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 .
This is the First Office Action on the Merits of US 18/615,960 filed on 03/25/2024 which is a CON of 18/319,670 filed on 05/18/2023 which is a CON of 16/983,388 filed on 08/03/2020 (now US Patent 11692213) which is a CON of 15/537,962 filed on 06/20/2017 (now US Patent 10774365) which is a 371 of PCT/US2015/066949 filed on 12/19/2015 which claims US priority benefit of US Provisionals 62/198,097 filed on 07/28/2015 and 62/094,980 filed on 12/20/2014.
Claims 21-70 are cancelled.
Claims 1-20 are pending and under examination.
Claim Objections
Claim 14 is objected to because of the following informalities: The term “incudes” should be amended to: “includes”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 15 and 17-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation "the extracted nucleic acids" in line 2. There is insufficient antecedent basis for this limitation in the claim because claim 15 depends from claim 1 which does not recite extracted nucleic acids. It would be remedial to amend claim 15 to depend from claim 2.
Claims 17-20 are unclear because these claims require that the CRIPSR/Cas protein is catalytically dead (claims 17-18), or a nickase (claims 19-20). These claims do not correspond to the base claim 1 which requires that the gRNA are complementary to the targeted sequences for depletion, and whereby the target sequences are cleaved. Such cleavage would require that the CRISPR/Cas protein was an active nuclease.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over US2014/0356867 to Peter et al (filed on May 29, 2014, published 12/04/2014).
Regarding claims 1 and 16, Peter et al disclose a method “to reduce the sequence complexity of a genome prior to analysis, or to enrich for genomic regions with fewer repeated sequences” (e.g. para 0094, lines 3-4). Peter et al disclose a method for processing a genome by enriching for wanted sequences of interest while depleting unwanted sequences of interest. Peter et al disclose: (a) contacting a genomic sample with one or more Cas9-gRNA complexes where the gRNA is complementary to and thus targets and cleaves the target sequence, wherein the target sequence for depletion is within a repetitive sequence. Further, Peter et al discloses the non-host (unknown; valued) nucleic acids are less than 50% or 5%, respectively, of the total nucleic acids in the sample. (See para [0095] shown below.)
[0095] In certain embodiments the method may be used to enrich for one or more fragments (i.e., one or more regions of a genome), where the resultant sample is at least 50% free, e.g., at least 80% free, at least 90% free, at least 95% free, at least 99% free of the remainder of the genome, where at least 10%, at least 30%, at least 50%, at least 80% or at least 90% or at least 95% of the chosen genomic regions are partitioned into the isolated products and the remainder is partitioned into the unisolated products. As noted above, in addition to isolating a single genomic region, the method (when used with a plurality of different oligonucleotides in a multiplex reaction) can be used to enrich for a plurality of (i.e., at least 2, e.g., at least 5, at least 10, at least 50, at least 100, at least 500, at least 1,000, at least 5,000, at least 10,000 up to 50,000 or more) different genomic regions.
Regarding claims 2-3, Peter et al disclose extracting the sequences and further fragmenting the sequences. Peter et al recite: producing (i.) fragments of the repetitive sequence and (ii.) fragments comprising non-repetitive sequence; and (b) enriching for the fragments comprising non-repetitive sequence (e.g., para 0125).
[0126] Some sequencing applications, such as whole genome sequencing for copy number estimation, require unbiased sequence representation of the entire genome. However, these methods are hindered by the repeat structure of the genome, since over half of the human genome is comprised of repeated sequences which do not map uniquely, and these are typically not useful for estimating copy number. This problem is worse in many plants, which have an even greater fraction of their genome made up by repeat elements. The Cas9/CRISPR system may offer one solution to this problem (FIG. 2). By programming the Cas9 protein with RNAs targeting repeat sequences, repeat elements could be selectively targeted and cleaved. Though this can already be done with restriction enzymes (note that the prevalent Alu sequence in the human genome is cleaved by the AluI restriction enzyme), the shorter recognition sequences of restriction enzymes will cause extensive fragmentation of non-repeat sequences. By targeting the most prevalent repeat elements with one or more guide RNAs, the repeat sequences could be fragmented, leaving the rest of the genomic sequence intact. As the recognition sequence for the Cas9/CRISPR system is 13-20 bp, even short fragments of repetitive elements could be targeted. A size selection step would substantially enrich the DNA for non-repeat-containing sequences.
Regarding claim 4, Peter et al disclose a sample containing adaptor-ligated fragments of genomic DNA in a Cas9-gRNA complex (e.g., para 0060). Peter et al disclose using adapter-ligated to the 5’ end and 3’ end of a nucleic acid molecule (e.g., para 0024). Peter et al teach adapter-ligated host nucleic acid and non-host nucleic acid range from 50-1000 bp (e.g., para 0155).
Regarding claim 5, Peter et al disclose removing cut nucleic acid fragments by size-exclusion (e.g., para 0124). Peter et al disclose that a size selection step would substantially enrich the DNA for non-repeat-containing sequences.
Regarding claim 6, Peter et al teach amplification the sequences of interest (e.g., paragraphs 0151-0152, 0153,0156).
Regarding claim 7, Peter et al disclose a sample with at least 10,000 (aka 104) unique Cas9-gRNA complexes.
[0067] The method described above may be done using a single Cas9-gRNA complex or a plurality of Cas9-gRNA complexes that contain a Cas9 protein and a plurality (i.e., at least 2, at least 5, at least 10, at least 50, at least 100, at least 500 or at least 1,000, up to 10,000 or 100,000 or more) of Cas9 gRNAs in a multiplex reaction that can be used to isolate a plurality of different genomic regions. In certain embodiments, if a plurality of different Cas9-gRNA complexes are used, they may all contain the same affinity tag. In certain embodiments, if a plurality of different Cas9-gRNA complexes are used, several of the Cas9-gRNA complexes may bind to different sites in the same genomic region.
Further, Peter et al disclose in paragraph 0071: that their methods may use a Cas9-gRNA complex comprising a Cas9 protein which is able to cleave target DNA and a Cas9-associated guide RNA that is complementary to a site in genomic DNA. “In certain embodiments, the composition may comprise a plurality of such guide RNAs, where each guide RNA in the population hybridizes to a different sequence in the genome. As would be apparent, the composition may contain a single Cas9 protein and a plurality of guide RNAs, e.g., at least 2, at least 10, at least 50, at least 100, at least 500, at least 1,000, at least 5,000 or at least 10,000 or more guide RNAs. The composition may also contain fragmented mammalian genomic DNA”.
Regarding claim 8, Peter et al discloses wherein the sample is any one of a biological sample, a clinical sample, a forensic sample or an environmental sample. Peter et al recite in paragraph 0029 that “[t]he term "target sequence" refers to a sequence in a double-stranded DNA molecule, where the target sequence is bound, and, optionally cleaved or nicked by Cas9. In many cases, a target sequence may be unique in any one starting molecule. Peter et al contemplate genomic DNA from a plurality of sources: As would be appreciated, the method described below may be employed to enrich for sequences from many different types of nucleic acid sample, e.g., a cDNA sample or genomic sample. For example, the method described below could be readily modified to isolate particular cDNAs from total cDNA. (para0048).
In certain embodiments, the sample may comprise a pool of fragmented genomic DNA from a plurality of samples, wherein the fragments in the sample have a molecular barcode to indicate their source. In some embodiments the double-stranded DNA being analyzed may be derived from a single source (e.g., a single organism, virus, tissue, cell, subject, etc.), whereas in other embodiments, the nucleic acid sample may be a pool of nucleic acids extracted from a plurality of sources (e.g., a pool of nucleic acids from a plurality of organisms, tissues, cells, subjects, etc.), where by "plurality" is meant two or more. As such, in certain embodiments, a nucleic acid sample can contain nucleic acids from 2 or more sources, 3 or more sources, 5 or more sources, 10 or more sources, 50 or more sources, 100 or more sources, 500 or more sources, 1000 or more sources, 5000 or more sources, up to and including about 10,000 or more sources. Molecular barcodes may allow the sequences from different sources to be distinguished after they are analyzed. (para 0065).
Regarding claims 10-12, and 14, Peter et al disclose in paragraph 0050 that their method may be used to isolated DNA fragments from total genomic DNA and complementary DNA (cDNA), plasmid DNA, mitochondrial DNA, synthetic DNA, and BAC clones, etc. and that “any organism, organic material or nucleic acid-containing substance can be used as a source of nucleic acids to be processed in accordance with the present invention including, but not limited to, plants, animals (e.g., reptiles, mammals, insects, worms, fish, etc.), tissue samples, bacteria, fungi (e.g., yeast), phage, viruses, cadaveric tissue, archaeological/ancient samples, etc.” and human. Further, in paragraph 0051 Peter et al disclose the genomic DNA may be from a prokaryote or from a eukaryote, including “plant, e.g., Arabidopsis or maize, or an animal, including reptiles, mammals, birds, fish, and amphibians”, “human or rodent, such as a mouse or a rat”.
Regarding clam 13, Peter et al recite:
[0126] Some sequencing applications, such as whole genome sequencing for copy number estimation, require unbiased sequence representation of the entire genome. However, these methods are hindered by the repeat structure of the genome, since over half of the human genome is comprised of repeated sequences which do not map uniquely, and these are typically not useful for estimating copy number. This problem is worse in many plants, which have an even greater fraction of their genome made up by repeat elements. The Cas9/CRISPR system may offer one solution to this problem (FIG. 2). By programming the Cas9 protein with RNAs targeting repeat sequences, repeat elements could be selectively targeted and cleaved. Though this can already be done with restriction enzymes (note that the prevalent Alu sequence in the human genome is cleaved by the AluI restriction enzyme), the shorter recognition sequences of restriction enzymes will cause extensive fragmentation of non-repeat sequences. By targeting the most prevalent repeat elements with one or more guide RNAs, the repeat sequences could be fragmented, leaving the rest of the genomic sequence intact. As the recognition sequence for the Cas9/CRISPR system is 13-20 bp, even short fragments of repetitive elements could be targeted. A size selection step would substantially enrich the DNA for non-repeat-containing sequences.
Regarding claims 9 and 15, Peter et al discloses the non-host (unknown; valued) nucleic acids are less than 50% or 5%, respectively, of the total nucleic acids in the sample.
[0095] In certain embodiments the method may be used to enrich for one or more fragments (i.e., one or more regions of a genome), where the resultant sample is at least 50% free, e.g., at least 80% free, at least 90% free, at least 95% free, at least 99% free of the remainder of the genome, where at least 10%, at least 30%, at least 50%, at least 80% or at least 90% or at least 95% of the chosen genomic regions are partitioned into the isolated products and the remainder is partitioned into the unisolated products. As noted above, in addition to isolating a single genomic region, the method (when used with a plurality of different oligonucleotides in a multiplex reaction) can be used to enrich for a plurality of (i.e., at least 2, e.g., at least 5, at least 10, at least 50, at least 100, at least 500, at least 1,000, at least 5,000, at least 10,000 up to 50,000 or more) different genomic regions.
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have been motivated to combine the elements disclosed in the Peter et al reference to deplete unwanted/abundant nucleic acid sequences such as in a biological or clinical sample for the rationale of enriching for less abundant sequences of interest in such sample. The rationale to target the unwanted sequence for depletion using gRNAs specific to the unwanted nucleic acids, such as the abundant repeat sequences found in human cell samples, is explicitly suggested in the Peter et al reference which is that gRNAs can be designed to target generally any sequence desired for depletion and when complexed with Cas9 nuclease perform the cleavage in a cost-effective and efficient manner.
It would have been obvious to one of ordinary skill in the art to have combined the elements of the cited reference to arrive at the presently claimed invention because
these elements are the preferred embodiments disclosed in Peter et al for enriching for genomic sequences of value (i.e., less abundant, unknown sequence) in mixtures of known/abundant genomic sequences).
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited reference before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to combine the elements of the cited reference to arrive at the presently claimed invention.
.
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 1-4, 6, 8-10, and 12-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,774,365 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Claim 16 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,774,365 B2 in view of Peter et al (above). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Regarding instant claim 1, patented claim 8 depends from patented claim 1 and recites a method of enriching a sample for sequences of interest, comprising providing a sample comprising nucleic acid sequences of interest (non-host )and targeted nucleic acid sequences for deletion (host), wherein sequences are adaptor-ligated, where sequence are DNA, and wherein the sequences of interest are less than 10% of extracted nucleic acids. Further, patented claim 1 recites contacting the sample with a plurality of CRISPR/Cas system protein-gRNA complexes, where the gRNAs are complementary to targeted sequence for deletion, and whereby the targeted sequences are cleaved. Patented claim 18 recites the sequence of interest comprise less than 5% of the total nucleic acids in the sample.
Regarding instant claim 2, patented claims 8 and 15 disclose extraction of the sequences of interest and the targeted sequences for depletion from the sample.
Regarding instant claims 3-4, patented claim 15 recites fragmenting the extracted sequences and adapter ligating the 5' and 3' ends of the fragmented extracted sequences.
Regarding instant claim 6, patented claim 1 recites amplifying the sequences of interest.
Regarding claim 8, patented claims 3, 9, 13-14, and 17 recite the sample is any one of a biological sample, a clinical sample, a forensic sample or an environmental sample.
Regarding claim 9, patented claim 4 recites the sample comprises host nucleic acid sequences targeted for depletion and non-host nucleic acid sequences of interest.
Regarding claim 10, patented claim 5 recites the non-host nucleic acid sequences comprise microbial nucleic acid sequences.
Regarding instant claim 12, patented claim 6 recites that the sample is contacted with CRISPR/Cas system protein-gRNA complexes, wherein the gRNAs are complementary to mitochondrial DNA. (targeted for depletion).
Regarding instant claim 13, patented claims 7 recites the sample is contacted with CRISPR/Cas system protein-gRNA complexes, wherein the gRNAs are complementary to DNA corresponding to ribosomal RNA sequences, and a list which is the same as instant claim 13.
Regarding instant claim 14, patented claims 1, 6, 7, 12, and 15 disclose that the extracted nucleic acids include DNA and specifically genomic DNA (claim 15) which meets the limitations of any one of single stranded DNA, double stranded DNA, single stranded RNA, double stranded RNA, cDNA, synthetic DNA, artificial DNA, and DNA/RNA hybrids.
Regarding instant claim 15, patented claim 8 recites that the sequences of interest comprise less than 10% of the extracted nucleic acids.
Regarding instant claim 16, patented claim 1 recites a CRISPR/Cas system protein but patented claims do not recite Cas9. It would have been prima facie obvious for a POSITA to use Cas9 because it was the most known and well-used Cas nuclease. For example, Peters et al disclose a method for processing a genome by enriching for wanted sequences of interest while depleting unwanted sequences of interest. Peter et al disclose: (a) contacting a genomic sample with one or more Cas9-gRNA complexes where the gRNA is complementary to and thus targets and cleaves the target sequence, wherein the target sequence for depletion is within a repetitive sequence. (e.g., para 0029, 0060).
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the limitations of the patented claims to arrive at the presently claimed invention because the patented claims recite the preferred embodiments of such invention.
Claims 1-4, 6-11, and 14-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,669,571 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,669,571 B2 in view of Peter et al (above). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Regarding instant claim 1, patented claim 1 recites a method for enriching a sample for sequences of interest (non-host nucleic acids), the method comprising contacting a sample with a plurality of CRISPR/Cas system protein-gRNA complexes, where the gRNAs are complementary to targeted sites in the host nucleic acids (sequences to be depleted). Patented claim 1 recites amplifying for uncut non-host nucleic acids. Also, regarding instant claim 1, patented claim 11 recites that the non-host (sequences of interest) comprise less than 50% of the total nucleic acids in the sample but not less than 30%. However, since the patented claims also recite that the sample is a forensic sample, it would be prima facie obvious to construe a forensic sample to have forensic (non-host) sequences of interest comprising less than 30% of the host DNA/nucleic acid sample. In addition, patented claim 20 recites that the sequences of interest comprise less than 5% of the extracted nucleic acids.
Regarding instant claim 2, patented claim 1 disclose extracting the sequences of interest and the targeted sequences for depletion from the sample.
Regarding instant claims 3-4, patented claim 16 recites fragmenting the extracted sequences and adapter ligating the 5' and 3' ends of the fragmented extracted sequences.
Regarding instant claim 6, patented claims 1and 16 recite amplifying the sequences of interest.
Regarding instant claim 7, patented claim 2 recites the method comprises contacting the sample with at least 102 unique CRISPR/Cas system protein-gRNA complexes.
Regarding claim 8, patented claim 12 recite the sample is any one of a biological sample, a clinical sample, a forensic sample or an environmental sample.
Regarding claim 9, patented claim 1 recites the sample comprises host nucleic acid sequences targeted for depletion and non-host nucleic acid sequences of interest.
Regarding claim 10, patented claim 9 recites the non-host nucleic acid sequences comprise microbial nucleic acid sequences.
Regarding claim 11, patented claim 9 recites the microbial nucleic acid sequences are bacterial, or viral.
Regarding instant claim 14, patented claims 24-27 recite that the extracted nucleic acids include DNA and specifically genomic DNA, and cDNA) which meets the limitations of any one of single stranded DNA, double stranded DNA, single stranded RNA, double stranded RNA, cDNA, synthetic DNA, artificial DNA, and DNA/RNA hybrids.
Regarding instant claim 15, patented claim 20 recites that the sequences of interest comprise less than 5% of the extracted nucleic acids.
Regarding instant claim 16, patented claim 4 recites a CRISPR/Cas system protein is Cas9.
Regarding instant claim 13, patented claims recite gRNA complementary to unwanted host nucleic acids but DO NOT explicitly recite the sample is contacted with gRNAs that are complementary to DNA corresponding to repeat sequences of the list of instant claim 13. Peter et al disclose a method for processing a genome by enriching for wanted sequences of interest while depleting unwanted sequences of interest. Peter et al disclose: (a) contacting a genomic sample with one or more Cas9-gRNA complexes where the gRNA is complementary to repeat sequences and thus targets and cleaves the target sequence, wherein the target sequence for depletion is within a repetitive sequence. (e.g., para 0125).
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the limitations of the patented claims to arrive at the presently claimed invention because the patented claims recite the preferred embodiments of such invention.
Claims 1, 6, 8, and 13-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,761,039 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Claim 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,761,039 B2, in view of Peter et al (above). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Regarding instant claim 1, patented claim 1 recites a method for enriching for sequences of interest by contacting a sample comprising unwanted DNA sequences and DNA sequences of interest with a CRISPR/Cas system protein-gRNA complexes where the gRNAs are complementary to the unwanted DNA sequences. Patented claim 1 recites the sequences of interest are less than 50% of the DNA. Patented claim 5 recites the sequences of interest are less than 5% of the DNA.
Regarding instant claim 2, patented claim 1 disclose extracting the sequences of interest and the targeted sequences for depletion from the sample.
Regarding instant claims 3-4, patented claim 16 recites fragmenting the extracted sequences and adapter ligating the 5' and 3' ends of the fragmented extracted sequences.
Regarding instant claim 6, patented claim 1 recites amplifying the sequences of interest.
Regarding instant claim 8, patented claim 2 recites a clinical sample.
Regarding instant claim 13, patented claim 3 recites the sample types of gRNA.
Regarding instant claim 14, patented claim 1 recites ds DNA.
Regarding instant claim 15, patented claim 5 recites the sequences of interest are less than 5% of the DNA.
Regarding instant claim 16, patented claim 1 recites a CRISPR/Cas system protein but patented claims do not recite Cas9. It would have been prima facie obvious for a POSITA to use Cas9 because it was the most known and well-used Cas nuclease. For example, Peter et al disclose a method for processing a genome by enriching for wanted sequences of interest while depleting unwanted sequences of interest. Peter et al disclose: (a) contacting a genomic sample with one or more Cas9-gRNA complexes where the gRNA is complementary to and thus targets and cleaves the target sequence, wherein the target sequence for depletion is within a repetitive sequence. (e.g., para 0029, 0060).
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the limitations of the patented claims to arrive at the presently claimed invention because the patented claims recite the preferred embodiments of such invention.
Claims 1-4, 6, 8-11, and 13-14, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-32 of U.S. Application No. 18/734,997. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the present claims.
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-32 of U.S. Application No. 18/734,997, in view of Peter et al (above). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims render obvious the present claims.
Regarding instant claim 1, copending claim 1 recites a method of enriching a sample for sequences of interest, comprising providing a sample comprising sequences of interest and targeted sequences for depletion. Copending claim 1 recites contacting the sample with guide-nuclease complexes, and copending claim 19 specifies Crisper/Cas system protein-gRNA complexes. Also, copending claim 23 recites that the sequence of interest is less than 50% of sample but copending claims do not specify less than 30%. However, since the copending claims also recite that the sample is a forensic sample (claim 25), it would be prima facie obvious to construe a forensic sample to have forensic (non-host) sequences of interest comprising less than 30% of the host DNA/nucleic acid sample.
Regarding instant claim 2, copending claims 1, 8 and 11 disclose extraction of the sequences from the sample.
Regarding instant claims 3-4, copending claim 9 recites fragmenting the extracted sequences and adapter ligating the 5' and 3' ends of the fragmented extracted sequences.
Regarding instant claim 6, copending claim 9 recites amplifying the sequences of interest.
Regarding instant claim 8, copending claim 25 recites a clinical sample.
Regarding instant claims 9-11, copending claims 26-28 are the same as claims 9-11.
Regarding instant claim 13, copending claim 29 recites the sample types of gRNA.
Regarding instant claim 14, copending claim 24 recites DNA.
Regarding instant claim 16, copending claim 19 recites a CRISPR/Cas system protein but patented claims do not recite Cas9. It would have been prima facie obvious for a POSITA to use Cas9 because it was the most known and well-used Cas nuclease. For example, Peter et al disclose a method for processing a genome by enriching for wanted sequences of interest while depleting unwanted sequences of interest. Peter et al disclose: (a) contacting a genomic sample with one or more Cas9-gRNA complexes where the gRNA is complementary to and thus targets and cleaves the target sequence, wherein the target sequence for depletion is within a repetitive sequence. (e.g., para 0029, 0060).
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the limitations of the copending claims to arrive at the presently claimed invention because the patented claims recite the preferred embodiments of such invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 7, and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-90 of U.S. Application No. 18/599,123. Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims render obvious the present claims.
Regarding instant claim 1, copending claim 59 recites a method comprising providing a sample of nucleic acids comprising at least one sequence of interest. Copending claim 80 depends from claim 59 and recites providing CRISPR/Cas system complexes comprising guide nucleic acids. Copending claim 86 recites gRNAs. The guide nucleic acids are complementary to unwanted nucleic acids targeted for depletion. Copending claim 80 recites cleavage of such targeted sequence. Also, regarding instant claim 1, copending claims 59 and 76 recite the sequence of interest may be one sequence in the sample which renders obvious that the sequence of interest is at least 30% of the sample. Regarding instant claim 7, copending claim 87 recites at least 102 unique CRISPR/Cas system protein-gRNA complexes. Regarding instant claim 16, copending claim 83 recites Cas9.
The level of skill in the art was high before the effective filing date of the presently claimed invention. One of ordinary skill in the art would have been motivated to combine the limitations of the patented claims to arrive at the presently claimed invention because the patented claims recite the preferred embodiments of such invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Related art which may be applied in a future office action if appropriate:
Morlan et al “Selective Depletion of rRNA Enables Whole Transcriptome Profiling of Archival Fixed Tissue” (PLOS ONE published 08/10/2012; Vol. 7, No. 8: pages 1-8). Especially regarding claims 8-9, Morlan et al disclose a method for selective depletion of known host nucleic acid in a human sample using adapter-ligation while preserving clinically valuable “unknown” untargeted RNA, “enabling routine whole transcriptome analysis of clinically valuable archival tissue specimens by Next-Generation Sequencing (e.g., abstract). Morlan et al removing/depleting 98% of targeted RNA while preserving “relative abundance profiles of non-targeting RNAs” (e.g., abstract). Morlan et al used a method of hybridizing DNA oligonucleotide probes to targeted RNA and then cleaving such complexes with the RNAase H nuclease and leaving the “unknown” or less abundant, non-targeted RNA intact for isolation and sequencing.
US2016/0208241 to Tsai et al entitled “Compositions And Methods For Enrichment Of Nucleic Acids” (published 07/21/2016 with US priority to 62/039,319 filed on 08/19/2014, now US Patent 10,435,685). Tsai et al disclose a composition comprising a mixture of DNA from a two different host genomes where this DNA is adapter-ligated, where one DNA of one host genome is complexed to a CRISPR/Cas system Cas9 or Cpf1 (e.g. ref claims 1 and 26)-guide RNA (gRNA) complexes. Tsai et al disclose the mixture of DNA may be from two different hosts, “different individuals of different species” for example, from an intestinal sample (e.g., para 25, lines 2-3 and with priority to the Tsai et al ‘319 Provisional: para 0018, lines 4-6; para 0005, ref claim 15). Tsai et al disclose the DNA library may be a “whole-genome DNA library, double-stranded” per ref claim 10 and where the double-stranded fragments in the library are not amplified prior to enrichment (e.g. para 0009, line 10; ‘319 Provisional: abstract, para 0032, line 9-14).
Feehery et al (2013 “A method of selectively enriching microbial DNA from contamination vertebrate host DNA: PLOS ONE Vol 8 No. 10: pages 1-13). Especially regarding claims 10-11, Feehery et al disclose a method of “selectively enriching microbial DNA from contamination vertebrate host DNA” (e.g., entire document, title, abstract). Feehery et al disclose that DNA samples from vertebrate skin, bodily cavities and body fluids inherently contain both host and microbial (non-host) DNA; “the latter often present as a minor component (e.g., abstract, lines 1-2). Thus, Feehery et al teach that “DNA sequencing of a microbiome sample frequently yields reads originating from the microbe(s) of interest, but with a vast excess of host-genome-derived reads” (e.g., abstract, lines 2-3).
Wang et al in “Genetic screens in human cells using the CRISPR/Cas9 system” (Science published 01/03/2014; Vol. 343 No. 6166: pages 80-84). Wang et al disclose a composition of genome DNA complexed to a plurality of Cas9-guide RNA complexes using a library of 73,000 sgRNAs (i.e., 7.3 X 104 unique complexes). Wang et al conclude that their results “establish Cas9/sgRNA screens as a powerful tool for systematic genetic analysis in mammalian cells” (e.g., abstract).
Makarov et al (US2017/0088887 with US priority to March 2014). Makarov et al disclose a method of enhanced adapter ligation to the ends of fragmented double-stranded DNA molecules using Exonuclease III, stating the inclusion of Exo III “significantly enhanced the blunt ligation” (e.g., para 0326, lines 9-10 of published application and in 61/947,235 Provisional on page 37, “Conclusion”, lines 8-12”).
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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