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 the Claims
The claim set received 08/29/2022 has been entered into the application.
Claims 2-29 are new.
Claims 1-29 are pending.
Priority
This application is a Continuation of U.S Patent Application 16/119,993 filed 30 August 2018 which is a Continuation of U.S Patent Application 15/382,508 (Now: U.S Patent 10,095,831) filed 16 December 2016 which claims benefit to U.S Provisional Application 62/290,891 filed 03 February 2016.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 24 October 2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings were received on 22 July 2022. These drawings are accepted.
Specification
The specification filed 22 July 2022 has been entered into the application.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The hyperlink(s) are located page 169 [00520] and page 171 [00522].
It is recommended to amend the hyperlink to state “beckmangenomics.com/products/ AMPureXPProtocol _ 000387v001”.
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 1-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Following the flowchart of the MPEP 2106
Step I - Process, Machine, Manufacture or Composition
Claims 1-20 are drawn to a method, so a process.
Claim 21 is drawn to a system, so a machine.
Claim 22 is drawn to a method, so a process.
Claim 23-28 are drawn to a method, so a process.
Claims 29 is drawn to a system, so a machine.
Step 2A Prong One - Identification of an Abstract Idea
Claims 1, 21-23, and 29 encompasses similar limitations. Thus, claims 1, 21-23, and 29 are examined similarly.
Claims 1, 21-23, and 29 recite:
(b) aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins.
This step encompasses performing mathematical computations for aligning sequence reads and aligning sequence reads to binds of a reference gene to provide sequences tags. For example, aligning sequence reads encompasses using matrix mathematics (e.g., scoring matrices), match/mismatch scoring systems, and scoring matrix generation. As such, this process converts biological sequences into mathematical objects (strings) and uses numerical scoring systems to calculate the optimal alignment. See MPEP 2106.04(a)(2)(I)(A)(iv). This step can be performed in the human mind by organizing data (e.g., reference genome) into bins and is therefore an abstract idea. This step encompasses the mathematical concepts of equalities and inequalities in order to divide information (e.g., reference genome) into bins and/or categorize information into bins which reads on abstract ideas.
Claims 1, 21, 23, and 29 recites:
(c) determining fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample.
This step can be performed in the human mind by observing, comparing, and evaluating cell-free nucleic acid (cfDNA) to determine fragment sizes and is therefore an abstract idea.
Claim 22 recites:
(c) calculating coverages of the sequence tags for the bins of the reference genome
This step can be performed in the human mind by following instructions to calculate sequence tag coverages of the binned reference genome and is therefore an abstract idea. This step encompasses performing calculations to calculate bin coverages of the reference genomes which reads on abstract ideas. For example, calculating coverages contain calculations to find the average number of times a genome is sequenced (depth, e.g., 30x) or the percentage of the genome covered, using formulas like Total Data / Genome Size or ((Read Length * Num Reads) / (Genome Size)). To exemplify, determining coverage can encompass average coverage (Depth/Fold Coverage) which is how many times, on average, each base is read (i.e., (Total Number of Bases Sequenced) / (Genome Size)).
Claims 1 and 21 recite
(d) determining coverages of the sequence tags for the bins of the reference genome.
This is step can be performed in the human mind by following instructions to determine data (e.g., coverages) for data bins (i.e., reference genome bins) and is therefore an abstract idea. This step can be performed in the human mind by following instructions to calculate sequence tag coverages of the binned reference genome and is therefore an abstract idea. This step encompasses performing calculations to calculate bin coverages of the reference genomes which reads on abstract ideas. For example, calculating coverages contain calculations to find the average number of times a genome is sequenced (depth, e.g., 30x) or the percentage of the genome covered, using formulas like Total Data / Genome Size or ((Read Length * Num Reads) / (Genome Size)), but it also involves complex bioinformatics algorithms for accurate mapping and analysis. To exemplify, determining coverage can encompass average coverage (Depth/Fold Coverage) which is how many times, on average, each base is read (i.e., (Total Number of Bases Sequenced) / (Genome Size)). Here, it is noted that “determining” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Claim 22 recites:
(d) determining a t-statistic for the sequence of interest using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest.
This step can be performed in the human mind by organizing data (e.g., the coverages of bins of interest and reference regions bins for the sequence of interest) to determine a t-statistic for a sequence of interest and is therefore an abstract idea. This step encompasses performing mathematical/statistical computations using the coverages of bins of interest and reference regions bins for the sequence of interest to determine a t-statistic which reads on abstract ideas. Here, it is noted that “determining” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Claims 23 and 29 recite:
(d) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain.
This step can be performed in the human mind by organizing data (i.e., sized sequence tag data) to calculate sequence tag coverage for the bins and is therefore an abstract idea. This step encompasses performing mathematical computations to calculate coverages which reads on abstract ideas.
Claims 1 and 21 recite:
(e) determining a t-statistic for the sequence of interest using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest.
This step can be performed in the human mind by organizing data (e.g., the coverages of bins of interest and reference regions bins for the sequence of interest) to determine a t-statistic for a sequence of interest and is therefore an abstract idea. This step encompasses performing mathematical/statistical computation using the coverages of bins of interest and reference regions bins for the sequence of interest to determine a t-statistic which reads on abstract ideas.
Claim 22 recites:
(e) estimating one or more fetal fraction values of the cell-free nucleic acid fragments in the test sample.
This step can be performed in the human mind by organizing and evaluating nucleic acid data (e.g., cell-free nucleic acid fragments) to estimate fetal fraction values and is therefore an abstract idea. This step encompasses performing mathematical/statistical computations for estimating data (e.g., fetal fractions value) which reads on abstract ideas. Here, it is noted that “estimating” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Claims 23 and 29 recite:
(e) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain.
This can be performing in the mind observing and evaluating the sizes of sequence tags of nucleic acid fragment having difference sizes from the first size domain and is therefore an abstract idea. This step encompasses performing mathematical operations for calcualting sequence tag coverages using sequence tags different from the first domain which reads on abstract ideas.
Claims 1 and 21 recite:
(f) determining a copy number variation in the sequence of interest in the test sample using a likelihood ratio calculated from the t-statistic and information about the sizes of the cell-free nucleic acid fragments.
This is step can be performed in the human mind by organizing data (e.g., likelihood ratio /t-statistic and nucleic acid fragment size) to determine copy number variation and is therefore an abstract idea. This step encompasses performing mathematical/statistical computations using t-statistic and nucleic acid fragment size for calculating a likelihood ratio for determining copy number variation which reads on abstract ideas. Here, it is noted that “determining” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Claims 22 recites:
(f) determining a copy number variation in the sequence of interest using the t-statistic and the one or more fetal fraction values
This is step can be performed in the human mind by organizing data (e.g., t-statistic and fetal fraction values) to determine copy number variation and is therefore an abstract idea. This step encompasses performing mathematical/statistical computations using t-statistic and fetal fraction values for determining copy number variation which reads on abstract ideas. Here, it is noted that “determining” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Claims 23 and 29 recite:
(f) calculating size parameters for the bins of the reference genome using the fragment sizes determined in (c), wherein each size parameter comprises a value related to fragment size.
This step can be performed in the human mind by organizing data (e.g., parameters/values related to fragment size determined in step (c)) for calculating size parameters and is therefore an abstract idea. This step encompasses performing mathematical computations for calcualting size parameters using the fragment size determined in step (c) which reads on abstract ideas.
Claim 23 and 29 recite:
(g) determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size parameters calculated in (f).
This step can be performed in the human mind by organizing data/information (e.g., coverages in step (d) and (e) and size parameters in step (f)) to determine a copy number variation. This step encompasses performing mathematical computations for determining a copy number variation which reads on abstract ideas. Here, it is noted that “determining” is interpreted as an alternative for the term “calculating”. See MPEP 2106.04(a)(2)(I)(C).
Step 2A Prong Two - Consideration of Practical Application
Claims 1, 21-23, and 29 do not contain any additional elements that integrate the recited judicial exception into a practical application because the claims are drawn to mere data analysis for determining copy number variation from a t-statistic and nucleic acid fragments (claims 1, 21, 23, 29) and determining copy number variation from a t-statistic and fetal fraction values (claim 22). Here, the claims drawn to merely detecting and determining the levels of nucleic acids in a sample (i.e., cell-free DNA) and analyzing the nucleic acids to provide sequence information for detecting allelic variants (i.e., copy number variants), providing nucleic acid fragment data, and determining fetal fraction values for calculating likelihood ratios and t-statistics for determining copy number variation. See MPEP 2106.05(d)(II) (i-iii, v, vii) and 2106.05(g). Thus, such a result only produces information and does not provide for a practical application in the physical-realm of physical things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(I)(A)(iv). Therefore, the claims do not utilize the sequenced and aligned nucleic acid data and the abstract ideas to construct a practical application such as treating a subject, transformation of matter, or improving upon an existing technology.
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses 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.
Step 2B: Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
The recited addition element of using cell-free nucleic acids of claims 1, 21-23, and 29 does not add more than the recited judicial exception because using sample cell-free nucleic acids as a source of nucleic acids is deemed well-known and conventional.
The recited addition element of nucleic acid sequencing claims 1, 21-23, and 29 does not add more than the recited judicial exception because sequencing nucleic acids to provide nucleic acid data that is subsequently analyzed by the abstract idea is deemed a well-known and conventional extra-solution activity. MPEP 2106.05(d)(II) (i-iii, v, vii) and 2106.05(g).
The recited addition element of data gathering of claims 1, 21-23, and 29 step (a) does not add more than the recited judicial exception because receiving sequenced nucleic acids data that is subsequently analyzed by the abstract idea is deemed a well-known and conventional extra-solution activity. MPEP 2106.05(d)(II) (i-iii, v, vii) and 2106.05(g).
The recited addition element of computer processes, components, and equipment of claims 21 and 29 does not add more than the recited judicial exception because using computer elements to process and evaluate sequencing nucleic acids data is merely tangential to the claimed invention. MPEP 2106.05(b), 2106.05(d)(II), and 2106.05(g).
The recited addition element of using computer and nucleic acid sequencer of claims 21 and 29 does not add more than the recited judicial exception because using computer and nucleic sequencer elements is well-known and conventional. MPEP 2106.05(d)(II) (vii). To provide evidence of conventionality, Applied Biosystems teaches using a Solid 3 Plus system which encompasses combination of a sequencer and a computer system (Applied Biosystems Solid 3 Plus system 2009). To provide further evidence of conventionality, Rava et al. (Rava) discloses using a method for determining presence or absence of a copy number variation in a chromosome of interest that uses a sequencer and a processor [claim 1, page 246] (WO 2014/015319; Date: 23 January 2014).
In conclusion, and when viewed as a whole, these additional claim element(s) do not provide meaningful limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory 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.
Claim(s) 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Rava et al. (WO 2014/015319; Date: 23 January 2014).
Claim 23 recites a method for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes.
Claim 23 step (a) recites receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample.
Claim 23 step (b) recites aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins.
Claim 23 step (c) recites determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample.
Claim 23 step (d) recites calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain.
Claim 23 step (e) recite calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain.
Claim 23 step (f) recites calculating size parameters for the bins of the reference genome using the fragment sizes determined in ( c ), wherein each size parameter comprises a value related to fragment size.
Claim 23 step (g) recites determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size parameters calculated in (f).
Rava et al. (Rava) discloses a system that uses a sequencer and computer processor for determining the presence or absence of a copy number variation in a chromosome of interest is a sample of one of more genomes [Rava, claim 1]. Rava discloses receiving sequence reads [Rava, claim 1 step (a)] which reads on receiving sequence read from a sequencer because claim 1 of Rava encompasses a combination sequencer and computer.
Rava discloses codes that can be used to align sequence reads to a reference [Rava, claim 1 step b]. Rava discloses that determining CNV of a chromosome segment entails first subdividing the chromosome of interest into section or bins [Rava, disclosure, page 14 lines 30-35], as in instant claim 23 step (b).
Rava discloses binning chromosomes into multiple blocks with block length containing lengths of sequences of about 1kb, 10kb, or 100kb, for example [Rava, disclosure, 163 lines 20-36], as in claim 23 step (c).
Rava discloses determining the presence or absence of a copy number variation by comparing the values (i.e., counts, coverages) to a threshold [Rava, claim 1 step (e)], as in instant claim 23 step (g).
Rava does not explicitly teach claim 23 steps (d), (e), and (f). Rava does not explicitly teach claims 24-25.
Rava discloses binning chromosomes into multiple blocks with the block length containing lengths of sequences of about 1kb, 10kb, or 100kb, for example [Rava, disclosure, 163 lines 20-36]. Rava discloses coverage is the total number of reads or tags mapped to a particular site of a polymorphism [disclosure, page 155, lines 5-10]. Rava discloses that for each bin the mapped tags are counted and optionally converted into bin doses [Rava, disclosure, page 163 lines 24-30]. Rava discloses calculating a chromosome or segment doses using the number of sequence tags of interest and/or chromosome and the number of sequence tags of interest for normalized chromosome sequence or segment [Rava, claim 1 step (d)]. Rava discloses binning the sequences of the first chromosome of interest into portions and determining if the portions contain more or less nucleic acids than one or more portions or bins [disclosure, page 13-14, page 14 lines 1-15]. Rava discloses bins can be of variable length 1kbp, 10, kbp [Rava disclosure, page 61 lines 24-29], as in claim 23 step (d) and (e). Thus, it is obvious that coverage or counts of sequences tags of different sizes and categories (i.e., first and second domains) are calculated for the domains of different fragment sizes such as 1kb, 500kb, or 100kb, for example.
Rava discloses the blocks or bins are converted into bin doses for indicating an aneuploid. Rava discloses the bins are normalized to account for inter-bin variation such as G-C content [page 163 lines 25-35], as in claim 23 step (f). Here, because the bins are categorized by fragment size (i.e., 10kbp, 100kbp) and the bins are normalized to account for inter-bin variation it is obvious that size parameters based on the size of the bins are being calculated.
Rava discloses binning chromosomes into multiple blocks with the block length containing lengths of sequences of about 1kb, 10kb, or 100kb, for example [Rava, disclosure, 163 lines 20-36]. Rava discloses coverage is the total number of reads or tags mapped to a particular site of a polymorphism [disclosure, page 155, lines 5-10]. Rava discloses that for each bin the mapped tags are counted and optionally converted into bin doses [Rava, disclosure, page 163 lines 24-30]. Rava discloses binning the sequences of the first chromosome of interest into portions and determining if the portions contain more or less nucleic acids than one or more portions or bins [disclosure, page 13-14, page 14 lines 1-15]. Rava discloses bins can be of variable length 1kbp or 10kbp [Rava disclosure, page 61 lines 24-29], as in claim 24. Here, because the chromosome segment bins are categorized by size it makes obvious a first domain can contain fragments of all sizes and other domains can encompass fragments than a smaller a threshold.
Rava discloses that sequences reads can comprises 20bp-450bp [Rava, disclosure, page 50 lines 8-15], as in instant claim 25. Here, because Rava uses different size sequence reads it makes obvious that a domain would/could encompass sequence read fragment less than about 150bp.
It would be obvious to combine the teachings of using a sequencer and computer system as taught by Rava with the sequencing analysis methods as taught by Rava. Here, it would be obvious to apply the sequencing analysis methods of using the number sequence tags, binning methods, and calculating chromosome segment dose as taught by Rava to analyze the sequence data obtained from the sequencer/computer of Rava for determining nucleic acid fragment variation (i.e., copy number variation). As such, one of ordinary skill in the art would be motivated to utilize Rava because Rava discloses methods for receiving sequence data, aligning sequence data, binning sequence data, and processing and evaluating the binned sequence data to determine copy number variation(s). Thus, one of ordinary skill in the art would expect a reasonable expectation of success using the methods of Rava to construct a predictable method using a sequencer/computer for producing sequencing data and analyzing the sequence data using analysis tools for determining copy number variation. Therefore, combining the sequencer and sequencing analysis elements as taught by Rava would yield a predictable method for determining copy variation in a sample.
Claim(s) 29 are rejected under 35 U.S.C. 103 as being unpatentable over Rava et al. (WO 2014/015319; Date: 23 January 2014).
Claim 29 recites a system for evaluation of copy number of a nucleic acid sequence of interest in a test sample a sequencer for receiving cell-free nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample.
Claim 29 step (a) recites receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample. Claim 29 step (b) recites aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins. Claim 29 recites (c) determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample.
Claim 29 step (d) recites calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain.
Claim 29 step (e) recites calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain. Claim 29 step (f) recites calculating size parameters for the bins of the reference genome using the fragment sizes determined in (c).
Claim 29 step (g) determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size parameters calculated in (f).
Rava et al. (Rava) discloses a system that uses a sequencer and computer processor for determining the presence or absence of a copy number variation in a chromosome of interest is a sample of one of more genomes [Rava, claim 1].
Rava discloses receiving sequence reads [Rava, claim 1 step (a)] which reads on receiving sequence read from a sequencer because claim 1 of Rava encompasses a combination sequencer and computer.
Rava discloses codes that can be used to align sequence reads to a reference [Rava, claim 1 step b]. Rava discloses that determining CNV of a chromosome segment is entails first subdividing the chromosome of interest into section or bins [Rava, disclosure, page 14 lines 30-35], as in instant claim 29 step (b).
Rava discloses binning chromosomes into multiple blocks with block length containing lengths of sequences of about 1kb, 10kb, or 100kb, for example [Rava, disclosure, 163 lines 20-36], as in claim 29 step (c).
Rava discloses determining the presence or absence of a copy number variation by comparing the values (i.e., counts, coverages) to a threshold [Rava, claim 1 step (e)], as in instant claim 29 step (g).
Rava does not explicitly teach claim 29 steps (d), (e), and (f).
Rava discloses binning chromosomes into multiple blocks with the block length containing lengths of sequences of about 1kb, 10kb, or 100kb, for example [Rava, disclosure, 163 lines 20-36]. Rava discloses coverage is the total number of reads or tags mapped to a particular site of a polymorphism [disclosure, page 155, lines 5-10]. Rava discloses that for each bin the mapped tags are counted and optionally converted into bin doses [Rava, disclosure, page 163 lines 24-30]. Rava discloses calculating a chromosome or segment doses using the number of sequence tags of interest and/or chromosome and the number of sequence tags of interest for normalized chromosome sequence or segment [Rava, claim 1 step (d)]. Rava discloses binning the sequences of the first chromosome of interest into portions and determining if the portions contain more or less nucleic acids than one or more portions or bins [disclosure, page 13-14, page 14 lines 1-15]. Rava discloses bins can be of variable length 1kbp, 10, kbp [Rava disclosure, page 61 lines 24-29], as in instant claim 29 step (d) and (e). Thus, it is obvious that coverage or counts of sequences tags of different sizes and categories (i.e., first and second domains) are calculated for domains of different fragment sizes such as 1kb, 500kb, or 100kb, for example.
Rava discloses the blocks or bins are converted into bin doses for indicating an aneuploid. Rava discloses the bins are normalized to account for inter-bin variation such as G-C content [page 163 lines 25-35], as in instant claim 29 step (f). Here, because the bins are categorized by fragment size (i.e., 10kbp, 100kbp) and the bins are normalized to account for inter-bin variation it is obvious that size parameters based on the fragment size of the bins are being calculating.
It would be obvious to combine the teachings of using a sequencer and computer system as taught by Rava with the sequencing analysis methods as taught by Rava. Here, it would be obvious to apply the sequencing analysis methods of using the number sequence tags, binning methods, and calculating chromosome segment dose as taught by Rava to analyze the sequence data obtained from the sequencer/computer of Rava for determining nucleic acid fragment variation (i.e., copy number variation). As such, one of ordinary skill in the art would be motivated to utilize Rava because Rava discloses methods for receiving sequence data, aligning sequence data, binning sequence data, and processing and evaluating the binned sequence data to determine copy number variation(s). Thus, one of ordinary skill in the art would expect a reasonable expectation of success using the methods of Rava to construct a predictable method using a sequencer/computer for producing sequencing data and analyzing the sequence data using analysis tools for determining copy number variation. Therefore, combining the sequencer and sequencing analysis elements as taught by Rava would yield a predictable method for determining copy variation in a sample.
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.
Claim 1, 2-10, 12, 14-16, 19-20, 21-23, 24-25, 27, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8, 12, 18-19, and 23-24 of U.S. Patent No. 10,095,831 (‘831) (Date of Patent: 09 October 2018).
Claim 1
(‘831) claim 1 discloses method, implemented using a computer system comprising one or more processors and system memory, for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes [claim 1, preamble], as in instant claim 1.
(‘831) discloses receiving, by the computer system, sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [(‘831), claim 1 step (a)], as in claim 1 step (a).
(‘831) claim 1 step (b) discloses aligning, by the one or more processors, the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [(‘831), claim 1 step (b)], as in claim 1 step (b).
(‘831) claim 1 step (c) discloses determining fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [(‘831), claim 1 step (c)], as in claim 1 step (c).
(‘831) claim 1 step (d) discloses for cell-free nucleic acid fragments determined as being in a first size domain, calculating, by the one or more processors, first coverages of the sequence tags for the bins of the reference genome and step (e) discloses for cell-free nucleic acid fragments determined as being in a second size domain, calculating, by the one or more processors, second coverages of the sequence tags for the bins of the reference genome [(‘831), claim 1 steps (d) and (e)], as in claim 1 step (d).
(‘831) claim 2 discloses likelihood ratio is calculated from a t-statistic of the first coverages and a t-statistic of the second coverages, wherein the t-statistic is calculated using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest [(‘831), claim 1 step (d)], as in claim 1 step (e).
(‘831) claim 18 discloses determining a size-based t-statistic for the sequence of interest using values of the size parameter of bins in the sequence of interest and values of the size parameter of bins in the reference region for the sequence of interest. (‘831) claim 19 discloses wherein the likelihood ratio of (f) is calculated from the first t-statistic, the second t-statistic, and the size-based t-statistic [(‘831), claims 18 and 19], as in claim 1 step (f).
Claim 21
(‘831) claim 1 discloses method, implemented using a computer system comprising one or more processors and system memory, for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes [claim 1, preamble], as in instant claim 21.
(‘831) discloses a sequencer for receiving cell-free nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample [‘831, claim 23], as in instant claim 21.
(‘831) discloses receiving, by the computer system, sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [(‘831), claim 1 step (a)], as in claim 21 step (a).
(‘831) claim 1 step (b) discloses aligning, by the one or more processors, the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [(‘831), claim 1 step (b)], as in claim 21 step (b).
(‘831) claim 1 step (c) discloses determining fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [(‘831), claim 21 step (c)], as in claim 21 step (c).
(‘831) claim 1 step (d) discloses for cell-free nucleic acid fragments determined as being in a first size domain, calculating, by the one or more processors, first coverages of the sequence tags for the bins of the reference genome and step (e) discloses for cell-free nucleic acid fragments determined as being in a second size domain, calculating, by the one or more processors, second coverages of the sequence tags for the bins of the reference genome [(‘831), claim 1 steps (d) and (e)], as in claim 21 step (d).
(‘831) discloses likelihood ratio is calculated from a t-statistic of the first coverages and a t-statistic of the second coverages, wherein the t-statistic is calculated using coverages of bins in the sequence of interest and coverages of bins in a reference region for the sequence of interest [(‘831), claim 2], as in claim 21 step (e).
(‘831) claim 18 discloses determining a size-based t-statistic for the sequence of interest using values of the size parameter of bins in the sequence of interest and values of the size parameter of bins in the reference region for the sequence of interest [’831, claim 18]. (‘831) discloses determining a copy number variation in the sequence of interest using a likelihood ratio calculated from the first coverages and the second coverages [(‘831), claim 1 step (f)], as in claim 21 step (f).
Claim 22
(‘831) claim 1 discloses method, implemented using a computer system comprising one or more processors and system memory, for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes [preamble], as in instant claim 22.
(‘831) discloses receiving, by the computer system, sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [(‘831), claim 1 step (a)], as in claim 1 step (a).
(‘831) claim 1 step (b) discloses aligning, by the one or more processors, the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [(‘831), claim 1 step (b)], as in claim 1 step (b).
(‘831) claim 1 step (c) discloses determining fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [(‘831), claim 1 step (c)], as in claim 1 step (c).
(‘831) claim 1 step (d) discloses for cell-free nucleic acid fragments determined as being in a first size domain, calculating, by the one or more processors, first coverages of the sequence tags for the bins of the reference genome and step (e) discloses for cell-free nucleic acid fragments determined as being in a second size domain, calculating, by the one or more processors, second coverages of the sequence tags for the bins of the reference genome [(‘831), claim 1 steps (d) and (e)], as in claim 1 step (d).
(‘831) discloses a value of fetal fraction is calculated by obtaining a frequency distribution of the sizes of the cell-free nucleic acid fragments and applying the frequency distribution to a model relating fetal fraction to frequency of fragment size to obtain the fetal fraction value [‘831, claim 8], as in instant claim 22 step (e).
(‘831) claim 1 step (d) discloses for cell-free nucleic acid fragments determined as being in a first size domain, calculating, by the one or more processors, first coverages of the sequence tags for the bins of the reference genome and step (e) discloses for cell-free nucleic acid fragments determined as being in a second size domain, calculating, by the one or more processors, second coverages of the sequence tags for the bins of the reference genome [(‘831), claim 1 steps (d) and (e)], as in claim 1 step (d).
(‘831) discloses determining a size-based t-statistic for the sequence of interest using values of the size parameter of bins in the sequence of interest and values of the size parameter of bins in the reference region for the sequence of interest [‘831, claim 18]. (‘831) discloses wherein the likelihood ratio of (f) is calculated from the first t-statistic, the second t-statistic, and the size-based t-statistic [‘831, claim 19]. (‘831) discloses the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t-statistic of all fragments, wherein the short fragments are cell-free nucleic acid fragments in a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments including the short fragments and fragments longer than the criterion size [‘831, claim 12], as in instant claim 22 step (f).
Claim 23
(‘831) discloses a method for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes, the method comprising [‘831, preamble, claim 24], as in claim 23 preamble.
(‘831) discloses receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘831, claim 24 step (a)], as in instant claim 23 step (a).
(‘831) discloses aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins, [‘831, claim 24 step (b)], as in instant claim 23 step (b).
(‘831) discloses determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample [‘831, claim 24 step (c)], as in instant claim 23 step (c).
(‘831) discloses calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘831, claim 24 step (d)], as in instant claim 23 step (d).
(‘831) discloses (e) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘831, claim 24 step (e)], as in instant claim 23 step (e)
(‘831) discloses calculating size characteristics for the bins of the reference genome using the fragment sizes determined in (c) [‘831, claim 24 step (f)], as in instant claim 23 step (f).
(‘831) discloses determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size characteristics calculated in (f) [‘831, claim 24 step (g)], as in instant claim 23 step (g).
Claim 29
(‘831) discloses a system for evaluation of copy number of a nucleic acid sequence of interest in a test sample [‘831, claim 23 preamble]. (‘831) discloses a sequencer for receiving cell-free nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample [‘831, claim 23], as in claim 29 preamble.
(‘831) discloses receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘831, claim 24 step (a)], as in instant claim 29 step (a).
(‘831) discloses aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising the sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins, [‘831, claim 24 step (b)], as in instant claim 29 step (b).
(‘831) discloses determining fragment sizes of the cell-free nucleic acid fragments existing in the test sample [‘831, claim 24 step (c)], as in instant claim 29 step (c).
(‘831) discloses calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘831, claim 24 step (d)], as in instant claim 29 step (d).
(‘831) discloses (e) calculating coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘831, claim 24 step (e)], as in instant claim 29 step (e).
(‘831) discloses calculating size characteristics for the bins of the reference genome using the fragment sizes determined in (c) [‘831, claim 24 step (f)], as in instant claim 29 step (f).
(‘831) discloses determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size characteristics calculated in (f) [‘831, claim 24 step (g)], as in instant claim 29 step (g).
Dependent claims 2-10, 12, 14-16, 19-20, 24-25, and 27
(‘831) discloses for cell-free nucleic acid fragments determined as being in a first size domain, calculate first coverages of the sequence tags for the bins of the reference genome by, for each bin [‘831, claim 23]. (‘831) discloses “In some implementations, the method includes performing (d) and (e) twice, once for fragments in a first size domain and again for fragments in a second size domain.” [‘831, col 3 lines 4-6], as in instant claim 2.
(‘831) discloses wherein the first size domain comprises cell-free nucleic acid fragments of substantially all sizes in the test sample, and the second size domain comprises only cell-free nucleic acid fragments smaller than a defined size [‘831, claim 3], as in instant claims 3 and 24.
(‘831) discloses wherein the second size domain comprises only the cell-free nucleic acid fragments smaller than about 150 bp [‘831, claim 4], as in instant claims 4 and 25.
(‘831) discloses the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t-statistic of all fragments, wherein the short fragments are cell-free nucleic acid fragments in a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments including the short fragments and fragments longer than the criterion size [‘831, claim 12]. (‘831) discloses wherein the likelihood ratio of (f) is calculated from the first t-statistic, the second t-statistic, and the size-based t-statistic [‘831, claim 19], as in instant claim 5.
(‘831) discloses the likelihood ratio is calculated as a first likelihood that the test sample is an aneuploid sample over a second likelihood that the test sample is a euploid sample [‘831, claim 5], as in instant claim 6.
(‘831) discloses wherein the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t-statistic of all fragments, wherein the short fragments are cell-free nucleic acid fragments in a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments including the short fragments and fragments longer than the criterion size [‘831, claim 12], as in instant claim 7.
(‘831) discloses wherein the likelihood ratio is calculated from one or more values of fetal fraction in addition to the first coverages and the second coverages [‘831, claim 6]. (‘831) discloses wherein the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t-statistic of all fragments, wherein the short fragments are cell-free nucleic acid fragments in a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments including the short fragments and fragments longer than the criterion size [‘831, claim 12], as in instant claim 8.
(‘831) discloses a likelihood ratio [‘831, claim 13], as in instant claim 9.
(‘831) discloses determining a size-based t-statistic for the sequence of interest using values of the size parameter of bins in the sequence of interest and values of the size parameter of bins in the reference region for the sequence of interest [‘831, claim 18], as in instant claim 10.
(‘831) discloses first size domain comprises cell-free nucleic acid fragments of substantially all sizes in the test sample, and the second size domain comprises only cell-free nucleic acid fragments smaller than a defined size [‘831, claim 3], as in instant claims 12 and 27.
(‘831) discloses determining a size-based t-statistic for the sequence of interest using values of the size parameter of bins in the sequence of interest and values of the size parameter of bins in the reference region for the sequence of interest [‘831, claim 18]. (‘831) discloses wherein the likelihood ratio of (f) is calculated from the first t-statistic, the second t-statistic, and the size-based t-statistic [‘831, claim 19], as in instant claim 14.
(‘831) discloses the method wherein the likelihood ratio of (f) is calculated from the size-based t-statistic and a fetal fraction [‘831, claim 20], as in instant claim 15.
(‘831) discloses comprising comparing the likelihood ratio to a call criterion to determine a copy number variation in the sequence of interest [‘831, claim 21], as in instant 16.
(‘831) discloses further comprising obtaining a plurality of likelihood ratios and applying the plurality of likelihood ratios to a decision tree to determine a ploidy case for the test sample [‘831, claim 22], as in instant claim 19.
(‘831) discloses applying coverage values of a plurality of bins to a model relating fetal fraction to coverage of bin to obtain the fetal fraction value [‘831, claim 10]. (‘831) discloses further comprising obtaining a plurality of likelihood ratios and applying the plurality of likelihood ratios to a decision tree to determine a ploidy case for the test sample [‘831, claim 22], as instant claim 20.
Although the claims at issue are not identical, they are not patentably distinct from each other because US Patent No.10,095,831 and the instant claims both disclose methods for determining copy number variation and fetal fractions using samples of cell-free nucleic acids and sequencing methods to provide sequence read and sequence coverage data for calcualting t-statistics and fetal fractions for determining copy number variation.
Claim 1-12, 14-15, and 24-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 10-11, 13-14, 16, and 19 of U.S. Patent No. 16/119,993 (‘993) (Date of Patent: 30 August 2022).
Claim 1
(‘993) discloses a method, implemented using a computer comprising one or more processors and system memory, for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes, the method comprising [‘993, claim 1 preamble], as in claim 1 preamble.
(‘993) discloses receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘993, claim 1 (a)], as in claim 1 step (a).
(‘993) discloses aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising a sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [‘993, claim 1 step (b)], as in claim 1 step (b).
(‘993) discloses determining fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [‘993, claim 1 step (c)], as in claim 1 step (a).
(‘993) discloses determining first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 1 step (d)]. (‘993) discloses determining second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 1 step (e)], as in instant claim 1 step (d).
(‘993) discloses wherein (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses wherein the size characteristic for a bin comprises a ratio of fragments of size smaller than a defined value to total fragments in the bin [‘993, claim 14], as in instant claim 1 step (e).
(‘993) discloses comprises calculating a likelihood ratio from a first t-statistic for the sequence of interest using the first coverages, a second t-statistic for the sequence of interest using the second coverages, and third t-statistic for the sequence of interest using the size characteristics [‘993, claim 16], as in instant claim 1 step (f).
Claim 21
(‘993) discloses a system for evaluation of copy number of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments, the system comprising a sequencer for receiving nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample [‘993, claim 19], as in claim 21 preamble.
(‘993) discloses receive at least 10,000 sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘993, claim 19 step (a)], as in instant claim 21 step (a).
(‘993) discloses align the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising a sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [‘993, claim 19 step (b)], as in instant claim 21 step b).
(‘993) discloses determine fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [‘993, claim 19 step (c)], as in instant claim 21 step (c).
(‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in instant claim 21 step (d).
(‘993) discloses determine second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 19 step (e)], as in instant claim 21 step (e).
(‘993) discloses (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in claim 21 step (e).
(‘993) discloses (f) determining a copy number variation in the sequence of interest using the first coverages and the second coverages [‘993, claim 1]. (‘993) discloses (f) comprises calculating a likelihood ratio from a first t-statistic for the sequence of interest using the first coverages, a second t-statistic for the sequence of interest using the second coverages, and third t-statistic for the sequence of interest using the size characteristics [‘993, claim 16], as in instant claim 21 step (f).
Claim 22
(‘993) discloses a method, implemented using a computer comprising one or more processors and system memory, for determining a copy number variation (CNV) of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments originating from two or more genomes, the method comprising [‘993, claim 1 preamble], as in claim 22 preamble.
(‘993) discloses receiving sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘993, claim 1 (a)], as in claim 22 step (a).
(‘993) discloses aligning the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising a sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [‘993, claim 1 step (b)], as in claim 22 step (b).
(‘993) discloses determining first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 1 step (d)]. (‘993) discloses determining second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 1 step (e)], as in instant claim 22 step (c).
(‘993) discloses wherein (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses wherein the size characteristic for a bin comprises a ratio of fragments of size smaller than a defined value to total fragments in the bin [‘993, claim 14], as in instant claim 22 step (d).
(‘993) discloses wherein the one or more values of fetal fraction comprise a value of fetal fraction calculated using the fragment sizes of at least some of the cell-free nucleic acid fragments [‘993, claim 8], as in claim 22 step (e).
(‘993) discloses (f) determining a copy number variation in the sequence of interest using the first coverages and the second coverages [‘993, claim 1 step (f)]. (‘993) discloses the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t-statistics of all fragments, wherein the short fragments are cell-free nucleic acid fragments in the first size domain [‘993, claim 10], as in instant claim 22 step (f).
Claim 23
(‘993) discloses a system for evaluation of copy number of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments, the system comprising a sequencer for receiving nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample [‘993, claim 19], as in claim 23 preamble.
(‘993) discloses receive at least 10,000 sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘993, claim 19 step (a)], as in instant claim 23 step (a).
(‘993) discloses align the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising a sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [‘993, claim 19 step (b)], as in instant claim 23 step b).
(‘993) discloses determine fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [‘993, claim 19 step (c)], as in instant claim 23 step (c).
(‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in instant claim 23 step (d).
(‘993) discloses determine second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 19 step (e)], as in instant claim 23 step (e).
(‘993) discloses (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in claim 23 step (e).
(‘993) discloses (f) determining a copy number variation in the sequence of interest using the first coverages and the second coverages [‘993, claim 1]. (‘993) discloses (f) comprises calculating a likelihood ratio from a first t-statistic for the sequence of interest using the first coverages, a second t-statistic for the sequence of interest using the second coverages, and third t-statistic for the sequence of interest using the size characteristics [‘993, claim 16], as in instant claim 23 step (f).
(‘993) discloses wherein (f) comprises determining the copy number variation in the sequence of interest using size characteristics of bins in the sequence of interest in addition to the first coverages and the second coverages, wherein the size characteristics of the bins were determined using fragment sizes of reads aligned to the bins [‘993, claim 2]. (‘993) discloses e) determining second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 1 step (e)]. Here, the claimed step discloses determining copy number variation for the coverages of the fragment sizes of the first and second domains which inherently encompasses a step for “(g) determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size parameters calculated in (f) of claim 23.
Claim 29
(‘993) discloses a system for evaluation of copy number of a nucleic acid sequence of interest in a test sample comprising cell-free nucleic acid fragments, the system comprising a sequencer for receiving nucleic acid fragments from the test sample and providing nucleic acid sequence information of the test sample [‘993, claim 19], as in claim 21 preamble.
(‘993) discloses receive at least 10,000 sequence reads obtained by sequencing the cell-free nucleic acid fragments in the test sample [‘993, claim 19 step (a)], as in instant claim 21 step (a).
(‘993) discloses align the sequence reads of the cell-free nucleic acid fragments or aligning fragments containing the sequence reads to bins of a reference genome comprising a sequence of interest, thereby providing test sequence tags, wherein the reference genome is divided into a plurality of bins [‘993, claim 19 step (b)], as in instant claim 21 step b).
(‘993) discloses determine fragment sizes of at least some of the cell-free nucleic acid fragments present in the test sample [‘993, claim 19 step (c)], as in instant claim 21 step (c).
(‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in instant claim 21 step (d).
(‘993) discloses determine second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 19 step (e)], as in instant claim 21 step (e).
(‘993) discloses (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses determine first coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a first size domain [‘993, claim 19 step (d)], as in claim 21 step (e).
(‘993) discloses (f) determining a copy number variation in the sequence of interest using the first coverages and the second coverages [‘993, claim 1]. (‘993) discloses (f) comprises calculating a likelihood ratio from a first t-statistic for the sequence of interest using the first coverages, a second t-statistic for the sequence of interest using the second coverages, and third t-statistic for the sequence of interest using the size characteristics [‘993, claim 16], as in instant claim 21 step (f).
(‘993) discloses wherein (f) comprises determining the copy number variation in the sequence of interest using size characteristics of bins in the sequence of interest in addition to the first coverages and the second coverages, wherein the size characteristics of the bins were determined using fragment sizes of reads aligned to the bins [‘993, claim 2]. (‘993) discloses e) determining second coverages of the sequence tags for the bins of the reference genome using sequence tags for the cell-free nucleic acid fragments having sizes in a second size domain, wherein the second size domain is different from the first size domain [‘993, claim 1 step (e)]. Here, the claimed step discloses determining copy number variation for the coverages of the fragment sizes of the first and second domains which inherently encompasses a step for “(g) determining a copy number variation in the sequence of interest using the coverages calculated in (d) and (e) and the size parameters calculated in (f) of claim 23.
Dependent claims 2-12, 14-15, and 24-25
(‘993) discloses wherein the short fragments are cell-free nucleic acid fragments in the first size domain, which is a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments in the second size domain [‘993, claim 10]. (‘993) discloses “method includes performing (d) and (e) twice, once for fragments in a first size domain and again for fragments in a second size domain.” [‘993, col 3 lines 10-13], as in instant claim 2.
(‘993) discloses the first size domain comprises cell-free nucleic acid fragments of substantially all sizes in the sample, and the second size domain comprises only cell-free nucleic acid fragments smaller than a defined size [‘993, claim 3], as in instant claims 3 and 24.
(‘993) discloses wherein the second size domain comprises only the cell-free nucleic acid fragments smaller than about 150 bp [‘993, claim 4], as in instant claims 4 and 25.
(‘993) discloses (f) comprises obtaining a first t-statistic using the first coverages and a second t-statistic using the second coverages [‘993, claim 13]. (‘993) discloses (f) comprises calculating a likelihood ratio from a first t-statistic for the sequence of interest using the first coverages, a second t-statistic for the sequence of interest using the second coverages [‘993, claim 16], as in instant claim 5.
(‘993) discloses the likelihood ratio comprises a first likelihood that the test sample is an aneuploid sample over a second likelihood that the test sample is a euploid sample [‘993, claim 6], as in instant claim 6.
(‘993) discloses he one or more values of fetal fraction comprise a value of fetal fraction calculated using the fragment sizes of at least some of the cell-free nucleic acid fragments [‘993, claim 8], as in instant claim 7.
(‘993) discloses the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t statistics of all fragments, wherein the short fragments are cell-free nucleic acid fragments in the first size domain, which is a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments in the second size domain, which includes the short fragments and fragments longer than the criterion size [‘993, claim 10], as in instant claim 8.
(‘993) discloses likelihood ratio [‘993, claim 11], as in instant claim 9.
(‘993) discloses wherein the size characteristics of the bins were determined using fragment sizes of reads aligned to the bins [‘993, claim 2]. (‘993) discloses (f) comprises obtaining a third t-statistic using the size characteristics of bins [‘993, claim 16], as in instant claim 10.
(‘993) discloses herein the short fragments are cell-free nucleic acid fragments in the first size domain, which is a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments in the second size domain, which includes the short fragments and fragments longer than the criterion size [‘993, claim 10], as in instant claim 12.
(‘993) discloses the likelihood ratio is calculated from a fetal fraction, a t-statistic of short fragments, and a t statistics of all fragments, wherein the short fragments are cell-free nucleic acid fragments in the first size domain, which is a first size range smaller than a criterion size, and the all fragments are cell-free nucleic acid fragments in the second size domain, which includes the short fragments and fragments longer than the criterion size [‘993, claim 10], as in instant claims 14-15.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘993 and the instant claims both disclose methods for determining copy number variation and fetal fractions using samples of cell-free nucleic acids and sequencing methods to provide sequence read and sequence coverage data for calcualting t-statistics and fetal fractions for determining copy number variation.
Conclusion
Claims 1-29 are rejected.
No claims are allowed.
Finality
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.
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/J.C.P./Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635