DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-17 and 19-21 are pending and examined herein.
Claim 18 is canceled.
Priority
As detailed on the 24 October 2023 filing receipt, the application claims priority as early as 01 February 2021 to provision application 63/144,235. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
Information disclosure statements (IDS) were filed on 07 June 2023 and 07 November 2023. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner.
Specification
The specification is objected to because paragraph [64] refers to the reference genome as Ref. 100 and 110, but Ref. 110 should indicate the fragments.
Appropriate correction is required.
Claim Interpretation
The claims recite a sample genome. The specification discloses the sample genome can be a subset of the genome, such as a gene locus.
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 1-17 and 19-21 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of structural variant evaluation.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to a method (claims 1-16) and a non-transitory computer-readable medium (claims 17 and 19-21), each of which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Claim 1 recites applying a putative variant event, which is a step of modifying the reference genome to obtain a sample genome. This step is considered to be a data organization step and thus a mental process.
Claim 1 recites mapping the reads to the sample. Mapping reads is a mental process involving pattern recognition and thus a step the human mind is practically equipped to perform.
Claim 1 recites determining a cost function, where a cost function is, under a broadest reasonable interpretation in light of the specification, a mathematical concept. The cost function is disclosed in mathematical terms (Fig. 3C) and results in a value being calculated (paragraph [105]).
Claim 1 recites retaining the updated sample and removing the event that was used to update the sample from the candidate set. This step is considered to be data selection and judgment and thus also a mental process.
Claims 2-3 recite additional information about the events, which are data per se and thus abstract.
Claims 4 and 19 recite steps similar to claim 1, including apply a variant event, mapping reads, determining a cost function, and rejecting the updated sample.
Claim 5 recites the evaluation of the cost function is based on likelihoods, where determination of likelihoods is a mathematical concept.
Claims 6 and 20 recite updating an alignment, which is interpreted as an alignment step and thus a mental process, as well as mapping, determining a cost function, and retaining an updated sequence, previously explained to be abstract ideas.
Claim 7 recites cost function comprises determining a degree of correspondence between a reference and updated genome based on the mapping. The specification discloses the degree of correspondence could be represented by a term related to the Chi-squared test statistics comparing the observed and theoretical coverage (paragraph [83]).
Claims 8-9 recite determining reads which are not mapped following the updated, which could be interpreted as either a mental step or mathematical step of counting reads..
Claim 10 recites evaluating the cost function based on the terms of the number of variants applied and number of mapped reads, and thus is directed to the mathematical concept that is the cost function.
Claim 11 recites determining a specific term of the cost function and thus is also directed to the mathematical concept of the cost function.
Claims 12 and 21 recite determining alignments, where aligning is a mental step.
Claim 13 recites data judgment of reads based on alignments, and thus is a mental process.
Claim 14 recites removing variant event options based on alignment results, where the step is interpreted as data organization or manipulation and thus a mental process.
Claim 15 recites applying a filter based on reads aligning and applying said variants to update the sample or removing them such that they are not used on the sample.
Claim 16 recites applying a filter and evaluating the reads aligned as positive or negative, thus describing data evaluation and a mental process.
Thus, the claims recite abstract ideas and thus must be examined further to determine whether elements in addition to the abstract ideas integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). [Step 2A Prong One: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Because the claims recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they recite elements in addition to the abstract ideas which integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)).
Claim 1 recites a computer. Claim 21 recites a non-transitory computer readable medium executable by a computing device.
The claims comprising computer components do not describe any specific computational steps by which the computer performs or carries out the abstract idea, nor do they provide any details of how specific structures of the computer are used to implement these functions. The claims state nothing more than that a generic computer performs the functions that constitute the abstract idea. Hence, these are mere instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
Thus, the claims recite elements in addition to the abstract ideas which do not integrate the abstract ideas into a practical application, and must be examined further to determine whether elements in addition to the abstract ideas provide significantly more (MPEP 2106.05). [Step 2A Prong Two: Yes]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Claim 1 recites a computer. Claim 21 recites a non-transitory computer readable medium executable by a computing device.
The claims recite a computer, interpreted as instructions to apply the abstract idea using a computer, where the computer does not impose meaningful limitations on the judicial exceptions, which can be performed without the use of a computer (MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
Therefore, the recited additional elements, alone or in combination, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-6, 9, 17, and 19-20 are rejected under 35 USC 103 as being unpatentable over Kaye (US 2019/0164320; previously cited on the 07 June 2023 IDS form) in view of Spies (Bioinformatics 31(24): 3994-3996, 2015; previously cited on the 07 November 2023 IDS form).
Claim 1 recites applying a first putative variant event, selected from a set of candidate variant events, to a sample genome based on the reference genome to update the sample genome.
Kaye teaches incorporating known polymorphic locations, interpreted as a variant event, into a reference (paragraph [6]).
Claim 1 recites mapping the plurality of read fragments to the updated sample genome.
Kaye teaches mapping at different variations (paragraph [6]) and mapping reads to different regions (paragraph [114]).
Claim 1 recites, based on the mapping of the plurality of read fragments to the updated sample genome, determining a first read mapping cost function.
Kaye teaches a cost function where there is a probability for a target genome having the indicated sequence (paragraph [62]), where the indicated sequence incorporates variation, and local alignment or mapping helps provide the score as a combination of placements (paragraph [28]).
Claim 1 recites based on the first read mapping cost function, retaining the updated sample genome and removing the first putative variant event from the set of candidate variant events.
Kaye teaches determining the optimal alignment (paragraph [106]), where determining the optimal candidate is interpreted as retaining or removing known polymorphic locations to obtain the best scoring alignment for the known reads.
Claim 1 recites the steps are performed using a computer.
Kaye teaches the method is computer-implemented (paragraph [25]).
Kaye teaches comparing all reads but not one reference versus one other reference.
Spies teaches comparison between a reference allele and candidate alternate allele indicating a structural variant by mapping the reads by Smith-Waterman alignment (pg. 3995, Section 2). It is determined which reads match between to one reference or the other (abstract).
Claim 17 recites a non-transitory computer readable medium having stored therein instructions executable by a computing device to perform the steps of claim 1.
Kaye teaches a computer-readable medium (paragraph [70]).
Claim 2 recites the set of candidate variant events includes events from a database of experimentally observed structural variations.
Kaye teaches the mutations, interpreted as variant events, are known from standard public databases (paragraph [91]).
Claim 3 recites the set of candidate variant events includes at least one variant event determined
from the plurality of read fragments.
Kaye teaches blocks with shared structural rearrangements, suggesting variant events (paragraph [32]).
Claims 4 and 19 recite, subsequent to retaining the updated sample genome and removing the first putative variant event from the set of candidate variant events: applying a second putative variant event, selected from the set of candidate variant events, to the updated sample genome to further update the sample genome; mapping the plurality of read fragments to the further updated sample genome; based on the mapping of the plurality of read fragments to the further updated sample genome, determining a second read mapping cost function; and based on the second read mapping cost function, rejecting the further updated sample genome.
Kaye teaches iterative updating the read alignment and weighting alleles frequently observed together (paragraph [104]) and selecting bridges, interpreted as variant paths in the sequence data, based on having probability greater than a confidence threshold (paragraph [189]), where selecting the data based on a threshold implies retraining or rejecting a candidate. Kaye also teaches removing superfluous edges after adding new edges (paragraph [132]).
Claim 5 recites determining the second read mapping cost function comprises evaluating a cost function that includes a term that is related to at least one of: (i) a likelihood of the second putative variant event appearing in a demographic group that includes a subject from which the read fragments were obtained, or (ii) a likelihood of the likelihood of the second putative variant event appearing in a genome given that the first putative variant event appears in the genome.
Kaye teaches the probabilistic weighting or likelihood of a path being present in a given sample (paragraph [53]).
Claims 6 and 20 recite, subsequent to retaining the updated sample genome and removing the first putative variant event from the set of candidate variant events: updating at least one of an alignment or a size of the first putative variant event within the updated sample genome to further update the sample genome; mapping the plurality of read fragments to the further updated sample genome; based on the mapping of the plurality of read fragments to the further updated sample genome, determining a third read mapping cost function; and based on the third read mapping cost function, retaining the further updated sample genome.
Kaye teaches updating with architecture with new edges (paragraph [146]), and processing following updating (paragraph [25]), and iteratively updating during analysis or alignment (paragraph [102]).
Claim 9 recites determining the first read mapping cost function comprises determining a number of read fragments of the plurality of read fragments that are partially mapped to at least one location within the updated sample genome after mapping the plurality of read fragments to the updated sample genome.
Kaye teaches information about partial matches (paragraph [114]).
Combining Kaye and Spies
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Spies with that of Kaye because while Kaye teaches comparing all putative polymorphisms simultaneously, it does not teach comparison of only two at a time. Spies teaches comparing two candidate structural variants at a time, which is taught as enabling more intuitive understanding of the mapping (abstract), where each read is assigned the reference or alternate allele (pg. 3995, col. 2, second paragraph). Both Kaye and Spies are directed to evaluating mapping with respect to references, and thus their combination is prima facie obvious.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Kaye in view of Spies as applied to claims 1-6, 9, 17, and 19-20 above, and further in view of Valiente-Mullor (Plos Computational Biology 17(1): 29 pgs., 2021; newly cited).
Claim 7 recites determining the first read mapping cost function comprises determining, for at least one region of the updated sample genome, a degree of correspondence between a specified reference distribution and a distribution of coverage of the updated sample genome by the plurality of read fragments after mapping the plurality of read fragments to the updated sample genome.
Valiente-Mullor teaches mapping statistics such as coverage with respect to reference choice (pg. 3, second paragraph).
Claim 8 recites determining the first read mapping cost function comprises determining a number
of read fragments of the plurality of read fragments that are not mapped to the updated sample genome after mapping the plurality of read fragments to the updated sample genome.
Valiente-Mullor teaches proportion of mapped reads (pg. 23, second paragraph), the inverse of which would be the reads not mapped.
Combining Kaye, Spies, and Valiente-Mullor
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Valiente-Mullor with that of Kaye because Kaye teaches single reference genome for mapping can mask sequence variation (pg. 1, col. 2, paragraph [6]) and representing all polymorphisms is preferable (paragraph [10]) and using a cost function to evaluate sequencing paths. This is corroborated by Valiente-Mullor were mapping statistics such as number of mapped reads and coverage are used to evaluate differences between references (pg. 2, second paragraph), as it is taught therein that genetic differences between the reference genome and the read sequences may produce incorrect alignments during mapping and mapping using different references can have downstream effects on the alignment and analysis of the sequence (abstract). Kaye, Spies, and Valiente-Mullor are directed to the shared field of endeavor of evaluating mapping metrics with respect to reference differences, and their combination is prima facie obvious.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kaye in view of Spies as applied to claims 1-6, 9, 17, and 19-20 above, and further in view of Liu (Oncotarget 6(8): 5477-5489, 2015; previously cited on the 07 November 2023 IDS form).
Claim 15 recites applying a filter to determine a second set of variant events that are highly likely to be represented in the sample genome and a third set of variant events that are highly unlikely to be
represented in the sample genome; prior to applying the first putative variant event to the sample genome to update the sample genome, applying the variant events of the second set of variant events to the reference genome to generate the sample genome; and prior to applying the first putative variant event to the sample genome to update the sample genome, removing the third set of variant events from the set of candidate variant events.
Liu teaches signature reads suggesting different types of structural variants, interpreted as variant events, including deletions, insertions, and inversions (Table 1).
Claim 16 recites applying the filter to determine the second and third sets of variant events comprises determining, for each of the variant events in the set of candidate variant events, at least one of: (i) the existence of a positive signature read within the plurality of signature reads, or (ii) the existence of a negative signature read within the plurality of signature reads, wherein determining the existence of a positive signature read within the plurality of signature reads for a particular variant event comprises determining that there exists, within the plurality of read fragments, a read fragment whose existence makes it highly likely that the particular variant event is represented in the sample genome, and wherein determining the existence of a negative signature read within the plurality of signature reads for a particular variant event comprises determining that there exists, within the plurality of read fragments, a read fragment whose existence makes it highly likely that the particular variant event is not represented in the sample genome.
Liu teaches programs which teach discordant and splitting read pairs, which in turn suggest the presence or absence of certain structural variants such as deletions, insertions, inversions, and duplications (Table 1).
Combining Kaye, Spies, and Liu
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Liu with that of Kaye because Kaye teaches the need for capturing polymorphism including structural changes such as duplications, inversions, and translocations and correlations between those variations (paragraph [20]) and Liu teaches signatures of different structural variant types are detectable using existing computational programs (abstract), which would be useful in suggesting which variant type may be most relevant in de novo alignment. Kaye, Spies, and Liu are directed to the shared field of endeavor of evaluating structural variation, and their combination is prima facie obvious.
Claims Free of the Prior Art
Claims 10-14 and 21 recite evaluation of variations in the sequences including the details of the cost function, which must include terms related to comparing reads mapped to variants and local effects versus global effects, and pre-alignment for analysis of reads to putative variations. These aspects of the claims are not taught by Kaye, Valiente-Mullor, or Liu and are considered free of the prior art.
Conclusion
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/Robert J. Kallal/Examiner, Art Unit 1685
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