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 .
Claim Status
Applicant’s claims filed 10/31/2023 has been entered. Claims 1-20 are pending and examined herein.
Priority
This application is a CON of 18/121,328 (filed 03/14/2023), which is a CON of 16/018,926 (filed 06/26/2018; ABN), which has PRO 62/672,217 (filed 05/16/2018) and PRO 62/526,091 (filed 06/28/2017). Accordingly, the EFD is 06/28/2017.
Claim Objections
Claim 3 is objected to because of the following informalities: Claim 3 reciting the phrase “Case endonuclease” appears to have “Case” misspelled with the “e” at the end. Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: on p. 2, line 3, "it Cas" should read "it" or "Cas".
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.
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 15 and 19 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 protein-bound target nucleic acid" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the protein-bound target nucleic acid" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 1-3 and 5-20 are rejected under 35 U.S.C. 103 as being unpatentable over Cann et al. (US20160017396A1, published January 21, 2016; Cite No. 14 in IDS filed 08/09/2024).
Cann’s disclosure is directed to enriching polynucleotides using CRISPR-Cas systems and teaches a variety of methods for enriching target nucleic acids (entire document).
Regarding claim 1, Cann teaches a method for enriching a target nucleic acid in a population of cell free DNA (cfDNA) from a subject's plasma or serum and providing a target-specific crRNA and a Cas protein variant and contacting the target nucleic acid with the endonuclease system to form a complex (see claim 22; paras 0023 and 0157).
However, Cann does not specifically teach introducing the Cas endonuclease to the bodily fluid sample directly.
Regarding claim 1, Cann further 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, para 0006, and Example 1). Cann further teaches obtaining the target DNA from bodily fluid samples, including a subject’s plasma or serum (see claim 22). Claim 1 recites “the method comprising”, which allows additional steps to achieve enriching a sample. Cann teaches isolating target nucleic acids before introducing Cas endonuclease (see para 0164) and after introducing Cas endonuclease (see claim 1, para 0006, and Example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Cann’s method of enriching target nucleic acids from bodily fluid samples by isolating the target nucleic acids after introducing Cas endonuclease because it would have amounted to a simple combination of Cann’s prior art elements according to known methods to yield predictable results. One would have had a reasonable expectation of success because Cann teaches several compositions and different uses of Cas endonucleases to bind target nucleic acids in samples collected from subjects. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 2, Cann teaches RNA-guided protein Cas endonuclease contains two catalytically inactive nuclease domains (see paras 0015, 0163, and 0167).
Regarding claim 3, Cann teaches contacting target nucleic acid with a population of Cas9 proteins programmed with a set of crRNAs that are complimentary to a series of different regions of the target nucleic acid (see claim 25). Cann further teaches a method for targeted haplotype sequencing using CRISPR-Cas systems where Cas9 proteins remain associated with the ends of cleaved DNAs (see para 0218).
Regarding claim 5, Cann teaches bodily fluid samples comprising plasma and serum (see claim 22) and maternal plasma and blood (see paras 0164 and 0168).
Regarding claim 6, Cann teaches the target nucleic acid comprising cell free DNA (cfDNA) (see claim 22; paras 0023 and 0157). Cann further teach methods of enriching and/or detecting target nucleic acids in circulating tumor DNA (ctDNA) from cancer patients (see paras 0156 and 0165).
Regarding claim 7, 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 paras 0122 and 0152).
Regarding claim 8, Cann teaches amplifying the targeted nucleic acid to yield amplicons (see paras 0007, 0140, 0155, and 0167; and Examples 2 and 4).
Regarding claim 9, Cann teaches methods for sequencing target DNA sequences from ctDNA isolated from cancer patients and analyzing the target DNA sequences to describe one or more mutations in a subject to detect mutations in key genes that have relevance for treatment decisions (see paras 0156 and 0167).
Regarding claims 10 and 11, Cann teaches methods used to diagnose a cancer having analyzed the target nucleic acid to describe one or more mutations specific to a tumor in a subject and to monitor tumor progression and/or test a tumor patient's response to targeted drug treatments (see paras 0165 and 0166).
Regarding claim 12, 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 13 and 14, Cann teaches detecting the target nucleic acid by hybridizing the target nucleic acid to a biotinylated capture probe or to a primer for detection or amplification (see Example 1, Fig. 9, Example 6, and 0151). Cann further teaches detecting the target nucleic acid by labelling the target nucleic acid with detectable capture tags, such as biotinylated dNTP, oligo probes, or double-stranded nucleic acid adapters (see para 0184).
Regarding claims 15 and 16, Cann teaches detecting the target nucleic acid with a CRISPR-Cas system containing a Cas9 protein and a crRNA-tracrRNA chimera added and binding to a target DNA sequence to form a complex. The Cas9 protein is labeled with a capture tag, through which the complex is separated. The target DNA is then isolated from the complex (see paras 0058, 0152; and Example 6).
Regarding claims 17-19, 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 20, Cann teaches enriching target DNA using a CRISPR-Cas system and detecting the target nucleic acid with gel electrophoresis (see paras 0232 and 0261).
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Cann et al. (US20160017396A1, published January 21, 2016; Cite No. 14 in IDS filed 08/09/2024) as applied to claims 1-3 and 5-20 above, and further in view of Gourguechon (WO2016100955A2; published June 23, 2016; Cite No. 34 in IDS filed 08/09/2024).
The teachings of Cann are applied to claim 4 as they are applied to claims 1-3 and 5-20 under 35 U.S.C. § 103 above.
However, Cann does not teach introducing an exonuclease to the bodily fluid sample to digest unbound nucleic acid.
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) that complex with guide RNAs bound to target nucleic acid sequences that prevent dCas9 from cutting the target nucleic acid (see para 0162-0164).
Regarding claim 4, 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).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Cann’s method of enriching nucleic acids with Cas endonuclease with the 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 have combined 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. One 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.
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.
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-11, and 13-20 of copending Application No. 18/128,328. Although the claims at issue are not identical, they are not patentably distinct from each other because there is significant overlap in the claims.
Claims 1-5, 7-11, and 13-20 of the '328 application encompass a method of enriching a sample, the method comprising: obtaining a bodily fluid sample comprising a target nucleic acid; introducing two or more Cas endonucleases directly into the bodily fluid to bind the ends of the target nucleic acid (which encompasses catalytically active and inactive) and that the target nucleic acid is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-5, 7-11, and 13-20 of the '328 application encompass a guide RNA that targets the target nucleic acid to a particle to form a particle-bound segment, digesting unprotected nucleic acids with an exonuclease, isolating the target nucleic acid. Claims 1-5, 7-11, and 13-20 of the ‘634 application further teach that the bodily fluid sample comprises 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, and that the target nucleic acid comprises cfDNA. Claims 1-5, 7-11, and 13-20 of the '634 application further teach detecting tumor mutations from the sample, amplifying the target nucleic acid to yield amplicons, analyzing sequence reads, applying magnetic fields to separate the target nucleic acids from the particle by applying the sample to a column, wherein the protein-bound target nucleic acid is separated from unbound nucleic acid in the sample by size exclusion, ion exchange, or adsorption, and detection comprises gel electrophoresis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-7, 9-14, and 16-21 of copending Application No. 18/131,634 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because there is significant overlap in the claims.
Claims 1, 3-7, 9-14, and 16-21 of the ‘634 application encompass a method of enriching a sample, the method comprising: obtaining a bodily fluid sample comprising a target nucleic acid; binding Cas endonuclease (which encompasses catalytically active and inactive) and guide RNA that targets the target nucleic acid to a particle to form a particle complex; digesting unprotected nucleic acids with an exonuclease; isolating the target nucleic acid; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1, 3-7, 9-14, and 16-21 of the ‘634 application further teach that the bodily fluid sample comprises 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, that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, and that the target nucleic acid is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1, 3-7, 9-14, and 16-21 of the '634 application further teach detecting tumor mutations from the sample, amplifying the target nucleic acid, analyzing sequence reads, and applying magnetic fields to separate the target nucleic acids from the particle.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 18/519,589 in view of Cann et al. (US20160017396A1, published January 21, 2016; Cite No. 14 in IDS filed 08/09/2024).
Claims 1-18 and 21-22 of the ‘589 application encompass a method of enriching a sample, the method comprising: obtaining a bodily fluid sample comprising a target nucleic acid; binding Cas endonuclease (which encompasses catalytically active and inactive) and guide RNA that targets the target nucleic acid to a particle to form a particle complex; digesting unprotected nucleic acids with an exonuclease; isolating the target nucleic acid; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1-18 and 21-22 of the '589 application further teach that the bodily fluid sample comprises 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, that the target nucleic acid comprises cDNA, cfDNA, or ctDNA, and that the target nucleic acid is present at no more than about 0.01% of cell-free DNA in the bodily fluid sample. Claims 1-18 and 21-22 of the '589 application further teach detecting tumor mutations from the sample, amplifying the target nucleic acid, analyzing sequence reads, and applying magnetic fields to separate the target nucleic acids from the particle.
The copending claims do not teach amplifying the target nucleic acid to yield amplicons (claim 8), the protein-bound target nucleic acid is separated from unbound nucleic acid in the sample by size exclusion, ion exchange, or adsorption (claim 19), and the detection step comprises gel electrophoresis (claim 20).
However, the teachings of Cann are discussed above. In particular the teachings of Cann regarding amplifying the target nucleic acid to yield amplicons, applying a magnetic field to separate components, and further using gel electrophoresis for detection 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 with the amplification and detection steps 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.
Claims 1-20 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 et al. (US20160017396A1, published January 21, 2016; Cite No. 14 in IDS filed 08/09/2024).
Claims 1-12 and 14-19 of the ‘333 application encompass a method of detecting a target nucleic acid, the method comprising: obtaining a liquid biopsy sample comprising a target nucleic acid; binding Cas endonuclease (catalytically active and inactive) and guide RNA that targets the target nucleic acid to a particle to form a particle complex; digesting unprotected nucleic acids with an exonuclease; isolating the target nucleic acid; and introducing the particle complex to the sample to bind to the target nucleic acid. Claims 1-12 and 14-19 of the ‘333 application further teach that the target nucleic acid is present at no more than about 0.01% of cell-free DNA in the sample. Claims 1-12 and 14-19 of the '333 application further teach detecting tumor mutations from the sample, amplifying the target nucleic acid, and analyzing sequence reads to provide genetic information to a subject.
The copending claims do not teach that the detection step comprises connecting the protein-bound target nucleic acid to a particle or column and removing other components of the bodily fluid sample (claim 15), the particle comprises an agent that binds to at least one protein to form a particle-bound segment (claim 16), the particle comprises magnetic or paramagnetic material and the detection step further comprises applying a magnetic field to separate the particle-bound segment from the other components (claim 17), the detection step comprises applying the sample to a column (claim 18), the protein-bound target nucleic acid is separated from unbound nucleic acid in the sample by size exclusion, ion exchange, or adsorption (claim 19), and the detection step comprises gel electrophoresis (claim 20).
However, the teachings of Cann are discussed above. In particular, the teachings of Cann regarding the detection steps comprising magnetic particles, applying a magnetic field to separate components, and further using gel electrophoresis for detection 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 with the detection steps as taught by Cann because Cann also teaches methods of enriching nucleic acids with Cas endonuclease and detecting nucleic acids from fluid samples.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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
Prosecution Insights