Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 1-5, filed May 10, 2023 are currently pending in the instant application.
Therefore, claims 1-5 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed May 10, 2023 is a CON of US Patent Application 13754817 (now US Patent 11697849); which is a CON of PCT/US2013/02290, filed January 18, 2013, which is a CIP of PCT/US2012/059123, filed October 5, 2012, which claims the benefit of US Provisional Patent Applications 61/709899, filed October 4, 2012; US61/663477, filed June 22, 2012; and US61/589202, filed January 20, 2012.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, US Patent Application 13754817, filed January 18, 2013, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 1 does not have support for; “which instructions executable by the one or more processors are configured to: (a) map the thousands to millions of nucleotide sequence reads for each test sample of the group of circulating cell-free nucleic acid test samples”; “(b) count the thousands to millions of nucleotide sequence reads for each test sample of the group of circulating cell-free nucleic acid test samples sequenced on the single flow cell mapped to the reference genome sections”; “(c) normalize the counts of the thousands to millions of nucleotide sequence reads for a chromosome for each test sample of the group of circulating cell-free nucleic acid test samples sequenced on the single flow cell”; “(d) determine an expected count for the chromosome based on the GC-normalized counts obtained in (c), wherein the expected count is a median GC-normalized count for the chromosome for the group of circulating cell-free nucleic acid test samples sequenced on the single flow cell”; and “(e) adjust the GC-normalized count for the chromosome for each test sample…cell according to (1) the GC-normalized count generated in (c), (2) the expected count determined in (d), and (3) a median absolute deviation (MAD) of the expected count.” Therefore, the priority date for the presently claimed invention is May 10, 2023, the filing date of US Patent Application 18/195,763.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 1 of the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 10, 2023 has been considered. An initialed copy of the IDS accompanies this Office Action.
Claim Objections/Rejections
Claim Interpretation: the system of claim 1 is interpreted comprise: (1) one or more processors, and (2) a memory, the memory comprising: (i) instructions executable by the one or more processors; and (ii) thousands to millions of nucleotide sequence reads obtained for each test sample in a group of circulating cell-free nucleic acid test samples.
Specification Objection
The disclosure is objected to because of the following informalities: the Specification, filed May 10, 2023, does not include the status of US Patent Application Nos. 13/754,817 (now US Patent
11697849). Appropriate correction is required.
Claim Rejections - 35 USC § 112, 2nd paragraph
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5 are rejected under 35 U.S.C. 112, 2nd paragraph as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1-5 are indefinite because the claims appear to recite both a product and process in the same claim. The examiner cautions that according to the MPEP 2173.05(p)(II) states that a single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b). PXL Holdings v. Amazon.com, Inc., 430 F.2d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112(b)). For example, claim 1 recites: “[A] system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors, and which comprises thousands to millions of nucleotide sequence reads obtained for each test sample” in lines 1-3; while claim 1 also recites: “each test sample of the group of circulating cell-free nucleic acid test samples is obtained from the blood of a pregnant female to determine the presence or absence of a genetic variation” in lines 5-7; “the thousands to millions of nucleotide sequence reads obtained for each test sample…the group of circulating cell-free nucleic acid test samples is sequenced on a single flow cell” in lines 8-11; and “wherein the presence of a genetic variation is determined based on detection of a numerical gain or a numerical loss…for the reference genome sections of the same chromosome” in lines 32-43. Such claims can also be rejected under 35 U.S.C. 101 based on the theory that the claim is directed to neither a “process” nor a “machine,” but rather embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. Id. at 1551.
Claim 1 is indefinite for the recitation of the term “thousands to millions of sequence reads” such as recited in claim 1, lines 3, 8, 15, 19, 22 and 25 because a computer memory cannot physically comprise “thousands to millions of sequence reads” obtained by massively parallel sequencing as recited in claim 1, such that it is unclear how the system memory comprises such sequence reads and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the blood” such as recited in claim 1, line 6. There is insufficient antecedent basis for the term “the blood” in the claim.
Claim 1 is indefinite for the recitation of the term “the same single flow cell” such as recited in claim 1, line 12. There is insufficient antecedent basis for the term “the same single flow cell” in the claim because claim 1, line 11 recites the term “a single flow cell.”
Claim 1 is indefinite for the recitation of the term “the presence or absence” such as recited in claim 1, lines 39-40. There is insufficient antecedent basis for the term “the presence or absence” in the claim.
Claim 1 is indefinite for the recitation of the term “the same chromosome” such as recited in claim 1, line 43. There is insufficient antecedent basis for the term “the same chromosome” in the claim.
Claims 2-4 are indefinite insofar as they ultimately depend from instant claim 1.
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 1-5 are rejected under 35 U.S.C. 101 because the claims are directed to neither a “process” nor a “machine,” but rather embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. Id. at 1551.
In the instant case, claim 1 is directed to “a system” such as recited in claim 1, line 1, where instant claim 1 recites, for example: “[A] system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors, and which comprises thousands to millions of nucleotide sequence reads obtained for each test sample” in lines 1-3; while claim 1 also recites: “each test sample of the group of circulating cell-free nucleic acid test samples is obtained from the blood of a pregnant female to determine the presence or absence of a genetic variation” in lines 5-7; “the thousands to millions of nucleotide sequence reads obtained for each test sample…are obtained by massively parallel sequence, wherein the group of circulating cell-free nucleic acid test samples is sequenced on a single flow cell” in lines 8-11; and “wherein the presence of a genetic variation is determined based on detection of a numerical gain or a numerical loss…for the reference genome sections of the same chromosome” in lines 32-43 (reciting a product and a process). Claims 2-5 depend from instant claim 1.
Thus, instant claims 1-5 recite both a product and process in the same claim and overlaps two statutory classes of invention.
(2) Claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at http://www.uspto.gov/patents/law/exam/mdc_examples_nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., abstract idea, a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In this case, the claims as a whole are directed to an abstract idea. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 1-5 do not recite something significantly different than the judicial exception. The rationale for this determination is explained below:
In the instant case, the claims broadly directed to a system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors and which memory comprises thousands to millions of nucleotide sequence reads obtained for each test sample in a group of circulating cell-free nucleic acid test samples, wherein: (i) each test sample of the group of circulating cell-free nucleic acid test samples is obtained from the blood of a pregnant female to determine the presence or absence of a genetic variation, and (ii) the thousands to millions of nucleotide sequence reads obtained for each test sample in the group of circulating cell-free nucleic acid test samples are obtained by massively parallel sequencing, wherein the group of circulating cell-free nucleic acid test samples is sequenced on a single flow cell, wherein the group of circulating cell-free nucleic acid test samples is sequenced on the same single flow cell; and which instructions executable by the one or more processors are configured to: (a) map the thousands to millions of nucleotide sequence reads for each test sample…(b) count the thousands to millions of sequence reads for each test sample for the reference genome sections of the same chromosome…(c) normalize the counts of the thousands to millions of sequence reads for each test sample; (d) determine an expected count for the chromosome based on the GC-normalized counts obtained in (c)…(e) adjust the GC-normalized count for the chromosome for each test sample…wherein the presence of a genetic variation is determined based on detection of a numerical gain or a numerical loss between the adjusted GC normalized count for genome sections of the chromosome and the expected count obtained for the reference genome sections of the same chromosome.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process, thus, the instant claims are directed to a statutory category. Step I: [YES].
Proceeding to revised Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 1-5 are directed to an abstract idea including: (a) mathematical concepts such as mathematical relationships, formulas or equations, and/or calculations that are executable using the one or more computer processors and memory including in the form of sequencing cell-free test samples on a flow cell; mapping thousands to millions of nucleotide sequence reads, counting thousands to millions of nucleotide sequence reads, normalizing the counts of thousands to millions of nucleotide sequence reads, determining an expected count based on a GC-normalized count (e.g., a median), adjusting the GC-normalized count for a chromosome, and assessing the presence or absence of a genetic variation using MAD of the expected count based on a numerical gain or numerical loss between the adjusted GC-normalized count for the genome sections and the expected count obtained for reference genome sections, which includes mental processes such as concepts performed in the human mind (e.g., observation, evaluation, judgement and opinion). The claims recite the judicial exception of an abstract idea that falls within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, mental processes that can be carried out in the human mind, and/or by using a generic computer that performs routine and conventional functions including concepts including executing mathematical concepts, such as mathematical relationships, formula, equations, calculations. Thus, under the revised Step IIA analysis, the claims are directed to an abstract idea. Step IIA – Prong One [YES].
Proceeding to revised Step IIA – Prong Two of the analysis, which asks if the claims recite additional elements that integrate the judicial exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of an abstract idea. Claim 1 recites: “[A] system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors, and which comprises thousands to millions of nucleotide sequence reads obtained for each test sample” in lines 1-3 (encompassing a generic computer that carries out general computer functions); “each test sample of the group of circulating cell-free nucleic acid test samples is obtained from the blood of a pregnant female to determine the presence or absence of a genetic variation” in lines 5-7; “the thousands to millions of nucleotide sequence reads obtained for each test sample…are obtained by massively parallel sequence, wherein the group of circulating cell-free nucleic acid test samples is sequenced on a single flow cell” in lines 8-11; and “instructions executable by the one or more processors are configured to: (a) map the thousands to millions of nucleotide sequence reads for each test sample…(b) count the thousands to millions of sequence reads for each test sample for the reference genome sections of the same chromosome…(c) normalize the counts of the thousands to millions of sequence reads for each test sample; (d) determine an expected count for the chromosome based on the GC-normalized counts obtained in (c)…(e) adjust the GC-normalized count for the chromosome for each test sample…wherein the presence of a genetic variation is determined based on detection of a numerical gain or a numerical loss between the adjusted GC normalized count for genome sections of the chromosome and the expected count obtained for the reference genome sections of the same chromosome” in lines 13-43, which resembles “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)), and are analogous to “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and are examples of “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and resembles “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Additionally, the dependent limitations of claims 2-5 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 2 provides, “wherein the adjusted GC-normalized count for the chromosome is a z-score or a robust z-score” in lines 1-2, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea? The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception related to the computer system. For instance, the claims are recited without any specificity as to the structure of the components of the system; the specific memory used; the software; the identity of the one or more processors; the algorithms used; the specific computer instructions that can be executed by the one or more processors; the number of nucleotide sequence reads; how the sequence reads are present in the memory and/or manipulated by the one or more processors; the identity of the nucleic acid test samples; the number of test samples; the number and identity of the pregnant female subjects (e.g., age, gestational age; disease status, etc.); the massively parallel sequencing technique(s) used; the mathematical formulas applied; the identity of the reference samples; the genome sections; the reference genome sections; the identity of the chromosome; the reference chromosome; the mapping; the counts; how the counts are normalized; how expected counts are determined; how the GC-normalized counts are adjusted; the MAD of the expected count; whether there is a numerical gain or numerical loss; whether there is determination of the presence or absence of a genetic variation, the specific genetic variation, etc. Step IIB: [NO].
For example, sequencing of cell-free DNA from the plasma of pregnant women using high-throughput shotgun sequencing and emulsion PCR; and obtaining ~5 million of reads mapped uniquely to the human genome, wherein the median count per 50-kb window for each chromosome was selected, and the median of the autosomal values was used as a normalization constant to account for differences in the total number of sequence tags as a non-invasive method of determining fetal aneuploidy was known in the art as evidenced by Fan et al. (PNAS, 2008, 105(42), 16266-16271; Abstract; pg. 16266, col 2, first full paragraph; pg. 16266, col 2, last partial paragraph; and pg. 16267, col 1, first partial paragraph); and various computational methods are known in the art that can be used to map each sequence read to a portion, wherein non-limiting examples of computer algorithms that can be used to align sequences include, without limitation, BLAST, BLITZ, FASTA, BOWTIE 1, BOWTIE 2, ELAND, MAQ, PROBEMATCH, SOAP or SEQMAP, or variations thereof or combinations thereof, wherein sequence reads can be aligned with sequences in a reference genome; and/or the sequence reads can be found and/or aligned with sequences in nucleic acid databases known in the art including, for example, GenBank, dbEST, dbSTS, EMBL and DDBJ, such that BLAST or similar tools can be used to search the identified sequences against a sequence database; counts (e.g., raw, filtered and/or normalized counts) can be processed and normalized to one or more levels; and one or more or all processing methods (e.g., normalization methods, portion filtering, mapping, validation, the like or combinations thereof) are performed by a processor, a micro-processor, a computer, in conjunction with memory and/or by a microprocessor controlled apparatus are known in the art as evidenced by Zhao (US20170351811, paragraphs [0215]; [0235] and [0238]). Moreover, it is known that massively parallel DNA sequencing of cell-free fetal DNA from maternal blood can detect fetal chromosomal abnormalities, wherein to minimize intra- and inter-run sequencing variation, an optimized algorithm was developed by using normalized chromosome values (NCVs) from the sequencing data as evidenced by Sehnert et al. (Clinical Chemistry, 2011, 57(7), 1042-1049; Abstract); and that computer-implemented methods to calculate a risk of fetal aneuploidy in a maternal sample comprising estimating the chromosome dosage for two or more fetal chromosomes in the maternal sample; determining a fetal nucleic acid proportion in the maternal sample; providing data on prior risk of aneuploidy for at least a first fetal chromosome based on one extrinsic characteristics; calculating a value of a likelihood that the first fetal chromosome is aneuploid by comparing the chromosome dosage of the first fetal chromosome to the chromosome dosage of a second fetal chromosome in view of the fetal nucleic acid proportion, wherein the maternal sample is a cell free maternal sample; that nucleic acid regions for use in the processing systems of the invention can be selected on the basis of DNA level variation between individuals, based on specificity for a particular chromosome, based on GC content and/or required amplification conditions of the selected nucleic acid regions, or other characteristics; and that chromosome dosage can be selected after detection, such as by filtering frequency data can be generated by massively parallel shotgun sequencing as evidenced by Oliphant et al. (US8700338; col 2, lines 9-21 and 32-34; col 7, lines 5-10; and col 11, lines14-17). Additionally, methods of massively parallel sequencing of DNA molecules including cell-free DNA in the plasma of pregnant women has been shown to allow accurate non-invasive prenatal detection of fetal trisomy 21; and improving the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome to increase the number of aligned sequence reads for each sample, where a bioinformatics approach was then applied to correct GC content bias in the sequencing data that samples from women pregnant with trisomic fetuses were identified by comparing the test samples with control samples within each sequencing run by a special statistical approaches developed for diagnosis of trisomy 13 and trisomy 18, the two statistical approaches comprising: (i) the standard z-score approach; and (ii) the z-score approach with GC correction; and that in order to quantitatively measure the over-representation for each tested sample, for the standard z-score approach, the z-score for the chromosome of interest (chr13/18) was calculated by the following equation:
z-score test sample = (GR test sample – GR mean reference sample)/SD reference sample
is known in the art as evidenced by Chen et al. (Nature Reviews, 2011, 6(7), 1-7; Abstract; and pg. 1, col 2; last partial paragraph, lines 1-3; pg. 3, col 1; third full paragraph; and pg. 3, col 2; first partial paragraph); and multiplexed massively parallel shotgun sequencing assay methods are known in the art for non-invasive trisomy 21 detection was evaluated using cell-free fetal DNA using 480 samples; and that a variety of analytical methods have been published to detect an overabundance of genetic material from chromosome 21, wherein the methods use some form of normalization to calibrate the results against a known set of euploid reference samples; and that the relationship between z-scores calculated based on 24 external samples using mean and SD (x-axis) and using median and median absolute deviation (y-axis) as evidenced by Ehrich et al. (American Journal of Obstetrics & Gynecology, 2011, 204(205), e1-11; Abstract; pg. 205e3, col 1, last partial paragraph; and pg. 205e4; Figure 2). Thus, the system as recited in the claims was well known, purely conventional or routine in the art before the effective filing date of the claimed invention. The claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (See; MPEP § 2106.05(d)).
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 1 DOES
NOT qualify as eligible subject matter.
Dependent claims 2-5 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the abstract idea of claim 1, significantly different. For example, claim 2 encompasses the methods of claim 1, wherein the adjusted GC-normalized count for the chromosome is a z-score or a robust z-score, but they do not add anything that makes the natural phenomenon in claim 1 significantly different.
Thus, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself.
In light of the above consideration and the new guidance, claims 1-5 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
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 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(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-5 are rejected under 35 U.S.C. 103(a) as being unpatentable over Cao et al. (hereinafter “Cao”) (US Patent Application Publication No. 20160265051, published September 15, 2016) in view of Deciu et. al. (hereinafter “Deciu”) (US Patent No. 11697849, issued July 11, 2023; effective filing date January 20, 2012).
Regarding claim 1, Cao teaches that high throughput sequencing is used to noninvasively detect fetal aneuploidy by searching for abnormal fetal chromosome distribution in circulating DNA of maternal blood, wherein sequencing artifacts due to difference of G/C content across the genome is a major reason affecting the sensitivity and accuracy of this method, such that the invention provides a method to minimize the influence of G/C-content in analyzing sequence tags and increase the sensitivity and robustness of this method in detecting aneuploid chromosome especially in sequencing data with lower quality and lower coverage (interpreted as a cell-free nucleic acid sample from a pregnant female; massively parallel sequencing; chromosomes or genome sections; and aneuploidy as a genetic variation, claim 1) (paragraph [0007]). Cao teaches a sensitive and robust method for detecting an abnormal distribution of a chromosome or chromosome portion of interest in a mixed DNA sample of normally and abnormally distributed chromosomes by counting sequence tags obtained from the high throughput sequencing of the mixed DNA sample to obtain a number of sequence tags of sufficient length to be assigned to a chromosome location within a genome, wherein the mixed DNA sample can be a maternal DNA sample from blood, urine or saliva, which contains both fetal and maternal DNA, and the length of the sequence tags can be 20 to 200 bp depending on the high throughput sequencing platform used (interpreted as a cell-free nucleic acid test samples from a pregnant female; massively parallel sequencing; chromosomes or genome sections; the number of tags indicating a numerical gain or loss in genome sections; detecting genetic variation; and interpreting sequencers as flow cells, claim 1) (paragraph [0008]). Cao teaches a method comprising: (1) map the sequence tags to the chromosome of origin by comparing the sequence in the sequence tags to a reference genome (interpreted as encompassing thousands to millions of sequence reads), such that when mapping the sequence tags, one mismatch is allowed to take consideration of polymorphism between the test chromosome and the reference genome; and dividing each chromosome into non-overlapping sliding windows of predefined length and determine sequence tag density mapped to each sliding window, wherein the length of the sliding windows can selected from 10 kb to 200 kb (interpreted as mapping thousands to millions of reads for each test sample sequenced on a flow cell; and compared to a reference genome, claim 1a) (paragraph [0009]). Cao teaches (2) calculating the G/C-content for each sliding window on the chromosome of interest and group sliding windows into different categories based on G/C-content; and select one or more G/C-content intervals in which majority of sequence tags fall and exclude G/C-content intervals with few sequence tags or low quality data, such that for each selected G/C-content interval, determine a mean or median value of the sequence tag density for all the sliding windows within the G/C content interval (interpreted as counting the nucleotide reads for each test sample; and calculating the GC-content, claim 1b) (paragraph [0009]). Cao teaches (3): compare the mean or median value of each selected G/C-content interval on the chromosome of interest in the mixed DNA sample to a mean or median value of the same selected G/C-content interval of normally distributed chromosome to obtain a statistic value; and compare sequence tag densities in the same G/C-content interval so as to minimize the influence of sequencing artifacts caused by the difference of G/C content in the sequence comparisons (interpreted as comparing) (paragraph [0011], lines 1-9). Cao teaches (4): to account for difference in sequence tag counts in different samples, the sequence tag density needs to be normalized to the average sequence tag density for all the autosomes in each sample, the mean or median sequence tag density in each selected G/C-content interval of the first chromosome is compared to the mean or median sequence tag density in the same G/C-Content interval of a second chromosome or chromosomes which have a normal distribution in the same test sample, wherein he second chromosomes can be all the autosomes in the testing sample, excluding the first chromosome (interpreted as normalizing the counts, claim 1c) (paragraph [0011], lines 18-28). Cao teaches (5): the statistic value for each G/C-content interval is combined to obtain a weighted statistic value, which is weighted by the percentage of sequence tags in each interval; and the existence of abnormal distribution of the chromosome of interest is determined in the test sample based on the weighted statistic value, wherein if the weighted statistic value falls within the boundary of a predefined confidence interval (e.g. 99% ), the chromosome of interest in the test sample is considered to be normal; and if the weighted statistic value falls outside the boundary of predefined confidence interval (e.g. 99%), the chromosome of interest is considered to be abnormally distributed and an aneuploid chromosome is detected in the test sample (interpreted as determining an expected count for the chromosome based on the GC-normalized counts; and adjusting the GC-normalized counts for each test sample; and determining the presence of a genetic variation, claim 1d and 1e) (paragraph [0012]). Cao teaches that the present invention provides a computer program that can detect an abnormal distribution of chromosome or chromosome portion of interest in a mixed DNA sample of normally and abnormally distributed chromosomes by counting sequence tags obtained from a high throughput sequencing of the mixed DNA sample, wherein the computer program takes sequence tag reads of the high throughput sequencing of the mixed DNA sample as the input data; then divides each chromosome of a reference genome into non-overlapping windows and maps the input sequence tags to these windows; counts numbers of sequence tags in each window on each chromosome, wherein the number of sequence tags in each window is normalized to the average value of sequence tag counts in all the windows of all the autosomes in the sample, such that the computer can group the windows based on selected G/C-content intervals for each chromosome and calculate the mean or median value of sequence tag counts in each selected G/C-content interval, wherein the computer makes comparison of the mean or median sequence tag counts between any two chromosomes within the same sample or compare sequence tag counts of chromosome of interest between the test sample and normal samples stored in the system; wherein the computer can also make comparison between one chromosome vs. multiple chromosomes, or between one sample vs. multiple normal samples; and the computer outputs a weighted statistic value based on individual statistic values of each selected G/C-content interval and make a decision call on the existence of chromosome abnormality based on a pre-selected confidence interval, wherein the computer program can be used to analyze sequencing data from different sequencing platforms including Illumina high throughput sequencing platform and Ion Proton high throughput sequencing system (interpreted as one or more processors and memory; comprising thousands to millions of sequence reads; instructions configured to carry out steps (a)-(e); and interpreting calculating the mean or median to encompass determining a median absolute deviation, claim 1) (paragraph [0013]). Cao teaches that an online computer program iNIPT was developed to implement the method of the invention to detect an abnormal distribution of chromosome or chromosome portion of interest in a maternal DNA sample, wherein the program was designed for detecting T21, T18 and T13 fetal trisomies, but can also adapted to detect other abnormal fetal chromosomes, where the program allows selection of G/C-adjusted or conventional algorithm for analyzing fetal sequence tags obtained from any sequencing platform (interpreted as one or more processors and memory; maternal sample; adjusting GC-normalized counts; and trisomy 13, 18 and 21, claims 1-5) (paragraph [0056]).
Regarding claims 2-5, Cao teaches that Figure 3 shows a diagram of an online computer program (iNIPT, Non-Invasive Prenatal Test) workflow for detecting fetal Trisomy 13, 18 and 21 in a maternal sample; and that Figure 5 shows the output and report page of iNIPT, where the output page shows the G/C-adjusted Z-score for chromosome 21, 18 and 13 and corresponding probabilities that accept the null hypothesis (the chromosome is normally distributed) (interpreted as a GC-adjusted z-score and chromosomes 13, 18 and 21, claims 2-5) (paragraphs [0016]; and 0018]; and Figures 3 and 5). Figure 3 is shown below:
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Cao teaches that an online computer program iNIPT was developed to implement the method of the invention to detect an abnormal distribution of chromosome or chromosome portion of interest in a maternal DNA sample, wherein the program was designed for detecting T21, Tl8 and Tl3 fetal trisomies, but can also adapted to detect other abnormal fetal chromosomes, where the program allows selection of G/C-adjusted or conventional algorithm for analyzing fetal sequence tags obtained from any sequencing platform (interpreted as one or more processors and memory; and trisomy 13, 18 and 21, claims 1-5) (paragraph [0056]).
Cao does not specifically exemplify a median absolute deviation (claim 1, in part).
Regarding claim 1 (in part), Deciu teaches a method for detecting the presence or absence of a microdeletion, including: (a) obtaining a sample including a circulating, cell-free nucleic acid sample from a pregnant female; (b) isolating sample nucleic acids from the sample; (c) obtaining nucleotide sequence reads from a sample nucleic acid; (d) mapping to reference genome sections nucleotide sequence reads obtained from sample nucleic acid including circulating, cell-free nucleic acid from a test subject; (e) counting the number of nucleotide sequence reads mapped to each reference genome section, thereby obtaining counts; (f) adjusting the counted, mapped sequence reads in (b) according to a selected variable or feature, which selected feature or variable minimizes or eliminates the effect of repetitive sequences and/or over or under represented sequences; (g) normalizing the remaining counts after (c) for a first genome section, or normalizing a derivative of the counts for the first genome section, according to an expected count, or derivative of the expected count, thereby obtaining a normalized sample count, which expected count, or derivative of the expected count, is obtained for a group including samples, references, or samples and references, exposed to one or more common experimental conditions; and (h) providing an outcome determinative of the presence or absence of a genetic variation in the test subject from the normalized sample counts (col 2, lines 28-46; and col 5, lines 32-52). Deciu teaches that the normalized sample count is obtained by a process including subtracting the expected count from the counts for the first genome section, thereby generating a subtraction value, and dividing the subtraction value by an estimate of the variability of the count, wherein the normalized sample count is obtained by a process including subtracting the expected first genome section count representation from the first genome section count representation, thereby generating a subtraction value, and dividing the subtraction value by an estimate of the variability of the first genome section count representation, such that the estimate of the variability of the expected count is a median absolute deviation (MAD) of the count, wherein the estimate of the variability of the count is an alternative to MAD as introduced by Rousseeuw and Croux or a bootstrapped estimate (interpreted as MAD, claim 1) (col 6, lines 41-56). Deciu teaches an apparatus including memory in which a computer program product embodiment described herein is stored including a processor that implements one or more functions of the computer program product embodiment described herein, wherein the one or more functions of the computer program product specified herein, is implemented in a web based environment (interpreted as one or more processors and memory, claim 1) (col 8, lines 55-63). Deciu teaches that the apparatus comprises a web-based system in which a computer program product specified herein is implemented including computers, routers and telecommunications equipment sufficient for web-based functionality comprising network cloud computing, network cloud storage, or network cloud computing and network cloud storage (interpreted as one or more processors and memory, claim 1) (col 8, lines 55-63 and col 9, lines 1-5). Deciu teaches that quantifying or counting sequence reads can be performed in any suitable manner including but not limited to manual counting methods and automated counting methods including an automated counting method can be embodied in software that determines or counts the number of sequence reads or sequence tags mapping to each chromosome and/or one or more selected genomic sections, wherein software generally are computer readable program instructions that, when executed by a computer, perform computer operations (interpreted as instructions, claim 1) (col 44, lines 28-37).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of a assessing genetic variations such as fetal aneuploidy in a maternal sample as exemplified by Deciu, it would have been prima facie obvious for one of ordinary skill in the art at the time the invention was made to modify the method of non-invasively detecting fetal chromosomal abnormality in maternal samples using computer programs and high throughput sequencing technologies as disclosed by Cao to include the computer program product including processors, memory, programs, algorithms, routers, and/or web-based systems for determining the presence or absence of a genetic variation in a test sample as taught by Deciu with a reasonable expectation of success in increasing the sensitivity and robustness in the analysis of sequencing reads in a mixed DNA sample that comprises both maternal DNA and fetal DNA by minimizing the influence of sequencing artifacts due to differences in C/C content across the genome; and/or in providing a system for the non-invasive detection of fetal chromosomal abnormalities in a maternal sample using high throughput sequencing technologies.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
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.
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Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claim 34 of copending Application No. 17/538,812, which teaches a system of processing a sample nucleic acid to identify a target mutation, comprising: a sequencer configured to sequence the sample nucleic acid; a processor configured to control the sequencer to perform a method according to claim l; and a memory operably connected with the processor (claim 34).
Claims 2-20 of copending Application No. 17/870,178, which teaches a computer-implemented method for determining the presence or absence of a chromosome aneuploidy in a sample, comprising: (a) receiving input information comprising nucleic acid sequence reads of circulating cell-free nucleic acid from a test sample, mapping the nucleic acid sequence reads to portions of a reference genome, and determining counts of the nucleic acid sequence reads mapped to portions of the reference genome; (b) determining a chromosome count representation according to the counts determined in (a); (c) calculating a log odds ratio (LOR), wherein the LOR is the log of the quotient of (i) a first multiplication product of (1) a conditional probability of having a chromosome aneuploidy and (2) a prior probability of having the chromosome aneuploidy, and (ii) a second multiplication product of (1) a conditional probability of not having the chromosome aneuploidy and (2) a prior probability of not having the chromosome aneuploidy; and (d) identifying the presence or absence of a chromosome aneuploidy according to the LOR and the chromosome count representation (claim 2).
Claims 1-20 of copending Application No. 17/933,938, which teaches a system comprising one or more processors and a memory, which memory comprises: (1) counts of nucleic acid sequence reads mapped to genomic sections of a reference genome, which sequence reads are reads of circulating cell-free nucleic acid for a test sample from a pregnant female, (2) a median X chromosome representation for a set of pregnant females bearing a female fetus, and (3) a slope and intercept from a linear regression of X chromosome representations and Y chromosome representations determined for a set of pregnant females bearing a male fetus, and which memory comprises instructions executable by the one or more processors configured to: (a) from the counts in (1), generate an experimental Y chromosome representation, and (b) determine a fraction of fetal nucleic acid in the test sample according to the experimental Y chromosome representation generated in (a), the median X chromosome representation for the set of pregnant females bearing a female fetus in (2), and the slope and the intercept in (3) (claim 1).
Claims 1-20 of copending Application No. 18/317,573, which teaches a computer-implemented method, comprising: obtaining nucleic acid from a biological sample that was obtained from a subject; sequencing the nucleic acid from the biological sample or derivatives thereof to obtain thousands to millions of sequence reads; and determining a presence or absence of a copy number variation based on an analysis of the thousands to millions of sequence reads, wherein the analysis comprises determining a plurality of sequence read quantifications corresponding to a plurality of segments (claim 1).
Claims 1-14 of copending Application No. 19/320,132, which teaches a system comprising one or more processors and memory, which memory comprises instructions executable by the one or more processors and which memory comprises counts of nucleic acid sequence reads mapped to a reference genome, which sequence reads are reads of circulating cell-free nucleic acid from a test sample from a pregnant subject; and which instructions executable by the one or more processors are configured to: (a) generate three ratios from the counts, wherein the three ratios comprise: (i) a ratio between counts mapped to chromosome 13, or segment thereof, to counts mapped to chromosome 21, or segment thereof, (ii) a ratio between counts mapped to chromosome 13, or segment thereof, to counts mapped to chromosome 18, or segment thereof, and (iii) a ratio between counts mapped to chromosome 18, or segment thereof, to counts mapped to chromosome 21, or segment thereof; (b) compare the three ratios generated in (a) with one or more corresponding ratios from one or more euploid reference samples to generate a comparison; and (c) determine, based on the comparison, a classification of a presence or absence of a chromosome aneuploidy for the test sample (claim 1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US Application 18/195,763 and the copending claims of US Applications 17/538,812, 17/870,178, 17/933,938, 18/317,573 and 19/320,132 encompasses a system comprising one or more processor and memory comprising instructions and thousands to millions of nucleotide sequence reads.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-29 of U.S. Patent No. 11929146, which teaches a system comprising memory and one or more microprocessors, which memory comprises instructions and which one or more microprocessors are configured to perform, according to the instructions, a process for determining a presence or absence of one or more chromosome alterations in a test sample of nucleic acids, which process comprises: (a) identifying discordant read pairs from paired-end sequence reads; (b) characterizing a mappability of a plurality of sequence read subsequences of each discordant read mate aligned to a reference genome; (c) selecting a subset of the discordant read mates according to a change in the mappability; (d) comparing (i) the number of discordant read mates from the sample associated with the candidate breakpoints; and (e) determining the presence or absence of one or more chromosome alterations for the sample according to the comparison in d) (claim 1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US Application 18/195,763 and the pending claims of US Patent 11929146 encompass a system comprising one or more processor and memory comprising instructions and thousands to millions of nucleotide sequence reads.
Conclusion
Claims 1-5 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684