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 .
Application Status
This action is written in response to applicant’s correspondence received 01/27/2025. Claim 15 is cancelled. Claims 1-14 and 16-20 are currently pending and are examined herein.
Applicant amended claim 1 to incorporate the limitations of dependent claim 15, which was rejected in the Non-Final office action mailed 10/07/2024.
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 § 112 – new necessitated by amendment to claim 1
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-14 and 16-20 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 1 recites the limitation "the bodily fluid sample" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitations “biological sample” and “bodily fluid sample”. It is unclear whether or not the biological sample is limited to a bodily fluid sample.
Claims 2, 6, 16, and 17 recite "sample" and directly or indirectly depend from claim 1. Amended claim 1 recites the limitations “biological sample” and “bodily fluid sample”. It is unclear whether “sample” refers to “biological sample” or “bodily fluid sample”.
Claims 2, 6, 16, and 17 recite "sample". There is insufficient antecedent basis for this limitation in the claim.
Claim 13 recites the limitation “biological sample” in line 2. Claim 1 now recites a “biological sample” and “bodily fluid sample”. It is unclear whether the one or more variants identified are in a “biological sample” or a “bodily fluid sample”. It is further unclear whether or not the biological sample is limited to a bodily fluid sample.
Claim 19 recites the limitations “nucleic acid sample” in lines 1-2 and “biological sample”, then use the term “sample” in lines 5, 6, and 11 and “target nucleic acid sample” in line 12. It is unclear whether “the sample” refers to the entire “nucleic acid sample”, “biological sample”, or the “target nucleic acid sample”.
Claim 19 recites the limitations “biological sample” and “bodily fluid sample”. It is unclear whether or not the biological sample is limited to a bodily fluid sample.
Claim 19 recites the limitation "sample" in lines 5, 6, and 11. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the bodily fluid sample" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the target nucleic acid sample" in line 12. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the bodily fluid sample" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2 and 8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 reciting “the sample comprises bodily fluid” depends from amended claim 1, which now recites “the bodily fluid sample”. Accordingly, claim to fails to further limit the subject matter of claim 1.
Claim 8 reciting the limitation “wherein the target nucleic acid comprises cDNA, cfDNA, or ctDNA” depends from amended claim 1, which now recites “wherein the target nucleic acid is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample”. The specification indicates that cfDNA is an abbreviation of cell-free DNA (see at least page 1, para 3; page 4, para 4; and page 14, para 5). Claim 8 is of improper dependent form when the target nucleic acid comprises cfDNA because it fails to further limit the subject matter of the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102 – new rejection necessitated by amendment
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.
Claims 1-5, 7-8, 10-14, and 16-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cann (US20160017396A1, published January 21, 2016). This rejection is modified as necessitated by Applicant’s amendment to incorporate the limitations of claim 15 into claim 1 and cancel claim 15.
Regarding claim 1, Cann teaches using CRISPR-Cas systems to form a complex with the target nucleic acids, separating the complex, and thereby enriching the target nucleic acid (see abstract and para 0006). Cann further teaches that the guide RNA is biotinylated (particle; see Fig. 1) or the Cas protein is labeled with a capture tag (see para 009 and see Example 1). Cann further teaches obtaining the target DNA from a subject's plasma or serum (see claim 22). Claim 1 recites, “the method comprising”, which allows additional steps to achieve enriching the sample. Cann teaches isolating target nucleic acids before introducing Cas endonuclease (para 0164) and after introducing Cas endonuclease (claim 1, para 0006, and Example 1). Cann teaches more sensitive methods of enriching and detecting single nucleotide variants (SNV), including point mutations and SNPs, present in cell free DNA sample in the 0.01% to 0.1% frequency range (see para 0166).
Regarding claims 2 and 7, Cann teaches the bodily fluid samples comprising plasma and serum (see claim 22) and maternal plasma and blood (see paras 0164 and 0168).
Regarding claim 3 and 4, Cann teaches that the particle is magnetic streptavidin beads (see paras 0038 and Example 7).
Regarding claim 5, Cann teaches that the guide RNA is biotinylated (see Fig. 1).
Regarding claim 8, Cann teaches the target nucleic acid is cell free DNA (cfDNA) (see claim 22 and para 0157). Cann further teaches methods of enriching and/or detecting target nucleic acids in circulating tumor DNA (ctDNA) from cancer patients (see paras 0156 and 0165).
Regarding claim 10, Cann teaches isolating the target nucleic acid from the CRISPR-Cas and gRNA complex and further teaches isolating the target nucleic acid from the polynucleotide population (see para 0122 and 0152).
Regarding claim 11, Cann teaches separating the target nucleic acid from the particle by applying a magnetic field to the particle complex, then treating the complex with proteases or a detergent washing step (see paras 0138, 0155 and 0167; and claim 22).
Regarding claims 12-14, Cann teaches methods for sequencing target DNA sequences from ctDNA isolated from cancer patients, wherein the variant comprises a mutation specific to a tumor (see para 0156 and 0167) to obtaining sequence reads (see para 204). Cann further teaches analyzing the sequence reads to identify variants to monitor tumor progression and/or test a tumor patient’s response to targeted drug treatments (see para 0165).
Regarding claim 16, Cann teaches detection of target nucleic acids where Cas9 complexes with fragmented target BRAF DNA are isolated using streptavidin coated magnetically responsive beads (see para 0058, Fig. 14, and Example 7).
Regarding claim 17, Cann teaches detecting the presence of target nucleic acids by applying a magnetic field to separate the particle complex from the sample (see paras 0166-0167).
Regarding claim 18, Cann teaches methods for detecting target nucleic acids and further amplifying the target nucleic acid sequences (see paras 0024 and 0158).
Regarding claim 19, Cann teaches a method for detecting a variant in a nucleic acid sample, the method comprising obtaining cfDNA from a subject's plasma or serum from a subject suspected of having a variant in a target nucleic acid (see claims 22 and 23 and para 0028. Cann further teaches enriching the sample using CRISPR-Cas systems to form a complex with the target nucleic acids and separating the complex (see abstract and para 0006). Cann teaches more sensitive methods of enriching and detecting single nucleotide variants (SNV), including point mutations and SNPs, present in cell free DNA sample in the 0.01% to 0.1% frequency range (see para 0166).
Regarding claim 20, Cann further teaches detecting the variant in the target nucleic acid sample with gel electrophoresis (see para 0261).
Claim Rejections - 35 USC § 103 - maintained
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.
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Cann (US20160017396A1, published January 21, 2016) as applied to claims 1-5, 7-8, 10-14, and 16-20 above, and further in view of Gourguechon (WO2016100955A2; published June 23, 2016; as cited as #34 in the 17 page IDS filed on August 9, 2024).
The teachings of Cann are applied to claims 6 and 9 as they are applied to claims 1-5, 7-8, 10-14 and 16-20 under U.S.C. § 102 above.
However, Cann does not teach introducing an exonuclease to the bodily fluid sample to digest unbound nucleic acid (claim 6). Cann further does not teach that the target nucleic acid is from a genome of a pathogen (claim 9).
Gourguechon's disclosure is directed to methods and compositions for depleting targeted nucleic acid sequences from a sample, enriching for sequences of interest from a sample, and/or partitioning of sequences from a sample using CRISPR-Cas system protein-gRNA complexes (see abstract and para 0010). Gourguechon teaches embodiments with catalytically active Cas9 endonuclease (see para 1060).
Regarding claim 6, Gourguechon teaches a method of enriching a sample by contacting target nucleic acids with a plurality of CRISPR-Cas system protein-gRNA complexes and treating the sample with exonucleases to enrich the bound nucleic acids (see para 0181-0182).
Regarding claim 9, Gourguechon teaches a method of enriching a sample wherein the target nucleic acid is obtained from the genome of a pathogen (see para 0086 and 0105).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of enriching and detecting target nucleic acids disclosed by Cann with introducing exonucleases described by Gourguechon because it would have amounted to a simple combination of prior art elements according to known methods to yield predictable results. Gourguechon teaches enriching for sequences from a sample by treating the sample with exonucleases, as discussed above. One would have been motivated to combine the methods of Cann and Gourguechon to provide improved methods of enriching and detecting tumor mutations in cancer patients with increased sensitivity by digesting and removing unwanted nucleic acids. It would have been further obvious to have applied the Cann’s methods to enrich and detect a target nucleic acid from a genome of a pathogen instead of tumor mutations or other nucleic acid variants, as described by Cann, as it is a simple substitution of known DNA elements for another that would obtain predictable results. The ordinary artisan would have had a reasonable expectation of success because both Cann and Gourguechon are directed to improved methods of detecting target nucleic acids and can be used to diagnose and/or treat patients. Thus, the claimed invention as a whole is prima facie obvious.
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 01/27/2025 have been fully considered but they are not persuasive. Applicant argues on pages 2-5 that the cited references do not teach or render obvious the limitations of the amended claims that introducing the particle complex directly into the sample.
In response to applicant's argument that Cann and Gourguechon do not teach do not teach or render obvious the limitations of the amended claims that introducing the particle complex directly into the sample, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Double Patenting – Statutory – withdrawn in view of Applicant’s amendment
Provisional rejection of claims 1-18 under 35 U.S.C. 101 as claiming the same invention as that of claims 1-18 of copending Application No. 18/519,589 (reference application) is withdrawn in view of Applicant’s amendment to claims filed 01/27/2025.
However, the Office has issued a provisional NSDP rejection detailed below.
Double Patenting – modified in view of Applicant’s amendment to claims
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 1-14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-20 of copending Application No. 18/121,328, in view of Cann (US20160017396A1) and Gourguechon (WO2016100955A2; published June 23, 2016; as cited as #34 in the 17 page IDS filed on August 9, 2024).
Claims 1-11 and 13-20 of the ‘328 application encompass a method for enriching a sample, the method comprising: obtaining a biological sample (bodily fluid) comprising a target nucleic acid; binding Cas endonuclease and guide RNA that targets the target nucleic acid to a particle to form a particle complex; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1-11 and 13-20 of the ‘328 application teach digesting unbound nucleic acids with exonucleases, using magnetic particles, and isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle. Claims 1-11 and 13-20 of the ‘328 application further teach the bodily fluid sample comprising bile, blood, plasma, serum, sweat, saliva, urine, feces, phlegm, mucus, sputum, tears, cerebrospinal fluid, synovial fluid, pericardial fluid, lymphatic fluid, semen, vaginal secretion, products of lactation or menstruation, amniotic fluid, pleural fluid, rheum, or vomit. Claims 1-11 and 13-20 of the ‘328 application further teach that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, and is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-11 and 13-20 of the ‘328 application teach detecting the target nucleic acid in the sample comprising gel electrophoresis, amplifying the target nucleic acid sequence, sequencing the target nucleic acid to obtain sequence reads, and analyzing the sequence reads to identify one or more variants in the biological sample, wherein the variant comprises a mutation specific to a tumor.
The copending claims do not teach that the guide RNA is biotinylated (claim 5) and further do not teach that the target nucleic acid is from a genome of pathogen (claim 9).
However, the teachings of Cann and Gourguechon are discussed above. In particular, the teachings of Cann regarding the guide RNA that is biotinylated and Gourguechon regarding the target nucleic acid being from a genome of a pathogen are discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the method of the copending claims to include a guide RNA that is biotinylated as taught by Cann and further to apply the methods to a target nucleic acid that is a from a genome of a pathogen as taught by Gourguechon because Cann and Gourguechon also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from bodily fluid samples.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/385,649, in view of Cann (US20160017396A1) and Gourguechon (WO2016100955A2; published June 23, 2016; as cited as #34 in the 17 page IDS filed on August 9, 2024).
Claims 1-20 of the ‘649 application encompass a method for enriching a sample, the method comprising: obtaining a biological sample (bodily fluid) comprising a target nucleic acid; binding Cas endonuclease and guide RNA that targets the target nucleic acid to a particle to form a particle complex; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1-20 of the ‘649 application teach digesting unbound nucleic acids with exonucleases, using magnetic particles, and isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle. Claims 1-20 of the ‘649 application further teach the bodily fluid sample comprising bile, blood, plasma, serum, sweat, saliva, urine, feces, phlegm, mucus, sputum, tears, cerebrospinal fluid, synovial fluid, pericardial fluid, lymphatic fluid, semen, vaginal secretion, products of lactation or menstruation, amniotic fluid, pleural fluid, rheum, or vomit. Claims 1-20 of the ‘649 application further teach that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, and is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-20 of the ‘649 application teach detecting the target nucleic acid in the sample comprising gel electrophoresis, amplifying the target nucleic acid sequence, sequencing the target nucleic acid to obtain sequence reads, and analyzing the sequence reads to identify one or more variants in the biological sample, wherein the variant comprises a mutation specific to a tumor.
The copending claims do not teach that the guide RNA is biotinylated (claim 5) and further do not teach that the target nucleic acid is from a genome of pathogen (claim 9).
However, the teachings of Cann and Gourguechon are discussed above. In particular, the teachings of Cann regarding the guide RNA that is biotinylated and Gourguechon regarding the target nucleic acid being from a genome of a pathogen are discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the method of the copending claims to include a guide RNA that is biotinylated as taught by Cann and further to apply the methods to a target nucleic acid that is a from a genome of a pathogen as taught by Gourguechon because Cann and Gourguechon also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from bodily fluid samples.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-19 of copending Application No. 18/128698, in view of Cann (US20160017396A1) and Gourguechon (WO2016100955A2; published June 23, 2016; as cited as #34 in the 17 page IDS filed on August 9, 2024).
Claims 1-12 and 14-19 of the ‘698 application encompass a method for enriching a sample, the method comprising: obtaining a biological sample (bodily fluid) comprising a target nucleic acid; binding Cas endonuclease and guide RNA that targets the target nucleic acid to a particle to form a particle complex; introducing the particle complex to the sample to bind to the target nucleic acid; and digesting unbound nucleic acids with exonucleases. Claims 1-12 and 14-19 of the ‘698 application further teach that the sample comprises a liquid biopsy sample and that the sample is from a patient. Claims 1-12 and 14-19 of the ‘698 application further teach that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, includes a mutation specific to a tumor, and is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-12 and 14-19 of the ‘328 application teach amplifying the target nucleic acid sequence.
The copending claims do not teach that using magnetic beads (claims 3-4), the guide RNA is biotinylated (claim 5), that the target nucleic acid is from a genome of pathogen (claim 9), isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle (claim 11), sequencing the target nucleic acid to obtain sequence reads (claim 12), and analyzing the sequence reads to identify one or more variants in the biological sample (claim 13).
However, the teachings of Cann and Gourguechon are discussed above. In particular, the teachings of Cann regarding using magnetic beads (claims 3-4), that the guide RNA is biotinylated (claim 5), that the target nucleic acid is from a genome of pathogen (claim 9), isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle (claim 11), sequencing the target nucleic acid to obtain sequence reads (claim 12), and analyzing the sequence reads to identify one or more variants in the biological sample (claim 13) and Gourguechon regarding the target nucleic acid being from a genome of a pathogen (claim 9) are discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the method of the copending claims to include isolating steps using a guide RNA that is biotinylated, magnetic beads complexed with the guide RNA and Cas, and applying a magnetic field to separate the target nucleic acid from the particle, and further to include sequencing and analyzing steps to identify the variants in the biological sample as taught by Cann. It would have been further obvious to one of ordinary skill in the art to have modified the method of the copending claims to apply the methods to a target nucleic acid that is a from a genome of a pathogen as taught by Gourguechon because Cann and Gourguechon also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from bodily fluid samples.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-19 of copending Application No. 18/514,333, in view of Cann (US20160017396A1) and Gourguechon (WO2016100955A2; published June 23, 2016; as cited as #34 in the 17 page IDS filed on August 9, 2024).
Claims 1-12 and 14-19 of the ‘333 application encompass a method for enriching a sample, the method comprising: obtaining a biological sample (bodily fluid) comprising a target nucleic acid; binding Cas endonuclease and guide RNA that targets the target nucleic acid to a particle to form a particle complex; introducing the particle complex to the sample to bind to the target nucleic acid; and digesting unbound nucleic acids with exonucleases. Claims 1-12 and 14-19 of the ‘333 application further teach that the sample comprises a liquid biopsy sample and that the sample is from a patient. Claims 1-12 and 14-19 of the ‘333 application further teach that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, includes a mutation specific to a tumor, and is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-12 and 14-19 of the ‘333 application teach amplifying the target nucleic acid sequence.
The copending claims do not teach that using magnetic beads (claims 3-4), the guide RNA is biotinylated (claim 5), that the target nucleic acid is from a genome of pathogen (claim 9), isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle (claim 11), sequencing the target nucleic acid to obtain sequence reads (claim 12), and analyzing the sequence reads to identify one or more variants in the biological sample (claim 13).
However, the teachings of Cann and Gourguechon are discussed above. In particular, the teachings of Cann regarding using magnetic beads (claims 3-4), that the guide RNA is biotinylated (claim 5), that the target nucleic acid is from a genome of pathogen (claim 9), isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle (claim 11), sequencing the target nucleic acid to obtain sequence reads (claim 12), and analyzing the sequence reads to identify one or more variants in the biological sample (claim 13) and Gourguechon regarding the target nucleic acid being from a genome of a pathogen (claim 9) are discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the method of the copending claims to include isolating steps using a guide RNA that is biotinylated, magnetic beads complexed with the guide RNA and Cas, and applying a magnetic field to separate the target nucleic acid from the particle, and further to include sequencing and analyzing steps to identify the variants in the biological sample as taught by Cann. It would have been further obvious to one of ordinary skill in the art to have modified the method of the copending claims to apply the methods to a target nucleic acid that is a from a genome of a pathogen as taught by Gourguechon because Cann and Gourguechon also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from bodily fluid samples.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/519,589, in view of Cann (US20160017396A1).
Claims 1-18 of the ‘649 application encompass a method for enriching a sample, the method comprising: obtaining a biological sample (bodily fluid) comprising a target nucleic acid; binding Cas endonuclease and guide RNA that targets the target nucleic acid to a particle to form a particle complex; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1-18 of the ‘649 application teach digesting unbound nucleic acids with exonucleases, using magnetic particles, and isolating target nucleic acids by applying a magnetic field to separate the target nucleic acid from the particle. Claims 1-18 of the ‘649 application further teach the bodily fluid sample comprising bile, blood, plasma, serum, sweat, saliva, urine, feces, phlegm, mucus, sputum, tears, cerebrospinal fluid, synovial fluid, pericardial fluid, lymphatic fluid, semen, vaginal secretion, products of lactation or menstruation, amniotic fluid, pleural fluid, rheum, or vomit. Claims 1-18 of the ‘649 application further teach that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, and is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-18 of the ‘649 application the guide RNA is biotinylated and that the target nucleic acid is from a genome of pathogen.
The copending claims do not teach a method of detecting a variant in a nucleic acid sample comprising obtaining a biological sample comprising nucleic acid from a patient suspected of having a variant in a target nucleic acid; enriching the sample by introducing a Cas endonuclease guide RNA particle complex directly into the sample to bind to the target nucleic acid wherein the guide RNA targets the target nucleic acid; separating the particle complex with the bound target nucleic acid from the sample; and detecting the variant in the target nucleic acid sample (claim 19) and that the detecting step comprises gel electrophoresis (claim 20).
However, the teachings of Cann are discussed above. In particular, the teachings of Cann regarding a method for detecting a variant in a nucleic acid sample, the method comprising obtaining cfDNA from a subject's plasma or serum from a subject suspected of having a variant in a target nucleic acid and detecting the variant in the target nucleic acid sample with gel electrophoresis are discussed above.
It would have been obvious to one of ordinary skill in the art to have modified the method of the copending claims to include the methods of detecting a variant in a nucleic acid sample comprising gel electrophoresis as taught by Cann because Cann also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from bodily fluid samples.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 01/27/2025 have been fully considered but they are not persuasive. Applicant requests that the non-statutory double patenting rejections be held in abeyance until allowable subject matter is identified, at which stage Applicant will consider filing a terminal disclaimer to overcome the non-statutory double patenting rejections. However, such a response is not a proper reply to the outstanding rejection of record.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHALEDA B HASAN/Examiner, Art Unit 1636 /BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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