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 .
Claims 1-8 and 10-45, of record 7/10/2025, are pending. Claims 1-8 and 10-15 are subject to prosecution. Claims 16-45 remain withdrawn. Claims 1, 3-6, 8, and 14 are amended. Claim 9 is cancelled.
Status of Prior Rejections/Response to Arguments
RE: Objection to the specification:
The amendment to the specification is effective to obviate the objection. The objection is withdrawn.
RE: Objection to claims 1 and 4-5:
The amendments to claims 1 and 4-5 are effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claim 9 under 35 U.S.C. 112(a):
The cancellation of claim 9 renders the rejection thereto moot.
RE: Rejection of claims 3 and 9 are rejected under 35 U.S.C. 112(b):
The cancellation of claim 9 renders the rejection thereto moot.
The amendment is claim 3 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1, 3, and 9-15 under 35 U.S.C. 103 over Barrett et al. (US 20190192691 A1):
RE: Rejection of claims 1-3, and 9-15 under 35 U.S.C. 103 over Barrett et al. (US 20190192691 A1) in view of Minkenberg et al. (Progress in Molecular Biology and Translational Science, 2017):
RE: Rejection of claims 1, 3-6, and 8-15 under 35 U.S.C. 103 over Barrett et al. (US 20190192691 A1) in view of Mandell et al. (US 20180259541 A1):
RE: Rejection of claims 1 and 3-15 under 35 U.S.C. 103 over Barrett et al. (US 20190192691 A1) in view of Mandell et al. (US 20180259541 A1), further in view of Minkenberg et al. (Progress in Molecular Biology and Translational Science, 2017):
The amendment to claim 1 to require a DRD derived from a CA2 parent protein comprising one or more mutations relative to instant SEQ ID NO 5 is effective to obviate the rejections. The rejections are withdrawn.
New Rejections
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al. (US 20190192691 A1), of record, in view of Daigle et al. (US 20060257990 A1).
Regarding claims 1 and 10-15: Barrett et al. teach one or more polynucleotides encoding regulatable biocircuit systems, wherein the regulatable biocircuit systems comprise one or more effector modules (See Abstract, 0091 and fig. 1). Each effector module comprises a stimulus response element and one or more payloads, wherein the stimulus response element is responsive to at least one stimulus (See ¶0053, 0093, and 0489 and fig. 2-6).
Barrett et al. disclose the stimulus response element is joined, attached, linked to the one or more payloads of the effector molecule, thus reading on wherein the payload is “operably linked” to the stimulus response element (See ¶0094 and 0107 and fig. 2-6). The stimulus response element can be a destabilizing domain protein, such as CA2 stabilized by acetazolamide or celecoxib (which read on “responsive to or interacts with… Acetazolamide… or Celecoxib”) (See ¶0006-0008, 0089, 0092, 0208, and 0644 and table 4). Barrett et al. disclose that, in the presence of a ligand that binds to, or interacts with, the destabilizing domain, the stability of, and consequently the function, of the payload is modulated (See ¶0208). Thus, the destabilization domains read on “a drug responsive domain”. The payload can be Cas9 or a variant thereof (which reads on “a Cas protein” and “the nucleic acid sequence encoding the Cas protein is derived from a parent Cas9… sequence”) (See ¶0074, 0420-0426, and 0698 and fig. 19A). The Cas9 can be derived from Streptococcus pyogenes or Neisseria meningitidis (See ¶0423-0424 and 0586).
The expression vector encoding the effector modules can comprise promoters including the PGK (which reads on “Pol II promoter”) or U6 (which reads on “Pol III promoter”) promoters (See ¶0485). Barrett et al. teach in Example 9 a first vector comprising an sgRNA and constitutive promoter (which reads on “a third nucleic acid sequence that encodes a first guide RNA” and “a second promoter operably linked to the third nucleic acid sequence”) and a second vector encoding a promoter linked to a stimulus response element linked to Cas9 (which reads on “a first nucleic acid sequence that encodes a Cas protein”, “a first promoter operably linked to the first nucleic acid sequence”, and “a second nucleic acid sequence”) (See ¶0698).
The systems can be used in cells such as T cells or NK cells (which read on “immune cell”, muscle cells, ocular cells, or embryonic stem cells (which read on “stem cells”) (See ¶0361, 0463, 0472, and 0698).
Barrett et al. do not expressly teach the destabilization domain operably linked to Cas9. However, it would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the construct of Barrett et al. to select the stimulus response element of a destabilizing domain such as CA2 and a payload, such as Cas9, because Barrett et al. disclose that any destabilization domain, used as a stimulus response element, can be in association with any of the payloads therein to modulate the function of the payload (See ¶0208). It would have further been obvious to use PGK and U6 as first and second promoters, respectively because Barrett et al. teach that the biocircuits and effector modules can encompass such components. Such modifications could be readily performed.
Barrett et al. also do not expressly teach the use of a CA2 mutant.
Daigle et al. teach human CA2 variants having increased thermal stability relative to the native protein at 25°C-70°C (See Abstract and ¶0016, 0019, and 0034-0036). Daigle et al. teach CA2 polypeptides having 99.7% sequence identity (which reads on “one or more mutations”) to the sequence of instant SEQ ID NO 5 (See ¶0034-0036, SEQ ID NOs 2 and 11, and alignments below (first 120 aa displayed)). SEQ ID NO 2 taught by Daigle et al. has a single mutation at position 65, while SEQ ID NO 11 has a single mutation at position 247.
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the Cas of Barrett et al. to comprise a mutant CA2, such as is taught by Daigle et al. One would be motivated to make this modification because Daigle et al. teach that the mutant CA2 proteins have increased activity at high temperatures, including biologically-relevant temperatures (See ¶0016 and 0019). There would be a reasonable expectation of success in doing so because the CA2 mutants taught by Daigle et al. could be readily appended to Cas.
Regarding claim 3: Following the discussion of claims 1 and 10-15, Barrett et al. teach that components of the biocircuit systems may be encoded by one or more nucleic acids (which would read on “components of the same polynucleotide construct”) (See ¶0107).
Claims 1-3, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al. (US 20190192691 A1), of record, in view of Daigle et al. (US 20060257990 A1), further in view of Minkenberg et al. (Progress in Molecular Biology and Translational Science, 2017), of record.
The teachings of Barrett et al. and Daigle et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 2: Following the discussion of claims 1, 3 and 10-15, Barrett et al., modified by Daigle et al., render obvious a modified cell comprising polynucleotides comprising Cas9 operably linked to a first promoter and a drug responsive CA2 domain and a gRNA operably linked to a second promoter but do not teach a second gRNA operably linked to a third promoter.
Minkenberg et al. teach strategies for CRISPR/Cas9 multiplex genome editing for efficiently targeting multiple sites (See Abstract and page 213, ¶1-2). Multiple gRNAs (which read on “second guide RNA, wherein the second guide RNA is different from the first guide RNA”) can be expressed in a cell from multiple expression cassettes, each with its own promoter (See page 113, ¶2-3; page 114, ¶1; and fig. 1A). Minkenberg et al. teach that the use of individual gRNA cassettes is the most common approach for expressing multiple gRNAs and that it provides for efficient editing (See page 113, ¶3 and page 115, full ¶3).
It would have been obvious to one having ordinary skill in the art prior to the effective filling date of the claimed invention to modify the system of Barrett et al., modified by Daigle et al., to comprise an additional gRNA and promoter to enable the editing of multiple sites, as taught by Minkenberg et al. One would be motivated to make this modification for increasing the efficiency of CRISPR/Cas9 editing (See page 115, full ¶3), and such a modification of the system of Barrett et al., modified by Daigle et al., could be readily performed.
Claims 1, 3-6, 8, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al. (US 20190192691 A1), of record, in view of Daigle et al. (US 20060257990 A1), further in view of Mandell et al. (US 20180259541 A1), of record.
The teachings of Barrett et al. and Daigle et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 4-6: Following the discussion of claims 1, 3 and 10-15, Barrett et al., modified by Daigle et al., render obvious a modified cell comprising polynucleotides comprising Cas9 operably linked to a first promoter and a drug responsive CA2 domain and a gRNA operably linked to a second promoter. Barrett et al. disclose that the biocircuit system can be used to regulate expression levels of a payload (See ¶0006-0007) but do not teach the expression of Cas as regulated by transcription factor under the control of a drug responsive domain.
Barrett et al. also do not expressly teach exogenous promoters for Cas9 and the gRNA. However, Barrett et al. teach that the expression vectors can have promoters that are non-native or viral (which read on “exogenous… promoter”), inducible, or chosen according to specific requirements of gene expression for a particular purpose (See ¶0485 and 0520-0521).
Mandell et al. teach biosensors that enable orthogonal control of transcription (See Abstract). The biosensor can comprise a ligand-binding domain fused to a transcription factor (See ¶0005 and 0083). The ligand-binding domain can be destabilized or conditionally stable (See ¶0004). The conditionally-stable ligand-binding domain can be placed between a DNA binding domain and a transcriptional activation domain (which reads on “the combination of the transcription factor activation domain and the transcription factor DNA binding domain is operably linked to the DRD”) (See ¶0012 and fig. 2A). The ligand can be an exogenous chemical (See ¶0085).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the system of Barrett et al., modified by Daigle et al., to comprise modulation of Cas9 transcription by a transcription factor tunable by binding of an exogenous ligand. One would be motivated to make this modification because Mandell et al. teach that the use of transcription factors amplifies the biosensor response (See ¶0013). There would be a reasonable expectation of success in doing so because polynucleotides encoding a drug responsive domain and transcription factor activation and DNA binding domains and encoding Cas9 and a promoter comprising a binding site for the transcription factor could be readily used with the biocircuit system taught by Barrett et al., who teach that constructs encoding proteins which can attenuate transgene activity may be co-expressed with a biocircuit (See ¶0325). Exogenous promoters could also be used for the expression of Cas and any gRNAs. The use of an exogenous promoter with a specific binding site for a tunable transcription factor would read on “an exogenous inducible first promoter”.
Regarding claim 8: Following the discussion of claims 1, 3-6, and 10-15, Barrett et al. teach that the drug responsive domain can be derived from CA2 (See ¶0208 and table 4).
Claims 1, 3-8, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Barrett et al. (US 20190192691 A1), of record, in view of Daigle et al. (US 20060257990 A1), further in view of Mandell et al. (US 20180259541 A1), of record, further in view of Minkenberg et al. (Progress in Molecular Biology and Translational Science, 2017), of record.
The teachings of Barrett et al., Daigle et al., and Mandell et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 7: Following the discussion of claims 1, 3-6, 8, and 10-15, Barrett et al., modified by Daigle et al. and Mandell et al., render obvious a modified cell comprising a system comprising gRNA and Cas9 under transcriptional control of a transcription factor stabilized by an exogenous ligand but do not teach a second gRNA with its own promoter.
Minkenberg et al. teach strategies for CRISPR/Cas9 multiplex genome editing for efficiently targeting multiple sites (See Abstract and page 213, ¶1-2). Multiple gRNAs (which read on “second guide RNA, wherein the second guide RNA is different from the first guide RNA”) can be expressed in a cell from multiple expression cassettes, each with its own promoter (See page 113, ¶2-3; page 114, ¶1; and fig. 1A). Minkenberg et al. teach that the use of individual gRNA cassettes is the most common approach for expressing multiple gRNAs and that it provides for efficient editing (See page 113, ¶3 and page 115, full ¶3).
It would have been obvious to one having ordinary skill in the art prior to the effective filling date of the claimed invention to further modify the system of Barrett et al., modified by Daigle et al. and Mandell et al., to comprise an additional gRNA and promoter to enable the editing of multiple sites, as taught by Minkenberg et al. One would be motivated to make this modification for increasing the efficiency of CRISPR/Cas9 editing (See page 115, full ¶3), and such a modification of the system of Barrett et al., modified by Daigle et al. and Mandell et al., could be readily performed.
Conclusion
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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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633