. Regarding any software-embodied steps, it should be clear whether such steps are in fact software-embodied, and it should be clear whether such software is comprised by the claimed machine or manufacture. MPEP 2173.05(p).II pertains regarding a claim directed to both product and process. Similarly rejected are those dependent claims which similarly and directly recite a process step.
In the "applies a neighbor" element of both claim 1 and 14, the relationship is unclear between the "one or more neighbor k-mer sequences" and "one or more k-mer pair sequences" in "to identify one or more neighbor k-mer sequences to form one or more k-mer pair sequences." It is interpreted that one k-mer pair sequence is formed from two neighbor k-mer sequences. Therefore, there is a lack of clarity in the embodiment when one neighbor k-mer sequence is identified to form one or more k-mer pair sequences. Possibly amending to recite "to identify two or more neighbor k-mer sequences to form one or more k-mer pair sequences" would help overcome the rejection.
Both claim 9 and claim 22 have the following three clarity issues:
First, both claims 9 and 22 recite "the amount of density difference" which requires but lacks clear antecedent. If this recitation refer to a previously instantiated instance, then it is not clear which instance that is. If this recitation instantiates this claim elements, this is not clear. This rejection might be overcome by for example amending to recite "[[the]]an amount of density difference."
Second, in both claims 9 and 22, there is a lack of clarity as to what makes up the "amount of density difference." It is unclear if the difference is between the control genetic sequence samples and the experimental genetic sequence samples. Possibly amending claims 9 and 22 to recite "[[the]]an amount of density difference [[in]]between the control genetic sequence samples and the experimental genetic sequence samples" would help overcome the rejection. The claims will be interpreted as suggested to amend.
Third, in both claims 9 and 22, there is a lack of clarity as to what is "compensated," specifically, if the amount of density difference, the control genetic sequences, or the experimental genetic sequences are "compensated." and a lack of clarity as to what "compensated by their neighbor k-mer sequences" entails. " This of clarity extends to what "compensated by their neighbor k-mer sequences" entails. Because an interpretation regarding what is "compensated" cannot be construed, this element "compensated by their neighbor k-mer sequences" will not be examined with regard to the prior art. (See associated 112(a) rejection for this element.)
The claims recite the following elements listed directly below which require but lack clear antecedent. If these recitations refer to previously instantiated instances, then it is not clear which instances those are. If these recitations instantiate the claim elements, this is not clear. These rejections might be overcome by for example amending to recite the article "a" instead of "the." The following elements lack antecedent basis:
• "the plurality of k-mer sequences" (claims 1 and 14). Possibly amending claims 1 and 14 to recite, for example, a prior step of "identifying a plurality of k-mer sequences from the count of unique k-mer sequences" might help overcome the rejection.
• "each detected sequence genetic variant" (claims 1 and 14). Possibly adding a prior step of detecting sequence variants might help overcome the rejection. Alternatively, a prior step of identifying and amending "each detected sequence genetic variant" to recite "each identified sequence genetic variant" might help overcome this and the following rejection.
• "the one or more identified sequence genetic variants" (claims 2 and 15). Possibly adding a prior step of identifying sequence genetic variants would help overcome the rejection.
• "the genetic variants" (claims 3 and 16). Possibly amending to "the sequence genetic variants" as is previously instantiated in claims 1 and 14 would help overcome the rejection.
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 1-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 details the following framework to analyze Subject Matter Eligibility:
• Step 1: Are the claims directed to a category of statutory subject matter (a process, machine, manufacture, or composition of matter)? (see MPEP § 2106.03)
• Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. an abstract idea, a law of nature, or a natural phenomenon? (see MPEP § 2106.04(a)).
• Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application? (see MPEP § 2106.04(d))
• Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? (see MPEP § 2106.05)
Step 1:
Claims 1-23 are directed to a 101 machine or manufacture, here a system comprising a server. Claims 14-26 are directed to a 101 process, here a method. As such, claims 1-26 are directed to a related system and method, which fall under categories of statutory subject matter. (See MPEP § 2106.03). (Step 1: Yes.)
Step 2A, Prong One:
The claims recite judicial exceptions of abstract ideas in the form of mental processes (and mathematical concepts where indicated) as follows:
• perform a count of unique k-mer sequences from the dataset (claims 1 and 14)
• sort the plurality of k-mer sequences based on density (claims 1 and 14)
• apply a neighbor detection function to the k-mer sequences to identify neighbor k-mer sequences to form k-mer pair sequences; (claims 1 and 14; also considered to recite a mathematical concept)
• filter the k-mer pair sequences based on a distance (claims 1 and 14)
• merge the filtered k-mer pair sequences into genetic variant candidates (claims 1 and 14)
• compare the genetic variant candidates against a pre-populated variant database to specify each sequence genetic variant as novel or already annotated in a target disease (claims 1 and 14)
• the neighbor detection function comprises a dimensionality reduction transformation on the plurality of k-mer sequences (claims 2 and 15; also considered to recite a mathematical concept)
• (considering the data of) the genetic variants are a SNP, MNP, and/or an INDEL (claims 3 and 16)
• trim low quality regions from control and experimental genetic sequence samples (claims 5 and 18)
• sorting the k-mer sequences based on density values in descending order (claims 6 and 19)
• filter the k-mer sequences by calculating a ratio of k-mer density in one subset of k-mer sequences as compared to a second subset of k-mer sequences (claims 7 and 20; also considered to recite a mathematical concept)
• apply a T-test filter that performs an unequal variance T-test on the k-mer sequences (claims 8 and 21; also considered to recite a mathematical concept)
• filter the k-mer pair sequences based on the amount of density difference in the control genetic sequence samples and experimental genetic sequence samples as compensated by their neighbor k-mer sequences (claims 9 and 22)
• filtered k-mer pair sequences are merged based on overlap (claims 10 and 23)
• localize the plurality of genetic variant candidates in a reference genome to validate their existence and type (claims 11 and 24)
• performs a check on the genetic variant candidates to determine whether an annotation is associated with said genetic variant candidates at a specific location on the reference genome (claims 12 and 25)
Step 2A Prong One Summary: The claims recite mental processes and mathematical concepts. When considering the broadest reasonable interpretation (BRI) of the claims, the mental processes recited in independent claims 1 and 14 (e.g., "perform a count of k-mer sequences;" "sort the k-mer sequences based on density;" "apply a neighbor detection function;" "filter...(and) merge ...K-mer sequences;" compare variants to a database;" etc.) are directed to processes that may be performed in the human mind, or with pen and paper, as there are no particular limitations recited in claims 1 and 14 which would prevent the mental processes from being performed in the human mind or with pen and paper. The claims recite inherent mathematical processes in e.g., performing "neighbor detection function," "a dimensionality reduction transformation," "calculating a ratio of k-mer density," etc., while details may not be explicitly shown in the claim, are discussed throughout the Specification, e.g., at [0027-0032], [0040-0043], etc. Such analysis performed mentally, or with paper and pencil, may take considerable time and effort, and although a general-purpose computer can perform these calculations at a rate and accuracy that can far exceed the mental performance of a skilled artisan, the nature of the activity is essentially the same, and therefore constitutes an abstract idea. Therefore, the claims recite elements that constitute a judicial exception in the form of an abstract idea(s). (Step 2A, Prong One: Yes.)
Step 2A, Prong Two:
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs). Here at Step 2A, Prong Two, any remaining steps and/or elements not identified as JEs are therefore in addition to the identified JE(s), and are considered additional elements. Because the claims have been interpreted as being directed to judicial exceptions (abstract ideas in this instance) then Step 2A, Prong Two provides that the claims be examined further to determine whether the judicial exception is integrated into a practical application [see 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.
MPEP § 2106.04(d)(I) lists the following five example considerations for evaluating whether a judicial exception is integrated into a practical application:
(1) An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a).
(2) Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2).
(3) Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b).
(4) Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c).
(5) Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
The claims recite additional elements as follows:
Additional elements of data gathering, inputting, and outputting steps: Claims 1 and 14 recite receiving a dataset, and outputting data. Claims 4 and 17 recite the dataset is RNA data in a FASTQ/A format for healthy and unhealthy individuals. Claims 13 and 26 recite the output is in variant call format (VCF). Data gathering steps are additional elements which perform functions of inputting, collecting, and outputting the data needed to carry out the abstract idea. These steps are considered insignificant extra-solution activity, and are not sufficient to integrate an abstract idea into a practical application as they do not impose any meaningful limitation on the abstract idea or how it is performed, nor do they provide an improvement to technology (see MPEP § 2106.04(d)(I)).
Additional elements of computer components: Claim 1 recites a system comprising a server; claims 5, 7-8, 11-12, and 24 also recite a server. Claim 14 recites a computer and a graphic user interface. The claims require only generic computer components, which do not improve computer technology, and do not integrate the recited judicial exception into a practical application (see MPEP § 2106.04(d)(1) and MPEP § 2106.05(f)).
Step 2A Prong Two summary: The claims have been further analyzed with respect to Step 2A, Prong Two, and no additional elements have been found, alone or in combination, that would integrate the judicial exception into a practical application. At this point in examination, it is not yet the case that any of the Step 2A Prong Two considerations enumerated above clearly demonstrates integration of the identified JE(s) into a practical application. Referring to the considerations above, none of: (1) an improvement, (2) a treatment, (3) a particular machine, or (4) a transformation is clear in the record. For example, regarding the first consideration for improvement at MPEP 2106.04(d)(1), the record, including the Specification, does not yet clearly disclose an explanation of improvement over the previous state of the technology field, and the claims do not yet clearly result in such an improvement. (Step 2A, Prong Two: No).
Step 2B analysis:
Because the additional claim elements do not integrate the abstract ideas into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept. An inventive concept is furnished by an element or combination of elements that is recited in the claim in addition to the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself (see MPEP § 2106.05).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are well-understood, routine, and conventional. Those additional elements are as follows:
Additional elements of data gathering, inputting, and outputting steps: The additional elements of receiving a dataset and outputting data (claims 1 and 14), the dataset is RNA data in a FASTQ/A format for healthy and unhealthy individuals (claims 4 and 17), and the output is in variant call format (VCF, claims 13 and 26) do not cause the claims to rise to the level of significantly more than the judicial exception. The courts have recognized receiving or transmitting data over a network; storing and retrieving information in memory; and analyzing DNA to provide sequence information or detect allelic variants [see MPEP§2106.05(d)(II)], as well-understood, routine, conventional activity when they are claimed in a merely generic manner (e.g., at a high level of generality) or as extra-solution activity.
Additionally, the dataset of RNA data in a FASTQ/A format for healthy and unhealthy individuals, and the variant call format (VCF) is shown to be conventional by the following references:
Yang (Genomics & informatics, vol. 13(4):119, pages 1-7 (2015); cited on the attached form PTO-892) presents a review on of whole transcriptome sequencing data, and shows RNA-studies to identify differentially expressed genes between healthy and diseased groups (p.119, col.1); RNAseq data formatted in FASTQ (p.120, col.1; and p.122, table 1); transcript data in FASTA format (p.121, col.2).
Pereira (Journal of clinical medicine, vol. 9(1):132, pages 1-30 (2020); cited on the attached form PTO-892) presents a review on biocomputational pipelines for NGS in clinical genetics, and shows variant calling format (VCF) on pp. 7, 14, 16, 17.
Additional elements of computer components: The system (claim 1), the server (claims 1, 5, 7-8, 11-12, and 24), and the computer with graphic user interface (claim 14) do not cause the claims to rise to the level of significantly more than the judicial exception, and as such do not provide an inventive concept; these are conventional computer components.
Further regarding the conventionality of additional elements, the MPEP at 2106.05(b) and 2106.05(d) presents several points relevant to conventional computers and data gathering steps in regard to Step 2A Prong 2 and Step 2B, including:
• A general purpose computer that applies a judicial exception, such as an abstract idea, by use of conventional computer functions, does not qualify as a particular machine (see 2106.05(b)(I)), as in the case of the system, server, and computer of the claims which are interpreted to recite conventional computer components.
• Use of a machine that contributes only nominally or insignificantly to the execution of the claimed method (e.g., in a data gathering step or in a field-of-use limitation) would not integrate a judicial exception or provide significantly more (see 2106.05(b)(III). The system, server, and computer used in performing sequence data analysis does not impose meaningful limitations on the claims.
• The courts have recognized “receiving or transmitting data over a network”, “performing repetitive calculations”, and “storing and retrieving information in memory”, as well-understood, routine, and conventional functions when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (see MPEP 2106.05(d)(II)). The receiving and outputting of data in claims 1 and 14 is recited in a generic manner.
All limitations of claims 1-26 have been analyzed with respect to Step 2B, and none provides a specific inventive concept, as they all fail to rise to the level of significantly more than the identified judicial exception, and thus do not transform the judicial exception into a patent eligible application of the exceptions. Step2B: NO.
Therefore, the claims, when the limitations are considered individually and as a whole, are rejected under 35 U.S.C. § 101 as being directed to non patent-eligible subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-26 are rejected under 35 U.S.C. 103 as being unpatentable over Pajuste (Scientific reports, vol. 7(1):2537, pages 1-10, plus 10 pages supplemental material, document total 20 pages (2017); cited without supplemental material on the 08/14/2023 IDS; cited with supplemental material on the attached form PTO-892) in view of Laczny (Scientific reports, vol. 4(1):4516, pages 1-12 (2014); cited on the attached form PTO-892) in view of Lee (Nucleic acids research, vol. 45(11):e103, pages 1-10 (2017); cited on the attached form PTO-892) in view of Kingsmore (U.S. 2015/0310163 A1, published 10/29/2015; cited on the 08/14/2023 IDS as "The Children's Mercy Hospital).
Regarding claims 1 and 14, the recited system for variant analysis comprised of a server (claim 1), and method (claim 14), for receiving a dataset of genetic sequence samples, and performing a count of unique k-mer sequences from the dataset, reads on "a computational method that counts the frequencies of unique k-mers in FASTQ formatted genome data and uses this information to infer the genotypes of known variants. FastGT can detect the variants in a 30x genome in less than 1 hour using ordinary low-cost server hardware..." (Pajuste, p.1, paragraph 1; and see p.2, fig. 2), and reads on "FASTQ files were downloaded from the European Nucleotide Archive..." (Pajuste, p.8, paragraph 2).
Regarding claims 1 and 14, the recitation to sort the plurality of k-mer sequences based on density (note, "density" is interpreted as "count") reads on: "The Glistcompare tool, which performs set operations with sorted k-mer lists, was used..." (Pajuste, p.7, paragraph 2).
Regarding claims 1 and 14, the recitation to identify k-mer pair sequences reads on "All non-unique k-mer pairs were removed from the list....The k-mer pairs demonstrating uniqueness even with one mismatch were preferred." (Pajuste, p.7, paragraph 2).
Regarding claims 1 and 14, the recitation to filter the k-mer sequences based on distance reads on "...(the) filtering step removed all of the SNVs that were located between two other SNVs (or indels) with less than 25 bp between them" (Pajuste, p.7, paragraph 1) and "All non-unique k-mer pairs were removed from the list" (Pajuste, p.7, paragraph 2); also see "all 25-mers..." (Pajuste, Supplemental Fig.S5, p.18 of 20 page document).
Regarding claims 1 and 14, the recitation to merge the filtered k-mer pair sequences into genetic variant candidates reads on "The final set contained 30,238,283 SNVs usable by FastGT..." (Pajuste, p.7, paragraph 4) ; also see "final list of SNVs" (Pajuste, Supplemental Fig.S5, p.18 of 20 page document).
Regarding claims 3 and 16, the recited SNP and INDEL are shown by "single nucleotide variants (SNVs), as well as the validated and common indels, were extracted from the dbSNP database build 146" (Pajuste, p.7, paragraph 1).
Regarding claims 4 and 17, the recited FASTQ format is shown by "FASTQ files" (throughout Pajuste, esp. at p.6 and 8).
Regarding claims 5 and 18, the recited trimming low quality regions from genetic sequence samples reads on "High-quality genotypes were retrieved from the Illumina Platinum Genomes FTP site" (Pajuste, p.8, paragraph 1).
Regarding claims 6 and 19, the recited sorting k-mer sequences based on their density in descending order reads on "storing 20-mer in trie" and "Simplified layout of the tree storing 20-nucleotide (40-bit) k-mer" (Pajuste, p.12 of 20 page document, text and Figure S3); and reads on a "major advantage of trie over hastable-based storage is the inherent ordering" (Pajuste, p.13 of 20 page document, paragraph 1).
Regarding claims 7 and 20, the recited calculating a ratio of k-mer density in one subset compared to a second subset of k-mer sequences reads on "to calculate the probability of a true genotype given the k-mer counts CA, CB, the Bayes formula can be used: P(GT|CA,CB) = P(CA|GT) ⋅ P(CB|GT) ⋅ P(GT)/P(CA,CB)" (Pajuste, p.15 of 20 page document, paragraph 1).
Regarding claims 8 and 21, the recited applies a T-test filter that performs an unequal variance T-test reads on "The distribution of differences between the two sets for different genotypes is shown in Table 2" (Pajuste, p.4, paragraph 1 and Table 2).
Regarding claims 9 and 22, the recited filtering of the k-mer pair sequences is based on the amount of density difference between the sequence samples reads on "the k-mer counts and genotypes were calculated for all SNVs of 50 random individuals...Twenty-five men and 25 women were used for filtering the autosomal SNVs; for chrX and chrY, 50 men were used...different criteria were used for removing k-mer pairs and SNVs in this step...First, excluded all chrY markers that had k-mer frequency higher than 3 in more than one woman... Second, autosomal k-mers showing abnormally high frequencies (greater than 3 times the median count) in more than one individual were removed..." (Pajuste, p.7, paragraph 3).
Regarding claims 10 and 23, the recited filtered k-mer pair sequences are merged based on overlap reads on " Principles of using redundant k-mer pairs for genotyping of a given SNV. Three k-mer pairs that overlap the SNV are selected (Pajuste, p. 19 of 20 page document, Figure S6).
Regarding claims 11 and 24, the recited localizing the plurality of genetic variant candidates in a reference genome to validate their existence and type reads on "From 47 million validated markers, 7–17% markers are removed in filtering step 1 due to closely located SNVs (Fig. 5). In filtering step 2 markers are removed if they have no unique k-mer pairs in the expanded reference genome." (Pajuste, p.5, paragraph 5).
Regarding claims 13 and 26, the recited variant call format (VCF) is shown by "VCF files." (Pajuste, p.5, paragraph 2; p.7, paragraph 7)
While Pajuste shows identifying neighbor k-mer sequences, Pajuste does not explicitly state a neighbor detection function of claims 1 and 14, nor the recited neighbor detection function comprises a dimensionality reduction transformation of claims 2 and 15 (shown by Laczny).
While Pajuste shows receiving a dataset of genetic sequence samples of claims 1 and 14 as stated above, Pajuste does not show receiving data of control and experimental genetic sequence samples of claims 1 and 14 (note, control and experimental genetic sequence samples are interpreted respectively as genetic sequence samples from healthy subjects and unhealthy subjects, as in Specification [0023]) (shown by Lee).
While Pajuste shows FASTQ format of claims 4 and 17 as stated above, Pajuste does not show a dataset of RNA data of healthy and unhealthy individuals of claims 4 and 17 (shown by Lee).
Pajuste does not show comparing the plurality of genetic variant candidates against a pre-populated variant database to specify if each detected sequence genetic variant is novel or has been already annotated in a targeted disease of claim 1 and 14 (shown by Kingsmore).
Pajuste does not show determining whether an annotation associated with a genetic variant candidate is at a specific location on the reference genome of claim 12 and 25 (shown by Kingsmore).
Regarding claims 1-2 and 14-15, the recitations of a neighbor detection function (claims 1 and 14) and a dimensionality reduction transformation (claims 2 and 15) read on "alignment-free metagenomic data visualization based on Barnes-Hut Stochastic Neighbor Embedding (BH-SNE)... BH-SNE is an efficient...nonlinear dimension reduction method" (Laczny, p.1, ¶ 5), and "...the count of occurrences for every kmer along an input sequence was calculated. Pairs of reverse complementary kmers were summed up... Overall signature counts were incremented by a single unit to remove zero-counts...The implementation of BH-SNE used in this work performs an initial dimension reduction to a default of 50 dimensions using Principal Component Analysis (PCA)" (Laczny, p.10, paragraph 10).
Regarding claims 1 and 14, the recited control and experimental genetic sequence samples (interpreted respectively as genetic sequence samples from healthy subjects and unhealthy subjects) reads on "TCGA data ...included 106 WGS pairs (cancer and matched normal tissue or blood) from stomach and colorectal cancer patients, 984 WES pairs from 10 cancer types and 108 RNA-seq profiles from stomach and colon cancer samples." (Lee, p.5, col.1, ¶ 1) and "Single-cell WGS files from post-mortem human brains of three neurologically normal individuals and two glioblastoma patients were obtained..." (Lee, p.5, col.2, ¶ 3).
Regarding claims 4 and 17, the recited dataset of RNA data of healthy and unhealthy individual reads on "108 RNA-seq profiles from stomach and colon cancer samples." (Lee, p.5, col.1, ¶ 1) and "Single-cell WGS files from post-mortem human brains of three neurologically normal individuals and two glioblastoma patients were obtained..." (Lee, p.5, col.2, ¶ 3).
Regarding claim 1 and 14, the recitation comparing the plurality of genetic variant candidates against a pre-populated variant database to specify if each detected sequence genetic variant is novel or has been already annotated in a targeted disease reads on: "Comparison with Variant Warehouse database to identify novel variants" (Kingsmore, p.37, [0095-0096]).
Regarding claim 12 and 25, the recitation determine whether an annotation associated with a genetic variant candidate is at a specific location on the reference genome reads on "The de-redundification processes require input variant lists to be sorted lexically by reference sequence (Chr), start position, stop position and variant allele" (Kingsmore, p.37, [0101]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the alignment free SNV calling method and server of Pajuste with the dimension reduction technique of Laczny, the RNA samples of Lee, and the detecting novel variants and use of annotations of Kingsmore. One of ordinary skill in the art would have understood how to and been motivated to modify Pajuste, because Laczny shows the dimension reduction technique improves computational efficiency by creating smaller matrices for storage and processing, while Lee states many projects generate multiple types of data for each individual. Additionally, the discovery of novel variants and use of annotations of Kingsmore would bolster variant calling in sequencing technology. Also, one of ordinary skill in the art would have understood how to and been motivated to modify Pajuste with Laczny, Lee, and Kingsmore because the references are generally drawn to related teaching, and as such, the combination would have been obvious.
Conclusion
No claims are allowed.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Meredith A Vassell whose telephone number is (571)272-1771. The examiner can normally be reached 8:30 - 4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, KARLHEINZ SKOWRONEK can be reached at (571)272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/M.A.V./Examiner, Art Unit 1687
/G. STEVEN VANNI/Primary patents examiner, Art Unit 1686
Prosecution Insights