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 .
Previous Rejection
Status of Prior Rejections/Objections:
The objection to the specification is maintained and further clarified.
The objection to claim 31 is withdrawn in view of the amendment.
The 112(b) rejections to claim(s) 2, 5, 11, 16, 19, 27, 35, 37, 42, and 45, is/are withdrawn in view of the amendments to or cancellation of the claims. See 112(b) section for additional rejections necessitated by amendments.
The prior art rejection(s) under 35 USC 103 directed as being unpatentable over Abudayyeh and over Abudayyeh in view of Myhrvold are withdrawn in view of the amendments, which integrate the limitations of claim 3 and a subset of claim 5. Accordingly, the rejections over Abudayyeh in view of Webster and further in view of Myhrvold have updated in view of the amendments.
The non-statutory double patenting rejections have likewise been updated to reflect the art rejections.
Status of Claims
Applicant' s amendment filed 11/26/2025 is acknowledged. Claims 1, 9, 16, 19, 27, 31, 35, 37, 42, and 45 have been amended. Claims 2-3, 5-6, 8, 10, 12-13, 17, 20, 22-23, 26, 30, 33, 38, 43, 46, 48, 50, 54-55, 57, 61 are cancelled. Claims 1, 4, 7, 9, 11, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45, 47, 49, 51-53, 56, and 58-60 are pending in the instant application. Claims 7, 47, 49, 51-53, 56, and 58-60 are withdrawn and claims 1, 4, 9, 11, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45 are the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Specification
The use of the terms including “Tye”, “Triton”, and “HEX”, each which is a trade name or a mark used in commerce, has been noted in this application. The such terms should be accompanied by the generic terminology; furthermore, such terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP 2111.
Regarding claim 1, claim 1 recites “one or more optimized guide molecules designed to bind one or more corresponding target molecules”. This limitation is interpreted to recite a product-by process because it requires (explicitly or inherently) the steps of designing and optimizing, wherein it is noted that the goal of optimization is undisclosed and therefore implies no specific structural requirements beyond the recited SEQ ID NOs. See MPEP 2113 and 2173.05(p)(I).
Regarding claims 9, 39-42, and 44, as above, the claims recite or imply manipulations (i.e., a method) for generating “the optimized guide”. This claims are therefore interpreted to recite a product-by-process limitations. As above, it is noted that product-by-process claims are not limited to the manipulations of the recited steps, only the structures implied by the steps. See MPEP 2113 and 2173.05(p)(I).
Claim 9 requires that the optimized guide be optimized for a Cas13 ortholog. However, it fails to recite or imply specific structures and fails to specify what goal of the optimization is with respect to the Cas13 ortholog (e.g., specificity, cutting efficiency, speed of cutting, etc.).
Claims 39-41 do not require particular structures of a nucleic acid detection system, and are directed to the training model, which appears to be part of the optimization (see original claim 2).
Claims 42 and 44 recite requirements for the predicting that restricts the highly activity guides used in the “identifying”; however, as the “selecting optimized guides” does not require either that the guides be selected from amongst the highly active guides. Further, it is noted that activity of the guides is measured by relative, rather than absolute, means within the process and therefore fails to imply particular structures.
Claim Rejections - 35 USC § 112(b)
Claims 39-42 and 44 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
Regarding claim 39, the claim recites “the training model”. There is insufficient antecedent basis for this limitation in the claim. Further, the nexus between the training model and the elements of claim 1 is unclear.
Claims 40-41 are indefinite for depending from claim 39 and not rectifying the deficiency.
Regarding claim 42, the claim recites “the predicting highly active guides” and “the target molecule”. There is insufficient antecedent basis for this limitation in the claim. Further, the nexus between the predicting and the elements of claim 1 is unclear.
Claim 44 is indefinite for depending from claim 42 and not rectifying the deficiency.
Claim Rejections - 35 USC § 103
Claims 1, 4, 9, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34, 36-37, 39-42, and 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (WO 2018/107129 A1; published 06/14/2018; as cited in the IDS dated 09/06/2022) in view of Webster (WO 2012/135340 A2; published 10/04/2012).
Regarding claims 1 and 4, Abudayyeh teaches a nucleic acid detection system comprising:
a detection CRISPR system comprising an effector protein and one or more guide
RNAs designed to bind to corresponding target molecules; and
an RNA-based masking construct (claim 1).
Abudayyeh teaches that the effector protein may be a C2c2 [i.e., Cas13a; see para 0006] effector protein (claim 13) and that the one or more guide RNAs are designed to bind to target molecules that are diagnostic for cancer (claim 38).
Abudayyeh teaches that its invention may be used to detect genes and mutations associated with cancer, wherein it attempts to incorporate by reference papers related to chronic lymphocytic leukemia [a cancer of white blood cells] (para [0423]; see also para [0141]).
Abudayyeh teaches that the guide RNAs are designed to bind to one or more target molecules comprising cancer specific somatic mutations, wherein the specific mutations may be from a gene selected from BCR-Abl (instant claim 4) and EML4-ALK [i.e., cancer fusion genes] (para [0008]).
A single embodiment of Abudayyeh fails to explicitly teach that the designed guide RNA targeting a cancer fusion gene is optimized in some way.
Abudayyeh rectifies this by teaching a designing process to optimize on-target collateral cleavage and minimize collateral cleavage of a target that differs by a target mismatch, wherein this was performed to increase specificity (para [0482]). Abudayyeh further teaches a method for identifying the optimal crRNA for detection by varying spacer length in order to investigate the robustness of targeting (para [0515]; Fig. 99).
A single embodiment of Abudayyeh fails to explicitly teach that the designed guide RNA targeting a cancer fusion gene is optimized in some way.
Abudayyeh rectifies this by teaching a designing process to optimize on-target collateral cleavage and minimize collateral cleavage of a target that differs by a target mismatch, wherein this was performed to increase specificity (para [0482]). Abudayyeh further teaches a method for identifying the optimal crRNA for detection by varying spacer length in order to investigate the robustness of targeting (para [0515]; Fig. 99).
Abudayyeh fails to explicitly state that the cancers detected are selected from APML, CML, and/or ALL and the specific genes targeted are those of the claimed SEQ ID NOs.
Webster rectifies this by teaching compositions and methods for diagnosing cancer (Title), wherein when the fusion gene is detected the subject is diagnosed with leukemia, a specific subtype of leukemia or the genetic aberration underlying leukemia in a subject is determined (para [15]). Webster teaches that the leukemia can be chronic myelogenous leukemia, acute myeloid leukemia or acute lymphoblastic leukemia (para [14]).
Webster teaches the BRC-ABL is a known fusion gene in leukemia, and is correlated with the onset and progression of various types of leukemia (para [04]).
Webster further teaches that recurrent chromosomal translocations characterize a substantial proportion of leukemias, resulting in the formation of unique fusion genes, wherein the identification of particular fusion gene abnormalities is of considerable diagnostic and prognostic importance, and that there is a need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias and sub-types of leukemias based on gene fusion (para [03]).
Webster teaches at least SEQ ID NO: 198, which comprises instant SEQ ID NO: 2671, which is identified as a “target sequence” for PML-RARA (Table 2; instant claim 4).
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the nucleic acid detection system for cancer using crRNAs targeting cancer fusion genes of Abudayyeh with the optimization of guide RNAs of Abudayyeh, motivated by the desire to increase specificity and robustness of targeting, as taught by Abudayyeh. There would have been a strong expectation for success as this is applying a known method to a known product and all of these embodiments of Abudayyeh are directed to the same classes of CRISPR-Cas systems.
Further, it would have been obvious to one the ordinary skill in the art before the effective filing date of the claimed invention to combine the nucleic acid detection system of Abudayyeh with the cancer targets, i.e., leukemias, of Webster, motivated by the uniqueness of the fusion genes, the considerable diagnostic and prognostic importance for said cancers, and the need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias, as taught by Webster. In doing so, it would have been obvious to select from among the “target sequences” of Webster that comprise SEQ ID NO 2671 and to apply the optimization of Abudayyeh. There would have been a strong expectation of success as the gene targets overlap of Webster and Abudayyeh overlap and such are known genes in the class of cancers, which were likewise contemplated by Abudayyeh.
Using the methods of optimization taught by Abudayyeh discussed above, it would have been within routine experimentation to arrive at the claimed sequence (and its inherent coordinates in the genome/transcriptome). It is noted that the courts have found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II. Thus, the claimed sequence (coordinates) merely represents routine optimization of the values of the cited prior art.
Regarding claims 9, 39-42, and 44, in the system of Abudayyeh in view of Webster. Abudayyeh teaches the optimized guide for the target molecule, as discussed in claim 1. See also the claim interpretation section.
For the sake of argument, for claim 9, Abudayyeh teaches designing robust crRNAs for LwaCas13a (para [0515]) and engineering increased specificity through design of crRNAs in LwCas13 [interpreted to be LwaCas13; see instant para 0181] (para [0482]).
Regarding claim 14, in the system of Abudayyeh in view of Webster, Webster teaches BCR-ABL targets corresponding to b2a2 (SEQ ID NO: 138), b3a2 (SEQ ID NO: 141), and e1a2 (SEQ ID NO: 144) in Table 2.
Regarding claim 15, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the RNA-based masking construct
comprises a silencing RNA that suppresses generation of a gene product encoded by a reporting
construct, wherein the gene product generates the detectable positive signal when expressed (para [0013]).
Regarding claim 16, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the RNA-based masking construct is a ribozyme that generates the negative detectable signal, and wherein the positive detectable signal is generated when the ribozyme is deactivated, or the ribozyme converts a substrate to a first color and wherein the substrate converts to a second color when the ribozyme is deactivated (para [0014]).
Abudayyeh teaches that detection technologies that provide high specificity and sensitivity at low cost would be of great utility in both clinical and basic research settings (para [0003]).
While Abudayyeh does not explicitly teach that the ribozyme performs both the negative to positive and the color conversion, such a combination would be obvious to the artisan before the effective filing date of the claimed invention as Abudayyeh teaches each element. The artisan would be motivated by the desire to improve the sensitivity and specificity of such a detection system, as taught by Abudayyeh. There would be a strong expectation for success as both elements are taught for ribozymes in similar systems.
Regarding claim 18, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the RNA-based masking agent is an RNA aptamer (para [0015]).
Regarding claim 19, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the RNA-based masking agent is an RNA aptamer, or the aptamer sequesters an enzyme, wherein the enzyme generates a detectable signal upon release from the aptamer by acting upon a substrate, or the aptamer sequesters a pair of agents that when released from the aptamers combine to generate a detectable signal (para [0015]).
Therefore, Abudayyeh teaches at least that the aptamer sequesters a pair of agents, one of which may be an enzyme, that when released from the aptamers combine to generate a detectable signal (para [0015]).
Regarding claim 21, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that an existing aptamer that inhibits an enzyme with a colorimetric readout is used, such as thrombin, protein C, neutrophil elastase, and subtilisin (para [0224]).
Regarding claim 24 and 31, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the masking construct may comprise an RNA oligonucleotide to which are attached a detectable label and a masking agent of that detectable label (para [0230]; instant claim 24). Abudayyeh also teaches that the RNA-based masking construct comprises an RNA oligonucleotide to which a detectable ligand and a masking component are attached, wherein the detectable ligand may be a fluorophore and the masking component may be a quencher (para [0016]; instant claims 24 and 31).
Regarding claim 25, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that RNA-based masking construct comprises
a nanoparticle held in aggregate by bridge molecules, wherein at least a portion of the bridge
molecules comprises RNA, and wherein the solution undergoes a color shift when the
nanoparticle is disbursed in solution, wherein nanoparticle is a colloidal metal (claim 29).
Regarding claim 27, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the masking construct may comprise one or more RNA oligonucleotides to which are attached one or more metal nanoparticles, such as
gold nanoparticles (para [0231]).
Regarding claim 28, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the masking construct may comprise a quantum dot, wherein quantum dot may have multiple linker molecules attached to the surface; at least a portion of the linker molecule comprises RNA; and the linker molecule is attached to the quantum dot at one end and to one or more quenchers along the length or at terminal ends of the linker such that the quenchers are maintained in sufficient proximity for quenching of the quantum dot to occur (para [0233]).
Regarding claim 29, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the masking construct comprises the use of intercalating dyes which change their absorbance in response to cleavage of long RNAs to short nucleotides, wherein such dyes include pyronine-Y and methylene blue (para [0235]).
Regarding claim 32, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the masking construct comprises an RNA oligonucleotide designed to bind a G-quadruplex forming sequence, wherein a G-quadruplex structure is formed by the G-quadruplex forming sequence upon cleavage of the masking construct, and wherein the G-quadruplex structure generates a detectable positive signal (claim 93), wherein such G-quadraplexes in DNA can complex with heme to form a DNAzyme with peroxidase activity (para [0226]).
Regarding claim 34, in the system of Abudayyeh in view of Webster, Abudayyeh teaches that the RNA-based masking construct comprises an RNA oligonucleotide with a detectable ligand on a first end of the RNA oligonucleotide and a masking component on a second end of the RNA oligonucleotide (para [0029]). Abudayyeh teaches the reporter constructs of Table 5 that comprise a 5’ fluorophore and a 3’ antigen/quencher.
It is noted that, broadly interpreted, a nucleotide is “a group of atoms bonded together” and so any unmodified oligonucleotide also would be encompassed by this limitation. Therefore, Abudayyeh, as previously cited, teaches all of the previously discussed RNA-based masking constructs (i.e., aptamers, ribozymes, quantum dot on an RNA linker, etc.).
Regarding claims 36 and 37, in the system of Abudayyeh in view of Webster, Abudayyeh, as cited in the rejection of claim 1, teaches that the Cas protein is a Cas13. Instant claim 37 teaches that Cas13 is a species of Type VI Cas.
Regarding claim 45, in the system of Abudayyeh in view of Webster, Abudayyeh teaches a one-pot system with RPA and C2c2 [Cas13a] detection, comprising reagents for each (para [0464]). Abudayyeh teaches that the RPA amplifies target molecules (Fig. 17).
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Abudayyeh (WO 2018/107129 A1; published 06/14/2018; as cited in the IDS dated 09/06/2022) in view of Webster (WO 2012/135340 A2; published 10/04/2012) applied to claim 1 above, and further in view of Myhrvold (Myhrvold C, et al. Field-deployable viral diagnostics using CRISPR-Cas13. Science. 2018 Apr 27;360(6387):444-448.).
Regarding claim 35, in the system of Abudayyeh in view of Webster, Abudayyeh teaches a masking construct that binds to an immobilized reagent and that a labeled binding partner may be biotin and that the label on the binding partner may be any detectable label known in the art (para [0220]) but fails to teach specific fluorophores.
Myhrvold rectifies this by teaching the LF-polyU reporter comprising 5’FAM and 3’Bio [i.e., biotin] (Supplementary Material, pg. 62), used in lateral flow experiments of Fig. 2 and Fig. 4.
Myhrvold teaches that their direct detection with a colorimetric readout using lateral flow strips can directly detect their target from bodily fluids with minimal equipment (pg. 1, col 3, para 2, spanning pg. 3). Myhrvold teaches that their platform is field-deployable with high performance, is sensitive and specific, and can be easily adapted and scaled to enable multiplexed detection (pg. 5, col 1, para 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the masking construct of Abudayyeh for the LF-polyU reporter and lateral flow detection of Myhrvold, motivated by the desire to enable sensitive and specific field-deployable detection that requires minimal equipment, as taught by Myhrvold. There would have been a strong expectation for success as both are directed toward detection techniques with CRISPR-Cas13.
Double Patenting
Claims 1, 4, 9, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 17/495,219 in view of Webster (WO 2012/135340 A2; published 10/04/2012) and Myhrvold (Myhrvold C, et al. Field-deployable viral diagnostics using CRISPR-Cas13. Science. 2018 Apr 27;360(6387):444-448.). This is a provisional nonstatutory double patenting rejection.
Both sets of claims are drawn to a nucleic acid detection system comprising a CRISPR system comprising an effector protein (that can be a LwaCas13a/L. wadei C2c2 protein) and one or more guide polynucleotides capable of binding a target sequence and design to for a complex with the Cas protein (including a LwaCas13a/L. wadei C2c2 protein); an RNA-based masking construct (and the variety of embodiments thereof); and nucleic acid amplification reagents. ‘219 claim 12 recites that the guide polynucleotides are designed to bind to one or more target sequences that are diagnostic for a disease state, wherein the disease state is a cancer, and wherein the cancer specific mutations are present in one or more genes encoding a protein selected from BCR-Abl and EML4-ALK [i.e., cancer fusion genes].
Any additional limitations of the ‘219 patent are encompassed by the open claim language “comprising” found in the instant claims. As in the 103, see claim interpretation for discussion of the product-by-process limitations.
The claims of ‘219 do not discuss:
Particular cancers (instant claim 1), particular guide sequences targeting cancer fusion genes (instant claim 1), and particular BCR-ABL fusion targets (claim 14)
Particular fluorophores or biotin/DIG (claim 35)
Particular systems of amplification the nucleic amplification reagents belong to (instant claim 45)
Webster rectifies this in part by teaching the cancers APML, CML, and ALL (as cited in the rejection of instant claim 1 above); the gene fusion targets for diagnosing these leukemias including PML-RARA and the sequence as cited in the rejection of instant claim 1 above directed to the gene fusion; and particular BCR-ABL fusions including the b2a2 fusion (as cited in the rejection of instant claim 14 above).
Webster teaches the BRC-ABL is a known fusion gene in leukemia, and is correlated with the onset and progression of various types of leukemia (para [04]).
Webster teaches that recurrent chromosomal translocations characterize a substantial proportion of leukemias, resulting in the formation of unique fusion genes, wherein the identification of particular fusion gene abnormalities is of considerable diagnostic and prognostic importance, and that there is a need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias and sub-types of leukemias based on gene fusion (para [03]).
Myhrvold then rectifies this by teaching the LF-polyU reporter comprising 5’FAM and 3’Bio [i.e., biotin] (Supplementary Material, pg. 62), used in lateral flow experiments of Fig. 2 and Fig. 4. Myhrvold teaches that the systems of Fig. 2 and Fig. 4 utilize RPA (Fig. 2A; Fig. 4F).
Myhrvold teaches that their direct detection with a colorimetric readout using lateral flow strips can directly detect their target from bodily fluids with minimal equipment (pg. 1, col 3, para 2, spanning pg. 3). Myhrvold teaches that their platform is field-deployable with high performance, is sensitive and specific, and can be easily adapted and scaled to enable multiplexed detection (pg. 5, col 1, para 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the nucleic acid detection system of ‘219 with the targets, i.e., leukemias, gene fusion targets, and sequences, of Webster, motivated by the considerable diagnostic and prognostic importance of the uniqueness of the fusion genes and the need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias, as taught by Webster. There would be a strong expectation for success as the gene targets already overlap.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the masking construct of ‘219 for the LF-polyU reporter, RPA amplification system, and lateral flow detection of Myhrvold, motivated by the desire to enable sensitive and specific field-deployable detection that requires minimal equipment, as taught by Myhrvold. There would have been a strong expectation for success as both are directed toward detection techniques with CRISPR-Cas13.
Claims 1, 4, 9, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, 23, 26, 29, 34, 39-40, 43, 47, 49-50, 71, 106, 109-112, 115-116, 129-136, 137-138, 140-155, 165-168, and 172 of copending Application No. 16/955,380 in view of Webster (WO 2012/135340 A2; published 10/04/2012).
Both sets of claims are drawn to a nucleic acid detection system comprising two or more CRISPR systems, each CRISPR system comprising a Cas protein (that may be a Cas13a derived from Leptotrichia) and one or more guide molecules (that can be a LwaCas13a/L. wadei C2c2 protein) capable of binding a corresponding target nucleic acid and design to form a complex with one or more Cas proteins; and a set of detection [i.e., masking] constructs. ‘380 claim 154 recites that the guide polynucleotides are designed to bind to one or more target sequences that are diagnostic for a disease state, wherein the disease state is a cancer.
Any additional limitations of the ‘380 patent are encompassed by the open claim language “comprising” found in the instant claims. As in the 103, see claim interpretation for discussion of the product-by-process limitations.
The claims of ‘380 do not discuss:
That the target is a gene fusion (instant claim 1), particular cancers (instant claim 3), particular guide sequences targeting cancer fusion genes (instant claim 5), and particular BCR-ABL fusion targets (claim 14)
Webster rectifies this by teaching the cancers APML, CML, and ALL (as cited in the rejection of claim 1 above); the use of gene fusion targets for diagnosing these leukemias including PML-RARA and the sequence as cited in the rejection of claim 1 above directed to the gene fusion; and particular BCR-ABL fusions including the b2a2 fusion (as cited in the rejection of claim 14 above).
Webster teaches that recurrent chromosomal translocations characterize a substantial proportion of leukemias, resulting in the formation of unique fusion genes, wherein the identification of particular fusion gene abnormalities is of considerable diagnostic and prognostic importance, and that there is a need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias and sub-types of leukemias based on gene fusion (para [03]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the nucleic acid detection system of ‘380 with the targets, i.e., leukemias, gene fusion targets, and sequences, of Webster, motivated by the considerable diagnostic and prognostic importance of the uniqueness of the fusion genes and the need in the art for reliable diagnostic compositions for the detection and diagnosis of leukemias, as taught by Webster. There would be a strong expectation for success as the gene targets already overlap.
There would be a strong expectation for success as the as both are directed to detection of cancers.
Claims 1, 4, 9, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following patents and claims in view of over Abudayyeh (WO 2018/107129 A1; published 06/14/2018; as cited in the IDS dated 09/06/2022), Webster (WO 2012/135340 A2; published 10/04/2012), and Myhrvold (Myhrvold C, et al. Field-deployable viral diagnostics using CRISPR-Cas13. Science. 2018 Apr 27;360(6387):444-448; as cited in the IDS dated 10/27/2022).
Patent:
Rejected over Application Claims:
Fails to recite:
Other notes:
10266887
1-14
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene • Cancer detected is a leukemia
Method that teaches the system limitations renders the system obvious
11174515
1-29, 31-32, 36-43, 56-60
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene (guides may be diagnostic for cancer, e.g., claim 28); • Cancer detected is a leukemia
Instant claims teach BCR-Abl a cancer fusion gene; A fusion is interpreted to be a type of mutation; Method that teaches the system limitations renders the system obvious
Abudayyeh rectifies the sets of masking constructs as cited above in claims 15-16, 18-19, 21, 24-25, 27-29, 31-32, and 34 above in the 103 rejection.
Abudayyeh rectifies the design of guides toward cancer fusion genes in part by teaching BCR-ABL as cited in the rejection of claim 4 above.
Abudayyeh teaches use of an RNA-based masking construct with an RNA targeting effector [Cas] (Fig. 7) and that Cas13/type IV Cas are RNA-targeting enzymes (para [0511]; [0520]).
Abudayyeh teaches that the Cas protein may be LawCas13a, as cited in the rejection of claim 5 above.
Abudayyeh teaches that its RNA targeting effectors provide robust CRISPR-based diagnostic with attomolar sensitivity and that its embodiments can be prepared in freeze-dried format for convenient distribution and point-of-care (POC) applications (Abstract). Abudayyeh teaches that the sensitivity of its invention may allow for noninvasive detection of clonal mutations arising during [cancer] treatment and can be used to detect a recurrence in the disease (para [0425])
Therefore, it would have been obvious to one the ordinary skill in the art before the effective filing date of the claimed invention to combine either of the above patents with Abudayyeh and/or substitute the masking constructs of the above patents with those of Abudayyeh. It further would have been obvious to choose RNA-based masking constructs given a Cas13 and/or type VI Cas given the teachings of Abudayyeh in the combined method. The artisan would have been so motivated by the desire to create a robust and sensitive POC system to test for mutations throughout cancer treatment, as taught by Abudayyeh. There would have been a strong expectation for success as all are directed to CRISPR-Cas-based systems.
Webster further rectifies the cancer fusion genes of specific BCR-ABL fusions as cited in the rejection of claim 14 above, the target for the guide sequences as cited in the rejection of claim 1 above, and that the cancer may be the one or more of APML, CML, and/or ALL)as cited in the rejection of claim 1 above, wherein it would be obvious to combine with the same expectation for success as discussed above.
Myhrvold further rectifies the sets of masking constructs by teaching a reporter with FAM and BIO, as cited in the rejection of claim 35, wherein it would be obvious to combine with the same expectation for success as discussed above.
It is noted that devices, kits, and/or compositions comprising a system with all of the claimed features anticipate the system and/or render it obvious when comprising a sufficient number of features modified as described.
It is also held to be obvious to look at other elements within the same claim set, motivated by the desire to improve the method with a strong expectation of success as the inventions are directed to CRISPR-Cas systems and/or use thereof.
Claims 1, 4, 9, 14-16, 18-19, 21, 24-25, 27-29, 31-32, 34-37, 39-42, and 44-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending Applications in view of Abudayyeh (WO 2018/107129 A1; published 06/14/2018; as cited in the IDS dated 09/06/2022), Webster (WO 2012/135340 A2; published 10/04/2012), and Myhrvold (Myhrvold C, et al. Field-deployable viral diagnostics using CRISPR-Cas13. Science. 2018 Apr 27;360(6387):444-448; as cited in the IDS dated 10/27/2022.). This is a provisional nonstatutory double patenting rejection.
Copending Application:
Rejected over Application Claims:
Fails to recite:
Other notes:
16645571
1-4, 7, 9-10, 15, 17, 20, 23, 25-26, 30-31, 35-36, 39, 41, 44, 46, 49, 69, 72, 74-75, 77-78, 81, 102, 105, 108, 111-114
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene (guides may be diagnostic for cancer; claim 47); • Cancer detected is a leukemia
A subset of the claims are a detection device that comprise a system with the claimed components
16753896
1-4, 6, 9, 12, 15, 21-22, 24, 26, 48-49, 55-57, 59, 64-65
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene (guides may be diagnostic for cancer; claim 26); • Cancer detected is a leukemia
Lateral flow device comprises a system with the claimed components
16961820
1-5, 10, 12-13, 17, 19-20, 39-40, 45-47, 49, 51, 54, 56, 69-75
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene (guides may be diagnostic for cancer; claim 20); • Cancer detected is a leukemia
16973061
61-62, 64, 66, 68-69, 71, 73-74, 78, 80, 86-89
• The full set of masking constructs and that the masking construct is RNA-based; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia
17065504
1, 5, 21, 26, 28, 31-34, 36-37, 40-41, 48, 50, 52
• The full set of masking constructs and that the masking construct is RNA-based; • Target of configured/designed guide is cancer fusion gene (guides may be diagnostic for cancer; claim 52); • Cancer detected is a leukemia; • Amplification reagents
17264340
331, 384, 389, 393
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia; • Specific amplification system reagents
Method that teaches the system limitations renders the system obvious
17294179
1-2, 5, 8, 10, 12, 19, 29-34, 40-41, 44-45, 47, 59-63
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia
Method that teaches the system limitations renders the system obvious
17413802
1, 115-128, 130-132
• The full set of masking constructs and that the masking construct is RNA-based; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia
17439063
1, 3-7, 9-15, 17-23, 25-30, 33-35
• The full set of masking constructs; • Cancer detected is a leukemia; • Specific BCR-Abl targets
Detection construct interpreted to be a masking construct; Method that teaches the system limitations renders the system obvious; Instant claims teach BCR-Abl and PML-RARA as cancer fusion genes
17761292
1-2, 7-8, 13, 19, 22, 52, 76-77, 80, 82, 85
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia
Method that teaches the system limitations renders the system obvious
18814007
1-2, 5, 7-10, 13, 15-16, 21, 25-26, 33, 35-36
• The full set of masking constructs; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia
18906750
1-4, 6-8, 17-18, 21-23-25, 29, 31, 33
• The full set of masking constructs and that the masking construct is RNA-based; • Target of configured/designed guide is cancer fusion gene; • Cancer detected is a leukemia; • Lwa2Cas13a guide
Abudayyeh rectifies the sets of masking constructs as cited above in claims 15-16, 18-19, 21, 24-25, 27-29, 31-32, and 34 above in the 103 rejection.
Abudayyeh rectifies the design of guides toward cancer fusion genes in part by teaching BCR-ABL as cited in the rejection of claim 4 above.
Abudayyeh teaches that the Cas protein may be LawCas13a, as cited in the rejection of claim 5 above.
Abudayyeh teaches use of an RNA-based masking construct with an RNA targeting effector [Cas] (Fig. 7) and that Cas13/type IV Cas are RNA-targeting enzymes (para [0511]; [0520]).
Abudayyeh teaches that its RNA targeting effectors provide robust CRISPR-based diagnostic with attomolar sensitivity and that its embodiments can be prepared in freeze-dried format for convenient distribution and point-of-care (POC) applications (Abstract). Abudayyeh teaches that the sensitivity of its invention may allow for noninvasive detection of clonal mutations arising during [cancer] treatment and can be used to detect a recurrence in the disease (para [0425])
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine either of the above patents with Abudayyeh and/or substitute the masking constructs of the above patents with those of Abudayyeh. It further would have been obvious to one ofchoose RNA-based masking constructs given a Cas13 and/or type VI Cas given the teachings of Abudayyeh in the combined method. The artisan would have been so motivated by the desire to create a robust and sensitive POC system to test for mutations throughout cancer treatment, as taught by Abudayyeh. There would have been a strong expectation for success as all are directed to CRISPR-Cas-based systems.
Webster further rectifies the cancer fusion genes of specific BCR-ABL fusions as cited in the rejection of claim 14 above, the target for the guide sequences as cited in the rejection of claim 1 above, and that the cancer may be the one or more cancers of claim 1 as cited in the rejection of claim 1 above, wherein it would be obvious to combine with the same expectation for success as discussed above.
Myhrvold further rectifies the sets of masking constructs by teaching a reporter with FAM and BIO, as cited in the rejection of claim 35 above, wherein it would be obvious to combine with the same expectation for success as discussed above.
It is noted that devices, kits, and/or compositions comprising a system with all of the claimed features anticipate the system and/or render it obvious when comprising a sufficient number of features modified as described.
It is also held to be obvious to look at other elements within the same claim set, motivated by the desire to improve the method with a strong expectation of success as the inventions are directed to CRISPR-Cas systems and/or use thereof.
Response to Arguments
Applicant's arguments filed 11/26/2025 have been fully considered but they are not persuasive.
Regarding the objection to the specification, while the usage of “FAM” appears to have been addressed, other trade names, including those specifically named in the updated objection and those further identified by the Applicant, should be treated likewise.
Regarding the 103 rejection, Applicant traverses the rejection under the grounds that the combination of Abudayyeh and Webster do not teach the specific optimize guide molecules targeting cancer fusion genes. Contrary to the assertions, as addressed in the 103 rejection above, Webster teaches a variety of “target sequences” in the cited Table 2 including SEQ ID NO: 2671 in Webster’s SEQ ID NO: 198, as discussed in the 103 rejection of claim 1 above.
Regarding the non-statutory double patenting rejections, the rejections have been updated. The later filing dates for applications ‘292, ‘007, and ‘750 are noted. However, such double-patenting rejections are not improper while there are other rejections outstanding. See MPEP 804(I)(B)(1)(b)(i): “If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date”. Further, the Office is not able to hold NSDP rejections in abeyance in such circumstances. See MPEP 804(B)(1).
Conclusion
No claims are allowed. Claim 11 is objected to for depending from claim 1. The sequences of claim 11 are free of the art.
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.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636