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 .
Status of Claims
Claims 1-206 are cancelled.
Claims 207-216 are pending.
Claims 207-216 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application, U.S. Nonprovisional App. No. 15/750,350 filed 05 Feb. 2018, PCT/uS16/45564 filed 04 Aug. 2026, and U.S. Provisional App. No. 62/201/923 filed 06 Aug. 2015 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 06 Aug. 2015.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 03 Jan. 2015 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing filed 22 Aug. 2024 has been entered. The application complies with the requirements of 37 CFR 1.831-1.835.
Drawings
The replacement drawing sheets filed 22 Aug. 2024 has been entered.
The drawings filed 22 Aug. 2024 have been accepted.
Claim Interpretation
Claim 207 recite the term “index”. Applicant’s specification at para. [0093] defines the term “index” to refer to any database that is used to optimize the access of data. The plan meaning of the term “database” is an organized collection of information. Therefore, the index is interpreted to refer to be an organized collection of information, wherein organized information necessarily optimizes access of data.
Claim 207 recites “c) querying…to an index of k-mer profiles from a reference sequence with alternate paths”. The limitation “from a reference sequence with alternate paths” is interpreted to define the process in which the index of k-mer profiles was previously generated. Therefore, the index of k-mer profiles is interpreted to be required to represent data from a reference sequence with alternate paths, but the index itself is not required to contain alternate paths. See MPEP 2113. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
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.
Claims 208-216 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 208-209, and claims dependent therefrom, are indefinite for recitation of “the k-mer profile”. Claim 207, from which claims 208-209 depend, recite “generating a k-mer profile from the read” and “k-mer profiles from a reference sequence”. As a result it is not clear if “the k-mer profile” in claims 208-209 is referring to the k-mer profile from the read or a k-mer profile of the k-mer profiles from the reference sequence. If Applicant intends the latter, it is further clear which k-mer profile from a reference sequence from the k-mer profiles of the reference sequence is being referenced. Furthermore, given claim 209 requires the k-mer profile condenses sequences at a frequency of 1 in 1,000,000 bases, it would further be unclear in what way a k-mer profile from a read would be condensed in this manner, given a single read is not 1 million bases long. For purpose of examination, the k-mer profile is interpreted to refer to either the k-mer profile from the read or the index of k-mer profiles. Clarification is requested.
Claim 210 is indefinite for recitation of “wherein an index of the alternate paths includes phased information”. Examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are: “wherein” clauses. The court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04. In the instant case, claim 207 does not recite an index of alternate paths, and instead only refers to “an index of k-mer profiles” derived from a reference sequence with alternate paths. As a result, it is unclear if claim 210 is intending to define the process in which the index of k-mer profiles was made from the reference sequence with alternate paths to have used an index of alternate paths, or if claim 210 is merely recited an intended use of the alternate paths of the reference sequence of creating an index. Clarification is requested via claim amendment.
Claim 211 recites “wherein only k-mers directly associated with differences between strains are used”. The metes and bounds of the claim are not clear because it is not clear which step or steps of claim 207 are restricted to using only-kmers associated with differences between strains. For example, it is not clear if the limitation intends to further limit the index of k-mer profiles from the reference sequence to only use k-mers directly associated with differences between strains, if the k-mer profile from the read only uses k-mers directly associated with differences between strains, and/or if the querying the k-mer profile to the index of k-mer profiles to call variants is only intended to use k-mers associated with the differences. In light of Applicant’s specification at para. [0072] and claim 214, the limitation is interpreted to mean that only k-mers directly associated with differences between strains are used for variant calling.
Claims 212-213 and 215-216 are indefinite for recitation of “the k-mer index”. There is insufficient antecedent basis for this limitation in the claim because claims 207 and 211 do not recite a k-mer index. As a result, it is not clear if the k-mer index is intended to refer to the “k-mer profile from the read”, the “index of k-mer profiles from a reference, or some other index. It is further noted that the claims require that the size of the k-mer index is reduced compared to the index of k-mer profiles from the reference sequence, suggesting the k-mer index does not intend to refer to the index of k-mer profiles. However, Applicant’s specification at para. [0199]-[0203] appears to refer to the k-mer index being reduced as only including the index related to alternate paths and its corresponding reference (i.e. a subset of the index of k-mer profiles from the reference sequence). If Applicant intends for the “the k-mer index” to actually refer to a separate k-mer index generated from the index of k-mer profiles and the k-mer profile is queried to this reduced index, then claims should be amended accordingly.
Clarification is requested via claim amendment.
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 207-216 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 207 being representative) is directed to a method. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 207 recite the following steps which fall under the mental processes grouping of abstract ideas:
a) retrieving a read;
b) generating a k-mer profile from the read;
c) querying the k-mer profile to an index of k-mer profiles from a reference sequence with alternate paths to call variants; and
d) determining a species or a strain present in the sample based on the called variants.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes for the following reasons. In this case, retrieving a read encompasses analyzing sequencing data to determine a read of interest, which can be practically performed in the mind. Generating a k-mer profile from the read can be practically performed in the mind by breaking the read into smaller k-sized parts (e.g. read ACTCGATGC to k-mers ACT, CGA, TGC). Querying the k-mer profile to an index of k-mer profiles from a reference sequence involves performing comparisons between each k-mer of the read to k-mers of the index of k-mer profiles to determine mismatches (i.e. call variants) between a k-mer of the read and a k-mer of the index of k-mer profiles, which is analogous to claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014). Last, determining a species or strain present in the sample based on called variants can be practically performed in the mind by analyzing known associations of variants to particular species or strains to identify which species or strain carries the called variants.
Dependent claims 208-216 further recite an abstract idea and/or are part of the abstract idea identified above. Dependent claim 208 further limits the mental process of generating a k-mer profile to include gapped k-mers. Dependent claim 209 further limits the index of k-mer profiles to comprise condensed sequences, which is part of the abstract idea of querying the k-mer profile to the index of k-mer profiles. Dependent claim 210 similarly further limits the index of k-mer profiles to have been generated from an index of alternate paths including phased information, and therefore is also part of the abstract idea of querying the k-mer profile to the index of k-mer profiles. Dependent claims 211 and 214 further limit the mental process of calling variants to only use k-mers directly associated with differences between strains. Dependent claims 212-213 and 215-16 further recite the mental process of reducing the index of k-mer profiles from the reference sequence to omit information. Therefore, claims 207-216 recite an abstract idea. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Claims 207-216 do not recite any elements in addition to the judicial exception. Therefore, the additionally recited elements amount to insignificant extra-solution activity and, as such, the claims as a whole do not integrate the abstract idea into practical application. Thus, claims 207-216 are directed to an abstract idea. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception.
Claims 207-216 do not recite any elements in addition to the judicial exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea (and/or natural correlation) without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 207 and 211 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Flygare (2015).
Cited reference: Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782.
Regarding claim 207, Flygare discloses a method for detecting the presence of taxa or strain (i.e. species) in a sample (Abstract [0061], e.g. strain identified), wherein the method comprises the following steps:
Flygare discloses a) providing sequence reads for polynucleotides of a sample, wherein each sequence read is processed (i.e. retrieving a read) ([0060]).
Flygare discloses b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]).
Flygare discloses c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed). Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification (i.e. the index of k-mer profiles is from reference sequences with alternate paths/variants), and that the comparing is used to identify one or more nucleotide differences in the sequence (i.e. calling variants) ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15).
Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Regarding claim 211, Flygare discloses the reference database may consist of a set of genes associated with contamination by microorganisms (i.e. only k-mers directly associated with differences between strains are used for variant calling) ([0075]).
Therefore, Flygare anticipates the claimed invention.
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 212-213 are rejected under 35 U.S.C. 103 as being unpatentable over Flygare (2015).
Cited reference: Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782; and
Regarding claims 212-213, Flygare discloses a method for detecting the presence of taxa or strain (i.e. species) in a sample (Abstract [0061], e.g. strain identified), wherein the method comprises the following steps:
Flygare discloses a) providing sequence reads for polynucleotides of a sample, wherein each sequence read is processed (i.e. retrieving a read) ([0060]).
Flygare discloses b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]).
Flygare discloses c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed). Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification (i.e. the index of k-mer profiles is from reference sequences with alternate paths/variants), and that the comparing is used to identify one or more nucleotide differences in the sequence (i.e. calling variants) ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15).
Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Further regarding claims 212-213, Flygare discloses the reference database may consist of a set of genes associated with contamination by microorganisms (i.e. only k-mers directly associated with differences between strains are used for variant calling) ([0075]).
Further regarding claims 212-213, Flygare discloses the reference database may consist of a set of genes associated with contamination by microorganisms or only include k-mers that are diagnostic ([0075]; [0176]), such that the reference database is reduced compared to a full reference database comprising the full genomes of microorganisms.
Flygare does not disclose the following limitations:
Regarding claims 212-213, Flygare does not explicitly disclose the reduction between the k-mer index and the index of k-mer profiles from the reference sequence is at least 99% or 99.9%.
However, Flygare discloses the choice of reference database can affect the specificity and sensitivity of classification, and that query sequences not represented in the reference database cause false-positive and false-negative classifications ([0153]-[0154]), and further discloses databases are constructed to maximize query speed ([0136]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have reduced the k-mer index by 99% or 99.9% through routine experimentation of the set of genes used as the reference database within the prior art conditions of increasing the number of genes to reduce false-positive and false-negative classifications and decreasing the number of genes to increase query speed and save computer memory, as shown by Flygare ([0154]-[0154]; [0136]). See MPEP 2144.05 II. A.
Therefore, the invention is prima facie obvious.
Claims 208 and 214-216 are rejected under 35 U.S.C. 103 as being unpatentable over Flygare (2015) in view of Homer (2009).
Cited references:
Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782; and
Homer et al., BFAST; An Alignment Tool for Large Scale genome Reseqeuncing, 2009, PLoS ONE, 4(11), pg. 1-12; cited in IDS filed 03 Jan. 2025.
Regarding claim 208, Flygare discloses a method for detecting the presence of taxa or strain (i.e. species) in a sample (Abstract [0061], e.g. strain identified), wherein the method comprises the following steps:
Flygare discloses a) providing sequence reads for polynucleotides of a sample, wherein each sequence read is processed (i.e. retrieving a read) ([0060]).
Flygare discloses b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]).
Flygare discloses c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed). Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification (i.e. the index of k-mer profiles is from reference sequences with alternate paths/variants), and that the comparing is used to identify one or more nucleotide differences in the sequence (i.e. calling variants) ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15).
Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Further regarding claim 208, Flygare does not disclose the k-mer profile includes gapped k-mers.
However, Homer discloses a sequence alignment tool (Abstract), which comprises generating a k-mer index from a reference sequence defined by a spaced seed (i.e. gapped k-mer) or a mask comprising of 1’s and 0’s, wherein 1’s are considered when querying the index and 0’s are not (pg. 2, col. 1, para. 3; Figure 1, e.g. an index of 1-mers in C), sliding the mask along a read to generate k-mers (i.e. gapped k-mers), and then querying the k-mer index with the generated k-mers (Figure 1). Homer further discloses this alignment algorithm achieves substantially greater sensitivity of alignment in the context of errors and true variants, while maintaining adequate speed compared to other current methods (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of generating a k-mer profile of Flygare to have utilized gapped k-mers according to the method of Homer above. One of ordinary skill in the art would have been motivated to combine the methods of Flygare with Homer in order to achieve greater sensitivity of alignment while maintaining query speed, as shown by Homer (Abstract). This modification would have had a reasonable expectation of success given Flygare and Homer both involve comparing k-mers of a read to an index of k-mers.
Regarding claim 214, Flygare in view of Homer disclose the method of claim 8 above. Flygare further discloses the reference database may consist of a set of genes associated with contamination by microorganisms (i.e. only k-mers directly associated with differences between strains are used for variant calling) ([0075]).
Regarding claims 215-216, Flygare in view of Homer disclose the method of claim 214 above. Flygare further discloses the reference database may consist of a set of genes associated with contamination by microorganisms ([0075]), such that the reference database is reduced compared to a full reference database comprising the full genomes of microorganisms.
Further regarding claims 215-216, Flygare does not explicitly disclose the reduction between the k-mer index and the index of k-mer profiles from the reference sequence is at least 99% or 99.9%.
However, Flygare discloses the choice of reference database can affect the specificity and sensitivity of classification, and that query sequences not represented in the reference database cause false-positive and false-negative classifications ([0153]-[0154]), and further discloses databases are constructed to maximize query speed ([0136]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have reduced the k-mer index by 99% or 99.9% through routine experimentation of the set of genes used as the reference database within the prior art conditions of increasing the number of genes to reduce false-positive and false-negative classifications and decreasing the number of genes to increase query speed and save computer memory, as shown by Flygare ([0154]-[0154]; [0136]). See MPEP 2144.05 II. A.
Therefore, the invention is prima facie obvious.
Claim 209 is rejected under 35 U.S.C. 103 as being unpatentable over Flygare (2015) in view of Marcais (2011).
Cited references:
Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782; and
Marcais et al., A fast, lock-free approach for efficient parallel counting of occurrences of k-mers, 2011, Bioinformatics, 27(6), pg. 764-770.
Regarding claim 209, Flygare discloses a method for detecting the presence of taxa or strain (i.e. species) in a sample (Abstract [0061], e.g. strain identified), wherein the method comprises the following steps:
Flygare discloses a) providing sequence reads for polynucleotides of a sample, wherein each sequence read is processed (i.e. retrieving a read) ([0060]).
Flygare discloses b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]).
Flygare discloses c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed). Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification (i.e. the index of k-mer profiles is from reference sequences with alternate paths/variants), and that the comparing is used to identify one or more nucleotide differences in the sequence (i.e. calling variants) ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15).
Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Further regarding claim 209, Flygare discloses the reference database is created by counting unique k-mers in difference taxonomic groups or gene sets ([0122]), which generally demonstrates the k-mer profile includes condensed sequences by removing redundant sequences in the reference sequences.
However, Flygare does not disclose the k-mer profile condenses different sequences at a frequency of up to 1 in 1,000,000 bases.
Furthermore, Marcais discloses a method for efficient parallel counting of occurrences of k-mers, Jellyfish (Abstract), which comprises storing each distinct k-mer in a reference genome in a hash table (i.e. k-mer index) (pg. 769, col. 2, para. 2; Table 1; pg. 767, col. 1, para. 2-3), and discloses the number of unique of k-mers in various genomes is approximately 25% to 80% of the number of total k-mers in the genomes (i.e. not more than 1 in 1,000,000 bases) (Table 1). Marcais further discloses the majority of k-mers appear only once, while a small number of k-mers, depending on the repetitiveness of the genome, occur a large number of times (pg. 767, col. 1, para. 3). Marcais further discloses the method offers a much faster and memory efficient solution to k-mer counting (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified reference database of Flygare to have condensed the sequences at a frequency of up to 1 in 1,000,000 bases according to Marcais, which discloses condensing every 1 in 4 to 8 in 10 bases, as discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Flygare with Marcais to facilitate faster and more memory efficient k-mer counting, as shown by Marcais (Abstract). This modification would have had a reasonable expectation of success because Flygare discloses Jellyfish (the method in Marcais) may be used to create the reference database of unique k-mers ([0122]).
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have condensed sequences at a frequency of up to 1 in 1,00,000 bases through routine experimentation of the k-mer length of the index within the prior art conditions of increasing k-mer length to produce more unique k-mers (i.e. less condensed sequences) and decreasing k-mer length to result in more redundant k-mers (i.e. greater condensing of sequences), as shown by Marcais (pg. 767, col. 2, para. 5). See MPEP 2144.05 II. A.
Therefore, the invention is prima facie obvious.
Claim 210 is rejected under 35 U.S.C. 103 as being unpatentable over Flygare (2015) in view of Dilthey (2015).
Cited references:
Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782; and
Dilthey et al., Improved genome inference in the MHC using a population reference graph, 2015, Nature Genetics, 47(6), pg. 682-688; cited in IDS filed 03 Jan. 2025.
Regarding claim 210, Flygare discloses a method for detecting the presence of taxa or strain (i.e. species) in a sample (Abstract [0061], e.g. strain identified), wherein the method comprises the following steps:
Flygare discloses a) providing sequence reads for polynucleotides of a sample, wherein each sequence read is processed (i.e. retrieving a read) ([0060]).
Flygare discloses b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]).
Flygare discloses c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed). Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification (i.e. the index of k-mer profiles is from reference sequences with alternate paths/variants), and that the comparing is used to identify one or more nucleotide differences in the sequence (i.e. calling variants) ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15).
Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Further regarding claim 210, Flygare does not disclose that an index of the alternate paths includes phased information.
However, Dilthey discloses a method for genome inference using a graph comprising alternate paths representing a population reference graph with catalogs of variation (Abstract), which includes a k-mer reference graph with each edge representing a k-mer (Supplementary Figure 1), searching for k-mers from a sample sequence to k-mers in the reference graph (pg. 683, col. 2, para. 2; Supplementary pg. 19, para. 1-3), and storing k-mers from the k-mer reference graph in a hash table (Supplemental pg. 43, para. 2-4). Dilthey further discloses the k-mer reference graph comprises haplotype information (i.e. an index of the alternate paths including phasing information) for the different paths in the graph (Figure 2; Supplemental pg. 15, para. 1-3). Dilthey discloses the population reference graph with phased information improves the characterization of regions in the genome with high sequence diversity and read alignment (Abstract; pg. 682, col. 2, para. 2; Figure 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Flygare to have utilized an index with phasing information for the alternate paths, as shown by Dilthey above. One of ordinary skill in the art would have been motivated to combine the methods of Flygare with Dilthey in order to improves the characterization of regions in the genome with high sequence diversity and read alignment (Abstract; pg. 682, col. 2, para. 2; Figure 2), thus facilitating the alignment of reads with variants to a reference in Flygare. This modification would have had a reasonable expectation of success because Flygare discloses the database of reference sequence k-mers includes a plurality of variants of known polynucleotide sequences for taxonomic classification ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15), and thus the population reference graph representing variants of Dilthey is applicable to method of Flygare.
Therefore, the invention is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 207-208, 211, and 214 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. US 11,929,149 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Reference claim 19 discloses the method of instant claim 207. It is noted reference claim 19 is narrower in scope than instant claim 207, and thus the claims are not identical.
Reference claim 19 discloses the uses of gapped k-mers (i.e. the k-mer profile is generated using a mask with 1’s and 0’s), as recited in instant claim 208.
Reference claim 20 discloses the variants used for determining a strain present are novel variants (i.e. k-mers associated with differences between strains), as recited in instant claims 211 and 214.
Claims 212-213 and 215-216 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. US 11,929,149 B2 as applied to claims 207, 208, 211, and 214 above, further in view of Flygare (2015).
Cited references: Flygare et al., US 2018/0365375 A1, effectively filed 17 May 2015 based on priority to U.S. Provisional App. No. 62/152,782; and
Regarding instant claims 212-213 and 215-216, the reference claims disclose the method of instant claims 207, 208, 211, and 214, as applied above.
The reference claims do not disclose the limitations of instant claims 212-213 and 215-216.
However, regarding instant claims 212-213 and 215-216, Flygare discloses a method for identifying a strain in a sample which includes, b) analyzing the sequence read in terms of component k-mers by dividing the read into k-mer subsequences (i.e. generating a k-mer profile from the read) ([0062]),
c) comparing one or more k-mers of the sequence read (i.e. the k-mer profile) to k-mers of one or more reference sequences stored in a database for maximizing query speed (i.e. an index of k-mer profiles) ([0063], e.g. comparison between k-mers; claims 2 and 15, e.g. database of reference sequence includes k-mers; [0117], [0122]; [0136], e.g. database with k-mers stored in lexicographical order or maximizing query speed), and identifying one or more nucleotide differences in the sequence (i.e. calling variants) based on the comparing ([0008]; [0061]; [0064], e.g. database comprises polymorphic reference sequences; claim 15). Flygare discloses identifying one or more taxa, including a first bacterial strain, present in the sample based on a single nucleotide difference in the sequence ([0006]; [0061] claims 2 and 3-4).
Regarding instant claims 212-213 and 215-216, Flygare further discloses the reference database may consist of a set of genes associated with contamination by microorganisms ([0075]), such that the reference database is reduced compared to a full reference database comprising the full genomes of microorganisms.
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims to have used a reference database consisting of a set of genes associated with microorganism contamination, thus reducing the reference database, as disclosed by Flygare above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims with Flygare in order to facilitate the identification of microorganisms in a sample, as shown by Flygare ([0075]). This modification would have had a reasonable expectation of success given both the reference claims and Flygare identified a strain based on querying a k-mer to a k-mer index.
Further regarding claims 215-216, the reference claims in view of Flygare do not explicitly disclose the reduction between the k-mer index and the index of k-mer profiles from the reference sequence is at least 99% or 99.9%.
However, Flygare discloses the choice of reference database can affect the specificity and sensitivity of classification, and that query sequences not represented in the reference database cause false-positive and false-negative classifications ([0153]-[0154]), and further discloses databases are constructed to maximize query speed ([0136]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have reduced the k-mer index by 99% or 99.9% through routine experimentation of the set of genes used as the reference database within the prior art conditions of increasing the number of genes to reduce false-positive and false-negative classifications and decreasing the number of genes to increase query speed and save computer memory, as shown by Flygare ([0154]-[0154]; [0136]). See MPEP 2144.05 II. A.
Therefore, the invention is prima facie obvious.
Claim 209 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. US 11,929,149 B2, as applied to claim 207 above, further in view of Marcais (2011)
Cited references: Marcais et al., A fast, lock-free approach for efficient parallel counting of occurrences of k-mers, 2011, Bioinformatics, 27(6), pg. 764-770.
Regarding claim 209, the reference claims disclose the method of claim 207 as applied above.
The reference claims do not disclose the k-mer profile condenses sequences at a frequency of up to 1 in 1,000,000 bases.
However, Marcais discloses a method for efficient parallel counting of occurrences of k-mers, Jellyfish (Abstract), which comprises storing each distinct k-mer in a reference genome in a hash table (i.e. k-mer index with reduced sequences given redundant k-mers are removed) (pg. 769, col. 2, para. 2; Table 1; pg. 767, col. 1, para. 2-3), and discloses the number of unique of k-mers in various genomes is approximately 25% to 80% of the number of total k-mers in the genomes (i.e. not more than 1 in 1,000,000 bases) (Table 1). Marcais further discloses the majority of k-mers appear only once, while a small number of k-mers, depending on the repetitiveness of the genome, occur a large number of times (pg. 767, col. 1, para. 3). Marcais further discloses the method offers a much faster and memory efficient solution to k-mer counting (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the reference index of the reference claims to have condensed the sequences at a frequency of up to 1 in 1,000,000 bases according to Marcais, which discloses condensing every 1 in 4 to 8 in 10 bases, as discussed above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims with Marcais to facilitate faster and more memory efficient k-mer counting, as shown by Marcais (Abstract). This modification would have had a reasonable expectation of success because both the reference claims and Marcais construct an index of k-mers.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have condensed sequences at a frequency of up to 1 in 1,00,000 bases through routine experimentation of the k-mer length of the index within the prior art conditions of increasing k-mer length to produce more unique k-mers (i.e. less condensed sequences) and decreasing k-mer length to result in more redundant k-mers (i.e. greater condensing of sequences), as shown by Marcais (pg. 767, col. 2, para. 5). See MPEP 2144.05 II. A.
Claim 210 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. US 11,929,149 B2, as applied to claim 207 above, further in view of Dilthey (2015).
Cited reference: Dilthey et al., Improved genome inference in the MHC using a population reference graph, 2015, Nature Genetics, 47(6), pg. 682-688; cited in IDS filed 03 Jan. 2025.
Regarding instant claim 210, the reference claims disclose the method of instant claim 207 above.
Further regarding instant claim 210, the reference claims do not disclose that an index of the alternate paths includes phased information.
However, Dilthey discloses a method for genome inference using a graph comprising alternate paths representing a population reference graph with catalogs of variation (Abstract), which includes a k-mer reference graph with each edge representing a k-mer (Supplementary Figure 1), searching for k-mers from a sample sequence to k-mers in the reference graph (pg. 683, col. 2, para. 2; Supplementary pg. 19, para. 1-3), and storing k-mers from the k-mer reference graph in a hash table (Supplemental pg. 43, para. 2-4). Dilthey further discloses the k-mer reference graph comprises haplotype information (i.e. an index of the alternate paths including phasing information) for the different paths in the graph (Figure 2; Supplemental pg. 15, para. 1-3). Dilthey discloses the population reference graph with phased information improves the characterization of regions in the genome with high sequence diversity and read alignment (Abstract; pg. 682, col. 2, para. 2; Figure 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims to have utilized an index with phasing information for the alternate paths, as shown by Dilthey above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims with Dilthey in order to improves the characterization of regions in the genome with high sequence diversity and read alignment, as shown by Dilthey (Abstract; pg. 682, col. 2, para. 2; Figure 2), thus facilitating the alignment of reads with variants to a reference in the reference claims. This modification would have had a reasonable expectation of success because the reference claims use an index of k-mers for alternative paths, and thus the population reference graph representing variants of Dilthey is applicable to method of Flygare.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
