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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/08/2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 08/08/2025. Claims 9, 16-24, 33-35, and 37-53 are currently pending. Claims 16-24 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 9, 33-35 and 37-53 are examined herein. The restriction requirement mailed 03/22/2021 is still deemed proper.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9, 33-35, 37, 40-41, 44-51 and 53 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO publication WO 2015/164432 A1 to Natera Inc. (hereinafter ‘Natera’) in view of WIPO Publication 2014/071361 A1 to Rubicon Genomics (hereinafter ‘Rubicon’).
Natera teaches a method for detecting both genetic (e.g., SNVs, splice variants, insertions, deletions, copy number variations or a combination thereof) and epigenetic (methylation) alterations in cell-free nucleic acids in biofluid samples from a human subject having cancer (underlines added for emphasis):
The invention provides methods, systems, and computer readable medium for detecting ploidy of chromosome segments or entire chromosomes, for detecting single nucleotide variants and for detecting both ploidy of chromosome segments and single nucleotide variants. (Abstract)
[00238] In addition to determining the presence or absence of copy number variation, one or more other factors can be analyzed if desired. These factors can be used to increase the accuracy of the diagnosis (such as determining the presence or absence of cancer or an increased risk for cancer, classifying the cancer, or staging the cancer) or prognosis. These factors can also be used to select a particular therapy or treatment regimen that is likely to be effective in the subject. Exemplary factors include the presence or absence of polymorphisms or mutation; altered (increased or decreased) levels of total or particular cfDNA, cfRNA, microRNA (miRNA); altered (increased or decreased) tumor fraction; altered (increased or decreased) methylation levels, altered (increased or decreased) DNA integrity, altered (increased or decreased) or alternative mRNA splicing.
[00241] In some embodiments, the methods are used to detect a deletion, duplication, or single nucleotide variant in an individual. A sample from the individual that contains cells or nucleic acids suspected of having a deletion, duplication, or single nucleotide variant may be analyzed. In some embodiments, the sample is from a tissue or organ suspected of having a deletion, duplication, or single nucleotide variant, such as cells or a mass suspected of being cancerous. The methods of the invention can be used to detect deletion, duplication, or single nucleotide variant that are only present in one cell or a small number of cells in a mixture containing cells with the deletion, duplication, or single nucleotide variant and cells without the deletion, duplication, or single nucleotide variant. In some embodiments, cfDNA or cfRNA from a blood sample from the individual is analyzed. In some embodiments, cfDNA or cfRNA is secreted by cells, such as cancer cells. In some embodiments, cfDNA or cfRNA is released by cells undergoing necrosis or apoptosis, such as cancer cells. The methods of the invention can be used to detect deletion, duplication, or single nucleotide variant that are only present in a small percentage of the cfDNA or cfRNA.
Natera further teaches separating the biofluid sample into ssRNA and dsDNA portions and barcoding both:
[0056] …measured genetic allelic data is obtained by dividing the DNA or RNA from the sample into a plurality of fractions, adding a different barcode to the DNA or RNA in each fraction (e.g., such that all the DNA or RNA in a particular fraction has the same barcode), optionally amplifying the barcoded DNA or RNA, combining the fractions, and then sequencing the barcoded DNA or RNA in the combined fractions.
Natera teaches reverse transcribing the ssRNA and barcoding the ssRNA:
[00572] …any of the methods disclosed herein for DNA can be readily adapted for RNA, for example, by including a reverse transcription step to convert the RNA into DNA.
[00367] …a reverse transcriptase is used produce cDNA amplicons using RNA as a template.
Natera further teaches performing bisulfite conversion on the dsDNA to produce ssDNA, wherein cytosine mutations are converted to uracil:
[00481] …there is a change in the methylation pattern RNA or DNA that is associated with a disease or disorder such as cancer, or an increased risk for with a disease or disorder such as cancer (e.g., hypermethylation of tumor suppressor genes)…methylation of the CpG islands in the promoter region of tumor-suppressor genes has been suggested to trigger local gene silencing.
[0057] ...the method includes determining the methylation level of one or more DNA or RNA molecules of interest…
[00482] bisulphite conversion or a non-bisulphite based strategy using methylation sensitive restriction enzyme digestion is used to determine the methylation pattern (Hung et al., J Clin Pathol 62:308-313, 2009, which is hereby incorporated by reference in its entirety). On bisulphite conversion, methylated cytosines remain as cytosines while unmethylated cytosines are converted to uracils…In some embodiments, the intact methylated sequences are detected. In some embodiments, stem-loop primers are used to selectively amplify restriction enzyme-digested unmethylated fragments without co-amplifying the nonenzyme-digested methylated DNA.
Natera further teaches assaying the barcoded DNA/RNA molecules/detecting the presence or absence of genetic/epigenetic alterations based at least in part on the sequence and methylation information obtained (see above, and below):
[00345] The selective enrichment and/or amplification may involve tagging each individual molecule with different tags, molecular barcodes, tags for amplification, and/or tags for sequencing. In some embodiments, the amplified products are analyzed by sequencing (such as by high throughput sequencing) or by hybridization to an array, such as a SNP array, the ILLUMINA INFINIUM array, or the AFFYMETRIX gene chip.
Natera does not teach converting the barcoded ssRNA or ssDNA molecules to dsDNA, or using a primer annealed to an oligonucleotide comprising an RNA-specific barcode and converting the barcoded ssRNA to ds-cDNA.
The broadest reasonable interpretation of an oligonucleotide is a short polynucleotide which exists either as an isolated molecule or complexed with, annealed with, or ligated to another polynucleotide, such as in a chimeric structure.
Rubicon teaches methods of barcoding nucleic acids, including cDNA/genomic DNA/amplified DNA/RNA, using a primer annealed to an oligonucleotide, wherein the primer or oligonucleotide comprise barcodes:
A. Preparation of Nucleic Acid Molecules of Interest
[0050] A nucleic acid molecule of interest can be a single nucleic acid molecule or a plurality of nucleic acid molecules. Also, a nucleic acid molecule of interest can be of biological or synthetic origin. Examples of nucleic acid molecules include genomic DNA, cDNA, RNA, amplified DNA, a pre-existing nucleic acid library, etc
[0053] …a stem-loop adaptor including the barcode may be coupled to one end of a target nucleic acid molecule or to both ends of a target nucleic acid molecule.
[0056] A second barcode or a second set of barcodes may be coupled to the first barcode or the first set of barcodes that is/are coupled to the nucleic acid molecule(s). In this manner, the first barcode may be an intermediate of the nucleic acid molecule and the second barcode. In some aspects, the second barcode may be provided within a primer, or a second set of barcodes may be provided as a population of primers. In some aspects, primer extension or PCR may be used to incorporate the second barcode. In some aspects, the primer may include a 3′ portion and a 5′ portion, where the 3′ portion may anneal to a portion of the first barcode and the 5′ portion comprises the second barcode.
Rubicon further teaches converting the ssRNA/ssDNA to dsDNA via amplification, i.e., generating successive copies using forward and reverse primers so as to generate a population of the target nucleic acid and complementary strands thereof (claim 16: The method of claim 1, further comprising amplification of at least part of the dual barcoded nucleic acid molecule).
Rubicon provides a motivation to adopt their method by disclosing that it would allow the ordinary artisan to identify the first barcode, second barcode and sequence from a single read instead of paired-end :
[0006] Embodiments of the present invention provide methods of making dual barcoded nucleic acid molecule for sequencing. Having a first and a second barcode on the same end of a nucleic acid molecule may permit a sequencing read to begin with the second barcode, continue through the first barcode and then into the nucleic acid molecule. Identification of the second barcode, first barcode, and sequence of the nucleic acid molecule may therefore be obtained in a single read as opposed to having to provide a sequencing read from each end of the nucleic acid molecule in order to read the sequence of a single barcode back from a distal end of the nucleic acid molecule, as is the case in traditional methods of using dual sequencing barcodes.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting both genetic and epigenetic mutations in cell-free biofluids to diagnose, classify or stage cancer in a subject, as taught by Dana Farber, by barcoding the populations of ssRNA and DNA using the specific dual barcoding method as taught by Rubicon. Dana Farber teaches adding different identifying tags, or barcodes, to samples, fractions and/or molecules. Rubicon provides a specific method of adding said tags which permits identification of two barcodes in a single read. Both teach methods which permit highly multiplexed library preparation and sequencing of both RNA and DNA, combining transcriptomic, genomic, and epigenetic analyses to identify cancer-associated mutations in cell-free samples.
Regarding claims 33-35 and 45, Natera teaches wherein the sample is a biofluid, including plasma, urine or saliva:
the sample comprises any tissue or bodily fluid suspected of containing cells, DNA, or RNA having a deletion or duplication, such as cancer cells, DNA, or RNA. The genetic measurements used as part of these methods can be made on any sample comprising DNA or RNA, for example but not limited to, tissue, blood, serum, plasma, urine, hair, tears, saliva, skin, fingernails, feces, bile, lymph, cervical mucus, semen, or other cells or materials comprising nucleic acids.
Regarding claim 37, Natera teaches wherein assaying the barcoded molecules comprises NGS, as described above.
Regarding claim 40, Natera teaches wherein the NGS comprises a methylation NGS assay, as described above.
Regarding claim 41, Natera teaches wherein assaying barcoded dsDNA molecules comprises PCR:
[00524] In certain embodiments, the present invention provides reagents, kits, and methods, and computer systems and computer media with encoded instructions for performing such methods, for detecting both CNV s and SNV s from the same sample using the multiplex PCR methods disclosed herein
Regarding claim 44, Natera teaches wherein assaying barcoded molecules comprises array-based technology:
[00345] the amplified products are analyzed by sequencing (such as by high throughput sequencing) or by hybridization to an array, such as a SNP array, the ILLUMINA INFINIUM array, or the AFFYMETRIX gene chip.
Regarding claims 46 and 47, Natera teaches wherein the alteration is the genetic mutation, SNV or splice variant, as described above.
Regarding claims 48 and 50-51, Natera teaches wherein the genetic alteration comprises a genetic mutation, long deletion or copy number variation:
[003] Copy number variation (CNV) has been identified as a major cause of structural variation in the genome, involving both duplications and deletions of sequences that typically range in length from 1,000 base pairs (1 kb) to 20 megabases (mb). Deletions and duplications of chromosome segments or entire chromosomes are associated with a variety of conditions, such as susceptibility or resistance to disease.
Regarding claim 49, Natera teaches wherein the alteration is an indel:
[00388] the method includes ranking (such as ranking from highest to lowest) loci by frequency or reoccurrence of a polymorphism or mutation (such as a single nucleotide variation, insertion, or deletion, or any of the other variations described herein) in each locus among subjects with the disease or disorder such as cancer.
Regarding claim 53, Natera teaches wherein the alteration comprises a DNA and RNA alteration, as described above.
Claims 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Natera in view of Rubicon, as applied to claims 9, 33-35, 37, 40-41, 44-51 and 53, further in view of Peng (Reducing amplification artifacts in high multiplex amplicon sequencing by using molecular barcodes. BMC Genomic 16, 589 (2015).; of record), Langmead (Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10, R25 (2009).; of record), and Kim (TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14, R36 (2013).; of record).
Natera and Rubicon render obvious the method of detecting a genetic and epigenetic alteration comprising assaying a mixture of barcoded dsDNA and ssRNA-derived molecules via NGS as recited in claims 9 and 37, from which instantly rejected claims 38 and 39 depend, as described above.
Natera and Rubicon do not teach mapping the dsDNA reads to a reference genome or the ssRNA reads to a reference transcriptome (relevant to claim 38).
Peng teaches that the molecular barcodes can be merged to build consensus reads (the two barcodes can be merged into a single barcode cluster. Then the barcode cluster is used for building consensus reads and counting molecules; pg 9; relevant to claim 39).
Langmead teaches the use of the tool Bowtie to align dsDNA reads against a reference genome (Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes.; abstract; relevant to claim 38).
Kim teaches the use of the tool TopHat2 to align ssRNA (transcript) reads against a reference transcriptome (Given RNA-seq reads as input, TopHat2 begins by mapping reads against the known transcriptome, if an annotation file is provided. This transcriptome mapping improves the overall sensitivity and accuracy of the mapping. It also gives the whole pipeline a significant speed increase, owing to the much smaller size of the transcriptome compared with that of the genome.; pg 9; relevant to claim 38).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the NGS assay taught by Natara and Rubicon to comprise mapping the obtained sequence reads to appropriate reference genomes/transcriptomes using the widely known bioinformatics tools taught by Peng, Kim and Langmead. Natera and Rubicon teach the upstream steps required to prepare the sequencing libraries and sequence the amplicons derived from the RNA and DNA. They do not teach the bioinformatics steps required to analyze the data. Peng, Kim and Langmead, in combination, provide publicly available tools and approaches to perform the sequence analysis with a reasonable expectation of success.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Natera in view of Rubicon, as applied to claims 9, 33-35, 37, 40-41, 44-51 and 53, further in view of Whale (Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation. Nucleic Acids Res. 2012 Jun:40(11):e82.; of record).
Natera and Rubicon render obvious the method of detecting a genetic or epigenetic alteration wherein assaying the mixture comprises PCR, from which instantly rejected claim 42 depends, as described above.
Natera and Rubicon do not teach wherein the PCR comprises digital droplet PCR (ddPCR).
Whale teaches that ddPCR is more sensitive and reliable than quantitative PCR (qPCR) for detecting genetic alterations such as copy number variations in cell free DNA (One of the benefits of Digital PCR (dPCR) is the potential for unparalleled precision enabling smaller fold change measurements. An example of an assessment that could benefit from such improved precision is the measurement of tumour associated copy number variation (CNV) in the cell free DNA (cfDNA) fraction of patient blood plasma…We showed that, with equal experimental replication, dPCR could measure a smaller CNV than qPCR; abstract; Furthermore, one of the major differences between qPCR and dPCR is that technical variability of qPCR can be high between and within laboratories (27). dPCR is notably less variable between experiments (28,29), which offers the possibility of reproducibly more accurate results.; pg 6).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting genetic alterations taught by Natera and Rubicon, whether array- or NGS-based, by utilizing ddPCR to achieve the predictable outcome of accurate quantification of rare tumor-associated mutations such as copy number variations.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Natera in view of Rubicon, as applied to claims 9, 33-35, 37, 40-41, 44-51 and 53, further in view of Hernández (Optimizing methodologies for PCR-based DNA methylation analysis. Forero Bio Techniques 2013.; of record).
Natera and Rubicon render obvious the method of detecting a genetic or epigenetic alteration wherein assaying the mixture comprises PCR, as recited in claim 41, from which instantly rejected claim 43 depends, as described above.
Natera and Rubicon do not teach wherein the PCR comprises methylation-specific PCR (MSP).
Hernández teaches the use of MSP to detect epigenetic modifications (Methylation specific PCR (MSP), first described by Herman et al. in 1996, determines the methylation status of an ROI [examiner’s note: region of interest] through selective amplification of methylated and unmethylated alleles…MSP is a simple method that requires resources commonly available in a molecular genetics laboratory and, once standardized, is effective for detecting methylated or unmethylated alleles; pg 188).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting genetic alterations taught by Natera and Rubicon by incorporating the step of using MSP as taught by Hernández to accurately, simply and cheaply detect epigenetic modifications.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Natera in view of Rubicon, as applied to claims 9, 33-35, 37, 40-41, 44-51 and 53, further in view of Zheng and Verhaak (Intragenic breakpoint: a marker of genome instability in glioblastoma. Cell Cycle. 2013 Dec 15;12(24):3705-6; of record).
Natera and Rubicon render obvious the method of detecting a genetic or epigenetic alteration as recited in claim 9, from which instantly rejected claim 52 depends, as described above.
Natera and Rubicon do not teach wherein the genetic alteration comprises a fusion.
Zheng and Verhaak teach that NGS can be used to detect fusions (Using matched RNA sequencing (RNAseq) data we observed direct gene fusions among the BER-related amplicons in 7 of 9 RNAseq available BER cases; pg 3705).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modify the method of detecting genetic alterations taught by Natera and Rubicon to detect gene fusions in the resulting sequence data, because Zheng and Verhaak teach that such methods can provide that information.
Response to Arguments
Applicant’s arguments with respect to claim(s) 9, 37, 40, 41, 44, 46, 48, 49, 50, 51 and 53 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 9, 33-35, 37-39, and 45-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 6, 16 and 17 of U.S. Patent No. 11174503 in view of Natera and Rubicon. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are obvious for the reasons discussed in the rejection of the claims under 35 U.S.C. 103 above.
Patented claim 5 teaches the limitations of instant claims 47-52. Patented claim 6 teaches the limitations of instant claims 33, 34, 35 and 45. Patented claim 4 teaches the limitations of instant claim 37. Patented claim 16 teaches the limitations of instant claim 38. Patented claim 17 teaches the limitations of instant claim 39. Patented claims 1 and 5 teach the limitations of instant claim 9 in regards to method for detecting genetic alterations.
Patented claims 1 and 5 do not teach the limitations of instant claim 9 in regards to the method for detecting epigenetic alterations, do not recite obtaining a biofluid sample from a human subject having cancer, wherein said biofluid sample comprises cell-free nucleic acids, and wherein said cell-free nucleic acids comprises single-stranded ribonucleic acid (ssRNA) molecules and double-stranded deoxyribonucleic acid (dsDNA) molecules; separating the sample into at least a first portion and a second portion, and do not recite the barcoding steps in amended claim 9.
Natera teaches methods of detecting various genetic alterations associated with cancer, as described above. Natera in view of Rubicon render obvious the barcoding steps recited in amended claim 9, also as discussed above.
Claims 9, 33-35, 37-39, and 45-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 4 of U.S. Patent No. 11702702 in view of Natera and Rubicon. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reason.
Patented claims 1 and 3 teach the limitations of instant claims 1, 38 and 39. Patented claim 3 teaches the limitations of instant claims 46-52. Patented claim 4 teaches the limitations of instant claims 33-35 and 45.
Patented claims 1 and 3 do not teach the limitations of instant claim 9 in regards to the method for detecting epigenetic alterations, do not teach separating the nucleic acids into first and second portions, and do not teach the barcoding steps of amended claim 9. However, those limitations are rendered obvious by Natera in view of Rubicon, as described above..
Claims 9, 33, 38 and 39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 19, 20, 23, 24, 25, 27 and 28 of U.S. Patent No. 11913063 B2 in view of Natera and Rubicon. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reason.
Patented claims 1, 2, 3, 4, 5, 7, 9, 11, 12, 13, 19, 20, 27 and 28 teach the limitations of instant claim 9. Patented claim 6 teaches the limitations of instant claim 33. Patented claims 23-25 teach the limitations of instant claims 38 and 39.
Patented claims 1, 2, 3, 4, 5, 7, 9, 11, 12, 13, 19, 20, 27 and 28 do not teach the limitations of instant claim 9 in regards to the method for detecting epigenetic alterations, do not teach separating the nucleic acids into first and second portions, and do not teach the barcoding steps of amended claim 9. However, those limitations are rendered obvious by Natera in view of Rubicon, as described above..
Response to Arguments
Applicant’s arguments with respect to claim(s) 08/08/2025 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636