DETAILED ACTION
Applicant’s response, filed 29 June 2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 Claims
Claims 1-56, 60, 62, 66-68, 70-71, and 73-75 are cancelled.
Claims 93-102 are newly added.
Claims 57-59, 61, 63-65, 69, 72, and 76-102 are pending.
Claims 57-59, 61, 63-65, 69, 72, and 76-102 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application, PCT/IB2020/060191 filed 30 Oct. 2020, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority to AU2019904119 filed 31 Oct. 2019 under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Accordingly, the effective filing date of the claimed invention is 31 Oct. 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 June 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The objection to the drawings in the Office action mailed 30 April 2026 has been withdrawn in view of the replacement drawing sheets filed 30 June 2026.
The drawings filed 30 June 2026 are accepted.
Specification
The objection to the disclosure for containing an embedded hyperlink and/or other form of browser-executable code in the Office action mailed 30 April 2026 has been withdrawn in view of the amendments to the specification received 29 June 2026.
The objection to the abstract in the Office action mailed 30 April 2026 has been withdrawn in view of the amendments to the abstract received 29 June 2026.
Claim Objections
The objection to claims 57-61, 63, and 72 in the Office action mailed 30 April 2026 has been withdrawn in view of claim amendments received 29 June 2026.
Claim Interpretation
Applicant’s specification at pg. 21, lines 8-13 defines “gene dosage” to refer to the number of copies of a particular gene present in a genome.
Applicant’s specification at pg. 21, lines 14-17 defines “gene dosage map” to refer to a pictorial showing the relative amounts of each and every loci of a gene complex relative to each other.
Claims 57-61 recite the term “gene complex”. In light of Applicant’s specification at pg. 23, lines 12-14, the term is interpreted to refer to a group of related genes that act as a functional unit, such as the HLA gene complex or MHC gene complex.
Claim 86 recites “wherein the nucleic acid samples…are genomic DNA extracted from respective biological samples”. Claim 72 from which claim 86 depends, recites “contacting each of the nucleic acid samples…with one or more oligonucleotide probes”. Claim 58, from which claim 86 ultimately depends, recites “…generating potential transplant donor sequences and recipient sequences of an HLA gene complex….from respective nucleic acid samples”. Therefore, the limitation of claim 86 regarding the nucleic acid samples of genomic DNA having been extracted from respective biological samples is interpreted as a product by process limitation that only serves to define the process in which the nucleic acid samples of genomic DNA were previously extracted. However, the claim does not require a step of extracting. Claim 87 further limits the biological samples from which the genomic DNA was previously extracted, and therefore is part of the product by process limitation.
Claim 94 recites “wherein the potential transplant donor sequences and the recipient sequences are generated from nucleic acid samples obtained from…”. Claim 93, from which claim 94 depends, recites “receiving the potential transplant donor sequences and the recipient sequences”. Therefore, claim 94 is interpreted to define the process in which the received donor and recipient sequences were previously generated, and the claims do not require an active step of generating the potential transplant donor sequences and the recipient sequences. "[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. See MPEP 2113 I.
Claim 98 recites “wherein in an instance wherein a plurality of transplant donors are identified as transplant matches, the method further comprises selecting the transplant donor having a closest correlation…”. The limitation of “selecting the transplant donor…” is a contingent limitation that is contingent upon multiple transplant donors being identified in claim 57. The broadest reasonable interpretation (BRI) 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. See MPEP 2111.04 II. Therefore, the step of selecting is not required under the BRI of the claim because the condition of identifying a plurality of transplant donors is not met.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 58-62, 69-85, and 89-92 under 35 U.S.C. 112(a) in the Office action mailed 30 April 2026 has been withdrawn in view of claim amendments and cancellations received 29 June 2026.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 60, 62, 66-68, 70-71, and 73-75 under 35 U.S.C. 112(b) in the Office action mailed 30 April 2026 has been withdrawn in view of the cancellation of these claims received 29 June 2026.
The previous rejection of claims 57-59, 61, 63-65, 69, 72, and 92 under 35 U.S.C. 112(b) in the Office action mailed 30 April 2026 has been withdrawn in view of claim amendments received 29 June 2026.
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.
Claims 57-59, 61, 63-65, 69, 72, and 76-102 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claims 57, and claims dependent therefrom, are indefinite for recitation of “b) determining a correlation between the locus-specific proportion….of the potential transplant donor gene dosage map”. Claim 57 previously recites “a) generating a respective potential transplant donor gene dosage map for each of the one or more potential transplant donors”, such that there are one or more potential transplant donor gene dosage maps. As a result, it is not clear if “the potential transplant donor gene dosage map” in b) is intended to refer to the gene dosage map for each of the one or more potential transplant donors or a single gene dosage map for a single potential transplant donor. If Applicant intends the latter, it is further unclear which potential transplant donor gene dosage map is being referenced in step b), given there may be multiple transplant donor gene dosage maps. For purpose of examination, b) will be interpreted to determine a single correlation between one of the transplant donors and the recipient.
Claim 58, and claims dependent therefrom, are indefinite for recitation of “e) determining a correlation between the locus-specific proportion of reads at each locus of the potential transplant donor gene dosage map…”. Claim 58 previously recites “d) generating a respective potential transplant donor gene dosage map for each of the one or more potential transplant donors”. Therefore, claim 58 is indefinite for the same reasons discussed above for claim 57. For purpose of examination, claim 58 is interpreted to mean that a single correlation between one of the transplant donors and the recipient is determined.
Claim 97 is indefinite for recitation of “wherein a percentage proportion of approximately 100 percent…approximately 50 percent.... approximately 0 percent…”. The term “approximately” in claim 97 is a relative term which renders the claim indefinite. The term “approximately” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As a result, it is not clear what ranges of percentages might correspond to “approximately 100”, “approximately 50”, or “approximately 0”.
Claim 99 is indefinite for recitation of “method of claim 57, further comprising: determining, based on the locus-specific proportion of reads, a zygosity for each locus…”. Claim 57, from which claim 99 depends, determines a gene dosage map comprising locus-specific proportion of reads for “each of the one or more transplant donors” and “a respective potential transplant donor”, and also refers to in step b) “the locus-specific proportion of reads…of the potential transplant donor gene dosage map…and the locus-specific proportion of reads…of the recipient gene dosage map”. Therefore, it is not clear which locus-specific proportion of reads claim 99 is referring to. For purpose of examination, the limitation is interpreted to mean a zygosity is determined for each locus based on the locus-specific proportion of reads for any one of the one or more transplant donors and the recipient.
Response to Arguments
Applicant's arguments filed 29 June 2026 regarding 35 U.S.C. 112(b) have been fully considered but they are not persuasive because they do not pertain to the new grounds of rejection set forth above.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 67 and 74 under 35 U.S.C. 112(d) in the Office action mailed 30 April 2026 has been withdrawn in view of the cancellation of these claims received 29 June 2026.
The rejection of claims 64-65 under 35 U.S.C. 112(d) in the Office action mailed 30 April 2026 has been withdrawn in view of claim amendments received 29 June 2026.
Claim Rejections - 35 USC § 101
The rejection of claims 60, 62, 66-68, 70-71, and 73-75 under 35 U.S.C. 101 in the Office action mailed 30 April 2026 has been withdrawn in view of the cancellation of these claims received 29 June 2026.
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 57-59, 61, 63-65, 69, 72, and 76-102 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 57-58 being representative) is directed to a method of identifying a transplant donor and preventing graft versus host disease (GVHD). Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 57 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
a) generating a respective potential transplant donor gene dosage map for each of the one or more potential transplant donors based on potential transplant donor sequences assigned among a plurality of loci of an HLA gene complex, and a recipient gene dosage map for the recipient based on recipient sequences assigned among the plurality of loci of the HLA gene complex wherein generating each gene dosage map comprises, for each locus of a gene complex the plurality of loci, dividing a number of the respective potential transplant donor sequences or recipient sequences assigned to that locus by a total number of the respective potential transplant donor sequences or recipient sequences assigned to all loci of the plurality of loci to obtain a locus-specific proportion of reads for each locus (mental process and mathematical concept);
b) determining a correlation between the locus-specific proportion of reads at each locus of the potential transplant donor gene dosage map and the locus-specific proportion of reads at each corresponding locus of the recipient gene dosage map (mental process and mathematical concept); and
c) identifying one or more transplant donors from the one or more potential transplant donors as a transplant match for the recipient based on the correlation, wherein a closer correlation indicates a higher probability of being a transplant match and/or best transplant match for the recipient (mental process).
Claim 58 recites the following steps which fall under the mathematical concepts, mental processes, and/or certain methods of organizing human activity groupings of abstract ideas:
b) assigning, using a sequence editing and alignment…, the sequences generated in step (a) among a plurality of loci of the HLA gene complex (mental process);
c) for each potential transplant donor and for the recipient, determining a gene dosage for each locus of the plurality of loci of the HLA gene complex from the sequences assigned in step (b), wherein determining the gene dosage comprises dividing a number of the respective potential transplant donor sequences or recipient sequences assigned to that locus by a total number of the respective potential transplant donor sequences or recipient sequences assigned to all loci of the plurality of loci to obtain alocus-specific proportion of reads for each locus (mental process and mathematical concept);
d) generating a respective potential transplant donor gene dosage map for each of the one or more potential transplant donors and the recipient from the respective gene dosage for each locus of the plurality of loci of the HLA gene complex determined in step (c) (mental process and mathematical concept);
e) determining a correlation between the locus-specific proportion of reads at each locus of the potential transplant donor gene dosage map and the locus-specific proportion of reads at each corresponding locus of the recipient gene dosage map (mental process and mathematical concept); and
(f) identifying one or more transplant donors from the one or more potential transplant donors as a transplant match for the recipient based on the correlation, wherein a closer correlation indicates a higher probability of being a transplant match and/or best transplant match for the recipient (mental process).
The identified claim limitations falls into the group of mental processes for the following reasons. In this case, assigning sequences to each locus of a plurality of loci in an HLA gene complex encompasses analyzing aligned locations of each sequence to determine sequences that are within a given locus, which can be practically performed in the mind. Determining a gene dosage for each locus of the gene complex and then generating a gene dosage map from the gene dosage encompasses counting a number of reads assigned to each locus and dividing the number for a given locus by a total number of sequences assigned to all loci to calculate a gene dosage, and then organizing the information into an graph depicting the relative counts, which can be practically performed in the mind aided with pen and paper. The claims require repeating this mental process of generating this gene dosage and gene dosage map for each of one or more transplant donors and a recipient. Determining a correlation between the locus-specific proportions between a transplant donor and recipient can be practically performed in the mind by analyzing a difference between the locus-specific proportions at each locus. Last, identifying one or more transplant donors as a transplant match can be practically performed in the mind by determining a transplant donor has a high correlation with the recipient. That is, other than reciting the steps are carried out by a computer, nothing in the claims precludes the steps from being practically performed in the mind.
The identified claim limitations falls into the group of mathematical concepts for the following reasons. The step of determining a gene dosage for each locus and gene dosage map requires performing mathematical calculations, including determining the locus-specific proportions (i.e. dividing a number…assigned to that locus by a total number..), as also defined in Applicant’s specification at pg. 21, lines 8-17, which states the gene dosage map shows the relative amounts of each and every loci of a gene complex relative to each other and that the gene dosages are relative amounts (e.g. division). Determining a correlation between proportions of reads at each locus similarly recites a mathematical calculation and a mathematical relationship between the proportion of reads of the donor and recipient. Therefore, these limitations recite a mathematical concept.
Dependent claims 63-65, 69, and 95-100 and further recite an abstract idea and/or are part of the abstract idea set forth above. Dependent claims 63 further limits the abstract idea of generating the gene dosage maps to comprise a relative copy number. Dependent claims 64-65 further recite the mental process of determining a zygosity at each locus based on relative copy numbers, including determining two alleles at a locus have an identical sequence (i.e. homozygosity). Dependent claim 69 further limits the mental process of assigning to be based on or more regions of each locus. Dependent claim 95 further limits the abstract idea of generating the gene dosage maps to be performed for two or more of the recited loci. Dependent claims 96-97 further limit the abstract idea of determining the locus-specific proportions to be expressed as a percentage corresponding to different copy numbers. Dependent claim 98 further recites the mental process of selecting the transplant donor having a closest correlation as a best transplant match if multiple transplant donors are identified. Dependent claim 99 further recites the mental process of determining a zygosity based on the locus-specific proportion of reads at each locus. Dependent claim 100 further limits the abstract idea of generating the gene dosage map.
Last, the claims further recite the law of nature of a natural correlation between copy numbers (i.e. gene dosages) of a gene complex, including HLA, and transplant donor compatibility or graph versus host disease (GVHD), analogous to a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). See MPEP 2106.04(b).
Therefore, claims 57-59, 61, 63-65, 69, 72, and 76-102 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
The additional elements of claims 57-58 include:
a computer;
a program (claim 58);
The additional elements of claims 91-92;
sequences are generated in computer readable form of a FASTQ (claims 91-92);
The additional elements of claims 93-94 include:
receiving the potential transplant donor sequences and the recipient sequences, wherein the potential transplant donor sequences and the recipient sequences are sequences that have been assigned among the plurality of loci of the HLA gene complex using a sequence editing and alignment program, wherein the potential transplant donor sequences and the recipient sequences are generated from nucleic acid samples obtained from the one or more potential transplant donors and the recipient (i.e. receiving data) (claims 93-94).
Regarding the additional elements of claims 57-58, 70-71, and 91-94 of a computer used to carry out the abstract idea, computer programs, computer-readable form, and receiving data, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
The additional elements of claim 58 further include:
a) generating potential transplant donor sequences and recipient sequences of an HLA gene complex, using a sequencing platform, from respective nucleic acid samples obtained from the one or more potential transplant donors and the recipient (claim 58);
The additional elements of claim 72 include:
(i) contacting each of the nucleic acid samples from the respective nucleic acid samples obtained from the one or more potential transplant donors and the recipient with oligonucleotide probes;
(ii) enriching a nucleic acid by hybridizing the nucleic acid to one or more oligonucleotide probes, wherein the one or more oligonucleotide probes, wherein the one or more oligonucleotide probes hybridize to gene target sequences in the nucleic samples;
(iii) separating nucleic acid hybridized to the one or more oligonucleotide probes from nucleic acid not hybridized to the one or more oligonucleotide probes; and
(iv) sequencing the enriched nucleic acid to identify one or more gene alleles, wherein the gene target sequences are in a non-coding region of the gene.
The additional elements of claims 76-90 include:
amplifying the nucleic acid bound to the one or more oligonucleotide probes (claim 76);
sequencing an HLA gene exon (claim 77);
sequencing the entire HLA gene (claim 78);
wherein the one or more oligonucleotide probes comprises a capture tag (claim 79);
wherein the capture tag is biotin or streptavidin (claim 80);
contacting the capture tag with a binding agent (claim 81);
wherein the binding agent is biotin or streptavidin (claim 82);
wherein each of the nucleic acid s from the one or more transplant donors and the recipient that is contacted with the one or more oligonucleotide probes comprises single stranded nucleic acid (claim 83);
wherein each of the nucleic acid samples are fragmented before or after being contacted with the one or more oligonucleotide probes (claim 84);
wherein the fragments of each of the nucleic acid samples have an average length greater than about 100 bp (claim 85);
wherein the nucleic acid samples from the one or more potential transplant donors and the recipient are genomic DNA extracted from respective biological samples (claim 86);
wherein at least one of the biological samples is whole blood (claim 87); and
wherein the genomic DNA is at a concentration of about 10 ng/ul to about 100 ng/ul (claim 88).
wherein sequencing is performed using high-throughput sequencing (claim 89); and
wherein the high-throughput sequencing is hybrid-capture next generation sequencing (claim 90);
The additional elements of claims 58, 72, and 76-90, of fragmenting a nucleic acid sample of genomic DNA at a concentration of 10 to 100 ng/ul, extracted from blood, to an average length of greater than 100 bp before contacting, contacting single-stranded nucleic acids of the one or more transplant donors and the recipient to one or more oligonucleotide probes comprising a biotin or streptavidin capture tag, contacting the capture tag with a biotin or streptavidin binding agent, enriching for nucleic acid bound to the probes, amplifying the nucleic acid bound to the probes, and then performing hybrid-capture next generation sequencing on the captured nucleic acid is not sufficient to integrate the recited judicial exception into a practical application for the following reason. The limitations only serve to collect data for use by the abstract idea, which amounts to insignificant extra-solution activity that is not sufficient to integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Last, the additional element of claim 92 of the generated sequences being stored in a FASTQ file only serves to generally link the abstract idea of analyzing sequences to a computer technological environment, which is not sufficient to integrate the judicial exception into a practical application. See MPEP 2106.05(h).
Therefore, the additionally recited elements merely invoke computers as tool to carry out the abstract idea, amount to insignificant extra-solution activity, and/or generally link the abstract idea to a technological environment, and as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 57-59, 61, 63-65, 69, 72, and 76-102 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The additional elements are outline in the Step 2A, Prong 2 section above.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
Regarding the additional elements of a computer used to carry out the abstract idea, computer programs, computer-readable form, and receiving data, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Furthermore, regarding the computer-readable FASTQ file of claims 91-92, Applicant’s specification at pg. 56, lines 5-10 discloses commercially available software that processes raw sequencing data in FASTQ file format, demonstrating the conventionality of the file format. Furthermore, Applicant’s specification also provides no detail as the actual format of FASTQ files, demonstrating that the element is so well-known that it need not be described in detail in the patent specification. SEE MPEP 2106.05(d) I.
The additional elements of claims 58-61, 72, 76-90, of fragmenting a nucleic acid sample of genomic DNA at a concentration of 10 to 100 ng/ul, extracted from blood, to an average length of greater than 100 bp before contacting, contacting single-stranded nucleic acids of the one or more transplant donors and the recipient to one or more oligonucleotide probes comprising a biotin or streptavidin capture tag, contacting the capture tag with a biotin or streptavidin binding agent, enriching for nucleic acid bound to the probes, amplifying the nucleic acid bound to the probes, and then performing hybrid-capture next generation sequencing of an HLA-gene on the captured nucleic acid describes a well-understood, routine, and conventional hybrid-capture sequencing process. This position is supported by Applicant’s own specification, Nagymihaly et al. (Next-generation Sequencing and its new possibilities in medicine, 2015, Acta Biologica Szegediensis, pg. 323-339; previously cited), Koboldt et al. (The Next-Generation Sequencing Revolution and Its Impact on Genomics, 2013, Cell, 155, pg. 27-38; previously cited), Chang et al. (Clinical application of amplicon-based next-generation sequencing in cancer, 2015, Cancer Genetics, 206, pg. 413-419; newly cited), and Yang et al. (Transplant genetics and genomics, 2017, Nature Reviews Genetics, 18, pg. 309-326; previously cited).
First, Applicant’s specification at pg. 36, lines 6-15 discloses that various suitable methods for extracting DNA from blood samples are known in the art, and rang e from solvent extraction to adsorption to silica-coated beads and anion exchange columns, and that automated systems for DNA extraction are also available. Applicant’s specification at pg. 37, lines 8-19 discloses the nucleic acid may be fragmented by physical shearing, sonication, restriction digestion, or other suitable technique known in the art, and at pg. 37 line 30 to pg. 38 line 3 that nucleic acid can be made single stranded using techniques known in the art. Applicant’s specification at pg. 39, lines 5-22 also describes hybridization conditions that are well-known in the art, demonstrating the conventionality of hybridization techniques.
Furthermore, Nagymihaly reviews next-generating sequencing techniques, and discloses high-throughput DNA sequencing is routinely used on a wide range of important fields in biology (Abstract). Nagymihaly discloses targeted enrichment sequencing techniques are based on either PCR or hybridization, and to capture a target sequence in hybridization, genomic DNA is sheared and processed into a sequencing library, library fragments are subject to hybridization to biotin-labelled oligonucleotide probes specific for target regions, and the biotin-labeled probes bind to streptavidin-coated magnetic beads (pg. 331, col. 2, para. 2). Nagymihaly discloses that, at the end, library fragments are removed from their binding and are sequenced (pg. 331, col. 2, para. 2). Nagymihaly further discloses that DNA samples must be fragmented into small pieces from 100-800 base pairs before sequencing (pg. 324, col 1.para. 2 and col. 2, para. 3). Chang reviews amplicon-based next-generation sequencing including hybrid-capture (Abstract), and discloses input DNA amounts for various DNA sequencing technologies from 10 to 100 ng per ul (Table 3; pg. 415, col. 2, para. 4 to pg. 416, col. 1, para. 1).
Kobolt similarly reviews next-generation sequencing and its impact on genomics (Abstract), and discloses genomic technologies including hybrid capture, which involves capturing DNA fragments using probes linked to biotin molecules and mixing the probe:library complexes with streptavidin-coated magnetic beads to selectively capture targeted regions of the genome (pg. 27, col. 2, para. 1). Kobolt similarly discloses subsequent denaturation releases the captured library fragments, so they’re ready for postcapture amplification and sequencing (pg. 27, col. 2, para. 1), demonstrating the conventionality of amplifying the enriched nucleic acids before sequencing. Therefore, the additional elements above pertaining to sample preparation and high throughput hybrid-capture sequencing of nucleic acid are well-understood, routine, and conventional.
Last, Yang reviews genetic analysis in transplantation (Abstract), and discloses the HLA complex in humans is the most immunologically and clinically relevant regions in the context of transplantation (pg. 309, col. 2, para. 3 to pg. 310, col. 1, para. 1). Yang discloses variations in HMC genes, including HLA-A, HLA-B, and HLA-DR have the greatest importance for successful HLA matching, and when HLA is matched, graft survival decreases in a manner that is dependent on the number of mismatches (i.e. HLA genes are analyzed in the donor and recipient) (pg. 311, col. 2, para. 2 to pg. 312, col. 1, para. 1). Yang further discloses that numerous methodologies have been developed for high-throughput typing of HLA genes, including using next-generation sequencing methods, and sequencing panels targeted at HLA loci have become routinely available in the clinic. (pg. 312, col. 1, para. 2). Therefore, even considering the additional elements in combination, performing targeted sequencing, such as hybrid-capture, on HLA loci in transplant donors and recipients is well-understood, routine, and conventional.
Taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 29 June 2026 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks claims 57 and 58 require a specific computational methodology that involves processing hundreds of thousands of sequencing reads across multiple HLC loci, which cannot be practically performed in the mind, and determining a correlation involves multi-variable computations on large genomic datasets that go beyond what can be practically performed mentally (Applicant’s remarks at pg. 18, para. 4 to pg. 19, para. 5).
This argument is not persuasive because it is not commensurate with the scope of the claims. The claims do not recite any particular number of sequence reads being analyzed, and only require analyzing 2 loci in an HLA gene, which is not a “large genomic datasets”.
Regardless, the amount of data, in and of itself is not a limitation which takes a process out of the realm of the human mind. Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also SiRF Tech., Inc. v. Int’l Trade Comm ’n, (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
Last, even if the step of determining a correlation was not considered a mental process, the limitation still recites a mathematical concept as discussed in the above rejection.
Applicant remarks the claims do not recite mathematical concepts because the division and correlation steps are not claimed as standalone mathematical operations divorced from any technological context, and instead are integral components of a technical process of biological sequencing data (Applicants’ remarks at pg. 19, para. 6 to pg. 20, para. 1).
This argument is not persuasive. Even though the mathematical concepts recited in the claim are being applied to biological sequencing data, and thus are not divorced from a context of sequencing data, the claims still recite a mathematical concept for the reasons discussed in the above rejection. Applicant appears to be arguing the claims are not directed to mathematical concepts because the math is an integral component of a technical process. However, this is evaluated under Step 2A, Prong 2 (discussed in further detail below).
Applicant remarks the claims do not merely observe a natural correlation, but rather recite specific computational method for quantifying a correlation, and the claims apply any such correlation through a specific technical process that yields an actionable result (Applicant’s remarks at pg. 20, para. 2).
This argument is not persuasive. It again appears Applicant is arguing the claims are not directed to a law of nature under Step 2A, Prong 2, because the claims recite computational steps to quantify the correlation. However, the computational steps mentioned by application that are the “technical process” is part of the abstract idea, and therefore cannot provide integration at step 2A, Prong 2. The claims recite a law of nature and abstract idea for the reasons set forth in the above rejection.
Applicant remarks that the claims integrate any alleged judicial exception into a practical application under step 2A, Prong 2 because claim 57 identifies one or more transplant donors, which employs the information provided by the preceding computational analysis, and further remarks that claim 58 further reinforces this integration by “using a sequencing platform”, and that ordered combination of sequencing and computational steps produce more than mere data gathering, but rather represents a specific integrated sample that moves from biological sample through sequencing to donor transplant identification, which is an “other meaningful limitation” (Applicant’s remarks at pg. 20, para. 3 to pg. 20, para. 1).
This argument is not persuasive. Under Step 2A, Prong 2, the additional elements are evaluated to determine whether additional elements integrate the judicial exception into a practical application. See MPEP 2106.04(d). The step of identifying a transplant donor is part of the abstract idea, and therefore cannot provide integration for the preceding computational steps that are also part of the abstract idea.
Regarding the step of sequencing, MPEP 2106.05(g) states examiners may consider the following: whether the limitation amounts to necessary data gathering and outputting, (i.e., all uses of the recited judicial exception require such data gathering or data output). See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015) (presenting offers and gathering statistics amounted to mere data gathering). In the instant case, all uses of the recited judicial exception require the generation of sequencing data, and therefore, the sequencing limitation amounts to insignificant extra-solution activity that does not provide integration.
Claim Rejections - 35 USC § 103
The previous rejections of claims 57-92 under 35 U.S.C. 103 in the Office action mailed 30 April 2026 have been withdrawn in view of claim amendments and cancelations received 29 June 2026. However, new grounds of rejection under 35 U.S.C. 103 is set forth below in view of the amendments.
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 57, 59, and 93-101 are rejected under 35 U.S.C. 103 as being unpatentable over McCaroll (2017) in view of Waszak (2010). This rejection is newly recited and necessitated by claim amendment.
Cited references:
McCarroll et al., US 2007/0172853 A1 (previously cited); and
Waszak et al. Systemic Inference of Copy-Number genotypes from Personal Genome Sequencing Data Reveals Extensive Olfactory Receptor Gene Content Diversity, 2010, PLoS Computational Biology, 6(11), pg. 1-20 (newly cited).
Regarding claim 57, McCarroll discloses a method for predicting the immuno-compatibility between a first subject that is a transplant recipient and a second subject that is a donor (Abstract; [0003]-[0004]; claim 19), wherein the method comprises the following steps:
McCarroll discloses a) generating a deletion variant pattern (i.e. a gene dosage map) for each of the first and second subjects (i.e. the donor and recipient) ([0019]), wherein a deletion variant pattern is a compilation of the determination of the presence or absence of deletion variants in the genes of a respective biological sample and includes relative copy numbers ([0037]; [0170] and Figure 4, e.g. determined deletion genotypes include 0 or 1 copy of the gene). McCaroll discloses the deletion variant patterns are determined for loci of an HLA gene ([0015]; [0036]-[0037], e.g. deletion variant pattern determined for in a gene, wherein the pattern is can be determined from a deletion variant antigen). McCaroll discloses the deletion variant patterns are determined from sequencing data ([0012]; [0037]) mapped to a reference genome (i.e. based on loci-assigned sequences) ([0098]).
McCaroll discloses b) comparing the deletion variant pattern (i.e. a gene dosage map) of the first subject (i.e. the recipient) with the deletion variant pattern of the second subject (i.e. the donor) to determine what percentage the deletion variant patterns (i.e. gene dosage maps) of the recipient and donor are identical (i.e. a correlation) ([0019], e.g. determining a 99% identical deletion pattern).
McCaroll discloses c) determining the first subject (i.e. recipient) is immuno-compatible (i.e. a transplant match) with the second subject (i.e. donor) if the first and subjects have substantially identical deletion variant patterns (e.g. at least 50%...100% identical) (i.e. based on the correlation) ([0019]). McCaroll discloses that higher similarity between the deletion variant patterns between the first and second subject are indicative of immune-compatibility, while lower similarities are indicative of the subjects not being immune-compatible ([0019]), demonstrating the closer the correlation between the deletion variant patterns, the higher probability of immune-compatibility.
Further regarding claim 57, McCaroll does not disclose the following:
Regarding claims 57, McCaroll does not explicitly disclose the method is computer-implemented, such that various steps are performed “using a computer”. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Further regarding claims 57, while McCaroll does disclose determining a deletion variant pattern of relative copy numbers for the first and second subjects (considered a deletion map showing a relative copy number of each locus), does not disclose wherein generating the gene dosage map comprises, for each locus of the plurality of loci, dividing a number of the respective potential transplant donor sequences or recipient sequences assigned to that locus by a total number of the respective potential transplant donor sequences or recipient sequences assigned to all loci of the plurality of loci to obtain a locus-specific proportion of reads for each locus, and further does not disclose the deletion variant pattern is a gene dosage map comprising a pictorial pattern showing copy numbers of each locus of the gene complex relative to other loci, as defined in Applicant’s specification at pg. 21, lines 13-17.
However, these limitations were known in the art before the effective filing date of the claimed invention, as shown by Waszak.
Waszak discloses a method for determining copy-numbers from personal genome sequencing data, called CopySeq (Abstract), which comprises determining locus read-depth ratios (i.e. locus-specific proportion of reads for each locus) (pg. 13, col. 1, para. 3). Wazak discloses determining the locus read-depth ratios comprise determining the observed locus read depth D (i.e. a number of sequences assigned to that locus) divided by the expected locus read-depth E, which includes the total number of uniquely aligned sequence reads against the reference genome (i.e. a total number of sequences assigned to all loci) (pg. 13, col. 1, para. 3-4). Wazak discloses a ratio of 1 corresponds to a copy number of 2, a ratio of 0.5 is a copy number of 1, and a copy number of 3 corresponds to a ratio of 1.5 (pg. 13, col. 1, para. 3-4). Waszak further discloses creating a pictorial representation of the read depth proportions showing copy numbers at each locus in the genome (Figure 3; Figure 5).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the deletion variant patterns of the recipient and donor of McCaroll to have been determined by calculating locus read-depth ratios and presented in pictorial form according to the method of Waszak, as discussed above, thus arriving at the inventions of claim 57. One of ordinary skill in the art would have been motivated to apply the known technique of determining and presenting copy number profiles of loci in pictorial form, as shown by Waszak to the known method of determining deletion variant patterns of loci comprising relative copy numbers of McCaroll, given one of ordinary skill in the art would recognize that the determination of relative copy numbers and visual representation of copy number profiles of Waszak could be applied to the deletion profile (i.e. copy number profiles) of McCaroll. Furthermore, one of ordinary skill in the art would have recognized that the known technique of determining and visually representing the copy number profile would have yielded the predictable result of displaying the deletion profiles between the donor and recipient of McCaroll, thus facilitating comparisons between copy number profiles of different samples, as performed in Waszak (Figure 5) and McCaroll ([0019]).
Regarding dependent claims:
Regarding claim 59, McCaroll discloses the determined first subject is immune-compatible with the second subject, ([0019]), as discussed above for claim 58, and further discloses the analysis is performed between a graft donor and graft recipient for the corresponding organ intended to be transplanted ([0011]; [0042], e.g. donor and recipient needing same organ, tissue, bone marrow; [0077]; [0094], e.g. analysis performed in organ to be transplanted), such that the graft from the transplant donor is determined.
Regarding claim 93, McCaroll discloses receiving DNA sequences of multiple genes relevant to the organ or tissue for which immune-compatibility is desired (i.e. a gene complex) by performing sequencing by hybridization on a biological sample from the first subject (the recipient) and a biological sample from the second subject (the donor) ([0012]; [0037]). McCarroll discloses the genes may be from the MHC complex ([0036]; [0045]; [0050]). McCaroll discloses the deletion variant patterns are determined from sequencing data ([0012]; [0037]) mapped to a reference genome (i.e. the sequences are assigned) ([0098]). Regarding the process in which the received sequences were previously assigned using a sequence editing and alignment program, this limitation is a product by process limitation that only serves to define the process in which the sequences were previously assigned, as explained in claim interpretation above. Given the mapped sequences of McCaroll are the same as those received in the claim (i.e. sequences assigned to loci), McCaroll discloses this limitation. See MPEP 2113 I.
Regarding claim 94, as explained in claim interpretation, the limitation is interpreted to define the process in which the received donor and recipient sequences were previously generated, and the claims do not require an active step of generating the potential transplant donor sequences and the recipient sequences. Given the sequences in of McCaroll are the same as those received in the claim (i.e. sequences assigned to loci), McCaroll discloses this limitation. See MPEP 2113 I.
Regarding claim 95, McCaroll further discloses identifying the deletion variants comprises performing DNA sequencing on a preferred subset of the whole genome, including DNA sequences encoding protein sequences known to be presented by the MHC (i.e. multiple HLA loci) ([0012]; [0045]). McCaroll discloses common HLA alleles include HLA-A, HLA-B, and HLA-DRB1 ([0042]; [0130]). Alternatively McCaroll discloses the deletion variant pattern may be determined for the entire genome ([0037]).
Regarding claims 96-97, McCaroll in view of Waszak, as applied to claim 57 above, make obvious determining locus specific ratios for each of multiple HLA loci in an HLA gene complex (i.e. locus-specific proportion of reads for each locus) to represent copy numbers corresponding to 0, 1, and 2 (Waszak; Figure 5).
Regarding claim 98, as discussed above in claim interpretation, the limitation of “selecting the transplant donor…” is contingent upon a plurality of transplant donors being identified. Because the condition precedent is not required by the claim, under the broadest reasonable interpretation of the claim, the step of “selecting” is not required. Therefore claim 98 is rejected for the same reasons as discussed above for claim 57. See MPEP 2111.04 II.
McCaroll in view of Waszak do not explicitly disclose the locus-specific proportion of reads are expressed as a percentage proportion representing copy numbers 0, 1, and 2. However, the expression of the proportion as a percentage is interpreted as a matter of design choice, and Applicant has not disclosed that this feature provides an advantage, is used for a particular purpose, or solves a stated problem when compared to using ratios, as shown by McCaroll in view of Waszak. Therefore, the ratios shown by McCaroll in view of Waszak would perform equally as well in representing copy numbers, and such a modification fails to patentably distinguish over McCaroll in view of Waszak. See MPEP 2144.04 I.
Regarding claim 99, McCaroll does not disclose determining, based on the locus-specific proportion of reads, a zygosity for each locus of the plurality of loci, wherein the zygosity distinguishes between homozygous, hemizygous, and nullizygous.
However, Waszak further discloses bi-allelic copy number variations enable distinguishing homozygous from heterozygous CNVs, including heterozygous deletions, homozygous deletions (i.e. nullizygous), or no deletion (pg. 3, col. 1, para. 1 to col. 2, para. 1; pg. 13, col. 1, para. 4; pg. 14, col. 1, para. 2). Waszak further discloses homozygous deletions are of particular interest due to their phenotypic affects, and that failure to discriminate heterozygotes from homozygotes limits statistical power in association studies (pg. 1, col. 2, para. 1; pg. 10, col. 1, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have further modified the method of McCaroll to have determined zygosity for each locus based on the relative copy number of each locus, as shown by Waszak above. One of ordinary skill in the art would have been motivated to further combine the methods of McCaroll and Waszak in order to detect deletions that have phenotypic affects and to facilitate association studies, as shown by Waszak (pg. 1, col. 1, para. 1; pg. 10, col. 1, para. 1). This modification would have had a reasonable expectation of success given both McCaroll and Waszak analzye copy numbers, and thus the method of determining zygosity using copy numbers of Waszak is applicable to McCaroll.
Regarding claim 100, McCaroll in view of Waszak, as applied to claim 57, make obvious each gene dosage map is a pictorial representation of the locus read ratios across the loci (Waszak Figure 5).
Regarding claim 101, McCaroll in view of Waszak do not explicitly disclose transplanting the graft, tissue, or organ from the transplant donor to the recipient.
However, McCaroll discloses that the disclosed method of screening immunocompatibility is used to identify donor/recipient matches for transplantation ([0071]; [0109]), thus suggesting that transplantation occurs after a donor match is identified. McCaroll discloses the method identifies immunocompatible transplant donors and recipients and reduces the likelihood of graft rejection ([0008]; [0094]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of McCaroll in view of Waszak to have further performed transplanting the graft or organ from the transplant donor to recipient, as suggested by McCaroll (([0071]; [0109]). One of ordinary skill in the art would have been motivated to combine the methods of McCaroll and Waszak in order to provide a transplant that reduces the likelihood of graft rejection, as shown by McCaroll ([0008]; [0094]). This modification would have had a reasonable expectation of success given McCaroll states the intent of the invention is to find a match for transplantation.
Therefore, the invention is prima facie obvious.
Claims 58, 61, 63-65, 69, 72, 76-91, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over McCaroll (2017) in view of Gnirke (2009) and Waszak (2010). This rejection is newly recited and necessitated by claim amendment.
Cited references:
McCarroll et al., US 2007/0172853 A1 (previously cited)
Gnirke et al., Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing, 2009, Nature Biotechnology, 27(2), pg. 182-189 (previously cited); and
Waszak et al. Systemic Inference of Copy-Number genotypes from Personal Genome Sequencing Data Reveals Extensive Olfactory Receptor Gene Content Diversity, 2010, PLoS Computational Biology, 6(11), pg. 1-20 (newly cited).
Regarding claim 58, McCarroll discloses a method for predicting the immuno-compatibility between a first subject that is a transplant recipient and a second subject that is a donor (Abstract; [0003]-[0004]; claim 19), wherein the method comprises the following steps:
McCarroll discloses a) determining DNA sequences of multiple genes relevant to the organ or tissue for which immune-compatibility is desired (i.e. a gene complex) by performing sequencing by hybridization on a biological sample from the first subject (the recipient) and a biological sample from the second subject (the donor) ([0012]; [0037]). McCarroll discloses the genes may be from the MHC complex ([0036]).
McCarroll discloses b) comparing the determined sequences to a reference genome to identify mismatch loci between the subjects and the reference genome (i.e. read mapping, which assigns the sequences to each locus of the gene complex) ([0098]).
McCarroll discloses c) determining the presence or absence of copy number deletion variants inferred by copy number for each gene (i.e. each locus) from the mapped sequences ([0012]; e.g. large deletions determined by sequencing; [0017]; [0078], e.g. deletion inferred from copy number; [0063] and FIG. 4, e.g. copy number variations determined, referred to as “Gene dosage” ). This is consistent with Applicant’s specification at pg. 21, lines 8-13 which defines a “gene dosage” to refer to a number of copies of a gene loci.
McCarroll discloses d) generating a deletion variant pattern (i.e. a gene dosage map) for each of the first and second subjects (i.e. the donor and recipient) ([0019]), wherein a deletion variant pattern is a compilation of the determination of the presence or absence of deletion variants in the genes of a respective biological sample and includes relative copy numbers ([0037]; [0170] and Figure 4, e.g. determined deletion genotypes include 0 or 1 copy of the gene). McCaroll discloses the deletion variant patterns are determined for loci of an HLA gene ([0015]; [0036]-[0037], e.g. deletion variant pattern determined for in a gene, wherein the pattern is can be determined from a deletion variant antigen).
McCaroll discloses e) comparing the deletion variant pattern (i.e. a gene dosage map) of the first subject (i.e. the recipient) with the deletion variant pattern of the second subject (i.e. the donor) to determine what percentage the deletion variant patterns (i.e. gene dosage maps) of the recipient and donor are identical (i.e. a correlation) ([0019], e.g. determining a 99% identical deletion pattern).
McCaroll discloses f) determining the first subject (i.e. recipient) is immuno-compatible (i.e. a transplant match) with the second subject (i.e. donor) if the first and subjects have substantially identical deletion variant patterns (e.g. at least 50%...100% identical) (i.e. based on the correlation) ([0019]). McCaroll discloses that higher similarity between the deletion variant patterns between the first and second subject are indicative of immune-compatibility, while lower similarities are indicative of the subjects not being immune-compatible ([0019]), demonstrating the closer the correlation between the deletion variant patterns, the higher probability of immune-compatibility.
Further regarding claim 58, McCaroll does not disclose the following:
Regarding claims 58, McCaroll does not explicitly disclose the method is computer-implemented, such that various steps are performed “using a computer”. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Further regarding claim 58, McCaroll does not disclose that in b), the computer program used to assign the plurality of sequences is a sequencing editing and alignment program.
However, Gnirke discloses a method for performing sequencing and determining base calls (Abstract; pg. 188, col. 1, para. 4 to col. 2, para. 1), which comprises computationally aligning reads to the human genome and excluding bases from the aligned sequences that failed a signal clarity filter (i.e. sequence editing) using an ARACHNE genome assembly suite (pg. 188, col. 1, para. 4 to col. 2, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of McCaroll in view of Waszak, as applied to claim 70 above, to have assigned the plurality of sequences using a sequencing editing and alignment program, as shown by Gnirke above. One of ordinary skill in the art would have been motivated to combine the methods of McCaroll in view of Gnirke in order to provide high-confidence base calls excluding low quality bases, as shown by Gnirke (pg. 188, col. 2, para. 1), thus facilitating the accurate identification of variants in McCaroll. This modification would have had a reasonable expectation of success given McCaroll discloses mapping sequence reads to a reference genome ([0098]), such that the alignment and editing program of Gnirke is applicable to the sequencing data of McCaroll.
Further regarding claims 58, while McCaroll does disclose determining a deletion variant pattern of relative copy numbers for the first and second subjects (considered a deletion map showing a relative copy number of each locus), McCaroll in view of Gnirke does not disclose wherein generating the gene dosage map comprises, for each locus of the plurality of loci, dividing a number of the respective potential transplant donor sequences or recipient sequences assigned to that locus by a total number of the respective potential transplant donor sequences or recipient sequences assigned to all loci of the plurality of loci to obtain a locus-specific proportion of reads for each locus, and further does not disclose the deletion variant pattern is a gene dosage map comprising a pictorial pattern showing copy numbers of each locus of the gene complex relative to other loci, as defined in Applicant’s specification at pg. 21, lines 13-17.
However, these limitations were known in the art before the effective filing date of the claimed invention, as shown by Waszak.
Regarding claim 58, Waszak discloses a method for determining copy-numbers from personal genome sequencing data, called CopySeq (Abstract), which comprises determining locus read-depth ratios (i.e. locus-specific proportion of reads for each locus) (pg. 13, col. 1, para. 3). Wazak discloses determining the locus read-depth ratios comprise determining the observed locus read depth D (i.e. a number of sequences assigned to that locus) divided by the expected locus read-depth E, which includes the total number of uniquely aligned sequence reads against the reference genome (i.e. a total number of sequences assigned to all loci) (pg. 13, col. 1, para. 3-4). Wazak discloses a ratio of 1 corresponds to a copy number of 2, a ratio of 0.5 is a copy number of 1, and a copy number of 3 corresponds to a ratio of 1.5 (pg. 13, col. 1, para. 3-4). Waszak further discloses creating a pictorial representation of the read depth proportions showing copy numbers at each locus in the genome (Figure 3; Figure 5).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the deletion variant patterns of the recipient and donor of McCaroll to have been determined by calculating locus read-depth ratios and presented in pictorial form according to the method of Waszak, as discussed above, thus arriving at the inventions of claim 57. One of ordinary skill in the art would have been motivated to apply the known technique of determining and presenting copy number profiles of loci in pictorial form, as shown by Waszak to the known method of determining deletion variant patterns of loci comprising relative copy numbers of McCaroll, given one of ordinary skill in the art would recognize that the determination of relative copy numbers and visual representation of copy number profiles of Waszak could be applied to the deletion profile (i.e. copy number profiles) of McCaroll. Furthermore, one of ordinary skill in the art would have recognized that the known technique of determining and visually representing the copy number profile would have yielded the predictable result of displaying the deletion profiles between the donor and recipient of McCaroll, thus facilitating comparisons between copy number profiles of different samples, as performed in Waszak (Figure 5) and McCaroll ([0019]).
Regarding the dependent claims:
Regarding claim 61, McCaroll discloses the determined first subject is immune-compatible with the second subject, ([0019]), as discussed above for claim 58, and further discloses the analysis is performed between a graft donor and graft recipient for the corresponding organ intended to be transplanted ([0011]; [0042], e.g. donor and recipient needing same organ, tissue, bone marrow; [0077]; [0094], e.g. analysis performed in organ to be transplanted), such that the graft from the transplant donor is determined.
Regarding claim 63, McCaroll further discloses the deletion variant map comprises the presence or absence of copy number deletion variants inferred by a relative copy number for each gene (i.e. the gene dosage for each locus is a copy number) ([0012]; e.g. large deletions determined by sequencing; [0017]; [0078], e.g. deletion inferred from copy number; [0063] and FIG. 4, e.g. relative copy numbers copy number variations determined, referred to as “Gene dosage” ). McCaroll in view of Waszak, as applied above, also disclose the gene dosage is a relative copy number (Waszak: pg. 13, col. 1, para. 3-4, e.g. ratio of 1 = copy number of 2 relative to diploid).
Regarding claims 64-65, McCaroll does not disclose determining zygosity for at least each locus based on the relative copy number for each locus, and determining, based on the relative copy number of each locus, whether two alleles at that locus have an identical sequence (i.e. are homozygous).
However, Waszak further discloses bi-allelic copy number variations enable distinguishing homozygous from heterozygous CNVs, including heterozygous deletions, homozygous deletions (i.e. nullizygous), or homozygous reference allele (i.e. two alleles having an identical sequence) or no deletion (pg. 3, col. 1, para. 1 to col. 2, para. 1; pg. 13, col. 1, para. 4; pg. 14, col. 1, para. 2). Waszak further discloses homozygous deletions are of particular interest due to their phenotypic affects, and that failure to discriminate heterozygotes from homozygotes limits statistical power in association studies (pg. 1, col. 2, para. 1; pg. 10, col. 1, para. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have further modified the method of McCaroll to have determined zygosity, including homozygosity, for each locus based on the relative copy number of each locus, as shown by Waszak above. One of ordinary skill in the art would have been motivated to further combine the methods of McCaroll and Waszak in order to detect deletions that have phenotypic affects and to facilitate association studies, as shown by Waszak (pg. 1, col. 1, para. 1; pg. 10, col. 1, para. 1). This modification would have had a reasonable expectation of success given both McCaroll and Waszak analzye copy numbers, and thus the method of determining zygosity using copy numbers of Waszak is applicable to McCaroll.
Regarding claims 72, 76, 79-85, and 88-90, McCaroll does not disclose the following limitations:
Regarding claim 72 and 89-90, while McCaroll discloses identifying the deletion variants comprises performing DNA sequencing on a preferred subset of the whole genome, including DNA sequences encoding protein sequences known to be presented by the MHC (i.e. HLA genes) ([0012]; [0045]), McCaroll does not disclose the sequencing comprises performing hybrid-capture next generation sequencing (claims 89-90) by: i) contacting each nucleic acid sample from the one or more transplant donors and the recipient with one or more oligonucleotide probes; ii) enriching a nucleic acid by hybridizing the nucleic acid to the one or more oligonucleotide probes, wherein the oligonucleotide probes hybridize to gene target sequences in the nucleic acid sample; iii) separating nucleic acid hybridized to the one or more oligonucleotide probes from nucleic acid not hybridized to the one or more oligonucleotide probes; and iv) sequencing the enriched nucleic acid to identify one or more gene alleles; wherein the gene target sequences are in a non-coding region of the gene (claim 72).
Regarding claim 76, McCaroll does not disclose amplifying nucleic acid bound to the one or more oligonucleotide probes.
Regarding claims 79-82, McCaroll does not disclose the oligonucleotide probes comprise a biotin or streptavidin capture tag and contacting the capture tag with a biotin or streptavidin binding agent.
Regarding claim 83¸ McCaroll does not disclose each of the nucleic acid samples from the transplant donor and recipient contacted with the oligonucleotide probes is single stranded nucleic acid.
Regarding claims 84-85, McCaroll does not disclose fragmenting the nucleic acid sample before or after being contacted with the oligonucleotide probes, wherein the fragments have an average length of over about 100 bp.
Regarding claim 88, McCaroll does not disclose the genomic DNA is at a concentration of about 10 to 100 ng/ul).
However, Gnirke discloses the above method of performing next-generation hybrid capture sequencing (Abstract) encompassed by claims 72, 76, 79-85, and 88-90 as follows.
Gnirke discloses fragmenting genomic DNA prior to contacted by oligonucleotide probes to 200-350 bp fragments with an average size of 250 bp (i.e. an average length of over 100 bp) (Figure 1; pg. 183, col. 2, para. 3), wherein the genomic DNA is at a concentration of 250 ng per ul (i.e. about 100 ng/ul) before hybrid selection (pg. 188, col. 1, para. 1).
Gnirke further discloses hybridizing (i.e. contacting) the single-stranded fragmented DNA to biotinylated RNA bait (i.e. oligonucleotide probes comprising a biotin capture tag) (pg. 183, col. 2, para. 3; Figure 1, e.g. single stranded fragment bound to RNA bait), capturing the DNA-RNA bait complex is on streptavidin-coated magnetic beads (Figure 1; pg. 183, col. 1, para. 2 to col. 2, para. 1), and then separating and enriching the bead-captured DNA via elution (Figure 1; pg. 188, col. 1, para. 2). Following elution, Gnirke discloses performing PCR amplification on the captured DNA and then performing next-generation sequencing the amplified fragments (Figure 1; pg. 183, col. 2, para. 3; pg. 188, col. 2, para. 2; pg. 186, col. 2, para. 5).
Gnirke further discloses that the simple pull-down technique with streptavidin-coated magnetic beads, discussed above, does not require any customized equipment and works well in combination with any sequencing platform, thus allowing extensive sequencing of targeted loci in genomes (pg. 186, col. 2, para. 5 to pg. 187, col. 1, para. 1; pg. 187, col. 2, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the targeted sequencing method of McCaroll to have utilized the hybrid-capture next-generation sequencing method of Gnirke, discussed above, and thus arriving at the inventions of claims 72, 76, and 79-85. One of ordinary skill in the art would have bene motivated to combine the methods of McCaroll and Gnirke to facilitate extensive sequencing of targeted loci without the need for any customized equipment or specific sequencing platforms, as shown by Gnirke (pg. 186, col. 2, para. 5 to pg. 187, col. 1, para. 1; pg. 187, col. 2, para. 2). This modification would have had a reasonable expectation of success given McCaroll discusses only sequencing a preferred subset of the genome, and thus the hybrid-capture method of sequencing targeted regions of Gnirke could be used to generate the sequencing data of preferred regions in McCaroll.
Regarding claims 77-78, McCaroll in view of Gnirke and Waszak disclose the method of claim 72, as applied above. McCaroll further discloses identifying the deletion variants comprises performing DNA sequencing on a preferred subset of the whole genome, including DNA sequences encoding protein sequences known to be presented by the MHC (i.e. an HLA gene exon and entire HLA gene complex) ([0012]; [0045]). In another embodiment, McCaroll discloses the preferred subset is all DNA sequences encoding proteins ([0045]), which necessarily includes an entire HLA gene complex.
Regarding claim 69, McCaroll further discloses the assigning is based on comparing the determined sequences (i.e. the entire sequence of each locus) to a reference genome ([0098]).
Regarding claims 86-87, McCaroll discloses nucleic acid from the first and second subject is extracted from a blood sample (claims 1 and 4-5; [0032]; [0177], e.g. DNA isolated).
Regarding claim 91, McCaroll does not explicitly disclose the sequences are generated in computer-readable form. However, the courts held that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III and MPEP 2114 IV.
Regarding claim 102, McCaroll in view of Waszak do not explicitly disclose transplanting the graft, tissue, or organ from the transplant donor to the recipient
However, McCaroll discloses that the disclosed method of screening immunocompatibility is used to identify donor/recipient matches for transplantation ([0071]; [0109]), thus suggesting that transplantation occurs after a donor match is identified. McCaroll discloses the method identifies immunocompatible transplant donors and recipients and reduces the likelihood of graft rejection ([0008]; [0094]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of McCaroll in view of Waszak to have further performed transplanting the graft or organ from the transplant donor to recipient, as suggested by McCaroll (([0071]; [0109]). One of ordinary skill in the art would have been motivated to combine the methods of McCaroll and Waszak in order to provide a transplant that reduces the likelihood of graft rejection, as shown by McCaroll ([0008]; [0094]). This modification would have had a reasonable expectation of success given McCaroll states the intent of the invention is to find a match for transplantation.
Claim 92 is rejected under 35 U.S.C. 103 as being unpatentable over McCaroll in view of Gnirke and Waszak, as applied to claim 91 above, and further in view of Roy (2016). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Roy et al., Next-Generation Sequencing Informatics: Challenges and Strategies for Implementation in a Clinical Environment, 2016, Arch Pathol Lab Med, 140, pg. 958-975 (previously cited).
Regarding claim 92, McCaroll in view of Gnirke and Waszak disclose the method of claim 91 as applied above.
Further regarding claim 92, McCaroll in view of Gnirke and Waszak, as applied to claim 91 above, does not disclose the sequences are generated in a FASTQ format.
However, Roy overviews informatics solutions to next-generation sequencing data (Abstract), and discloses that sequences reads generated during sequencing are stored in one of several file formats, including FASTQ, XSEQ, unaligned BAM, or FASTA (pg. 960, col. 1, para. 1-2). Roy discloses FASTQ files are smaller than raw data files and are platform-independent entry points into common bioinformatics tool, thus offering a much higher utility for the incurred cost of storage (pg. 969, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the computer-readable sequences of McCaroll in view of Gnirke and Waszak, to have been stored in a FASTQ file format, as shown by Roy above. One of ordinary skill in the art would have been motivated to combine the methods of McCaroll in view of Gnirke and Waszak with Roy in order to provide sequencing data in a platform-independent format that is smaller than raw data files, thus offering higher utility per storage cost, as shown by Roy (pg. 969, col. 1, para. 2). This modification would have had a reasonable expectation of success because Roy discloses FASTQ formats are used to store sequence reads generated during sequencing (pg. 960, col. 1, para. 1-2), and thus the sequencing data of McCaroll in view of Roy could be stored in a FASTQ format.
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 29 June 2026 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that McCaroll does not teach or suggest using its methodology with respect to an HLA gene complex as required by the independent claims, and instead discloses the deletion variant is not an MHC or HLA gene, and rather focusses on other genes such as UGT2B17, and that MCaroll further teaches that rejection issues are in part due to many other histocompatibility antigens that have not yet been identified (Applicant’s remarks at pg. 22, para. 2 to pg. 23, para. 2). Applicant remarks the express exclusion established that McCaroll does not teach the HLA gene complex, and states that McCaroll teaches “DNA sequences encoding protein sequences that are known to be presented by the MHC” which describes proteins displayed by MHC molecules to T cells and not the HLA genes themselves (Applicant’s remarks at pg. 23, para. 3).
This argument is not persuasive. MPEP 2123 states a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
In the instant case, McCaroll teaches that “preferably, a deletion variant antigen is not an HLA, MHC antigen, or Rh factor”, thus teaching that HLA is a nonpreferred embodiment and not completely excluded. McCaroll also explains that a “deletion variant pattern…can be determined for one gene, two genes, three or more genes, a genomic locus, a chromosome, or an entire genome for a subject sample” ([0037]), demonstrating the deletion analysis is applicable to all genes in the genome, inherently including HLA loci. Furthermore, regarding Applicant’s argument regarding McCaroll noting that graft rejection may still occur even when a transplant and recipient are HLA matched for all HLA antigens due in part to other antigens not having been identified, this citation in McCaroll is providing context for performing the deletion variant analysis in addition to HLA typing ([0038], e.g. deletion variant typing may be performed in combination with HLA typing or alone). Performing the deletion variant analysis for an HLA gene complex is not the same as HLA typing (i.e. determining specific alleles and not just copy numbers), and instead can be performed alone or in conjunction with HLA typing.
Applicant remarks that one of ordinary skill in the art would be dissuaded from applying McCaroll’s deletion variant analysis to HLA genes because McCaroll excludes HLA genes and teaches the deletion variant analysis is performed “in addition to” HLA typing would dissuade a skilled person (Applicant’s remarks at pg. 24, para. 1).
This argument is not persuasive. Performing the deletion variant analysis for an HLA gene complex is not the same as HLA typing, and instead can be performed in conjunction with HLA typing or completely without HLA typing, as described by McCaroll ([0038]). This does not teach away from performing a deletion variant analysis on an HLA gene instead of performing HLA typing.
Applicant remarks McCaroll does not teach generating a dosage map by determining a locus-specific proportion of reads for each locus, and instead concern binary representations and inferred copy numbers of 0, 1, or 2 copies of a gene (Applicant’s remarks at pg. 24, para. 2 to pg. 25, para. 1).
This argument is not persuasive because Jan, not McCaroll, is relied upon for the determination of locus-specific proportions of reads in the dosage maps.
Applicant remarks that Jan does not cure the deficiencies in McCaroll, because Jan uses the tool LOHHLA to estimate HLA allele-specific copy number because LOHHLA compares tumor and matched normal germline samples from the same individual and not samples from two different individuals such as a donor and recipient, and the logR in LOHHLA is a tumor/normal coverage ratio within a single HLA locus, and further remarks this is fundamentally different than the claimed method which divides the number of sequences assigned to each locus by the total sequences assigned to all loci (Applicant’s remarks at pg. 25, para. 2).
This argument is not persuasive because Jan is not relied upon in the above rejection.
Applicant remarks neither McCaroll nor Jan teach determining a correlation between the locus specific proportion of reads at each locus because McCaroll compares variants based on the presence or absence of deletions and not correlations between proportions (Applicant’s remarks at pg. 26, para. 1).
This argument is not persuasive. First, Jan is not relied upon in the above rejection. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
McCaroll discloses c) determining the first subject (i.e. recipient) is immuno-compatible (i.e. a transplant match) with the second subject (i.e. donor) if the first and subjects have substantially identical deletion variant patterns (e.g. at least 50%...100% identical) (i.e. based on the correlation) ([0019]). Determining a percent match is considered a “correlation” and the claims do not require calculating a correlation value (e.g. an R-squared value) specifically on the proportions, and instead generally determines “a correlation”. While McCaroll matches deletion patterns based on the presence or absence of deletions, Waszak teaches using copy numbers of locus specific ratios, which when combined with the method of McCaroll involve determining correlations between such proportions.
Applicant remarks the dependent claims are allowable for the same reasons discussed above (Applicant’s remarks at pg. 26, para. 4).
This argument is not persuasive for the same reasons discussed above.
Conclusion
No claims are allowed.
Claims 101-102 are patent eligible because they integrate the recited judicial exception into the practical application of effecting a particular treatment by requiring transplantation from the transplant donor to recipient.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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