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
Applicant’s claim set filed May 29, 2026 is acknowledged. No claims were amended, canceled or added. Claims 1, 3-5 and 7-21 are pending and under examination.
Response to Arguments
Applicant’s arguments regarding the nonstatutory double patenting (NSDP) rejections have been fully considered. Examiner also consulted with a Training Quality Assurance Specialist (TQAS) in TC1600 for their perspective and opinion on the NSDP rejections of record and Applicant’s arguments. The NSDP rejections are maintained. Examiner’s response to Applicant’s arguments follows the NSDP rejections.
Priority
As indicated in previous office actions, the disclosure of the prior-filed applications, Application Nos. 62351662, 62351803, 62376377, 62410366, 62410366 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The above Applications fail to disclose a “masking construct” or a “detector molecule” and/or fail to recite “collateral activity” of Cas13a species, and/or fail to disclose the species of Cas13a recited in claims 1 and 5. Application No. 62471792, filed March 15, 2017, first discloses the Cas13a species listed in claims 1 and 5 (pages 264-273). Because all claims depend from either claim 1 or 5, the effective filing date for all claims is March 15, 2017.
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, 3-5 and 7-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 10 and 12-19 of U.S. Patent No. 12415000 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). Claims 4 and 9 are further rejected further in view of Chu (WO 90/06376, published June 14, 1990; of record). This is a maintained rejection.
Patented claim 1 recites A Class 2, type VI CRISPR system effective to reduce a viral load in a subject and detect the presence of a virus, the system comprising (a) Cas13 protein and (b) twoThalassospira sp. TSL5-1. The patented Specification teaches that the Cas13a from Thalassospira sp. TSL5-1 has SEQ ID NO 23 (Table 5), which is 100% identical to SEQ ID NO 83 of the examined Application. Therefore, as properly construed, patented claim 13 encompasses a Cas13a that has SEQ ID NO 83.
The patented claims do not recite the features of patented claims 10 and 13 in a single claim. The patented claims do not recite the detector RNA has a fluorescent detectable signal. The patented claims do not recite amplification reagents. The patented claims do not recite the nature of the sample with the viral target RNA.
Doudna teaches methods of detecting a target RNA using LbuC2c2 (i.e., a Cas13a) loaded with (b) a lambda-targeting crRNA (i.e., a guide molecule capable of forming a complex to a target sequence of a target RNA) and introduced into a sample comprising lambda RNA spiked into HeLa cell total RNA ([0471]; Fig 13). Doudna teaches also including (c) a non-target RNA that has a fluorophore and a quencher conjugated to the ends such that when the non-target RNA is cleaved (i.e., deactivated) produces a fluorescent signal (i.e., an RNA-based masking construct comprising a non-target sequence ([0471], [0474]; FIG. 13). Doudna teaches that Cas13a will cleave the non-target sequence of the fluorescent reporter once activated by the target sequence ([0471], [0473]-[0474]; FIG. 13). Doudna teaches detecting the lambda RNA (i.e., a viral pathogen) based on the fluorescent output by the reporter (FIG. 13B). Doudna teaches two other Cas13a enzymes, LshC2c2 and LseC2c2, demonstrate pre-crRNA processing similar to LbuC2c2 (FIG 16). Doudna teaches C2c2 enzymes used in the invention can be naturally occurring C2c2 ([0192]-[0193]). Doudna also teaches a phylogenetic tree of naturally occurring C2c2, with LshC2c2, LseC2c2, and LbuC2c2 on diverging branches (Fig 22A) and an amino acid alignment of LshC2c2, LseC2c2, and LbuC2c2 (Fig 22B). Regarding claim 7, Doudna teaches introducing two crRNAs to detect a second RNA target along with lambda RNA in the sample ([0472], FIG 13C). Regarding claims 10-16 and 19-20, Doudna teaches contacting a HeLa total RNA sample (i.e., a cell-free sample, a cellular sample with the claimed composition and detecting fluorescence from the reporter. The sample in Doudna comprising HeLa cell total RNA ([0471]) is interpreted as being both 1) a cell-free biological sample because it does not contain any cells, and 2) a cellular sample because it is derived from HeLa cells. Doudna also teaches samples can be from biopsy samples (i.e., comprises a eukaryotic cell, and animal cell, a cancer cell), plant cells and bacterial cells (i.e., prokaryotic cells) ([0117]-[0118]).
Regarding claims 1, 3-5 and 7-9, it would have been obvious to combine the limitations of patented claims 10 and 13 in a single claim because Doudna teaches that using Cas13a in an assay to detect viral RNAs requires an RNA-based masking construct. Additionally, since viruses are known to cause cancer, cause plant diseases, and promote virulence in bacteria (i.e., prokaryotic cells), it would have been obvious to formulate the patented CRISPR system for detecting viral pathogens in those samples. It would have been obvious to use the patented device/composition in a method to detect a target RNA because Doudna teaches such a use for Cas13a, a guide RNA and an RNA-based fluorescent reporter.
Regarding claim 3 and 8, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the fluorescent reporter in Doudna (i.e., a masking construct). It would have amounted to the substitution of a generic masking construct for the specific one taught in Doudna by known means to yield predictable results. The skilled artisan would predict that it could be used with the patented composition and obvious methods of using the patented composition, and been motivated to do so, because Doudna teaches such a reporter can be used in Cas13a-based detection methods with high signal/noise and high sensitivity.
Regarding claims 4 and 9, Chu teaches a goal in the nucleic acid probe art is to detect target nucleic acids that are in small amounts, such as viral RNA, relative to other nucleic acids in a sample (¶ spanning pages 2-3). Chu teaches one way to detect RNAs present in low amounts is to increase the number of copies of the target RNA through amplification (page 3, lines 6-20). Chu teaches once the target RNA is amplified it can be reliably detected by any of the many techniques that have been developed for detection including use a reporter molecule (page 3, lines 20-29). Chu teaches the process of amplifying a target RNA: a primer (i.e., an amplification reagent) hybridizes to the target RNA, which is then used by an RNA-dependent RNA polymerase (i.e., an amplification reagent) to extend the RNA primer, thereby amplifying the target RNA (¶ spanning pages 5-6; FIG. 1).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have added amplification reagents to the copending method of RNA-detection using a Cas13a/guide RNA and non-target RNA reporter. It would have amounted to the simple combination of elements by known means to yield predictable results. It would have been predictable to add the amplification reagents described in Chu to the patented CRISPR system because Chu teaches that the amplification method can be combined with other detection methods in the art including reporter-based methods. The skilled artisan would have been motivated to add Chu's amplification reagents for the purpose of increasing the copy-number of rare RNAs such as viral RNAs to increase the sensitivity of the assay.
Regarding claims 10-21, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the patented system in a method to specifically detect pathogen RNAs in samples that are cell-free, cellular and contain prokaryotic, eukaryotic, plant, animal and/or cancer cells because the patented claims recite that the purpose of the system is to “detect” the presence of a virus and Doudna teaches Cas13a-based detection methods can be used to detect RNA in such samples. One would have been motivated to do so for the purpose of detecting pathogenic infection in those samples and because Doudna suggests it.
Claims 1, 3-5 and 7-11, 13, 15 and 17-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12467925 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). This is a maintained rejection.
Patented claim 1 recites A nucleic acid detection system for detecting the presence of hemorrhagic fever viruses in a sample comprising: a CRISPR system comprising a Cas13 effector protein and multiple guide molecules having a direct repeat and a guide sequence designed to bind to one or more corresponding target molecules of one or more hemorrhagic fever viruses (i.e., a pathogen) … and an RNA-based masking construct. Patented claim 22 recites wherein the Cas13 effector protein is a C2c2 effector protein from an organism selected from the group consisting of: Thalassospira sp. TSL5-1 (i.e., a Cas13a protein). The patented Specification states that the Cas13a protein from Thalassospira sp. TSL5-1 was disclosed in provisional application 62/471710 filed on March 15, 2017 (column 34). US Provisional Application 62/471710 defines the sequence of Cas13a from Thalassospira sp. TSL5-1 (Table 3), which is 100% identical to SEQ ID NO 83 of the examined application. Thus, as properly construed, patented claim 22 encompasses a nucleic acid detection system with the Cas13a with SEQ ID NO 83. Patented claim 6 recites wherein the RNA-based masking construct comprises a quantum dot linked to one or more quencher molecules by a linking molecule, wherein at least a portion of the linking molecule comprises RNA. Patented claim 11 recites a method of detecting a viral nucleic acid using the detection system of claim 1 and amplifying the sample nucleic acid using helicase-dependent, ligase-mediated or transposase-based amplification (i.e., using amplification reagents).
Therefore, as properly construed, patented claim 22 recites all the limitations of examined claim 1 except that the RNA-based masking construct comprises a non-target sequence. The patented claims do not recite the nature of the sample with the viral target.
The teachings of Doudna are recited above in paragraph 9.
Regarding claims 1, 3-5 and 7-11, 13, 15 and 17-21, it would have been obvious to have designed the patented RNA-based masking construct to comprise a non-target sequence because Doudna teaches that Cas13a-based detection systems use an RNA-based masking construct that has a different sequence than the targeted RNA.
Regarding claims 10-11, 13, 15 and 19-20, the obviousness of using the patented composition and method formulated detecting a viral RNA in cell-free samples or samples containing eukaryotic, animals is recited above in paragraph 10. It specifically would have been obvious to formulate the CRISPR system for use in a eukaryotic, animal sample because hemorrhagic fever viruses are known to affect humans.
Claims 1, 3-5 and 7-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 12559786 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). This is a maintained rejection.
Patented claim 1 recites a method of detecting a target nucleic acid sequence, comprising (c) amplifying the target nucleic acid sequence by generating RNA oligonucleotides comprising the target nucleic acid sequence via transcription from the inserted one or more T7 RNA polymerase promoters (i.e., amplification reagents) and (d) detecting the nucleic acid sequence using a CRISPR-Cas detection system, wherein the CRISPR-Cas detection system comprises a CRISPR effector protein and a guide sequence that is complementary to the target nucleic acid sequence. Patented claim 2 recites wherein the CRISPR-Cas detection system is a CRISPR Cas13-based detection system. Patented claim 13 recites where in the Cas13 enzymes from Thalassospira sp. TSL5-1 (i.e., Cas13a). The patented Specification states that the Cas13a protein from Thalassospira sp. TSL5-1 was disclosed in provisional application 62/471710 filed on March 15, 2017 (column 15). US Provisional Application 62/471710 defines the sequence of Cas13a from Thalassospira sp. TSL5-1 (Table 3), which is 100% identical to SEQ ID NO 83 of the examined application. Thus, as properly construed, patented claim 13 is directed to a nucleic acid detection system with the Cas13a with SEQ ID NO 83. Patented claims 24-27 recite wherein the target nucleic acid sequence comes from a sample, and wherein the sample is a biological sample including blood (i.e., a cellular sample comprising eukaryotic, animal cells), serum (i.e., a cell-free sample) or a plant sample.
The patented claims do not recite that the Cas13a detection system includes an RNA-based masking construct. The patented claims do not recite the nature of the sample with the viral target RNA or that the sample comprises a prokaryotic cell or a cancer cell. The patented claims do not recite using two or more crRNAs.
The teachings of Doudna are recited above in paragraph 9.
Regarding claims 1, 3-5 and 7-21, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have included in a fluorescent-based cleavable RNA-based masking construct with the patented “CRISPR-Cas detection system” comprising the Thalassospira sp. TSL5-1 Cas13a (i.e., having 100% identity to SEQ ID NO 83) because Doudna teaches that a Cas13a system with such a masking construct can be used as an RNA-detection system. The obviousness of using specifically a fluorescent reporter in Doudna as part of a Cas13a detection system is recited above in paragraph 11.
Regarding claim 7, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have added a second crRNA to the patented method because Doudna teaches Cas13a-based RNA-based detection methods can be multiplexed to detect different target RNAs. The skilled artisan would have been motivated to do so in order to increase the sensitivity of the detection assay for an RNA-based pathogen.
Regarding claim 12 and 16, the obviousness of using the patented composition and method for detecting an RNA derived a pathogen in samples that contain prokaryotic and/or cancer cells is recited above in paragraph 12.
Claims 1, 3-5 and 7-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 10, 12-13, 17, 19-20, 25, 27-29, 31, 33, 35, 37, 39-40, 43, 54, 59, 62 and 66 of copending Application No. 16961820 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). This is a maintained rejection.
Copending claim 1 a nucleic acid detection system comprising: one or more guide RNAs designed to base-pair to a complementary target nucleotide sequence of a target molecule, a Type VI CRISPR-Cas RNA targeting effector protein or a homolog, an ortholog, or a functional variant thereof, wherein complex formation between the CRISPR-Cas effector protein and the one or more guide RNAs annealed to the target nucleotide sequence triggers a non-specific collateral ribonuclease activity; and an RNA-based masking construct comprising an RNA having a quadruplex having enzymatic activity that produces a color signal, wherein the loss of the color signal being indicative of the presence of the target molecule. Copending claim 3 recites further comprising nucleic acid amplification reagents. Copending claims 10 and 13 recite the RNA-targeting effector protein is C2c2 (i.e., Cas13a), including from an organism from Thalassospira sp TSL5-1. The copending Specification teaches that the Cas13a from Thalassospira sp TSL5-1 has SEQ ID NO 316 (Table 2), which is 100% identical to SEQ ID NO 83 of the examined Application. Therefore, as properly construed, copending claim 13 encompasses a Cas13a that has SEQ ID NO 83. Copending claim 19 recites wherein the one or more guide RNAs are designed to detect a single nucleotide polymorphism in the target molecule, or a splice variant of an RNA transcript. Copending claim 20 recites wherein the one or more guide RNAs are designed to bind to one or more target molecules that are diagnostic for a disease state including cancer (i.e., the sample comprises a eukaryotic, animal, cancer cell), or an infection optionally caused by a virus, a bacterium (i.e., the sample comprises a prokaryotic cell) a fungus, a protozoan, or a parasite (i.e., the target is a viral, bacterial, fungal or parasite pathogen). Copending claim 54 recites a method for detecting target nucleic acids using the system of claim 1.
The copending claims do not encompass an RNA-based masking construct that uses a non-target RNA linked to a fluorophore and a quencher. The copending claims do not recite two or more guide RNAs. The copending claims do not recite the nature of the sample.
The teachings of Doudna are recited above in paragraph 9.
Regarding the masking construct, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have substituted the RNA aptamer-based detection molecule with the fluorescent reporter comprising a fluorophore, quencher and a non-target RNA sequence in the copending composition and method. It would have amounted to a simple substitution of one RNA-based reporter for another by known means to yield predictable results. The obviousness of using the fluorescent reporter in Doudna is recited above in paragraph 11.
Regarding claim 7, the obviousness of including two crRNA guide molecules in the copending composition is recited above in paragraph 26.
Regarding claims 10-21, the obviousness of using the copending composition and method for detecting an RNA from a viral pathogen in samples that are cell-free, cellular and contain prokaryotic, eukaryotic, plant, animal and/or cancer cells is recited above in paragraph 12.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-5 and 7-11, 13, 15-16, 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 8, 11-12, 17 and 30-32 of copending Application No. 17495219. Claim 7 is rejected in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). This is a maintained rejection.
Copending claim 1 recites A nucleic acid diagnostic kit comprising: a detection CRISPR system comprising an effector protein and one or more guide RNAs capable of binding to corresponding target molecules, wherein said target molecules comprise somatic mutations, germline mutations, and/or single nucleic acid polymorphisms (SNP) in mammalian cells; an RNA-based masking construct. Copending claims 34 recites further comprising nucleic acid amplification reagents. Copending claim 5 recites wherein the CRISPR system effector protein is an RNA-targeting effector protein, optionally wherein the CRISPR RNA-targeting effector protein is C2c2, and/or wherein the C2c2 effector protein is from an organism of a genus selected from the group consisting of: Thalassospira sp. TSL5-1 (i.e., a Cas13a protein). The copending Specification teaches that the C2c2 from Thalassospira sp. TSL5-1 has SEQ ID NO 316 (Table 2), which is 100% identical to SEQ ID NO 83. Thus, as properly construed, copending claim 5 includes a Cas13a protein with SEQ ID NO 83. Copending claim 8 recites wherein the RNA-based masking construct comprising a quantum dot linked to one or more quencher molecules by a linking molecule. Copending claim 12 recites wherein the one or more guide RNAs are designed to detect a single nucleotide polymorphism in a target RNA or DNA, or a splice variant of an RNA transcript (i.e., detect a target RNA). Copending claim 17 recites a method for detecting target nucleic acids in a sample using the detection system of claim 1 from samples including blood sample (i.e., a cellular sample from a eukaryotic and animal) and a sera sample (i.e., a cell-free sample). Thus, the copending claims anticipate examined claims 1, 3-5, 8-11, 13, 15-16, 19-20.
The copending claims do not recite multiple guide RNAs.
The teachings of Doudna are recited above in paragraph 9.
Regarding claim 7, the obviousness of including two crRNA guide molecules in the copending composition is recited above in paragraph 26.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-5 and 7-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 18772681 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record). This is a maintained rejection.
Copending claim 1 A nucleic acid detection system comprising: a detection CRISPR system comprising an a CRISPR-Cas effector protein having a non-sequence-specific collateral cleavage activity and one or more guide molecules comprising a polynucleotide sequence having sufficient complementarity with a target nucleic acid sequence to hybridize with the target nucleic acid sequence, and to direct sequence-specific binding of an RNA-targeting complex comprising the one or more guide molecules and the CRISPR effector protein to the target nucleic acid sequence; and an RNA-based masking construct comprising a non-target RNA oligonucleotide sequence, wherein activation of the CRISPR-Cas effector protein's collateral cleavage activity by the sequence-specific binding of the RNA-targeting complex to the target nucleic acid sequence triggers the cleavage of the non-target RNA oligonucleotide sequence of the RNA-based masking construct and generates a detectable signal indicating the detection of the target nucleic acid sequence. Copending claim 3 recites the system further comprises nucleic acid amplification reagents. Copending claims 9, 18-19 recites wherein the CRISPR effector protein comprises a CRISPR-Cas13 effector protein, including a Cas13 from Thalassospira sp. TSL5-1 (i.e., a Cas13a). The copending Specification teaches that the Cas13a from Thalassospira sp. TSL5-1 has SEQ ID NO 316 (Table 2), which is 100% identical to SEQ ID NO 83 of the examined application. Therefore, as properly construed, copending claim 19 includes a Cas13a with SEQ ID NO 83, which anticipates the claimed Cas13a. Copending claims 12 recites wherein the RNA-based masking construct comprises a fluorophore and a quencher of the fluorophore attached to the non-target RNA oligonucleotide sequence in sufficient proximity for quenching to occur, wherein cleavage of the non-target RNA oligonucleotide sequence by the CRISPR effector protein's non-sequence- specific collateral cleavage activity relieves the quenching to generate a detectable fluorescent signal.
The copending claims do not recite two or more guide RNAs. The copending claims do not recite the nature of the target is RNA or the nature of the samples comprising the target. The copending claims do not recite using the system in a method.
The teachings of Doudna are recited above in paragraph 9.
The obviousness of using the copending Cas13a detection system in a method to detect viral pathogen target RNAs in samples that are cell-free, cellular and contain prokaryotic, eukaryotic, plant, animal and/or cancer cells is recited above in paragraphs 12.
Regarding claim 7, the obviousness of including two crRNA guide molecules in the copending composition is recited above in paragraph 26.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-5 and 7-11, 13, 15 and 17-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 12, 15, 17, 28 and 38 of copending Application No. 19351824 in view of Doudna (US 20170362644A1, priority to June 16, 2016; of record).
Copending claim 1 recites A nucleic acid detection system for detecting the presence of hemorrhagic fever viruses in a sample comprising: a CRISPR system comprising an effector protein and one or more guide molecules designed to bind to one or more corresponding target molecules of one or more hemorrhagic fever viruses… and an RNA-based masking construct. Copending claim 4 recites the nucleic acid detection system of claim 1 further comprising nucleic acid amplification reagents. Copending claims 12 and 15 recite wherein the CRISPR RNA-targeting effector protein is C2c2 (i.e., a Cas13a), including from Thalassospira sp. TSL5-1. The copending Specification states that the Cas13a protein from Thalassospira sp. TSL5-1 was disclosed in provisional application 62/471710 filed on March 15, 2017 ([0124]). US Provisional Application 62/471710 defines the sequence of Cas13a from Thalassospira sp. TSL5-1 (Table 3), which is 100% identical to SEQ ID NO 83 of the examined application. Thus, as properly construed, copending claim 15 encompasses a nucleic acid detection system with the Cas13a with SEQ ID NO 83. Copending claims 17 and 28 recite wherein the RNA-based masking construct suppresses generation of a detectable positive signal, and wherein the RNA-based masking construct suppresses generation of a detectable positive signal by masking the detectable positive signal, wherein the RNA-based masking construct comprises an RNA oligonucleotide to which a detectable ligand and a masking component are attached, wherein the detectable ligand is a fluorophore and the masking component is a quencher molecule. Copending claim 38 recites A method for detecting viral nucleic acid in a sample comprising: amplifying the sample nucleic acid; combining the sample with an RNA effector protein… and an RNA-based masking construct… and wherein the sample is a biological sample comprising blood, plasma, serum, urine, or saliva.
Therefore, as properly construed, copending claim 15 recites all the limitations of examined claim 1 except that the RNA-based masking construct comprises a non-target sequence. The copending claims do not recite two or more guide RNAs.
The teachings of Doudna are recited above in paragraph 9.
Regarding claims 1, 3-5 and 7-11, 13, 15 and 17-21, it would have been obvious to designed the copending RNA-based masking construct to comprise a non-target sequence because Doudna teaches that Cas13a-based detection systems use an RNA-based masking construct that has a different sequence than the targeted RNA.
Regarding claims 10-11, 13, 15 and 19-20, the obviousness of using the copending composition and method formulated detecting a viral RNA in cell-free samples or samples containing eukaryotic, animals is recited above in paragraph 10. It specifically would have been obvious to formulate the CRISPR system for use in a eukaryotic, animal sample because hemorrhagic fever viruses are known to affect humans.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments – NSDP
Regarding the NSDP rejection over the ‘000 patent, Applicant argues that the rejection fails to (1) identify the difference between the patented claims and (2) articulate a motivation to combine the teachings of the references. Applicant argues there are more differences between the patented and examined claims than the identified masking construct – namely the patented claims require two or more guide RNAs that are tiled across a viral target. Applicant argues that Examiner has not provided any reason why the skilled artisan would eliminate the extra guide RNA. Applicant argues that the open comprising language of the patented claims does not cure this deficiency since it only operates in the additive direction to add more elements, not eliminate them. Applicant argues that Doudna does not render obvious removal of a guide RNA (page 5, ¶2 through page 6, ¶3). These arguments have been fully considered but are not persuasive.
First, the instant/examined claims also recite comprising. In the previous office action, Examiner stated that the examined claims are the claims that recite “comprising” and thus encompass any additional elements in the composition (see previous Office Action, ¶61). Thus, the examined claims do not require rendering obvious the removal of a guide RNA. Rendering obvious the removal of an element would only be necessary if the examined claims recited a system that “consists” of one guide RNA. Because the examined claims recite the system “comprising a guide molecule” that is generic as to its target, any system comprising one or more guide RNAs (i.e., up to and over 50 tiled guide RNAs) that target any specific sequence will anticipate the composition of the examined claims. Therefore, the only element required to render obvious in the examined claims in view of the patented claims is the combination of limitations of patented claims 10 and 13. Such a combination was rendered obvious in view of Doudna who teaches masking constructs with Cas13a enzymes, which Applicant does not dispute. Doudna is not required to render obvious the removal of a guide RNA since such a removal is not necessary because the examined claims use open claim language.
Regarding the NSDP rejection over the ‘925 patent, Applicant argues that the rejection fails to (1) identify the difference between the patented claims and (2) articulate a motivation to combine the references. Applicant argues there are more differences between the patented and examined claims than the quantum-dot variant of claim 6 – namely the patented claims require the detection system to detect the presence of a hemorrhagic fever virus and use of a specific guide sequence, whereas the examined claims cover without restriction any target sequence. Applicant also argues that claim 1 of the '925 patent is directed to any Cas13 protein, which is narrowed in patented claim 22 with a closed Markush of 33 specifically enumerated source organisms with no preference among them. Applicant argues the Examiner needed to render obvious choosing a specific Cas13 with a specific sequence and render obvious the generic guide RNA (Remarks, pages 8-10). Theses arguments having been fully considered but are not persuasive.
Frist, it is noted that even in obvious-type double patenting, a species anticipates a genus. Thus, 1) the specific guide RNA of the patented claims anticipates the generic guide RNA sequence of the examined claims, and 2) the human sample type anticipates the generic sample type of claim 1. It is also noted that only claims that are generic to or recite a eukaryotic, mammalian, and animal cells are rejected over the ‘925 patent since it would not have been obvious to use the patented composition in plant cells. Thus, the Examiner has taken into account only generic systems that encompass the human pathogenic virus. Additionally, the instant/examined claims also recite “the composition comprising”, i.e., the examined claims do not require rendering obvious the removal of an element. Rendering obvious the removal of an element would only be necessary if the examined claims recited a system that “consists of” the elements recited in the claims. Because the examined claims recite the system “comprising a guide molecule” that is generic as to its target, any system comprising one or more guide RNAs that target any specific sequence (i.e., including a target-specific guide RNA) will anticipate the guide RNA portion of the examined claims.
Second, the patented specification defines the Cas13a from Thalassospira sp. TSL5-1 as being disclosed in Provisional application 62/471710, which then defines the Cas13a in Table 3. The disclosed sequence for Thalassospira sp. TSL5-1 is 100% identical to SEQ ID NO 83. MPEP 804.B.1 states “The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim. In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02.” Therefore, as properly construed, patented claim 22 is directed to a Cas13a protein with 100% identity to instantly claimed SEQ ID NO 83. Regarding, the Markush group of Cas13a proteins in the patented claims, MPEP 2131.02.II states “a reference that clearly names the claimed species anticipates the claim no matter how many other species are named. Additionally, MPEP2177.I. explains a proper Markush groups requires their recognition as members of an art-recognized class and have functional equivalency. Thus, not only does the patented claim “name” the Cas13a proteins of the examined claims as properly construed thus anticipating the genus of the examined claim, it would have been prima facie obvious to select any Cas13a from the patented Markush group by virtue of their inclusion in the patented Markush group.
Regarding the NSDP rejection over the ‘786 patent, Applicant argues that the rejection fails to (1) identify the difference between the patented claims and (2) articulate a motivation to combine the references. Applicant argues there are more differences between the patented and examined claims than the Examiner recites. First, the patented claims are to a different statutory class – a method with a required series of steps. Second, the patented claims require a transposon architecture and T7-amplificaiotn steps. Applicant also argues that the rejection fails on the motivation prong since Examiner has provided no motivation as to why the skilled artisan would eliminate the transposase and T7-amplification steps (Remarks, pages 11-12). These arguments having been fully considered but are not persuasive.
As indicated above in paragraphs 56 and 59, the instant/examined claims recite a composition “comprising” and can encompass additional elements including transpose and T7 promoter elements. Rendering obvious the removal of an element would only be necessary if the examined claims recited a system that “consists” of the recited elements. Because the examined claims recite the system “comprising” a guide molecule and the recited Cas13a, any system comprising one or more guide RNAs, the Cas13a, and the masking construct anticipates the composition even if the patented claims use the system in the context of a method. As such, a method that uses a composition anticipates that composition even if the patented and examined claims are directed to different statutory classes. Nevertheless, the patented claims also recite the detection system. Therefore, the only element required to render obvious in the examined claims in view of the patented claims is the inclusion of an RNA-based masking construct in the Cas13a-based detection system of the patented claims. Because Doudna teaches Cas13a-based detection systems require an RNA-based masking complex, it would have been obvious to include one in the patented method, which then would anticipate the claimed composition in the examined claims.
Applicant argues that 16961820, 17495219, 18772681 and 19351824 each have a later PTA date than the present application (page 13). Examiner agrees that the co-pending applications have a later US filing date. However, MPEP 804.I.B.1.(b).(i) makes clear that a provisional double patenting rejection should be made and maintained by the examiner until the rejection has been overcome by amendment or the rejection is the only rejection remaining in an application having the earlier patent term filing date. Because the claims are still rejected for NSDP over patented claims, the provisional rejections for NSDP are maintained.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. 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 CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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