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 .
Claims 1-14 are pending in this application.
Applicant’s election without traverse of Group I, claims 1-7 in the reply filed on 7/1/2026 is acknowledged.
Claims 8-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/1/2026.
Claims 1-7 are under examination.
This application claims priority to a series of US Patent Applications, and one US provisional application, filed 9/26/2013. The examiner has reviewed the prosecution history in each listed parent application. The elected group most closely relates to originally restricted Group IV, in 14/499023. US provisional application 61/883,153, filed 9/26/2013 does not clearly provide support for the elected claims. The ‘153 provisional provides some support for “a library of known viral genome sequences (most typically from known viral tumor associated viruses). Conversely… could then be subject to analysis for the presence of human genomic sequences” at [011] and [012] provides the use of BAMBAM “where the healthy or reference tissue sample also includes one or more viral genome sequences.” This is not clearly supportive of the particular claim limitations regarding merging sequences, in a particular structure, for all the specifically listed viruses. Therefore, the effective filing date for these claims is that of the ultimate parent, 14/499023, 9/26/2014.
This application has published as US PG-Pub 2022/0277809 A1.
The Drawings as filed are suitable for examination.
Two IDS filed 4/19/2023, two IDS filed 2/27/2025, and one IDS filed 3/12/2025 have each been entered and considered.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation (BRI) using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
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 1-7 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental steps, mathematic concepts, organizing human activity, or a natural law without significantly more.
Applicant is directed to MPEP 2106 for the most current and complete guidelines in the analysis of patent- eligible subject matter. The current MPEP is the primary source for the USPTO’s patent eligibility guidance.
With respect to step (1): YES, the claims are drawn to statutory categories: Processes.
With respect to step (2A) (1): YES, the claims recite an abstract idea, law of nature and/or natural phenomenon. The claims explicitly recite elements that, individually and in combination, constitute one or more judicial exceptions (JE).
Mathematic concepts, Mental Processes or Elements in Addition (EIA) in the claim(s) include:
1. (original) A method of generating a chimeric reference nucleic acid sequence for identification of co-amplification of an oncogene sequence of a mammalian tissue and at least some of the nucleic acid sequence of at least one pathogen, comprising:
(Preamble identifying a method, and the goal of the method. The “for identification” limitation represents an intended use of the chimeric reference nucleic acid sequence.)
receiving, from a sequence database, a nucleic acid sequence from a mammalian tissue and a plurality of nucleic acid sequences from a plurality of respective distinct pathogens;
(EIA- a step of data gathering, of polynucleotide sequence data, and a description of the data gathered. MPEP 2106.05(g).)
merging the nucleic acid sequence from the mammalian tissue with the plurality of nucleic acid sequences from the pathogens to generate a single chimeric reference nucleic acid sequence file;
(Mental process of appending data to a file/ data manipulation. MPEP 2106.04(a).)
wherein the nucleic acid sequence from the mammalian tissue is organized in the single chimeric nucleic acid sequence file following a chromosomal structure, and wherein each of the plurality of nucleic acid sequences from the pathogens is organized in the single chimeric nucleic acid sequence file as a single chromosome;
(Mental process of data organization, following a format MPEP 2106.04(a).)
wherein the pathogen is a virus selected from the group consisting of HTLV-1 (Human T-Cell Leukemia Virus), an HPV virus (Human Papillomavirus), HHV-8 (Human Herpes Virus 8), EBV (Epstein-Barr Virus), HBV (Hepatitis B Virus), HCV (Hepatitis C Virus), SV40 (Simian Vacuolating Virus 40), BKV (BK virus), JCV (JC virus), a HERV (human endogenous retrovirus), HMTV (human mammary tumor virus), KSHV (Kaposi's Sarcoma-Associated Herpesvirus), and TTV (Torque teno virus); and
(EIA- related to the first step of data gathering, further describing the data gathered. MPEP 2106.05(g).)
updating the sequence database with the single chimeric genomic file.
(EIA- routine data storage in a generically described database. MPEP 2106.05(b))
2. (original) The method of claim 1, wherein the nucleic acid sequence from the mammalian tissue comprises at least 50% of an exome of the mammalian tissue.
(EIA- data gathering: a description of the data gathered. MPEP 2106.05(g).)
3. (original) The method of claim 1, wherein the nucleic acid sequence from the mammalian tissue comprises at least 50% of an entire genome of the mammalian tissue.
(EIA- data gathering: a description of the data gathered. MPEP 2106.05(g).)
4. (original) The method of claim 1, wherein the distinct pathogens are distinct viruses.
(EIA- data gathering: a description of the data gathered. MPEP 2106.05(g).)
5. (original) The method of claim 11 wherein the step of merging comprises appending to the nucleic acid sequence from the mammalian tissue the plurality of nucleic acid sequences from the pathogens.
(Mental step of data manipulation, or combination. MPEP 2106.04(a).)
6. (original) The method of claim 1, wherein at least one of the nucleic acid sequence from the mammalian tissue, the plurality of nucleic acid sequences of the pathogens, and the single chimeric nucleic acid sequence file is in BAM, SAM, FASTA, or FASTA index format.
(EIA- data gathering, related to the sequences obtained in the first step, further describing aspects of the data gathered. MPEP 2106.05(g).)
7. (original) The method of claim 1, wherein the nucleic acid sequence from the mammalian tissue, the plurality of nucleic acid sequences from the pathogens, and the single chimeric nucleic acid sequence file are in BAM format.
(EIA- data gathering, related to the sequences obtained in the first step, further describing aspects of the data gathered. MPEP 2106.05(g).)
With respect to step 2A (2): NO, the claims do not integrate the JE into a practical application (MPEP 2106.04(d)):
“Examiners evaluate integration into a practical application by: (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception(s); and (2) evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application, using one or more of the considerations introduced in subsection I supra, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h).”
Claim(s) 1-4, 6, 7 recite the additional non-abstract element(s) of data gathering, or a description of the data gathered.
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data necessary to carry out the JE. MPEP 2106.05(g).
The data gathering does not impose any meaningful limitation on the JE, or how the JE is performed. MPEP 2106.05(g).
The data gathering steps constitute a general link to a technological environment: the analysis of polynucleotides. (MPEP 2106.05(h), citing Mayo, Bilski, electric Power Group, Genetic Techs Ltd v Merial LLC.)
The additional limitation (data gathering) must have more than a nominal or insignificant relationship to the identified judicial exception to provide integration into a practical application. (MPEP 2106.05(g) citing Mayo, PerkinElmer, Inc. v. Interna Ltd, Intellectual Ventures LLC v. Erie Indem. Co., Electric Power Group LLC v. Alstom S.A.).
Claim(s) 1, 6 and 7 imply the additional non-abstract element (EIA) of a general-purpose computer system or parts thereof.
While the claims are not specifically computer-implemented, the claims recite the use of sequence files, and sequence databases.
The claims do not provide any details of how specific structures of the computer elements are used to implement the JE. MPEP 2106.05(a), contrasting decisions identifying how the computer implements an abstract idea, such as in McRo to decisions which found no specific interaction with the computer, such as in Affinity Labs of Tex v. DirecTV, LLC.
The computer elements of the claims do not provide improvements to the functioning of the computer itself. MPEP 2106.05(a) I, contrasting decisions indicating an improvement to the computer, such as DDR Holdings, LLC v. Hotels.com LP, with decisions that did not identify an improvement to the computer, such as FairWarning IP, LLC v. Iatrix Sys.
The computer elements of the claims do not provide improvements to any other technology or technical field. MPEP 2106.05(a) II: contrasting decisions indicating an improvement to the technology, such as Diamond v. Diehr, Trading Techs. Int’l v. CQG Inc, or Intellectual Ventures I v. Symantec Corp, with decisions that did not identify an improvement to the technology, such as Alice Corp, Versata Dev. Group, Inc. v. SAP AM. Inc, or TLI Communications.
The computer elements of the claims do not utilize a particular machine. MPEP 2106.05(b): contrasting decisions wherein a particular machine was identified, such as MacKay Radio & Tel. Co. v. Radio Corp. of America, Eibel Process Co. v. Minn. & Ont. Paper Co., with decisions where a general-purpose computer does not qualify as a particular machine, such as Ultramercial, Inc. v. Hulu, LLC, TLI communications, or Eon Corp. IP holdings LLC v. AT&T Mobility LLC.
Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not recite integrate that JE into a practical application.
Dependent claim(s) 5 recite(s) an abstract limitation to the JE reciting additional mathematic concepts, or mental processes. Additional abstract limitations cannot provide a practical application of the JE as they are a part of that JE.
In combination, the limitations of data gathering, for the purpose of carrying out the JE, using a general-purpose computer merely provide extra-solution activity, and fail to integrate the JE into a practical application.
With respect to step 2B: NO, the claims do not recite a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05).
“… an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim, as a whole, amounts to significantly more than the judicial exception itself. Alice Corp…”
With respect to claim(s) 1-4, 6 and 7: The limitation(s) identified above as non-abstract elements (EIA) related to data gathering do not rise to the level of significantly more than the judicial exception.
Xu (A) (Xu, G. Computational Pipeline for Human Transcriptome Quantification Using RNA-seq Data (2011). University of New Orleans Theses and Dissertations. 343, 75 pages.) discloses databases and receiving mammalian tissue sequences and pathogen sequences, including viral genome sequences.
Xu (B) et al. (2013: pto-1449) discloses databases and receiving mammalian tissue sequences and pathogen sequences, including viral genome sequences.
Watson (Watson et al. 2013 Viral population analysis and minority-variant detection using short read next-generation sequencing. Philosophical transactions of the royal society B, vol 368, 8 pages) receives viral genome sequences in a chromosomal format.
Koboldt (Koboldt et al. (June 2010; PTO-1449) Challenges of sequencing human genomes. Briefings in Bioinformatics, vol 11, no 5, p484-498.) receives both human and viral sequences in a chromosomal formal.
Strong (Strong et al. (2013) Epstein-Barr Virus and Human Herpesvirus 6 Detection in a Non-Hodgkin’s Diffuse Large B-Cell Lymphoma Cohort by Using RNA Sequencing. Journal of Virology, vol 87, no 23 p13059-13062.) receives human and viral sequences in a chromosomal format.
Wang (Wang et al. (Jan 2014) Genome sequencing accuracy by RCA-seq versus long PCR template cloning and sequencing in identification of human papillomavirus type 58. Cell & Bioscience vol 4, article 5, 9 pages) receives human and viral sequences in a chromosomal format.
These elements meet the BRI of the identified data gathering limitations. As such, the prior art recognizes that this data gathering element is routine, well understood and conventional in the art. MPEP 2106.05(d): “If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility.”
In the specification at [0060] it is disclosed that the steps of retrieving the sequences from patient samples are routinely performed using commercially available services such as the Illumina Clinical Services at [0060]. These commercial services may also provide the databases of nucleic acid sequences. It is further noted that retrieval of the needed sequences from publicly available databases, such as the known reference sequence HG19 and all known viral sequences, was possible from the NCBI databases at least as early as 3/5/2013. (previously provided).
Data gathering steps are not an abstract idea, they are extra-solution activity, as they collect the data necessary to carry out the JE. MPEP 2106.05(g).
The data gathering does not impose any meaningful limitation on the JE, or how the JE is performed. MPEP 2106.05(g).
The additional limitation (data gathering) must have more than a nominal or insignificant relationship to the identified judicial exception to provide an inventive concept. (MPEP 2106.05(g) citing Mayo, PerkinElmer, Inc. v. Interna Ltd, Intellectual Ventures LLC v. Erie Indem. Co., Electric Power Group LLC v. Alstom S.A.)
The data gathering steps constitute a general link to a technological environment: analysis of polynucleotide data. (MPEP 2106.05(h), citing Mayo, Bilski, electric Power Group, Genetic Techs Ltd v Merial LLC.)
Therefore, simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp.,).
With respect to claim(s) 1, 6 and 7: the limitations identified above as implying non-abstract elements (EIA) related to general-purpose computer systems do not rise to the level of significantly more than the judicial exception.
Each of Xu A and Xu B, Watson, Koboldt, Strong and Wang disclose computer systems or computing elements which meet the BRI of the claimed computer system or computer system elements, comprising input, output/ display, a processor, and memory.
As such, the prior art recognizes that these computing elements are routine, well understood and conventional in the art.
The claims do not provide any details of how specific structures of the computer elements are used to implement the JE. MPEP 2106.05(a), contrasting decisions identifying how the computer implements an abstract idea, such as in McRo to decisions which found no specific interaction with the computer, such as in Affinity Labs of Tex v. DirecTV, LLC.
The computer elements of the claims do not provide improvements to the functioning of the computer itself. MPEP 2106.05(a) I, contrasting decisions indicating an improvement to the computer, such as DDR Holdings, LLC v. Hotels.com LP, with decisions that did not identify an improvement to the computer, such as FairWarning IP, LLC v. Iatrix Sys.
The computer elements of the claims do not provide improvements to any other technology or technical field. MPEP 2106.05(a) II: contrasting decisions indicating an improvement to the technology, such as Diamond v. Diehr, Trading Techs. Int’l v. CQG Inc, or Intellectual Ventures I v. Symantec Corp, with decisions that did not identify an improvement to the technology, such as Alice Corp, Versata Dev. Group, Inc. v. SAP AM. Inc, or TLI Communications.
The computer elements of the claims do not utilize a particular machine. MPEP 2106.05(b): contrasting decisions wherein a particular machine was identified, such as MacKay Radio & Tel. Co. v. Radio Corp. of America, Eibel Process Co. v. Minn. & Ont. Paper Co., with decisions where a general-purpose computer does not qualify as a particular machine, such as Ultramercial, Inc. v. Hulu, LLC, TLI communications, or Eon Corp. IP holdings LLC v. AT&T Mobility LLC.
Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not provide significantly more.
Dependent claim(s) 5 recites a limitation requiring additional mathematic concepts or mental processes. Additional abstract limitations cannot provide significantly more than the JE as they are a part of that JE (MPEP 2106.05).
In combination, the data gathering steps providing the information required to be acted upon by the JE, performed in a generic computer or generic computing environment fail to rise to the level of significantly more than that JE. The data gathering steps provide the data for the JE, which is carried out by the general-purpose computers. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Concha (2012).
Concha et al. (2012) Identification of New Viral Genes and Transcript Isoforms during
Epstein-Barr Virus Reactivation using RNA-Seq. Journal of Virology vol 86, no 3 p 1458-1467.
Claim 1 is directed to a method of creating a chimeric reference sequence, wherein reference mammalian sequence data and viral pathogen sequence data are received, and merged into a chimeric genomic file, having a chromosomal structure.
Concha created a chimeric reference sequence, between human genomic reference sequences and EBV genomic sequences.
“RNA-Seq reads were aligned to a human (hg19 assembly) plus EBV genome [B95-8-Raji (National Center for Biotechnology Information [NCBI] accession number NC_007605) index using Novoalign). Splice junctions were identified using TopHat (17) run on a human plus EBV genome Bowtie index.” P1459.
The human hg19 assembly and EBV reference were obtained from sequence databases. The chimeric reference sequence was uploaded to a sequence database to be accessed by Novoalign. Novoalign works on refence files in a chromosomal format.
The chimeric reference sequence has use in the identification at least some viral sequences, as well as oncogene information.
“For the analysis performed here, we have generated the necessary tools to perform alignments and to visualize the data against the more common strain of EBV, type I. Accessory files required forthe analysis of both type I and type II virus sequence data are available at www.flemingtonlab.com (files include fasta files, Bowtie index files, genome viewer annotation files, and annotation files for EBV RPKM analysis [for the analysis of either EBV alone or the analysis of EBV in the context of the human genome]). The development of these tools for the analysis of the type I EBV strain is important since it is a more common strain observed in tissue culture models and in vivo. For most of the EBV genome, reasonable alignment data can be obtained even when using sequencing data from a type I strain and aligning to a type II strain genome (11). Nevertheless, the capture of sequences from less well-conserved regions, such as the EBNA2 locus, requires the use of the appropriate genome strain during the alignment process (11; data not shown).” P1464-1465.
With respect to claims 2 and 3, the RNA-seq and NGS provide exome or whole genome data as required. P1458-1459.
With respect to claim 4, distinct types of EBV are provided. P1459, 1464-1465.
With respect to claim 5, the pathogen sequences appear to be appended to the human sequences. 1459, 1464-1465.
With respect to claim 6-7, Concha provides SAM/BAM, FASTA files. Novoalign accepts SAM, BAM, FASTA files: p1459, 1464-1465.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Sanborn (2012).
Sanborn (US 2012/00596701 A1; PTO-1449)
SANBORN (SANBORN et al. US 2012 0059670 Al: PTO-1449) discloses a method of
deriving a differential genetic sequence object, the method comprising: (a') providing access to a genetic database storing a first genetic sequence string representing a first tissue and a second genetic sequence string representing a second tissue, wherein the first and second sequence strings have a plurality of corresponding sub-strings, and wherein the second tissue is a tumor tissue and the sub-strings comprise homozygous alleles; (a") providing access to a sequence analysis engine coupled with the genetic database; (b') producing, using the sequence analysis engine, a local alignment by incrementally synchronizing the first and second sequence strings using a known position of at least one of plurality of corresponding sub-strings; using, by the sequence analysis engine, the local alignment to generate a local differential string between the first and second sequence strings within the local alignment; (d') using, by the sequence analysis engine, the local differential string to update a differential genetic sequence object in a differential sequence database; and (d") producing, by the analysis engine, a patient-specific instruction based on the patient-specific data set (see claims 1, 6-9 and 28). Moreover, SANBORN discloses that the differential genetic sequence object (eg. cervix cancer 1} comprises insertion of viral genes (see claims 1, 17-22, 48-50).
With respect to claim 2-3, the nucleic acid sequence from the virus associated tumor comprises at least a part of one chromosome of the tumor, as shown in at least FIG 3, 4, 5 and their descriptions in the specification. SANBORN discloses that the first and second genetic sequence strings represent at least 10%, 50%, and substantially entire of a genome, transcriptome, or proteome of the first and second tissues, respectively (see claims 1-4).
With respect to claim 5, the two reference genomes can be appended.
With regard to the sequence formats of claim 6-7, SANBORN discloses the BAM format
and the derivative BAMBAM format, throughout.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Strong (2013).
Strong et al. (May 2013) Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLOS Pathogens, vol 9 issue 5, e1003341, 18 pages.
Strong creates a chimeric reference file comprising human genome sequences, and pathogen sequences, including EBV, HCMV and HCV.
“we have included features that allow the user to simultaneously analyze the human cellular genes in addition to pathogen discovery (recently coined as 'dual RNA-seq' by Westermann and colleagues [10]). Here we utilized this pipeline, RNA CoMPASS (RNA comprehensive multi-processor analysis system for sequencing, Xu et al., unpublished), for the detection of viral pathogens in clinical tumor samples by analyzing a cohort of gastric carcinomas generated by the Cancer Genome Atlas
initiative (SRA0354 l 0). EBV was detected in 12 out of 71 gastric carcinoma samples and the depth of coverage was sufficient to assess overall transcriptome structure in four cases.” P2
“Twelve samples showed evidence of human cytomegalovirus (HCMV) with read numbers ranging from 5 to 132.” P2
“To further analyze the EBV associated gastric carcinoma (EBVaGC) samples, the two lanes of
sequence per sample were combined to attain greater sequencing depth. These sequence files were aligned against a modified EBV B95-8 genome that contains Raji genome sequences inserted into
a deleted region of the B95-8 genome (Genbank accession number AJ507799) plus the hg 19 assembly of the human genome. Alignments were carried out using Novoalign V2.07.18 [-o SAM, paired-end, default options].” P2
“RNA CoMPASS (Xu et al. unpublished) a graphical user interface (GUI) based parallel computation pipeline, RNA comprehensive multi-processor analysis system for sequencing (RNA CoMPASS) for the analysis of both exogenous and human sequences from RNA-seq data (Figure S l ). Briefly, for the analysis of both exogenous and human sequences, raw sequence data is first processed through an in-house de-duplication algorithm. Following de-duplication, reads are aligned to a reference genome containing human (hg 19; UCSC) and abundant sequences (which include sequence adapters, mitochondrial, ribosomal, enterobacteria phage phiX174, poly-A, and poly-C sequences). Novoalign V2.07.18 (www.novocraft.com) [-o SAM, default options] is used to map reads to the reference genome and to eliminate low-quality reads (QC<20). TopHat V l .4.0 [default options] [21] is used to identify and isolate all sequences that map to human splice junctions. The results from these programs are compiled and separated into mapped reads (used for human transcriptome analysis) and unmapped reads (used for exogenous sequence analysis). Human mapped reads are analyzed using SAMMate [13] to quantify gene expression and to generate genome coverage information. Unmapped reads are subjected to consecutive BLAST V2.2.24 searches against the Human RefSeq RNA database (an additional "pre-clearing" step) and then to the NCBI NT database to identify reads corresponding to known exogenous organisms [86]. Results from the NT BLAST searches are filtered to eliminate matches with an E-value of less than 10e -6. The results are fed into MEGAN 4 [87] for convenient visualization and taxonomic classification of BLAST search results. RNA CoMPASS is designed to take advantage of parallel processing at several key steps to speed processing times. In our case, we used a four node, 12 core, Intel Xeon Mac Pro (64GB of memory per node) cluster.” P14.
“Samples containing evidence of EBV were identified using RNA CoMPASS. Since each sample contained sequence data from two runs, data from both runs were combined in order to generate a greater sequencing depth for transcript quantification. In addition, 20 EBV negative samples were randomly chosen for analysis. Samples were aligned to a reference genome containing human (hg 19) and a modified EBV B95-8 genome that contains Raji genome sequences inserted into a deleted region of the B95-8 genome (Genbank accession number AJ507799) using Novoalign V2.07.18 (www.novocraft.com) [-o SAM, default options]. Transcript data from Novoalign was analyzed using SAMMate for transcript quantification of human and EBV genes and to generate coverage (wiggle) files for visualization of read distributions. Splice junction data was generated using the junction aligner, TopHat V l .4.0 [default options]. Coverage data was visualized using the Integrative Genomics Viewer (IGV) [88].” P14
As such claims 1 and 5 are anticipated.
With respect to claims 2-3, the exome sequencing of Strong represents at least the appropriate amount of sequence information. P14.
With respect to claim 4, a plurality of distinct virus information can be included. (EBV I, EBVII, HCMV, HCV, HHV-4, HHV-5 et al. Fig 1).
With respect to claims 6-7, SAM, BAM, Fasta files are discussed throughout.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Akagi (2013).
Akagi, K. et al. (November, 2013) Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Research, vol 24, issue 2, p185-199.
Akagi takes human genome reference sequences, and HPV genome sequences and merges the two files. (Material and Methods, p196).
“To detect variants in both human and HPV genomes, we created a proxy reference assembly combining the human (hg19) and HPV genomes (called hg19+HPV; GenBank accession numbers: HPV16 [NC_001526.2]; HPV18 [NC_001357.1]; HPV31 [HQ537687.1]; HPV33 [HQ537707.1]; and HPV35 [M74117.1]). We used BWA (Li and Durbin 2010) to align WGS sequence reads against hg19+HPV. Mpileup function from SAMtools (Li et al. 2009) was used to detect SNPs and small INDELs in HPV genomes. HPV variants were classified by comparison of sequences to HPV16 lineage-specific SNPs as reported by the IARC HPV Variant Study Group (Cornet et al. 2012).” P196
As such, claims 1 and 5 are anticipated.
With respect to claims 2-3 Akagi provides whole genome sequencing as set forth at p196, meeting the at least 50% requirement. Whole Exome sequencing is provided at p197, RNA-seq.
With respect to claim 4, Multiple distinct HPV genomes were provided.
With respect to claims 6-7, Akagi uses file formats compatible with ELAND, CASAVA, SAMTOOLS, and BWA. These include SAM, BAM, FASTA etc.
Claim(s) 1-3, 5-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Xu (2013; PTO-1449)
Xu, B. et al. (June 2013) Multiplex Identification of Human Papillomavirus 16 DNA Integration Sites in Cervical Carcinomas. PLOs One, v 8 issue 6, e66693, 18 pages. PTO-1449.
Xu creates a chimeric reference sequence between human genome sequences (GRCh37) and HPV16 sequences as set forth at page 16.
“To identify potential HPV16-cellular junctions, the TEN16 read pairs were aligned to the combined ‘‘HPV16REF’’ and ‘‘GRCh37’’ human reference sequence first using BWA version 0.5.9-r16 [73] with default parameters. Mapped pairs with at least one read mapped to HPV16REF were extracted. Since BWA is unable to efficiently identify HPV16-cellular chimeric reads (see http://bio-bwa.sourceforge.net), many of them were reported as unmapped. Therefore, reads were re-mapped using BWA-SW version 0.5.9-r16 [74] with default parameters to identify chimeric reads containing both HPV16 and human sequences. Using custom scripts, four categories of mapped read pairs were identified from BWA and BWA-SW outputs: (1) pure HPV16 pairs, (2) pure cellular pairs, (3) pairs flanking HPV16-cellular junctions, and (4) pairs with at least one read containing the HPV16-cellular junction sequence (see Figure 2D). From categories 3 and 4, potential HPV16-cellular junctions were identified by visual inspection using a cutoff value of 15 read pairs.”
As such, claims 1 and 5 are anticipated.
With respect to claims 2-3, HPV genome was 100% amplified as set forth at p15, next generation sequencing is set forth at p16.
With respect to claims 6-7, Xu utilizes BWA, BWA-SW, SAMtools and IGV which work on SAM, BAM, FASTA files.
Claim(s) 1-7 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Wang (2013).
Wang, Q. et al. (May, 2013) VirusFinder: Software for Efficient and Accurate Detection of Viruses and Their Integration Sites in Host Genomes through Next Generation Sequencing Data. PLOS One, vol 8 issue 5, e64465, 5 pages.
Wang creates a chimeric reference sequence of human genome sequences and Virus genome sequences, in a chromosomal format.
“VirusFinder combines the human reference genome with the virus sequence (designated as a separate pseudo-chromosome, chrVirus) identified in previous step (2) or provided by the user. It then uses the mapping tool BWA [14] to align the reads recruited in step (1) to this new reference. Another tool VirusSeq [10] also concatenates the human genome with virus sequences. But VirusSeq includes a fixed set of, i.e. 18, virus sequences in its reference genome and hence cannot be applied directly to detect virus insertion sites in samples infected with viruses other than the18 predefined ones. By concatenating the viruses detected in step (2) on the fly, VirusFinder is readily applicable to samples harboring viruses of arbitrary types (as long as they are represented in the virus DB).” P2
As such, claims 1 and 5 are anticipated.
With respect to claims 2-3, whole genome/ exome sequencing are both provided. (Table 1)
With respect to claim 4, distinct viruses are provided. (Table 1) This includes HBV, HPV-18, MCV and JEV.
With respect to claims 6-7, Wang uses BLAST, BLAT, SAMTools, Bowtie2, BWA, SVDetect and Crest all of which use SAM, BAM, and FASTA formats.
Conclusion
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/MARY K ZEMAN/ Primary Examiner, Art Unit 1686
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