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 .
Priority
This application filed 06/16/2022 is a Continuation of 15755095, filed 02/26/2018, now U.S. Patent # 11393557, which is a National Stage entry of PCT/US16/48768 with an International Filing Date of 08/25/2016, and further claims priority from Provisional Application 62209858, filed 08/25/2015. The claims are therefore examined as filed on 08/25/2015, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Claim Status
Claims 1-19 are pending.
Claims 2 and 18 are objected to.
Claims 1-19 are examined.
Claims 1-19 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Claim Objections
Claims 2 and 18 are objected to because of the following informalities:
The “; and” at the end of claim 2 should be replaced by a period, and the word “and” should be added before the last clause (before the word “generating”).
The word “myobacteria” in claim 18 should be corrected to “mycobacteria”
Appropriate correction is required.
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 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental processes and mathematical concepts, without significantly more.
The MPEP at MPEP 2106 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of matter?
(2A)(1) Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
(2A)(2) Do the claims recite additional elements that integrate the judicial exception into a practical application?
(2B) If the claims recite a judicial exception and do not integrate the judicial exception, do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?
With regard to step (1) (Are the claims directed to a process, machine, manufacture or composition of matter?): Yes. The claims are directed to one of the statutory classes. Claims 1-19 are directed to a process (computer-based method).
With regard to step (2A)(1) (Do the claims recite a judicially recognized exception?): Yes. The claims recite the abstract ideas of processing data using mental steps and mathematical concepts, and observing the processed data. Claims that recite nothing more than abstract ideas, natural phenomena, or laws of nature are not eligible for patent protection (see MPEP 2106.04).
Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include but are not limited to:
Combining sequencing data into a de Bruijn graph/generating a de Bruijn graph from sets of k-mers (mental process/mathematical concept; the human mind is capable of breaking a sequence into substrings/k-mers and drawing edges to represent overlaps, comparing sequences to find matches is also a mental process/mathematical concept, and de Bruijn graph are performing an algorithm/mathematical calculation; claim 1-2)
Identifying a bubble in the de Bruijn graph as a structural variation where the bounding reference edges are separated beyond a user defined minimum genomic distance (mental process/mathematical concept; the human mind is capable of identifying a bubble in a graph based on a minimum distance; comparing distance values is a mathematical concept; claim 1)
Decomposing patient sequencing data into sets of k-mers (mental process; the human mind is capable of breaking a sequence into substrings; claim 2)
Dependent claims 3 and 5-19 further limit the abstract ideas recited in the independent claims (describing the data used in the analysis), and do not change their characterization as abstract ideas.
Therefore, the claims recite elements that constitute one or more judicial exceptions.
With regard to step (2A)(2) (Do the claims recite additional elements that integrate the judicial exception into a practical application?): No. The claims recite the additional elements of the method being computer-based and performed in silico via processors, and obtaining and storing sequencing data in a computer readable memory. Claim 4 also recites reporting the structural variations in a vcf format.
While the claims recite the additional element of receiving sequencing data and outputting it in vcf format, such steps that only amount to necessary data gathering and outputting, without any technical details of how the data is obtained/output that integrate the judicial exception, are insignificant extrasolution activities that do not add a meaningful limitation to the claims (see MPEP 2106.05(g)). As a result, the judicial exception is not integrated into a practical application. Similarly, while the claims recite additional elements related to the use of computers, they do not provide any specific details by which the computer, processor, or memory performs or carries out the judicial exception listed in step (2A)(1), nor do they provide any details of how specific structures of the computer are used to implement these functions. The judicial exception is therefore not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea, as they amount to simply implementing the abstract idea on a computer (see MPEP 2106.05(f)). Because the claims do not recite any additional elements that integrate the judicial exception into a practical application, the claims as a whole are directed to an abstract idea.
With regard to step (2B) (Do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?): No.
The claims recite an abstract idea with additional elements; however, these additional elements are general computer elements added to abstract ideas, and non-particular instructions to apply the abstract idea by linking it to a field of use or extrasolution activity of necessary data gathering/output (see MPEP 2106.05(f-h)). General computer elements used to perform an abstract idea do not provide an inventive concept, and similarly, non-particular instructions to gather or produce data do not provide an inventive concept. Non-particular instructions to gather or output data are also considered well-understood, routine and conventional activities (see MPEP 2106.05(d), which indicates that limitations such as “Receiving or transmitting data over a network” from Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362, and “Storing and retrieving information in memory” from Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93 are recognized as conventional activities). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As a result, the claims as a whole do not provide an inventive concept.
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 Rejection
Claims 1-3 and 5-14 are rejected under 35 U.S.C. 103 as being unpatentable over IQBAL 2012 “De novo assembly and genotyping of variants using colored de Bruijn graphs” (as cited on the IDS filed 03/18/2025) in view of LEGGETT 2013 “Identifying and Classifying Trait Linked Polymorphisms in Non-Reference Species by Walking Coloured de Bruijn Graphs”
Claim Interpretation and Scope and Contents of Prior Art
Claim 1 recites a method of identifying structural variants with respect to HLA type of a patient, the method comprising: obtaining, via at least one processor, reference and patient sequencing data from two genomic regions and storing the reference and patient sequencing data in a computer readable memory; using, via the at least one processor, reference and patient sequencing data to build a de Bruijn graph in the memory, wherein the reference sequencing data includes a plurality of sequences of known and distinct HLA alleles. With respect to this limitation, IQBAL (cited on the IDS) teaches a method of detecting structural variants using a software implementation (Abstract), in which an individual’s data was compared to a reference of known HLA alleles by building a de Bruijn graph (pg 228- 229).
Claim 1 also recites the limitation wherein at least some of the patient sequencing data include a sequence encoding a patient specific HLA; and identifying, via the at least one processor, a bubble in the de Bruijn graph as a structural variation where the bounding reference edges are separated beyond a user-defined minimum genomic distance or where the bounding reference edges are located on different chromosomes. With respect to this limitation, IQBAL teaches that tested sequences include individual-specific HLA alleles (pg 230 col 2) and identifying structural variations by identifying a bubble in the de Bruijn graph where the (pg 227, Fig 1). IQBAL teaches using a relaxed and stringent cleaning threshold for variant/bubble calling (pg 228 last par), but does not specify that bubbles are identified based on the bounding reference edges being separated beyond a user-defined minimum genomic distance or where the bounding reference edges are located on different chromosomes. However, LEGGETT teaches a method of bubble detection where attributes of bubbles, including length of the bubble (genomic distance from the reference), are used to rank their quality (pg 6 col 2) and also teaches determining if a bubble is greater or equal to a minimum contig length, and that the minimum length is required for effective biological application (pg 7 col 1). Therefore, it would be obvious to one of ordinary skill in the art to only identify bubbles as structural variants when a the bubble is a minimum length.
Claim 2 recites the limitation wherein the de Bruijn graph is built by the steps of: decomposing, via at least one processor, the patient sequencing data into a plurality of respective sets of k-mers; and generating, via the at least one processor, a composite de Bruijn graph using the reference sequence and the plurality of respective sets of k-mers. With respect to this limitation, IQBAL teaches building a de Bruijn graph be decomposing sequence data into k-mers and generating a colored de Bruijn graph composed of the reference sequence and variant samples (pg 2 par 4-6, pg 3).
Claim 3 recites the limitation wherein the two genomic regions comprise the two sides of putative structural variations. With respect to this limitation, IQBAL teaches that variation between genomes generates new nodes and edges, making the bubble in the graph (pg 2 last par, pg 4, Fig 1).
Claim 5 recites the limitation wherein the reference sequence includes alleles for at least one HLA type that have an allele frequency of at least 1%. With respect to this limitation, IQBAL teaches using a reference sequence with alleles for HLA genes that are combined in the graph with all known HLA-B alleles and the sample data (pg 6 par 3, pg 7 par 2-4). One of ordinary skill in the art would understand that some of the HLA-B alleles have a frequency above 1%, and that choosing a reference with an allele above 1% helps sequences to match correctly to the variant.
Claim 6 recites the limitation wherein the reference sequence includes at least ten different alleles for at least one HLA type, and claim 7 recites the limitation wherein the reference sequence includes alleles for at least two distinct HLA types. With respect to these limitations, IQBAL teaches using a reference sequence with alleles for HLA genes that are combined in the graph with all known HLA-B alleles and the sample data (pg 6 par 3, pg 7 par 2-4).
Claim 8 recites the limitation wherein the HLA type is an HLA-A type, an HLA-B type, an HLA-C type, a HLA-DRB-1 type, and/or a HLA-DQB-1 type. With respect to this limitation, IQBAL teaches that the HLA type is an HLA-B type (pg 6 par 3, pg 7 par 2-4).
Claim 9 recites the limitation wherein the plurality of patient sequencing data comprises at least one of a plurality of DNA sequencing data and RNA sequencing data. IQBAL refers to DNA sequencing (pg 7 par 3) but does not explicitly teach that the sequencing data contains both RNA and DNA. However one of ordinary skill would understand that either DNA or RNA can be sequenced and applied in a de Bruijn graph.
Claim 10 recites the limitation wherein the patient sequence reads map to chromosome 6p21.3. With respect to this limitation, IQBAL teaches that the sampled sequence reads map to the HLA gene, which is located on chromosome 6p21.3 (pg 7 par 2-4).
Claim 11 recites the limitation wherein the patient sequence reads are next generation sequencing reads and further comprise metadata. With respect to this limitation, IQBAL teaches that the sequence data is high throughput sequencing (pg 4 last par), which is a type of next generation sequencing, and that the sample sequencing data contains associated data (metadata) including ancestry and validation data (pg 5 par 3).
Claim 12 recites the limitation wherein the patient sequence reads have a length of between 50 and 250 bases. With respect to this limitation, IQBAL teaches that its method can be applied to various read lengths, and specifically teaches sample data with 100bp reads (pg 4 last par).
Claim 13 recites the limitation wherein the k-mers have a length of 10-20. With respect to this limitation, IQBAL teaches its algorithm performing at various k-mer sizes, including at length of 20 (Fig 2).
Claim 14 recites the limitation wherein the k-mers have a length of between 5% and 15% of a length of the patient sequence read. With respect to this limitation, IQBAL teaches its algorithm can be performed with 100bp reads with a k=20 (pg 4 last par, Fig 2), which would be 20% the length of the read. It would be obvious to one of ordinary skill in the art that this could also be done at 15% with a k=15, as well, but with slightly less detection power, as shown in Fig 2, and would be obvious as a result of routine optimization.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in de Bruijn graphs and identifying variants would have been motivated to combine the teachings of IQBAL with the teachings of LEGGETT, in order to achieve the claimed invention, because the de Bruijn graph bubble being above a minimum length is more likely to be a higher quality , accurate variant, rather than an error , and because a minimum length is required for effective biological application (pg 6 col 2, pg 7 col 1). A person of ordinary skill would reasonably expect success from combining these teachings, as both IQBAL and LEGGETT teach methods/algorithms of using de Bruijn graphs to detect variants that can be combined with one another. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Claim Rejection
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over IQBAL in view of LEGGETT as applied to claims 1-3 and 5-14 above, and further in view of PAVLOPOULOS “Unraveling genomic variation from next generation sequencing data.”
Claim Interpretation and Scope and Contents of Prior Art
IQBAL in view of LEGGETT teaches the limitations of claims 1-3 and 5-14 above.
Claim 4 recites the limitation of reporting the identified structural variations in a vcf format. IQBAL in view of LEGGETT does not teach this limitation, however PAVLOPOULOS teaches that vcf is a known file format introduced by the 1000 Genomes Project to store types of sequence variation (pg 10 par 2); it would be obvious to one of ordinary skill in the art to use this format to output structural variation data.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in variant calling would have been motivated to combine the teachings of IQBAL in view of LEGGETT with the teachings of PAVLOPOULOS, in order to achieve the claimed invention, because vcf is a commonly used and well known file format for outputting and storing sequence variation. A person of ordinary skill would reasonably expect success from combining these teachings, as both IQBAL in view of LEGGETT and PAVLOPOULOS teach detecting genomic variation, and it would be obvious to store the variations found in IQBAL in view of LEGGETT in the vcf format. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Claim Rejection
Claims 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over IQBAL in view of LEGGETT as applied to claims 1-3 and 5-14 above, and further in view of KUMAR 2014 “Method For Assembly Of Nucleic Acid Sequence Data” (US 20140249764 A1).
Claim Interpretation and Scope and Contents of Prior Art
IQBAL in view of LEGGETT teaches the limitations of claims 1-3 and 5-14 above.
Claim 15 recites the limitation wherein the reference sequence comprises pathogen variants to thereby identify typing of pathogens. Claim 16 recites that the pathogen is a viral pathogen, bacterial pathogen or parasitic pathogen, and claims 17-19 recite that the pathogens are HPV or coronavirus (claim 16), mycobacteria (claim 18) and Plasmodium falciparum (claim 19). IQBAL in view of LEGGETT does not teach that the reference sequence comprises pathogen variants to identify typing of pathogens. However KUMAR teaches methods of aligning sequence data to a reference (Abstract) that include de novo assembly methods with de Bruijn graphs [0076-77], and where the reference can be a pathogen that includes any prokaryotic, eukaryotic, or viral pathogen, for example those found in various databases [0056].
This also applies to the pathogens listed in claims 16-19, as one of ordinary skill in the art would recognize that any known pathogen sequence can be used as a reference sequence.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in sequence variants would have been motivated to combine the teachings of IQBAL in view of LEGGETT with the teachings of KUMAR in order to achieve the claimed invention, because any pathogen sequence can be used as a reference sequence in determining if a sequence contains pathogen variants, and such reference sequences are commonly available and used as references for sequencing [056]. A person of ordinary skill would reasonably expect success from combining these teachings, as both IQBAL in view of LEGGETT and KUMAR teach methods of comparing sequencing data using reference sequences. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz R. Skowronek can be reached at (571) 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/M.C.L./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687