Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Original claims 1-20 are pending and currently under examination.
Priority
This application filed 7/28/2021 is a divisional of 14/879533 filed 10/9/2015, now US Patent 11,094398, which claims benefit to US Provisional application 62/062312 filed 10/10/2014.
Examiner comment: Applicants have indicated that the instant application is a divisional, and in review of parent 14/879533 it is acknowledged that there was a restriction and method claims were examined in prosecution. The instant claim set also has method claims 17-20 which were examined, and claims directed to a readable medium, claims 9-16, outlining the method steps which each provide steps consistent with what the system is required to implement. In review of the pending claims and restriction of 910/5/2018 in the parent, the instant application does not appear to be a divisional application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/31/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Several of the cited references are Office actions are from foreign offices, some translated and some providing a summary. See NPL listed 009 for example. It is noted that for review of these, the pending claims that were reviewed in these actions were not provided, but for completeness and clarity of the record the cited references when provided in this prosecution were not considered in light of the instant claims. The foreign statutes and comments of the reviewers were not clearly in context of the pending claims and were not considered for their logic nor factual accuracy of comments in actions from other foreign offices.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,094398 (application 14/879533 filed 10/9/2015. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims provide method and readable instructions for the method steps which are commensurate in scope and limitation of the 11,049398. With respect to the system which was withdrawn and later cancelled during prosecution, review of the method steps required of the system are consistent with the amendments to the method that was examined and consistent with the instant method claims, and do not appear to provide a burden to examination nor substantiate a possible restriction between the statutory groups of method and products as now claimed.
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 1-20 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.
Claim analysis
Claim 1 is generally directed to a system that has a storage device and processor which together perform the method of identifying a copy number variation based in part on corrected amplicon coverage. More specifically, the claims have been amended for a method of identifying a copy number variation. The steps implemented by processor are steps of obtaining training reads, mapping the reads, calculating the coverage of the reads and determining values of a batch effect by applying a principal components the steps of the claim are directed to a computer implemented method where a plurality of reads are mapped to a reference sequence, amplicon coverage and total reads are calculated and a corrected amplicon coverage made by batch effect correction which has been amended with a wherein clause that further states that the batch effect correction includes multiplicative batch effect value of a training sample and is based on sample dependent scaling factor for the identification of the copy number variation. The computer readable memory claims and the method claims are consistent and provide for the same analysis steps. The claims set forth the data is derived from a NGS platform and in light of the specification provide a control and basis for analyzing other samples with unknown ploidy by using a set of training reads from a sample with a known ploidy. More specifically, in the specification at [0049] it is taught that batch effects may be detected and may be removed using principal components analysis ("PCA"), and that principal components analysis may depend on several assumptions and can be used to correct and/or adjust “observed values of a test by estimating a size of the batch effect and correcting and/or adjusting the size.” For various relationship that may exist in the resulting data depending on sample handling or platforms used, dependent claims set forth a correction step assessing coverage and likelihoods calculations, the specification teaches at [0048] ‘In various embodiments, unknown yet systematic differences in amplification efficiency (also referred to as "batch effects") may result in variations in amplification efficiencies of the same sequence of DNA between different batches of samples. These variations may be the result of differences in sample preparation conditions, such as differences in conditions like changes in concentration and/or pH in various solutions used during sample preparation and/or differences in the temperature.’, which appears to provide that this is not inherent, nor that a logarithm correlation exist.
Other dependent claims set forth the source of the read data such as obtaining a target region using multiplex amplification, and further calculation steps directed to the analysis of amplicon coverage such as normalization in the determination of copy number/ploidy state represented by the read data.
For step 1 of the 101 analysis, the claims are found to be directed to a statutory category of two products and a method (which is implemented on a computer system).
For step 2A of the 101 analysis, the judicial exception of the claims are the steps of using sequence read data for calculations of coverage. The step of aligning and comparing sequence to arrive at the identification of malicious sequences are instructional steps. In view of the specification, the claim requires calculating the number of reads over a sequence of interest in a reference mathematically analyzing them for batch effect. The judicial exception is a set of instructions for analysis of sequence data and appears to fall into the category of both Mathematical Concepts and the use of mathematical calculations to analyze reads (see for example [0128]-[0129] teaching specific formulas as evidence that PCA is used for the limitations set forth in the claim such as scaling factor set forth in formula 8 or claim 7 which specifically recites ‘estimating’ based on ‘calculated’ reads and ‘logarithm’ values); and into the category of Mental Processes, that is concepts performed in the human mind (including an observation, evaluation, judgment, opinion-in this case there is no requirement nor definition that any complex formula be used for the determination of ‘values’ set forth in the claims). Further, there is no specific complexity or size of the data being analyzed within the claim, and appears that the mapping reads and calculating the reads relative to how they map to a reference could be done in one’s mind or on paper.
Recent guidance from the office requires that the judicial exception be evaluated under a second prong to determine whether the judicial exception is practically applied. In the instant case, the claims do not have an additional element. As amended, the claim appears to provide instructions to provide for the ‘copy number’ calculated from the analysis steps of the claim. This judicial exception requires steps recited at high level of generality and as a computer implemented method are only stored on a non-transitory, and is not found to be a practical application of the judicial exception as broadly set forth.
For step 2B of the 101 analysis, in view of the guidance of the specification each of the independent claims can encompass additional elements for the steps of obtaining sequence data of the reads and reference. However, obtaining data from another source is conventional for computer implemented methods. As such, the claims do not provide for any additional element to consider under step 2B to which the judicial exception of analyzing the read data is applied.
As indicated in the summary of the judicial exception above and in view of the teachings of the specification, the steps are drawn to analysis of sequence data. While the instruction are stored on a medium and could be implemented on a computer, together the steps do not appear to result in significantly more than a means to compare sequences. The judicial exception of the method as claimed can be performed by hand and in light of the previous claims to a computer medium and in light of the teaching of the specification on a computer. In review of the instant specification the methods do not appear to require a special type of processor and can be performed on a general purpose computer.
One way to overcome a rejection for non-patent-eligible subject matter is to persuasively argue that the claimed subject matter is not directed to a judicial exception. Another way for the applicants to overcome the rejection is to persuasively argue that the claims contain elements in addition to the judicial exception that either individually or as an ordered combination are not well understood, routine, or conventional. Another way for the applicants to overcome the rejection is to persuasively argue that the claims as a whole result in an improvement to a technology. Persuasive evidence for an improvement to a technology could be a comparison of results of the claimed subject matter with results of the prior art, or arguments based on scientific reasoning that the claimed subject matter inherently results an improvement over the prior art. The applicants should show why the claims require the improvement in all embodiments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Life Technologies (WO 2014/138153) and Reese et al. (of record).
Claim 1 encompasses a system that has a storage device and processor which together perform the method of identifying a copy number variation based in part on corrected amplicon coverage performing a method of identifying a copy number variation. The steps implemented by processor are steps of obtaining training reads, mapping the reads, calculating the coverage of the reads and determining values of a batch effect by applying a principal components the steps of the claim are directed to a computer implemented method where a plurality of reads are mapped to a reference sequence, amplicon coverage and total reads are calculated and a corrected amplicon coverage made by batch effect correction which has been amended with a wherein clause that further states that the batch effect correction includes multiplicative batch effect value of a training sample and is based on sample dependent scaling factor for the identification of the copy number variation. The computer readable memory claims and the method claims are consistent and provide for the same analysis steps.
Generally, NGS platforms for providing sequence reads, and methods to analyze read data were known. For example with respect to the steps encompassed by the claims, Life Technologies discloses a computer-implemented (computer system; paragraph [0048]) method (abstract) for calculating (computing; paragraph [00105]) corrected (coverage mode can be corrected; paragraph [0016]) coverages for an amplified region (computing coverage for an amplified region; paragraph [00105]), the method comprising: mapping a plurality of reads (paragraph [0022]) of a plurality of amplicons (set of sample amplicons; paragraph [0022]) based on amplified target regions (amplified target regions; paragraphs [0088], [00105]) of a sample suspected of having one or more genetic abnormalities (sample from a cancerous tumor; paragraph [0092]) to a reference sequence (paragraph [0073]), the reference sequence (paragraph [0073]) including one or more nucleic acid sequences corresponding (target nucleic acids generated by the amplification of multiple target-specific sequences; paragraph [0040]) to the amplified target regions (paragraphs [0088], [00105]); calculating amplicon coverages (computing coverages; abstract; paragraph [0086]) and total reads (number of reads; paragraph [00105]), wherein amplicon coverages is a number of reads mapped to an amplicon (paragraphs [0085], [00105]), and total reads (paragraph [0022]) is a number of mapped reads (paragraph [0077]). LIFE TECHNOLOGIES does not disclose calculating corrected amplicon coverages based on the calculated amplicon coverages and calculated total reads by applying a ‘batch effect correction’ set forth in the claims. However, Reese discloses a procedure for applying a batch effect correction (page 6, paragraph; continued from page 5) in high-throughput genomic data (abstract).
Given the detailed teachings for obtaining read data and the known issues of processing read data in a sample and among samples, it would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have corrected the amplicon coverage, through routine experimentation and testing in a laboratory, provided the previous disclosure by LIFE TECHNOLOGIES, for removing any bias or batch effects, for calculating the coverages for an amplified region including amplicons. Additionally, it would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the method, as previously disclosed by LIFE TECHNOLOGIES, for integrating a batch effect correction, as previously disclosed by Reese, for calculating corrected amplicon coverages based on the calculated amplicon coverages and calculated total reads, in order to allow features with a true phenotypic effect, which is masked by a batch, to be identified as significant after batch correction, and to correct any probe-specific systematic variations between groups of samples (batches) resulting from experimental features that are not of biological interest in high-throughput genetic data (Reese, abstract, page 6, paragraph continued from page 5).
For dependent claims, LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 1, and LIFE TECHNOLOGIES discloses the method further comprising: amplifying the target regions of nucleic acids (target nucleic acids generated by the amplification of multiple target-specific sequences; paragraph [0040]) isolated from the sample (selected regions can be isolated from a sample; paragraph [00104]) suspected of having one or more genetic abnormalities (sample from a cancerous tumor; paragraph [0092]); producing the plurality of amplicons (generating a plurality of amplified target sequences; paragraph [0040]) based on the amplified target regions (paragraphs [0088], [00105]); and sequencing the plurality of amplicons (paragraph [0022]) to obtain the plurality of reads (paragraph [0022]). LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 2, and LIFE TECHNOLOGIES further discloses wherein amplifying the target regions of nucleic acids (target nucleic acids generated by the amplification of multiple target-specific sequences; paragraph [0040]) isolated from the sample (selected regions can be isolated from a sample; paragraph [00104]) suspected of having one or more genetic abnormalities (sample from a cancerous tumor; paragraph [0092]) includes multiplex amplification (paragraph [0022]). LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 1, and LIFE TECHNOLOGIES discloses the method further comprising: determining a maximum score path (determine a maximum score path; paragraph [0019]) for the plurality of amplicons (set of sample amplicons; paragraph [0022]) based on the corrected (coverage mode can be corrected; paragraph [0016]) amplicon coverages (coverage for an amplified region; paragraph [00105]) for a range of ploidy states (paragraph [0091]); and identifying copy number variations (abstract; paragraph [0015]) based on the maximum score path (maximum score path; paragraph [0015]). LIFE TECHNOLOGIES does not disclose the implementation of corrected amplicon coverages. Reese discloses a procedure for applying a batch effect correction (batch effect correction; page 6, paragraph continued from page 5) in high-throughput genomic data (high-throughput genomic data; abstract). It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have corrected the amplicon coverage, through routine experimentation and testing in a laboratory, provided the previous disclosure of LIFE TECHNOLOGIES, for removing any bias or batch effects, for calculating the coverages for an amplified region, including amplicons. Furthermore, it would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the method, as previously disclosed by LIFE TECHNOLOGIES, for integrating a batch effect correction, as previously disclosed by Reese, for calculating corrected amplicon coverages to allow features with a true phenotypic effect that is masked by a batch to be identified as significant after batch correction and to correct any probe-specific systematic variations between groups of samples (batches) resulting from experimental features that are not of biological interest in high-throughput genetic data (Reese, abstract, page 6, paragraph continued from page 5). LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 4, and LIFE TECHNOLOGIES discloses a method further comprising: normalizing (normalizing; paragraph [0015]), prior to (figure 4) calculating the maximum score path (determining the maximum score path; paragraph [0015]), the corrected (coverage mode can be corrected; paragraph [0016]) amplicon coverages (coverage for an amplified region; paragraph [00105]) based on the total reads (number of reads; paragraph [00105]). LIFE TECHNOLOGIES does not disclose the use of corrected amplicon coverages. Reese discloses a procedure for applying a batch effect correction (batch effect correction; page 6, paragraph continued from page 5) in high-throughput genomic data (high-throughput genomic data; abstract). It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have corrected the amplicon coverage, through routine experimentation and testing in a laboratory, provided the previous disclosure of LIFE TECHNOLOGIES, for removing any bias or batch effects, in order to calculate the coverages for an amplified region including amplicons. Furthermore, it would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the method, as previously disclosed by LIFE TECHNOLOGIES, for integrating a batch effect correction, as previously disclosed by Reese, for calculating corrected amplicon coverages, in order to allow features with a true phenotypic effect which is masked by a batch to be identified as significant after batch correction and to correct any probe-specific systematic variations between groups of samples (batches) resulting from experimental features that are not of biological interest in high-throughput genetic data (Reese abstract, page 6, paragraph continued from page 5). LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 1, and LIFE TECHNOLOGIES further discloses the implementation of a scaling factor (coverage scaling factor; paragraph [0086]). LIFE TECHNOLOGIES does not disclose wherein the batch effect correction includes a scaling factor and a batch effect value. Reese discloses wherein the batch effect correction (batch effect correction; page 6, paragraph continued from page 5) includes a scaling factor (scaling of the batch; page 6, fourth paragraph) and a batch effect value (batch effect values; page 2, sixth paragraph). It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the method, a previously disclosed by LIFE TECHNOLOGIES, for including a batch effect correction which includes a scaling factor and a batch effect value, as previously disclosed by Reese, for quantifying the proportion of variance owing to batch effects, and correcting any imbalance between batches with different sample sizes (Reese, page 2, sixth paragraph; page 6, fourth paragraph). Finally, as required of the dependent claims, LIFE TECHNOLOGIES and Reese, in combination, disclose the method of claim 1, but LIFE TECHNOLOGIES does not disclose the method further comprising: estimating the scaling factor and the batch effect value for the sample using principal components analysis. Reese discloses a method comprising: estimating (estimate the variance; page 6, third paragraph) the scaling factor (scaling of the batch; page 6, fourth paragraph) and the batch effect value (batch effect values; page 2, sixth paragraph) for the sample (page 6, fourth paragraph) using principal components analysis (principal component analysis; page 1. fourth paragraph). It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the method, as previously disclosed by LIFE TECHNOLOGIES, for including principal components analysis, as previously disclosed by Reese, for reducing and interpreting data, in order to explain the variance-covariance structure of a set of variables through linear combinations (Reese, page 1, fourth paragraph).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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/Joseph Woitach/Primary Examiner, Art Unit 1687
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