DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the claims
The claim set received 12 January 2023 is entered into the application.
Claims 1-20 are pending.
Priority
This Application is a 371 of PCT/US2021/018968 filed 22 February 2021 which claims benefit to U.S Provisional Application 62/982,286 filed 27 February 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 26 August 2022, 20 February 2025, and 09 July 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Drawings
The drawings were received on 26 August 2022. These drawings are accepted.
Specification
The specification received 26 August 2022 has been entered into the application.
The amendments to the specification and the substitute specification received 06 May 2026 have been entered into the application.
Claim Rejections - 35 USC § 112
l35 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.
Claim 12 is 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 12 recites “comprising providing the results to a caregiver and/or a transplant database to reduce a risk of graft vs host disease in a transplant recipient.” The claimed step is rendered indefinite because the claimed steps do not recite any limitations or active steps clarifying how providing results into a database or to a caregiver facilitate in reducing risk of a graft vs host disease. Thus, the limitation “…to reduce the risk…” is interpreted as an intended use and does not further limit the claim. . It recommended to amend the claim to provide as to how the results reduce of graph/host disease risk and/or cancel the claim. It is noted that any amendments should provide language consistent with and supported by the specification.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
Step I - Process, Machine, Manufacture or Composition
Claims 1-14 are drawn to a method, so a process.
Claim 15-17 are drawn to a system (i.e., computer), so a machine.
Claims 18 are drawn to computer-readable media (CRM), so a manufacture.
Step 2A Prong II - Identification of an Abstract Idea
It is noted claim 1 is drawn to a method, but claim 15 is drawn to a machine while claim 18 is drawn to CRM. However, claims 1, 15, and 18 recite similar limitations and are therefore examined similarly.
Claims 1, 15, and 18:
(b) aligning, using a computer-implemented alignment program, the query nucleic acid sequence from the subject to a reference nucleic acid sequence, the reference and query nucleic acid sequences comprising long read sequence data for at least exon 3 of DPB1
This step encompasses performing mathematical computations for aligning sequence reads of a query nucleic acid sequence to a reference nucleic acid sequence. For example, aligning sequence reads encompasses using matrix mathematics (e.g., scoring matrices), match/mismatch scoring systems, and scoring matrix generation. As such, this process converts biological sequences into mathematical objects (strings) and uses numerical scoring systems to calculate the optimal alignment. See MPEP 2106.04(a)(2)(I)(A)(iv).
(c) identifying, using a computer-implemented algorithm, whether the query nucleic acid sequence has a sequence characteristic of low levels of DPB1 expression or high levels of DPBI expression based on the aligned query nucleic acid sequence and the reference nucleic acid sequence
This step can be performed in the human mind by observing, comparing, and evaluating nucleic acid sequence (i.e., aligned query nucleic acid sequence and reference nucleic acid sequence) characteristics to identify low levels of DPB1 expression and/or high levels of DPBI expression and is therefore an abstract idea.
wherein the identifying comprises the following steps:
Step (c) (i) comparing nucleotides within the aligned query nucleic acid sequence and the reference nucleic acid sequence to identify differences between the query nucleic acid sequence and the reference nucleic acid sequence
This step can be performed in the human mind by observing, comparing, and evaluating information (i.e., aligned query and reference nucleic acid sequence) to identify differences between the query nucleic acid sequence and the reference nucleic acid sequence and is therefore an abstract idea.
Step (c) (ii) determining, based on the identified differences between the query sequence nucleic acid sequence and the reference nucleic acid sequence, an identity of the nucleotides for the query nucleic acid sequence as compared to the reference nucleic acid sequence at defined positions in the exon 3 of DPB 1
This step can be performed in the human mind by observing and evaluating information (i.e., identified differences between the query sequence nucleic acid sequence and the reference nucleic acid sequence of exon 3 of DPB 1) to determine an identity of the nucleotides for the query nucleic acid sequence (i.e., exon 3 DPB1) and is therefore an abstract idea.
Step (c) (iii) determining, based on the identity of the nucleotides for the query nucleic acid sequence at the defined positions in the exon 3, that the query sequence exhibits a sequence characteristic of a weak expression motif or a sequence characteristic of a strong expression motif or neither
This step can be performed in the human mind by observing and evaluating information (i.e., identity of the nucleotides for the query nucleic acid sequence (i.e., exon 3) to determine whether the query sequence exhibits a weak expression motif or a strong expression motif, or neither and is therefore an abstract idea.
Step (c) (iv) identifying the subject as having a low expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the weak expression motif, or identifying the subject as having a high expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the strong expression motif.
This step can be performed in the human mind by observing and evaluating information (i.e., query nucleic acid sequence data exhibits weak or strong expression motif sequence characteristics) to identify whether a subject has low or high DPB 1 expression levels and is therefore an abstract idea.
Claims 2-14, 16-17, and 19-20 are further drawn to limitations that describe the abstract ideas of claims 1, 15, and 18 and are therefore also abstract ideas.
Step 2A Prong II - Consideration of Practical Application
Here, in the instant case, claims 1, 15, and 18 merely set forth a method of nucleic acid sequence data analysis for predicting DPB1 gene expression levels by identifying whether query nucleic acid sequence characteristic(s) represents low or high DPB1 gene expression levels. As such, practicing the claims merely results in identifying nucleic acid sequence differences and/or characteristics. Such a result only produces information and does not provide for a practical application in the physical-realm of physical things and acts, i.e., the claims do not utilize the data generated by the judicial exception to affect any type of change. See MPEP 2106.04(a)(2)(A)(iv).
This judicial exception is not integrated into a practical application because the claims do not meet any of the following criteria:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
an additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
an additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
an additional element effects a transformation or reduction of a particular article to a different state or thing; and
an additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Step 2B - Consideration of Additional Elements and Significantly More
The claimed method also recites "additional elements" that are not limitations drawn to an abstract idea.
The recited additional element of using computers processes, components, and equipment of claims 1-20 does not add significantly more than the judicial exception because using computer as a tool to process abstract ideas in a computing environment and using a computer to evaluate, processes, and stores abstract ideas is tangential to the claimed invention and is conventional. See MPEP 2106.05(d)(II), and 2106.05(g).
The recited additional element of using sequencer to obtain sequencing of claims 1, 15, and 18 does not add significantly more than the judicial exception because using a sequencer to obtain sequence read data that is subsequently analyzed by the abstract ideas is well-known and conventional. See 2106.05(d)(II)(i-iii, v, vii-viii), and 2106.05(g). To provide evidence of conventionality, Schone et al. (Schone) teaches using single molecule real-time sequencing SMRT sequencing which is type of long-read sequencing [page 21 fig 1] (Hum Immunol. 2017 Nov 7;79(1):20–27). To provide further evidence of conventionality, Woodhouse et al. (Woodhouse) discloses long-read sequencing methods [Woodhouse page 10 right col para 0097]. Woodhouse discloses using long-read sequencing (LRS) [Woodhouse, claim 122] (US Patent Pub No.: US 2019/0203283, Patent Pub Date: 04 July 2019).
The recited additional element of data inputting by providing data to a database of claim 12 does not add significantly more than the judicial exception because inputting data into a database is well-known and conventional. See MPEP 2106.05(g).
In conclusion and when viewed as a whole, these additional claim element(s) do not provide meaningful, nonroutine and unconventional limitation(s) to transform the abstract idea recited in the instantly presented claims into a patent eligible application of the abstract idea such that the claim(s) amounts to significantly more than the abstract idea itself. Therefore, the claim(s) are rejected under 35 U.S.C. 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 6-7, 9-10, 14-15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Schone et al. (Hum Immunol. 2017 Nov 7;79(1):20–27) (Cited in the IDS received 26 August 2022, NPL 6).
It is noted that claim 1 is drawn to a method, but claim 15 is drawn to a machine while claim 18 is drawn to CRM. However, claims 1, 15, and 18 recite similar limitations and are therefore examined similarly.
Claim 1 step (a) recites obtaining, using a long-read sequencer, a query nucleic acid sequence from a sample of the subject.
Claim 1 (b) recites aligning, using a computer-implemented alignment program, the query nucleic acid sequence from the subject to a reference nucleic acid sequence, the reference and query nucleic acid sequences comprising long read sequence data for at least exon 3 of DPB1.
Claim 1 (c) recites identifying, using a computer-implemented algorithm, whether the query nucleic acid sequence has a sequence characteristic of low levels of DPB1 expression or high levels of DPBI expression based on the aligned query nucleic acid sequence and the reference nucleic acid sequence, wherein the identifying comprises the following steps.
Claim 1 (c)(i) recites comparing nucleotides within the aligned query nucleic acid sequence and the reference nucleic acid sequence to identify differences between the query nucleic acid sequence and the reference nucleic acid sequence.
Claim 1 (c) (ii) recites determining, based on the identified differences between the query sequence nucleic acid sequence and the reference nucleic acid sequence, an identity of the nucleotides for the query nucleic acid sequence as compared to the reference nucleic acid sequence at defined positions in the exon 3 of DPB 1.
Claim 1 (c)(iii) recites determining, based on the identity of the nucleotides for the query nucleic acid sequence at the defined positions in the exon 3, that the query sequence exhibits a sequence characteristic of a weak expression motif or a sequence characteristic of a strong expression motif or neither.
Claim 1 (c)(iv) recites identifying the subject as having a low expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the weak expression motif, or identifying the subject as having a high expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the strong expression motif.
Schone teaches using a method single molecule real-time (SMRT) sequencing [page 20]. Schone teaches targeting the whole gene with a long amplicon (black box) (i.e., gene) for secondary analysis using SMRT sequencing. Schone teaches the whole gene from 5’ to 3’ end is approximately 11,500 base pairs. Schone teaches full-length sequencing approach covers the whole DPB1 gene including rs9277534 in the 3′ UTR in one amplicon [page 21 left col top para], as in claim 1 step (a) obtaining, using a long-read sequencer, a query nucleic acid sequence from a sample of the subject. Here, although Schone does not directly teach a long-read sequencer, it would be obvious that the SMRT analysis (i.e., long-read sequencing method) of Schone would utilize a machine/device that can process long-read sequences to produce long-read sequence data because the DPBI Gene structure is shown as at least 11,000 base pairs (Figure 1)
Shone et al. (Schone) teaches using rd9277534 amplicon region as a reference [page 21 right col section 2.3.3]. Schone teaches regions of the analyzed HLA-DPB1 gene [page 21 figure 1]. Schone teaches aligned all known exon 3 sequence features of DPB1 to reveal common motifs [page 24 right col section 3.6], as in instant claim 1 (b) recites aligning, using a computer-implemented alignment program, the query nucleic acid sequence from the subject to a reference nucleic acid sequence, the reference and query nucleic acid sequences comprising long read sequence data for at least exon 3 of DPB1.
Schone teaches three most common sequence features (DPB1*02:01, DPB1*01:01 and DPB1*04:01) accounted for 99.15% of the observed alleles [page 24 right col third para]. Schone teach a table of sequence features (i.e., characteristics) related to exon 3 [page 24 figure 3]. Schone teaches features related to low and high expression [page 23 table 1]. Schone teaches alignment of sequence features [page 25 fig 5]. Schone teach sequence features (SF) [page 25 table 4], as in instant claim 1 recites (c) identifying, using a computer-implemented algorithm, whether the query nucleic acid sequence has a sequence characteristic of low levels of DPB1 expression or high levels of DPBI expression based on the aligned query nucleic acid sequence and the reference nucleic acid sequence, wherein the identifying comprises the following steps.
Schone teaches alignment of sequence features [page 25 fig 5]. Schone teaches linkage between rs9277534 and HLA-DPB1 alleles based on exons 2 and 3. Schone teaches these 64 allele groups represent 155 of the 630 described alleles, with a combined frequency of 99.2% in this study [page 23 table 1], as in instant claim 1 recites (c)(i) comparing nucleotides within the aligned query nucleic acid sequence and the reference nucleic acid sequence to identify differences between the query nucleic acid sequence and the reference nucleic acid sequence.
Schone teaches using two distinct sequences at the rs9277534 amplicon region as references [page 21 right col section 2.3.3]. Schone teaches identifying HLA-DPB1 allele with novel exon 2/3 combination [page 24 table 3]. Schone teaches a table showing identified nucleotide positions of exon 3 of HLA-DPB1 [page 25 figure 5]. Schone teaches nucleotide frequency [at page 13 Supplementary table 3], as in instant claim 1 (c) (ii) determining, based on the identified differences between the query sequence nucleic acid sequence and the reference nucleic acid sequence, an identity of the nucleotides for the query nucleic acid sequence as compared to the reference nucleic acid sequence at defined positions in the exon 3 of DPB 1.
Schone teaches all known exon 3 sequence features of DPB1 to reveal common motifs were aligned [page 24 right col section 3.3]. Schone teaches a table showing identified nucleotide positions of exon 3 of HLA-DPB1 [page 25 figure 5]. Schone teaches weak and strong DPB1 expression based on the sequence features at A and G positions [page 23 table 1, left col section 3.3], as in instant claim 1 (c)(iii) determining, based on the identity of the nucleotides for the query nucleic acid sequence at the defined positions in the exon 3, that the query sequence exhibits a sequence characteristic of a weak expression motif or a sequence characteristic of a strong expression motif or neither.
Schone teaches weak and strong DPB1 expression based on the sequence features at A and G positions [page 23 table 1, left col section 3.3]. Schone teaches DPB1*34:01 was found in subjects of German and Turkish decent [page 24 left col top para]. Schone teaches DPB1*34:01 was related to strong expression of DPB1 [page 23 table 1]. Schone teaches the sequence feature (i.e., 02:01) was detected in samples (i.e., subject), as in instant claim 1 (c) (iv) recites identifying the subject as having a low expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the weak expression motif, or identifying the subject as having a high expression level of DPB 1 when the query nucleic acid sequence exhibits the sequence characteristic of the strong expression motif. Here, even though Schone does not teach a single individual with low or strong expression of DPB1, Schone teaches using samples from USA, Germany, UK, Poland, and India. As such, because these samples are coming from an individual, the samples of Schone read on an individual or subject having low or string DPB1 expression.
Dependent claims(s): 6-7, 9-10, and 14
Schone teaches HLA-DPB1 alleles with novel exon 2/exon 3 combinations and difference between expected and detected exon 3 SF [page 24 table 3]. Schone teaches comparing nucleotides positions of exon 3 [page 25 table 4 fig 5], as in instant claims 6-7.
Schone teaches 11 different nucleotide 11 differences between the rs9277534-A/G of exon 3 of DPB1 [page 25 fig 5], as instant claim 8.
Schone teaches standard DPB1 genotyping linkage analysis of over 32,000 samples [title]. Schone teaches using the genotyping software neXtype [page 21 section 2.3.3]. Schone teaches linkage verification [page 22 left col section 2.5]. Schone teaches a linkage between rs9277534 and HLA-DPB1 allele based on exons 2 and 3 and teaches low and high expression of DPB1gene [page 23 table 1]. Schone teach revealing motifs [page 24 right col section 3.6], as in instant claim 9.
Schone teaches using SMRT (i.e., long-read sequencing) analysis on the whole DPB1 gene [page 21 fig 1], as in instant claim 10.
Schone teaches the decreasing risk for GvHD after HSCT by selecting HLA12/12-mathed donors or restricting DPB1-mismatched donors. Schone teaches when patients with one or two low-expression HLA-DP allotypes lack fully-matched donors, selecting a DPB1-mismatched donor that generates a mismatch against one low-expression recipient DPB1 allele may lower GvHD risk compared to mismatching against a high-expression allotype [Page 25 section 4], as in instant claim 14. Here, Schone teaches selecting a DPB1-mismatched donor that generates a mismatch against one low-expression recipient DPB1 allele may lower GvHD risk compared to mismatching against a high-expression allotype which reads on a potential donor.
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify the DPB1 gene analysis of Schone with the single molecule real-time (SMRT) sequencing of Schone because Schone teaches targeting the whole DPB1 gene (i.e., ~11,500 bp) for detecting nucleotide positional changes (i.e., SNP rs9277534) within specific regions of the DPB1 gene/allele. Here, although Schone does not explicitly teach a long-read sequencer as claimed, Schone does recite the DPB1 region is sequenced, and the region is greater than 11k base pairs which qualifies as a long-read. Thus, it would be obvious to combine the sequences (i.e., 11k base pair DPB1 region) as taught by Schone with read-long sequencer as suggested by Schone’s application of full-length (SMRT) sequencing that covers the whole BPB1 gene [Schone page 21 left col]. Here, one of ordinary skill would be motivated to combine the SMRT sequencing method of Schone to analyze exon 3 of DPB1 gene of Schone because the SMRT sequencing method of Schone can sequence/analyze long sequence reads such as the ~11,500 bp of DPB1whole gene [page 21 fig 1]. One of ordinary skill in the art would have a reasonable expectation of success combining the methods of Schone because Schone teaches using SMRT sequencing and sequencing analysis (i.e., long -read sequencing) for evaluating exons and SNPs associated with DPB1 gene for predicting low and/or high DPB1 gene expression levels. Therefore, combining SMRT sequencing analysis of Schone to produce long-read sequence data for the DPB1 gene, exon, SNP analysis of Schone would yield a predictable method for analyzing long read sequence data from a subject to predict DPB I expression levels.
Claim(s) 11 is rejected under 35 U.S.C. 103 as being unpatentable over Schone, as applied to claims 1, 6-10, 14-15, and 18, and in further view of Nelson et al. (Human immunology, 2015-12, Vol.76 (12), p.928-938).
Schone teaches claims 1, 6-10, 14-15, and 18.
Schone teaches a method for predicting DPB1 gene expression levels based on long-read sequencing data.
Schone does not teach claim 11.
Nelson et al. (Nelson) teaches analyzing HLA class I and II genotypes derived from amplicon sequencing of HLA-A, -B, -C for exons 1–7 and HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4, -DRB5 for exons 1–4 [abstract], as in claim 11. Here, even though Nelson does not teach long-read sequencing, it would be obvious to utilize the SMRT sequencing of Schone to yield long-read sequencing data for -DQB1, -DRB1, and -DRB3 genes.
It would be obvious to one of ordinary skill in the art by the effective filing date of the claimed invention to modify the DPB1 gene analysis and SMRT sequencing of Schone in further view of Nelson because Nelson teaches approaches for evaluating nucleic acids of exon 3 of DPB1 DRB1, DRB3 and DQB1. One of ordinary skill in the art would recognize that Schone and Nelson are in similar fields of endeavor such as using nucleic acid sequence data for predicting gene expression of DBP1. Thus, one of ordinary skill in the art would be motivated to sequence the DRB1, DRB3 and DQB1 genes of Nelson using the SMRT sequencing of Schone in order to produce long-read sequences of DRB1, DRB3 and DQB1 for subsequent analysis. Therefore, combining the SMRT sequencing of Schone to sequence the DRB1, DRB3 and DQB1 genes of Nelson would yield predictable long-read sequence data for at least one of DRB1, DRB3 and DQB1.
Conclusion
Claims 1-20 are rejected.
No claims are allowed.
Finality
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/J.C.P./Examiner, Art Unit 1687
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights