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 .
Claim Status
Claims 3, 7, 10, 15, 18-19, 23-24 and 27-73 are cancelled by Applicant.
Claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 are currently pending and are herein under examination.
Claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 are rejected.
Claims 2 and 21 are objected to.
Priority
This application claims priority as a CON of International Application No. PCT/US2022/019409, filed March 8, 2022, which claims priority to U.S. Provisional Application No. 63/158,306, filed March 8, 2021. The claim to priority is acknowledged for claims 1, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75. As such, the effective filing date for claims 1, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 is March 8, 2021.
However, neither the PCT nor Provisional Application disclose the limitation in claim 2 of “wherein the set of exon-resolution identifiers including a single exon-resolution identifier indicates that the allele pair is … or heterozygous at an exon level of resolution”. There is disclosure for a single exon-resolution identifier indicating homozygosity but not heterozygosity. As such, the claim to priority for claim 2 is not acknowledged. The effective filing date of claim 2 is September 7, 2023.
Information Disclosure Statement
The IDSs filed 09/15/2023, 06/15/2026 and 09/08/2026 follow the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of the list of references cited from these IDSs is included with this Office Action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: 734 in FIG 7B.
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because the view numbers recite “Fig.” instead of “FIG.”. Correct Figures 1-18 to recite, for example, “FIG. 1”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 2 and 21 are objected to because of the following informalities:
Claim 2 should recite “identifiers includes a single exon-resolution identifier indicating that”.
Claim 21, line 5, should recite “wherein [[the]] each”.
Appropriate correction is required.
Claim Interpretation
Claim 26 is interpreted as a product by process limitation. It defines the process previously performed (generated based on a series) to derive the product (the set of exon-resolution identifiers). MPEP 2113.I recites “[e]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Claim Rejections - 35 USC § 112
35 USC 112(b)
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 11-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 11 recites “the plurality of series formed by the final set of exon identifies for each exon position of the MHC gene” which lacks antecedent basis. Claim 9 recites a similar phrase but lacks “exon” before “position”. Provide antecedent basis or clarify to what the recitation refers.
Claim 12, line 5, recites “the potential exon-resolution candidate identifier”. It is unclear if this refers to claim 12, line 3, of “a potential exon-resolution candidate identifier”, or refers to one of the identifies from “a plurality of potential exon-resolution identifiers” in claim 12, lines 3-4. Clarify which identifier is referenced.
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 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant case, claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22 and 25-26 recite a method, claim 74 recites a system, and claim 75 recites a product. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claims 1 and 74-75 recites “A method for typing major histocompatibility complex (MHC) alleles, the method comprising: receiving a set of exon-resolution identifiers for an allele pair associated with an MHC gene, wherein an exon-resolution identifier of the set of exon-resolution identifiers for a corresponding allele of the allele pair describes an allele group, a specific allele protein, and exon region information for the corresponding allele; identifying, for each exon-resolution identifier of the set of exon-resolution identifiers, a set of intron-resolution identifiers to form a plurality of intron-resolution candidate identifiers, wherein an intron-resolution identifier of the set of intron-resolution identifiers for the corresponding allele describes the allele group, the specific allele protein, the exon region information, and intron region information for the corresponding allele; and generating a final set of intron-resolution identifiers for the allele pair from the plurality of intron-resolution candidate identifiers.”
Claim 2 recites “wherein the set of exon-resolution identifiers including a single exon-resolution identifier indicates that the allele pair is homozygous or heterozygous at an exon level of resolution.”
Claim 4 recites “wherein generating the final set of intron-resolution identifiers comprises: generating the final set of intron-resolution identifiers for the allele pair from the plurality of intron-resolution candidate identifiers using a plurality of reads for a sample and a set covering algorithm.”
Claim 5 recites “wherein generating the final set of intron-resolution identifiers comprises: applying a set covering algorithm to a plurality of reads for a sample to identify a set of solution pairs from the plurality of intron-resolution candidate identifiers, each solution pair of the set of solution pairs including two different intron-resolution candidate identifiers from the plurality of intron-resolution candidate identifiers.”
Claim 6 recites “wherein generating the final set of intron- resolution identifiers further comprises: performing, in response to the set of solution pairs including multiple solution pairs, a decomposition of the multiple solution pairs to form the final set of intron-resolution identifiers for the allele pair, wherein the decomposition comprises decomposing the multiple solution pairs using hierarchical clustering to form the final set of intron- resolution identifiers for the allele pair.”
Claim 8 recites “determining that the set of solution pairs includes a single pair of intron- resolution identifiers; and outputting a selected intron-resolution identifier of the single pair of intron-resolution identifiers as the final set of intron-resolution identifiers when the selected intron- resolution identifier provides a same amount of coverage of the plurality of reads as the single pair of intron-resolution identifiers.”
Claim 9 recites “generating the set of exon-resolution identifiers from a plurality of exon-resolution candidate identifiers using a set covering algorithm; evaluating alignment between at least a portion of a plurality of reads for a sample and a plurality of series formed by a final set of exon identifiers for each position of an MHC gene; and forming the plurality of exon-resolution candidate identifiers from the plurality of series based on exon coverage.”
Claim 11 recites “filtering the plurality of reads to form a filtered plurality of reads, wherein the alignment is evaluated between the filtered plurality of reads and the plurality of series formed by the final set of exon identifiers for each exon position of the MHC gene.”
Claim 12 recites “adding a potential exon-resolution identifier of a plurality of potential exon- resolution identifiers to the plurality of exon-resolution candidate identifiers if a plurality of exons associated with the potential exon-resolution identifier is covered by the plurality of reads by a coverage threshold.”
Claim 13 recites “applying a set covering algorithm to a plurality of reads for a sample to identify a set of solution pairs from a plurality of exon-resolution candidate identifiers, each solution pair of the set of solution pairs including two different exon-resolution candidate identifiers from the plurality of exon-resolution candidate identifiers.”
Claim 14 recites “performing, in response to the set of solution pairs including multiple solution pairs, a decomposition of the multiple solution pairs to form the set of exon-resolution identifiers for the allele pair, wherein the decomposition comprises decomposing the multiple solution pairs using hierarchical clustering to form the set of exon-resolution identifiers for the allele pair.”
Claim 16 recites “determining that the set of solution pairs includes a single pair of exon- resolution identifiers; and outputting a selected exon-resolution identifier of the single pair of exon-resolution identifiers as the set of exon-resolution identifiers when the selected exon-resolution identifier provides a same amount of coverage of the plurality of reads as the single pair of exon-resolution identifiers.”
Claim 17 recites “identifying the plurality of series for the MHC gene by constraining the plurality of series to a plurality of final candidate exons, wherein the plurality of final candidate exons are identified using a set covering algorithm; identifying a plurality of candidate MHC exons, wherein each of the plurality of candidate MHC exons is fully covered by at least one read of the at least a portion of the plurality of reads; and identifying the plurality of final candidate exons from the plurality of candidate MHC exons.”
Claim 20 recites “receiving a plurality of reads for a sample, wherein: the sample is selected as one of a group consisting of a sample of healthy tissue md a sample of unhealthy tissue; and the plurality of reads is generated via at least one of whole-exome sequencing (WES) or whole genome sequencing (WGS).”
Claim 21 recites “generating a first set of intron-resolution identifiers for a first allele of the allele pair for the MHC gene and a second set of intron-resolution identifiers for a second allele of the allele pair using the final set of intron-resolution identifiers, wherein the each of the first set of intron-resolution identifiers and the second set of intron-resolution identifiers includes a same, single intron-resolution identifier when the allele pair is homozygous.”
Claim 22 recites “receiving a plurality of reads for a sample; and evaluating MHC loss between the sample and another sample using the final set of intron-resolution identifiers, wherein the plurality of reads includes a plurality of paired-end reads, the MHC gene is a human leukocyte antigen (HLA) gene, and the MHC alleles are HLA alleles.”
Claim 25 recites “wherein the final set >f intron-resolution identifiers is generated based on at least one of: a series formed by a final set of exon identifiers for each exon position of the MHC gene; three set covering algorithms used at an exon identifier level, an exon-resolution identifier level, and an intron-resolution identifier level, or a three-tier refinement at an exon identifier level, an exon-resolution identifier level, and”
Claim 26 recites “wherein the set of exon-resolution identifiers is generated based on a series formed by a final set of exon identifiers for each exon position of the MHC gene.”
Limitations reciting a mental process.
Claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 contain limitations recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mental process.
Claims 1 and 74-75 include collecting data such as the exon-resolution identifiers, searching a IPD- IMGT/HLA database for correlating intron-resolution identifiers, then writing down on pen and paper a final set of intron-resolution identifiers identified from the IPD-IMGT/HLA database.
Claims 2 and 26 further limit the type of data collected in claim 1 and thus equates= to collecting data. Claims 4-5 and 13 include aligning reads of an HLA allele to a reference sequence to identify whether variant exists in an exon or intron of the allele. Claims 6 and 14 include performing an agglomerative hierarchical clustering algorithm, or equivalents thereof, on the solution pairs, such as those shown in the matrix of FIG. 5. Claims 8 and 16 include determining that the solution pairs indicate a homozygous allele and outputting the results of data analysis. Claim 9 includes aligning exon sequences to exon sequences of an MHC gene and writing on pen and paper the set of exon-resolution identifiers when exon coverage is exact or contains a variant compared to a reference. Claim 11 is so broadly recited that it includes selecting specific sequences. Claim 12 includes determining whether reads meet a threshold then adding more data to the identifiers. Claim 17 includes aligning reads and making determinations. Claims 20 and 22 include collecting data, analyzing it by sequence alignment, and making determinations. Claim 21 includes writing down MHC resolution identifiers on pen and paper. Claim 25 includes evaluating reads and writing down MHC resolution identifiers.
Limitations reciting a mathematical concept.
Claims 6 and 14 recite limitations that equate to a mathematical concept because they are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. Claims 6 and 14 use a hierarchical clustering which includes a mathematical function that performs calculations.
As such, claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 recite an abstract idea (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. Claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 do not recite additional elements. Claims 74-75 do recite additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 74 recites “A system comprising: one or more data processors; and a non-transitory computer-readable storage medium containing instructions which, when executed on the one or more data processors, cause the one or more data processors to”
Claim 75 recites “A computer-program product tangibly embodied in a non- transitory machine-readable storage medium, including instructions configured to cause one or more data processors to perform a method comprising:”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to an equivalent of the words “apply it” and/or to instructions to implement an abstract idea on a computer (MPEP § 2106.05(f)), insignificant extra-solution activity (MPEP § 2106.05(g)), and field of use limitations (MPEP § 2106.05(h)). The paragraphs below discuss the additional elements recited above in the instant claims.
Claims 74-75 recite a CRM and a system comprising processors and CRM. There are no limitations requiring anything other than a generic computer and/or generic computing system. Therefore, these limitations equate to mere instructions to implement an abstract idea on a generic computer, which the courts have established does not render an abstract idea eligible in Alice Corp. 573 U.S. at 223, 110 USPQ2d at 1983.
As such, claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B:
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). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to instructions to apply the recited exception in a generic way and/or in a generic computing environment (MPEP § 2106.05(f)) and to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The paragraphs below discuss the additional elements recited above in the instant claims.
Claims 74-75 recite a CRM and a system comprising processors and CRM. There are no limitations requiring anything other than a generic computer and/or generic computing system. Therefore, these limitations equate to instructions to implement an abstract idea on a generic computing environment, which the courts have established does not provide an inventive concept in Intellectual Ventures I LLC v. Capital One Bank (USA), 792 F.3d 1363, 1367, 115 USPQ2d 1636, 1639 (Fed. Cir. 2015).
Claims 74-75 store information in memory, which the courts have established as a WURC function of a generic computer in Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they equate to mere instructions to implement an abstract idea on a generic computer WURC functions/components of a generic computer. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 1-2, 4-6, 8-9, 11-14, 16-17, 20-22, 25-26 and 74-75 are not patent eligible.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Rejection Xie in view of Kawaguchi
Claims 1-2, 20-21, 25-26 and 74-75 are rejected under 35 USC 103 for being unpatentable over Xie et al. (“Xie”; NPL ref. 5 on IDS filed 09/15/2023; Proceedings of the National Academy of Sciences, 114(30), 8059-8064) in view of Kawaguchi et al. (“Kawaguchi”; Human mutation 38, no. 7 (2017): 788-797).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claims 1 and 74-75:
A method for typing major histocompatibility complex (MHC) alleles, the method comprising:
A system comprising: one or more data processors; and a non-transitory computer readable storage medium containing instructions which, when executed on the one or more data processors, cause the one or more data processors to:
A computer-program product tangibly embodied in a non- transitory machine-readable storage medium, including instructions configured to cause one or more data processors to perform a method comprising:
Xie discloses xHLA, an algorithm that obtains four-digit typing accuracy for class I and II HLA genes from short-read next-generation sequence data (abstract). The algorithm is computer-implemented, listing CPU and memory (pg. 8061, col. 2, para. 1).
receiving a set of exon-resolution identifiers for an allele pair associated with an MHC gene, wherein an exon-resolution identifier of the set of exon-resolution identifiers for a corresponding allele of the allele pair describes an allele group, a specific allele protein, and exon region information for the corresponding allele;
Xie acquires an initial set of HLA allele candidate identifiers such as HLA-A*01:02 and A*03:01 (FIG 1) (pg. 8060, col. 2, last para.). However, the HLA allele candidates only disclose allele group and a specific allele protein but not exon region information for the corresponding allele.
Kawaguchi determines HLA alleles with 6-digit precision from NGS reads using an algorithm called HLA-HD, wherein the fifth and sixth digit disclose exon region information (abstract).
It would have been prima facie obvious to have modified Xie’s 4-digit HLA typing method by extending to a 6-digit HLA because Kawaguchi recites “accurate typing of human leukocyte antigen (HLA) alleles is critical for a variety of medical applications, such as genomic studies of multifactorial diseases, including immune system and inflammation-related disorders, and donor selection in organ transplantation and regenerative medicine” (abstract). 6-digits is more accurate than 4-digits, resulting in better information for medical applications. There would have been a reasonable expectation of success to perform 6-digit resolution HLA typing in Xie because it requires NGS reads, which Xie already uses, and because it requires sequence alignment to reference alleles to identify variants, which Xie already performs.
identifying, for each exon-resolution identifier of the set of exon-resolution identifiers, a set of intron-resolution identifiers to form a plurality of intron-resolution candidate identifiers, wherein an intron-resolution identifier of the set of intron-resolution identifiers for the corresponding allele describes the allele group, the specific allele protein, the exon region information, and intron region information for the corresponding allele; and
Xie discloses full resolution typing after 4-digit typing (FIGs 1 & 4). Xie teaches that for each 4-digit allele in the solution set, which would be 6-digits in view of Kawaguchi, “reads that are unambiguously assigned to that allele are extracted and realigned to all DNA reference sequences from IMGT/HLA under the same four-digit allele type. For each pair of full-resolution types, all exons with reference sequences in IMGT are considered, and the type explaining the largest number of unambiguous reads in the pair is taken” (pg. 8063, col. 2, para. 2) FIG 4 shows that the full resolution typing is 8-digits (intron-resolution candidate identifiers).
generating a final set of intron-resolution identifiers for the allele pair from the plurality of intron-resolution candidate identifiers.
Xie recites “[t]he final full-resolution type is identified recursively based on these pairwise comparisons” (pg. 8063, col. 2, para. 2) (FIG 4).
Claim 2: Xie shows in FIG 3 a homozygous allele call for HLA-C and discloses a zygosity check (FIG. 1). The combination of Xie and Kawaguchi disclose the exon level of resolution at 6-digits.
Claim 20:
Xie teaches that xHLA was benchmarked on both whole-genome and exome sequencing datasets (pg. 8061, col. 1, last para. – col. 2, para. 2). Table 1 shows datasets which contain healthy individuals.
Claim 21:
Xie shows in FIG 4 that each allele of an allele pair is associated with an 8-digit HLA identifier (generating a first/second set of intron-resolution identifiers using the final set of intron-resolution identifiers). The wherein clause limitation of claim 21 is a contingent limitation as indicated by “when” and is thus not required by the claim.
Claims 25-26:
Xie determines 4-digit HLA identifiers of an allele by aligning reads to exons of MHC genes in the IMGT database (wherein the set of exon-resolution identifiers is generated based on a series formed by a final set of exon identifiers for each exon position of the MHC gene) (pg. 8060, col. 2, last para. – pg. 8061, col. 1, para. 1) (FIG 2). These 4-digit identifiers are used in full resolution to acquire 8-digit identifiers (FIG 4) (the final set of intron-resolution identifiers is generated based on at least one of).
Rejection over Xie and Kawaguchi in view of Szolek
Claims 4-6, 8-9, 11-14 and 16-17 are rejected under 35 USC 103 for being unpatentable over Xie et al. (“Xie”; NPL ref. 5 on IDS filed 09/15/2023; Proceedings of the National Academy of Sciences, 114(30), 8059-8064) in view of Kawaguchi et al. (“Kawaguchi”; Human mutation 38, no. 7 (2017): 788-797), as applied to claim 1, and in further view of Szolek et al. (“Szolek”; NPL ref. 4 on IDS filed 09/15/2023; Bioinformatics 30, no. 23 (2014): 3310-3316).
The limitations of claim 1 are taught above by Xie and Kawaguchi. The italicized text below are the limitations of the instant claims and serves to map the prior art onto the instant claims.
Claims 4-5:
Xie recites “[f]or each four-digit allele in the solution set, reads that are unambiguously assigned to that allele are extracted and realigned to all DNA reference sequences from IMGT/HLA under the same four digit allele type” (pg. 8063, col. 2, para. 2). FIG 4 shows the solution set for full-resolution HLA typing for each 4-digit allele (a set of solution pairs), wherein each 4-digit allele has several different 8-digit identifiers (two different intron-resolution candidate identifiers). However, Xie does not apply a set covering algorithm to the mapped reads to determine the intron-resolution identifiers or solution pairs.
Claim 6:
Claim 6 recites a contingent limitation and is thus not required to be performed and is rejected for its dependency upon rejected claim 5. MPEP 2111.04.II recites “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.” Claim 6 is contingent upon the set of solution pairs including multiple solution pairs, as indicated by “in response to”. Thus, claim 6 is not performed when the set of solution pairs does not contain multiple solution pairs.
Claim 8:
Xie shows in FIG 4 in the “solution_set” that each allele pair contains, for example, A*01:02 and A*03:01. Each allele in the allele pair will have an 8-digit identifier after aligning reads to IMGT (a single pair of intron-resolution identifiers) (FIG 4). The limitation of “outputting a selected intron-resolution identifier … when the selected …” recites a contingent limitation and is thus not required by the claim.
Claim 9:
Xie teaches “[p]otential HLA sequencing reads are extracted from the BAM file based on their mapping coordinates and aligned to the IMGT/HLA database … An initial set of HLA allele candidates is first selected in a similar way to the integer linear programing technique used in OptiType, by using only the core exons that are available for all HLA reference alleles in the IMGT/HLA database. Then, for each allele candidate (sol) in the initial solution set (solution set), all alternative alleles (comp) that explain the alignments nearly as well are collected” (pg. 8060, col. 2) (generating the set of exon-resolution identifiers from a plurality of exon-resolution candidate identifiers). FIG 2 in the “solution_set” shows the initial set derived from the IMGT database. The IMGT database contains exons of HLA genes (a plurality of series formed by a final set of exon identifiers for each position of an MHC gene). Xie recites “The current candidate, sol, is compared with alternative candidates, comp, based on the reads aligned to all of the exons available for both alleles in the IMGT/HLA database, rather than only the core exons as in the initial round” (pg. 8060, col. 2, last para. – pg. 8061, col. 1, para. 1) (forming the plurality of exon-resolution candidate identifiers from the plurality of series based on exon coverage). However, Xie does not apply a set covering algorithm to the mapped reads to determine the exon-resolution identifiers.
Claim 11:
Xie recites “[t]he current candidate, sol, is compared with alternative candidates, comp, based on the reads aligned to all of the exons available for both alleles in the IMGT/HLA database, rather than only the core exons as in the initial round (Fig. 2). When comparing the two alleles, sol and comp, only reads that are aligned to one of the two alleles, but not both, nor any other alleles in the current solution set, are considered (“is better” in Fig. 2). This filtering step is important because reads that align to other alleles in the solution set are not informative when comparing sol and comp because it is unclear whether those reads are derived from the alleles being compared or other alleles in the solution set” (pg. 8060, col. 2, last para. – pg. 8061, col. 1, para. 1).
Claim 12:
Claim 12 recites a contingent limitation as indicated by “if” and is thus not required to be performed and is rejected for its dependency upon rejected claim 9.
Claim 13:
Xie teaches “[p]otential HLA sequencing reads are extracted from the BAM file based on their mapping coordinates and aligned to the IMGT/HLA database … An initial set of HLA allele candidates is first selected … by using only the core exons that are available for all HLA reference alleles in the IMGT/HLA database. Then, for each allele candidate (sol) in the initial solution set (solution set), all alternative alleles (comp) that explain the alignments nearly as well are collected” (pg. 8060, col. 2). FIG 2 in the “solution_set” shows the initial set derived from the IMGT database. However, Xie does not apply a set covering algorithm to the mapped reads to determine solution pairs.
Claim 14:
Claim 14 recites a contingent limitation as indicated by “in response to” and is thus not required to be performed and is rejected for its dependency upon rejected claim 13.
Claim 16:
Xie shows in FIG 2 in the “solution_set” that each allele pair contains, for example, A*01:02 and A*03:01. The limitation of “outputting a selected exon-resolution identifier … when the selected …” recites a contingent limitation and is thus not required by the claim.
Claim 17:
Xie teaches that the core exons of MHC genes from the IMGT are used to generate the initial set of exon-resolution identifiers based on read alignment (FIG 2) (pg. 8060, col. 2, last para.) (identifying the plurality of series by constraining the plurality of series). Xie teaches that a key difference in their algorithm is the use of a fast and sensitive protein level aligner, DIAMOND, and the acceptance of only perfect matches for quality trimmed reads (identifying a plurality of candidate MHC exons, wherein each of the plurality of candidate MHC exons is fully covered by at least one read of the at least a portion of the plurality of reads) (pg. 8060, col. 2, para. 1). These are used to derive the solution set of HLA typing identifiers (FIG. 2) (identifying the plurality of final candidate exons from the plurality of candidate MHC exons). However, Xie does not apply a set covering algorithm to the mapped reads to determine the final candidate exons.
Prima facie obviousness rationale for claims 4-5, 9, 13 and 17:
As discussed above, Xie uses mapped reads to determine intron/exon-resolution identifiers, solution pairs, and final candidate exons but does not use a set cover problem to identify alleles based on the mapped reads.
Szolek discloses an HLA typing model for NGS data called OptiType (abstract). Szolek recites “from the initial read mapping results, a binary matrix is generated indicating which alleles a specific read could be aligned to with the least number of mismatches (Fig. 1B). Finally, based on this matrix, a special case of the set cover problem (Karp, 1972) is formulated as an integer linear program (ILP) that selects up to two alleles for each locus simultaneously, maximizing the number of mapped reads that can be explained by the predicted genotype (Fig. 1C).”
It would have been prima facie obvious to have modified Xie who uses mapped reads to determine intron/exon-resolution identifiers, solution pairs, and final candidate exons by using the hit matrix and ILP of Szolek. Motivation is that the set cover problem solved by the hit matrix and ILP selects the most probable genotype by maximizing the number of reads explainable by the predicted genotype, as taught by Szolek (pg. 3311, col. 2, para. 2) (FIG 1C caption). One of ordinary skill would realize that this maximization of reads for a target can be expanded not only to the alleles but also to the exons of target MHC genes to derive candidate exons. There would have been a reasonable expectation of success because the hit matrix and ILP require mapped reads from RNA-Seq, exome sequencing or WGS (sec. 4 of Szolek), which Xie provides.
Rejection over Xie and Kawaguchi in view of Filip
Claim 22 is rejected under 35 USC 103 for being unpatentable over Xie et al. (“Xie”; NPL ref. 5 on IDS filed 09/15/2023; Proceedings of the National Academy of Sciences, 114(30), 8059-8064) in view of Kawaguchi et al. (“Kawaguchi”; Human mutation 38, no. 7 (2017): 788-797), as applied above to claim 1, and in further view of Filip et al. (“Filip”; medRxiv (2020): 2020-09).
The limitations of claim 1 are taught in the rejection above by Xie and Kawaguchi. The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 22:
Xie collects a BAM file containing all sequenced reads (pg. 8060, col. 1, last para. – col. 2, para. 1) and discloses a final set of intron-resolution identifier as seen in the 8-digit identifiers in FIG 4. Whole genome sequencing was performed (paired-end reads) (Table 1). The MHC is human because of the HLA alleles. However, Xie and Kawaguchi do not evaluate MHC loss between the sample and another sample using the intron-resolution identifiers.
Filip quantifies HLA-I allele-specific expression (ASE) using whole-exome sequencing to determined allele-specific loss in cancer (abstract). FIG 1 shows that HLA typing is performed from a blood sample of a cancer patient to create reference HLA identifiers. Then tumor cells of the patient undergo RNA-seq, wherein the subsequent reads are aligned to the reference HLA identifiers to determine ASE loss.
It would have been prima facie obvious to have used the 8-digit HLA identifiers of Xie and Kawaguchi to determine MHC loss in a cancer sample as taught by Filip. Motivation is that somatic loss of HLA-I heterozygosity is an established factor in immune evasion of cancers (abstract of Filip). Thus, one of skill would want to determine MHC loss to evaluate the cancer. There would have been a reasonable expectation of success because the combination requires using the sequences of the 8-digit HLA identifiers of Xie as a reference to align cancer RNA-seq reads against.
Conclusion
No claims are allowed.
Notable, but not relied upon, prior art includes: Kishore et al. (Frontiers in genetics 9 (2018): 503) discloses in Table 1 HLA typing tools for NGS data. Shiina et al. (Tissue antigens 80, no. 4 (2012): 305-316) discloses 8-digit HLA typing using NGS. Wang et al. (US-20140206547-A1).
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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