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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 2/24/2026 has been considered. Claims 1 and 3 have been amended. Claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 28, 31, 33, 35, 37-38, 40, 43-49, 51, 53, 55, 57-62, 64, 66 and 68-69 are pending. Claims 49, 51, 53, 55, 57-62, 64, 66 and 68-69 are currently withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 28, 31, 33, 35, 37-38, 40 and 43-48 are the subject of the present Official 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.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 62/962,672, PCT/US2021/013753 and CON of 17/793,115 filed on 1/17/2020, 1/15/2021 and 9/19/2023, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 1/17/2020.
Withdrawn Rejections
The 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 1, 3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 31, 33, 35, 37-38, 40 and 43-48 as anticipated by Severinov is withdrawn in light of applicants claim amendments which move limitations from dependent claim 2 into independent claim 1.
The nonstatutory double patenting rejection of claims 1, 3, 17, 19, 20, 28, 35, 37, 40 and 43-48 over claims 1-21 of US Patent NO. 12,252,705 has been withdrawn in light of applicant’s submission of a terminal disclaimer on 2/24/2026.
Claim Interpretation
Taking the broadest reasonable interpretation, there is no express requirement in claim 1 that the Cas protein actually forms a complex with a nucleic acid guide molecule, only that the Cas protein is “capable” of such. A similar analysis is applied to the “capable” language used in dependent claims 8, 10, 20, 28, 30, 31 and 33. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure, see MPEP 2111.04.
Furthermore, a similar analysis is applied to the “optionally” language used in claims 8, 17, 31, 33, 38 and 40 when describing the target sequence being on the same/different target polynucleotide, functional domains, operably coupled reverse transcriptase, target polynucleotide modifications, human/nonhuman codon optimization and regulatory elements.
Although claim 3 describes specific embodiments to Cas proteins which are 70-100% identical to any one of the elected SEQ ID NO: 31, 37, 39 and 40 sequences, it is emphasized that the current claim language recites “any combination of (a)-(c)”. Thus, one or more of the conditions of (a)-(c) would fulfil the limitations of claim 3.
Maintained 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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 31, 33, 35, 37-38, 40 and 43-48 stand rejected under 35 U.S.C. 103 as being unpatentable over Severinov et al. US 2019/0382800, published 12/19/2019 (hereinafter Severinov, reference of record) in view of Tan et al. US 2019/0382775, published 12/19/2019 (hereinafter Tan, reference of record). This rejection is applied in modified form to address applicants claim amendments on 2/23/2026. A response to applicant’s traversal follows the rejection below.
Claim 1: Severinov describes engineered nucleic acid targeting systems comprising a Cas protein and an engineered guide molecule (Severinov, para 9, 37, 44). Severinov describes Cas proteins comprising a RuvC domain and a HNH domain with a size of about 950 amino acids (Severinov, para 44, 52, 59, 946). For example, Severinov states that type II multidomain effector protein Cas9 has been functionally and structurally characterized in exquisite detail, ranging in size from about 950-1,600 amino acids. Cas9 proteins contain two nuclease domains including Ruv-C and HNH nucleases (Severinov, para 946). Severinov describes engineered guide molecules which are capable of forming complexes with the Cas proteins and directing sequence specific binding to a target polynucleotide (Severinov, para 45). Severinov describes the development of inactive type VI Cas effector proteins through mutations of the HEPN domain catalytic residues to convert C2c2 into an inactive programable RNA-binding protein (Severinov, para 11). Although Severinov describes the development of inactive type VI Cas proteins, Severinov does not expressly describe the development of inactive type II Cas protein (dCas9) as described in newly amended claim 1.
Claim 3: Severinov describes embodiments wherein the Cas protein has no association with Csn2 (Severinov, para 945-949). Although claim 3 describes specific embodiments to Cas proteins which are 70-100% identical to any one of the elected SEQ ID NO: 31, 37, 39 and 40 sequences, it is emphasized that the current claim language recites “any combination of (a)-(c)”. Thus, one or more of the conditions of (a)-(c) would fulfil the limitations of claim 3.
Claims 8 and 10: Severinov describes Cas proteins which are complexed with two or more nucleic acid molecules that are capable of sequence-specific binding of multiple target sequences (Severinov, para 36, 37, 243). Severinov describes engineered guide molecules which are capable of forming complexes with the Cas proteins and directing sequence specific binding to a target polynucleotide in vitro, in vivo or within a eukaryotic cell (Severinov, para 45, 243).
Claim 12: Severinov describes Cas proteins which are operably coupled to one or more nuclear localization signals (NLS) (Severinov, para 76).
Claim 14: Severinov describes Cas effector proteins which have modified nuclease activities including catalytically inactive variants (dCas9) and fusion constructs to one or more functional domains (Severinov, para 11, 44, 854).
Claims 17, 19, 20, 35: Severinov describes Cas proteins which are operably associated with functional domains including transcriptional repressors and activators (Severinov, para 308, 310, 523, 796).
Claim 22-23: Severinov describes the further inclusion of a recombination template which is associated with the Cas protein (Severinov, para 805).
Claim 25: Severinov describes nucleic acid targeting system comprising a tracrRNA (Severinov, para 239, 265).
Claim 31: Severinov describes Cas proteins which are complexed with two or more nucleic acid molecules that are capable of sequence-specific binding of multiple target sequences (Severinov, para 36, 37, 243).
Claim 33: Severinov describes using the engineered nucleic acid targeting system to modify a target polynucleotide sequence via the insertion or deletion of one or more polynucleotides (Severinov, para 691, 700).
Claim 37, 40 and 43-48: Severinov describes the use of a delivery composition comprising a vector encoding one or more components of the engineered nucleic acid system (Severinov, para 145). Severinov describes delivery into eukaryotic cells and mammalian organisms (Severinov, para 33, 75, 248, 843).
Claim 38: Severinov describes procedures for codon-optimization for expression in eukaryotic cells (Severinov, para 807, 841).
Although Severinov describes Cas proteins comprising a RuvC domain and a HNH domain with a size of about 950 amino acids, Severinov does not describe Cas proteins with a size equal or less than 780 amino acids (Severinov, para 44, 52, 59, 946) or expressly describe the use of type II dCas9 proteins.
Claim 1: Tan describes truncated CRISPR-Cas proteins for DNA targeting and modification (Tan, abstract). Tan describes the importance of the RuvC and NHN domains as acting as the two nuclease domains which cut opposite strands of the DNA which is to be modified (Tan, para 5). Tan provides preferred embodiments towards the use of inactive type II dCas9 proteins (Tan, para 114). Importantly, Tan notes that these types of dCas9 systems are ideal for targeting double stranded DNA (dsDNA).
Claim 2: Tan describes the current issues with the large size of most Cas9 proteins, which affects their AAV packing and delivery potential (Tan, para 6). Tan describes methods to truncate Cas proteins so that they better fit into AAV vectors by deleting at least one from the group consisting of ΔNHN (Δ775-909) ΔRuvCIII-b (Δ1002-1074), ΔREC1-a (Δ510-655), ΔREC1-b (Δ525-587), ΔREC1-C (Δ662-710), ΔREC2 (Δ180-308), REC2-a (Δ212-244), ΔREC2-b(Δ244-276), ΔREC2-c (Δ276-308), ΔREC2-d (Δ199-283). REC2-e (Δ198-257), ΔREC2-f(Δ235-286), ΔREC2-g (Δ217-266), ΔREC3 (Δ498-712) and combinations thereof for an overall size of at least 500 amino acids, preferably 600 or 700 amino acids (Tan, para 8, 48, 49).
It would have been prima facie obvious to one of ordinary skill in the art to truncate a type II dCas9 protein using the methods outlined by Tan to arrive at a size of less than or equal to 780 amino acids so that the Cas protein would better fit into an AAV delivery vector. It would have been a matter of combining prior art elements according to known method to yield predictable results given that Tan outlines predictable methods for truncating Cas proteins while still retaining their endonuclease capabilities via inclusion of the RuvC and NHN domains. One would have been motivated to make this combination since compact Cas variants are better suited for AAV vector delivery. One of ordinary skill would select a type II dCas9 protein outlined by Tan over the type IV Cas effector protein (dC2c2) described by Severinov in order to target DNA rather than RNA. One would have a reasonable expectation of success given that Tan discloses several exemplary truncated Cas variants and predictable methods which represent routine protein engineering design choices. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 31, 33, 35, 37-38, 40 and 43-48 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that Severinov does not mention type II D Cas effector proteins. Applicant points to the specification which provides an extensive disclosure of type II D Cas effector proteins and argues that nothing in Severinov would direct one of ordinary skill in the art to select a type II D Cas effector protein.
This argument has been fully considered, but is not found persuasive since Tan provides preferred embodiments towards the use of inactive type II dCas9 proteins (Tan, para 114). Importantly, Tan notes that these types of dCas9 systems are ideal for targeting double stranded DNA (dsDNA). Thus, one of ordinary skill would be motivated to select a type II dCas9 protein outlined by Tan over the type IV Cas effector protein (dC2c2) described by Severinov in order to target DNA rather than RNA. By using dCas9, one of ordinary skill could directly regulate genes at the genomic level rather than single stranded RNA. Although Severinov may not disclose type II D cas proteins, it is argued that it would be obvious to combine the disclosure of Tan to arrive at the claimed invention since Tan provides preferred embodiments towards the use of inactive type II dCas9 proteins (Tan, para 114). One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145.
Claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 28, 31, 33, 35, 37-38, 40 and 43-48 stand rejected under 35 U.S.C. 103 as being unpatentable over Severinov (supra) and Tan (supra) as applied to claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 31, 33, 35, 37-38, 40 and 43-48 above in further view of Gu et al. "Highly efficient base editing in Staphylococcus aureus using an engineered CRISPR RNA-guided cytidine deaminase." Chemical science 9.12 (2018): 3248-3253 (hereinafter Gu, reference of record). This rejection is applied in modified form to address applicants claim amendments on 2/23/2026.
A description of Severinov and Tan can be found above with respect to claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 31, 33, 35, 37-38, 40 and 43-48. Although Severinov describes Cas proteins which are operably associated with functional domains including transcriptional repressors and activators, Severinov does not describe wherein one or more functional domains have deaminase activity like those of adenosine deaminase or cytidine deaminase (Severinov, para 308, 310, 523, 796).
Claim 28: However, engineered nucleic acid targeting systems fused to functional domains with deaminase activity are known in the art as demonstrated by Gu. For example, Gu describes a CRISPR RNA-guided cytidine deaminase, which enabled highly efficient gene inactivation and point mutations via base editing (Gu, abstract). Gu discloses plasmid constructs (pnCasSA-BEC), wherein deaminase activity was linked to the N-terminus of the Cas9 protein via a XTEN linker (Gu, Results and Discussion, Fig 2).
It would have been prima facie obvious to one of ordinary skill in the art to operably couple a cytidine deaminase functional domain to the Cas protein disclosed by Severinov to generate an engineered nucleic acid targeting system with deaminase activity. It would have been a matter of combining prior art elements according to known method to yield predictable results given that Gu successfully linked a cytidine deaminase to the N-terminus of a Cas9 protein via a XTEN linker and showed efficient base editing. One would have been motivated to make this combination since the cytidine base editor-mediated genome editing method allows for genome editing without using donor repair templates. One would have a reasonable expectation of success given that prime editing offers a reliable method to generate base-to-base conversions without requiring double-stranded DNA breaks or donor DNA templates. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that neither Tan nor Gu remedies the lack of disclosure of Severinov to teach type II D cas proteins. Applicant states that Gu teaches linking deaminase functional domains to generic Cas9 proteins, but provides no disclosure of type II D cas proteins.
This argument has been fully considered, but is not found persuasive since, as stated previously, Tan provides preferred embodiments towards the use of inactive type II dCas9 proteins (Tan, para 114). The Examiner maintains that it would have been prima facie obvious to one of ordinary skill in the art to truncate a type II dCas9 protein using the methods outlined by Tan to arrive at a size of less than or equal to 780 amino acids so that the Cas protein would better fit into an AAV delivery vector.
Conclusion
Claims 1-3, 8, 10, 12, 14, 17, 19-20, 22-23, 25, 28, 31, 33, 35, 37-38, 40 and 43-48 are rejected.
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 Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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