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 .
Amendments Received
Amendments to the claims were received and entered on 06/05/2026.
Status of Claims
Claims 139-164 are currently pending and under consideration.
Priority
The present application is a continuation of PCT/US2021/049931 filed on 09/10/2021. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 63/077,060, filed on 09/11/2020. The present application and all claims are being examined with an effective filing date of 09/11/2020. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Rejections
In view of Applicant’s amendments, rejections of claims 143, 147, and 151 under 35 USC § 112(b) are hereby withdrawn.
In view of Applicant’s statement establishing common ownership or an obligation of assignment pursuant to 35 USC 102(b)(2)(C), all rejections under 35 USC § 102 relying upon “Thomas” as prior art under 35 USC § 102(a)(2) are hereby withdrawn.
In view of Applicant’s remarks regarding the disclosure of the nRRnMC PAM sequence associated with SEQ ID NO: 23, the separate rejection of claim 151 under 35 USC § 112(a) is hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 139-141 and 143-164 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that “[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.” Claim 139 has been broadly interpreted as encompassing a genus of engineered nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23. Claims 140-141 encompass a genus of nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 90% or 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23, respectively. Claims 149-150 encompass a genus of nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23 and a genus of tracr sequences having at least 80% identity to any 60-90 consecutive nucleotides of SEQ ID NO: 29 or the full-length sequence set forth in SEQ ID NO: 29, respectively. Claim 152 encompasses a genus of nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23 and a genus of base editors comprising a sequence having at least 70% sequence identity to any one of SEQ ID NOs: 1-17. Claims 154 and 156 encompass a genus of engineered nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23, and a genus of adenosine deaminases comprising at least 80% sequence identity to SEQ ID NOs: 8 or 164, or a genus of cytosine deaminases comprising at least 80% sequence identity to any one of SEQ ID NOs: 1-7 and 9-17, respectively. Claim 164 encompasses a genus of engineered nucleic acid editing systems comprising, inter alia, a genus of endonucleases having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 23 and a genus of uracil deoxyribonucleic acid glycosylase inhibitors comprising at least 70% sequence identity to SEQ ID NO: 18.
MPEP 2163 I states that to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. MPEP 2163 II.A.3(a) further provides that possession may be shown by an actual reduction to practice, by a clear depiction of the invention, or by disclosure of sufficient relevant identifying characteristics such that one skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163 II.A.3(a)(ii), satisfactory disclosure of a “representative number” of species depends on whether one of skill in the art would recognize that applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus embracing widely variant species cannot necessarily be achieved by disclosure of only a limited number of species within the genus.
In the instant case, the recited SEQ ID NOs define biological macromolecules, including proteins and RNAs, that are required to possess particular structural and/or functional properties. The specification discloses specific sequences and certain specific variants thereof. The specification further provides structure-function information concerning certain disclosed endonucleases. In particular, FIG. 4 depicts an alignment of a portion of the RuvCI domains of several disclosed endonucleases, identifies conserved and variable positions among the particular sequences shown, and identifies a predicted catalytic aspartate that may be mutated to disrupt nuclease activity for nickase generation. The specification further identifies the corresponding catalytic aspartate in SEQ ID NOs: 21-23. FIG. 7 provides experimental results demonstrating nickase activity for multiple specifically identified mutated endonucleases, including SEQ ID NOs: 21 and 22. FIGS. 8A and 8B further provide evidence of base-editing activity for particular disclosed systems. Thus, the specification identifies a structural feature associated with nickase generation and provides functional validation of particular disclosed species. However, these disclosures do not reasonably convey possession of the full breadth of the sequence-identity genera encompassed by the claims. SEQ ID NO: 23 is approximately 1,154 amino acids in length. Accordingly, sequence identity thresholds of 95%, 90%, and 80% encompass approximately 58, 115, and 231 amino acid differences, respectively. The claims do not restrict such differences to the variable positions depicted in FIG. 4 or otherwise require preservation of particular residues or structural features outside the expressly recited limitations. FIG. 4 provides sequence comparison and structure-function information concerning only a limited portion of the RuvCI domain. Although the alignment illustrates conserved and variable positions among the particular sequences shown, the observed variation among those sequences does not establish that every nonconserved position constitutes a permissible site of substitution throughout the claimed genus, nor does it establish which combinations of substitutions throughout the remainder of the full-length protein are compatible with the structural and functional requirements of the claimed engineered nucleic acid editing system. In particular, the disclosure does not provide a corresponding identification of the residues, motifs, domains, or permissible substitutions throughout the remainder of the full-length endonuclease necessary to retain the structural and functional characteristics required for operation in the claimed system.
Likewise, FIG. 7 demonstrates nickase activity for selected, specifically disclosed endonucleases containing particular catalytic mutations. Such results establish functionality of the tested species and provide evidence of a structure-function relationship associated with mutation of the identified RuvCI catalytic aspartate. However, the results do not establish that the disclosed species are representative of the extensive structural diversity encompassed by endonucleases having at least 80%, 90%, or 95% sequence identity to SEQ ID NO: 23. Similarly, the base-editing results shown in FIGS. 8A and 8B demonstrate functionality of particular disclosed systems, but do not establish that the extensive sequence variation permitted by the claimed identity-defined genera can be distributed throughout the endonuclease while retaining the structural and functional characteristics necessary for operation in the claimed nucleic acid editing system. Thus, while the specification provides experimental support for particular species and a particular catalytic-residue modification, such disclosure does not establish possession of the substantially broader population of sequence variants encompassed by the claimed identity thresholds.
Moreover, the claims encompass additional sequence-identity genera as low as 70%, directed to tracr sequences, base editors, adenosine deaminases, cytosine deaminases, and uracil deoxyribonucleic acid glycosylase inhibitors. The disclosure of particular sequences and examples does not provide a representative number of species commensurate with these broad identity ranges or identify structural features common to the full scope of these genera that would permit one of ordinary skill in the art to recognize which sequence variants possess the required biological function.
Thus, while the specification provides specific species and some structure-function information relevant to the disclosed endonucleases, the disclosure does not provide a representative number of species or sufficient identifying structural characteristics reasonably commensurate with the full breadth of the claimed sequence-identity genera. Accordingly, one of ordinary skill in the art would not reasonably recognize that applicants were in possession of the full scope of the claimed invention at the time of filing.
Accordingly, claims 139-141 and 143-164 are rejected under 35 U.S.C. § 112(a), or 35 U.S.C. § 112, first paragraph (pre-AIA ), as failing to comply with the written description requirement.
Claims 139-141 and 143-164 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an engineered nucleic acid editing system comprising an endonuclease having the amino acid sequence set forth in SEQ ID NOs: 21-23, an engineered tracr sequence comprising SEQ ID NO: 27-29, a base editor comprising a sequence corresponding to one of SEQ ID NOS: 1–17 and 19-20, an adenosine deaminase comprising SEQ ID NO: 164, and a UGI comprising SEQ ID NO: 18, does not reasonably provide enablement for the full scope of the claimed genus of engineered nucleic acid editing systems, including a genus of endonucleases with as little as 80% sequence identity to SEQ ID NO: 23, a genus of tracr sequences comprising as little as 80% sequence identity to any 60 consecutive nucleotides of SEQ ID NO: 29, a genus of base editors comprising as little as 70% identity to any of SEQ ID NOs: 1-17, a genus of adenosine deaminases comprising as little as 80% sequence identity to SEQ ID NO: 164, and a genus of UGIs comprising as little as 70% identity to SEQ ID NO: 18. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims without undue experimentation.
The specification fails to enable the claim (or the full scope of the claim) if a person of ordinary skill in the art would be faced with an undue burden of experimentation when trying to implement the invention based on the disclosure. In re Wands (858 F.2d 731 at 737, 8 USPQ2d 1400 at 1404 (Fed. Cir. 1988)) sets forth a non-exclusive list of factors by which this burden of experimentation may be judged to be due or undue; factors that are germane to the instant case include the breadth of the claims, nature of the invention, the amount of direction provided by the inventor, the existence of working examples, the state of the prior art, and quantity of experimentation required.
Breadth of the Claims and Nature of the Invention
As indicated above, claim 139 encompasses a genus of systems comprising, in part, endonucleases having as little as 80% sequence identity to SEQ ID NO: 23. Because SEQ ID NO: 23 encodes a protein approximately 1,154 amino acids in length, an 80% identity limitation permits extensive amino acid variation distributed throughout the molecule. Similar breadth arises from the claimed identity ranges for tracr RNA sequences, base editor enzymes, deaminases, and UGI proteins. This scope encompasses large genera of biological macromolecules extending substantially beyond the specifically disclosed sequences to include numerous structurally distinct and uncharacterized variants.
State of the Prior Art and Level of Predictability
CRISPR technology and techniques for generating and testing engineered Cas endonucleases were known in the art at the time of filing. It is further acknowledged that catalytic residues associated with Cas nuclease activity were known and that mutation of catalytic residues, including aspartate-to-alanine substitutions, had been used to generate nickase variants. However, such knowledge does not establish predictability across the full sequence diversity encompassed by the claimed percentage-identity genera. The claimed systems depend upon biological macromolecules retaining appropriate structural and functional properties, including protein folding, guide RNA interaction, target recognition, nuclease deficiency or nickase activity, and base-editing activity. The disclosure does not establish that sequence identity alone predicts retention of these properties across the full claimed ranges. Accordingly, although individual techniques for constructing and assaying variants were known, substantial uncertainty remains as to which of the numerous sequence variants encompassed by the claims would possess the required properties.
Amount of Direction and Presence of Working Examples
The specification provides working examples involving specific identified endonucleases and editing-system components. FIG. 4 depicts predicted catalytic residues within aligned RuvCI domains that may be mutated to disrupt nuclease activity for nickase generation. FIG. 7 reports nickase activity assays for selected mutated effectors, and the specification provides methods for mutagenesis, expression, purification, and functional testing. The specification further provides sequence-comparison methodology, including BLASTP parameters, that may be used to determine whether candidate sequences satisfy the recited sequence-identity thresholds. These teachings provide guidance for identifying candidate sequences and experimentally determining whether particular candidates possess desired activity. However, they do not provide guidance sufficient to predict which of the numerous variants encompassed by the broad sequence-identity ranges will retain the combination of structural and functional properties required by the claims. In particular, although FIG. 4 and paragraph 001008 in the Specification provide guidance for identifying conserved and non-conserved positions by comparison of homologous endonucleases, such guidance does not establish that each non-conserved position, or combinations of such positions, may be varied throughout the full-length SEQ ID NO: 23 while retaining the structural and functional properties required by the claims. FIG. 4 identifies a conserved catalytic residue and demonstrates sequence variation within a limited RuvCI region among particular functional endonucleases, but does not provide comparable predictive guidance regarding permissible variation throughout the remainder of the approximately 1,154-amino-acid protein. FIG. 7 establishes functionality of selected specifically tested endonucleases, but does not demonstrate functionality across the extensive sequence variation encompassed by the claimed genus.
Likewise, the specification does not provide comparable guidance sufficient to predict functionality throughout the broad sequence-identity genera encompassing the claimed tracr RNAs, base editors, adenosine and cytosine deaminases, and UGIs.
Undue Experimentation
Absent additional guidance, a person of ordinary skill in the art seeking to practice the full scope of the claims would be required to identify numerous candidate variants satisfying the claimed identity thresholds and empirically determine which candidates retain the required structural and functional properties. Such experimentation would include generating candidate variants, testing nuclease deficiency or nickase activity, validating RNA-protein complex formation and target recognition, evaluating base-editing activity, and, where applicable, confirming the required activity of the deaminase or DNA-repair inhibitor.
The fact that sequence alignment, mutagenesis, protein expression, purification, and activity assays were individually known or routine techniques does not resolve the full-scope enablement issue. The relevant consideration is the quantity and nature of experimentation required to identify operative species throughout the breadth of the claimed genera. Here, the disclosure provides methods by which individual candidates may be identified and tested, but does not provide a predictive principle or sufficient guidance that would materially narrow the extensive number of variants requiring empirical evaluation.
In view of the breadth of the claims relative to the disclosed species, the limited working examples compared with the structural diversity encompassed by the sequence-identity ranges, the incomplete predictability of the relationship between sequence variation and the required biological functions, and the amount of empirical testing necessary to extend the disclosed examples throughout the claimed scope, one of ordinary skill in the art would be required to engage in undue experimentation to practice the full scope of the claimed invention.
Thus, claims 139-141 and 143-164 are rejected under 35 U.S.C. § 112(a), or 35 U.S.C. § 112, first paragraph (pre-AIA ), for lack of enablement.
Response to Arguments for Rejections under 35 USC § 112(a) or First Paragraph (pre-AIA )
In the response filed June 5, 2026, Applicant argues, inter alia, that the Specification discloses multiple species within the claimed genus, identifies conserved and variable residues through the alignment of FIG. 4, identifies the catalytic RuvCI aspartate associated with nickase generation, and provides experimental validation of selected species in FIGS. 7 and 8A–8B. Applicant therefore contends that the Specification provides representative species and sufficient structure-function information to demonstrate possession of the claimed genus. Additionally, Applicant argues that the claimed genus is structurally defined by reference to SEQ ID NO: 23 and the recited sequence-identity thresholds; that the structure-function relationships of Cas endonucleases and techniques for generating nuclease-deficient variants were known in the art; and that the Specification provides sufficient guidance for identifying, designing, generating, and testing variants, including sequence-alignment methodology, FIG. 4, and the experimental procedures and working examples. Applicant contends that any experimentation necessary to identify and validate variants would therefore have been routine and would not constitute undue experimentation. Applicant’s arguments have been fully considered but are not persuasive for the reasons set forth in the written description and enablement rejections above.
Although the Specification provides specific species, working examples, and certain structure-function guidance, including identification of a conserved RuvCI catalytic residue and experimental validation of selected variants, these disclosures do not provide a representative number of species or sufficient identifying characteristics reasonably commensurate with the full breadth of the claimed sequence-identity genera. Likewise, the availability of known techniques for identifying, generating, and testing candidate variants does not establish that the full scope of the claimed genera can be practiced without undue experimentation, particularly where the disclosure does not provide sufficient predictive guidance for determining which of the numerous sequence variants encompassed by the claims will retain all of the required structural and functional properties. Accordingly, the written description and enablement rejections are maintained.
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 139-142, 144-146, 148, 155, 157-164 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 112-114, 116, and 118 of copending Application No. 17431135 in view of Liu (WO2018176009, cited in the IDS).
Claim 116 of application ‘135 recites an engineered nuclease system comprising:(a) an endonuclease comprising a RuvC_III domain and an HNH domain, wherein said endonuclease is derived from an uncultivated microorganism, wherein said HNH domain comprises a sequence having at least 80% sequence identity to SEQ ID NO: 131, and wherein said endonuclease is a class 2, type II Cas endonuclease; and(b) an engineered guide ribonucleic acid structure that forms a complex with said endonuclease, wherein said engineered guide ribonucleic acid structure comprises: i) a guide ribonucleic acid sequence that hybridizes to a target deoxyribonucleic acid sequence; and ii) a tracr ribonucleic acid sequence that binds to said endonuclease; wherein said endonuclease comprises the amino acid sequence of SEQ ID NO: 43 or a variant thereof having at least 80% sequence identity thereto. It is noted that the endonuclease set forth in instant SEQ ID NO: 23, shares 99.9% sequence identity with SEQ ID NO: 43 of application ‘135 (see application file for sequence alignment), and therefore is a variant of SEQ ID NO: 43 having at least 80% sequence identity thereto. Claim 112 recites wherein said guide ribonucleic acid sequence is complementary to a eukaryotic, fungal, plant, mammalian, or human genomic sequence.
Claim 113 recites wherein said guide ribonucleic acid sequence is 15-23 nucleotides in length.
Claim 114 recites wherein said endonuclease comprises one or more nuclear localization sequences (NLSs) proximal to an N- or C-terminus of said endonuclease.
Claim 118 recites wherein said sequence identity is determined by a BLASTP homology search algorithm using parameters of a wordlength (W) of 3, an expectation (E) of 10, and a BLOSUM62 scoring matrix setting gap costs at existence of 11, extension of 1, and using a conditional compositional score matrix adjustment.
As described above, Liu teaches that targeted editing of nucleic acid sequences, for example, the targeted cleavage or the targeted introduction of a specific modification into genomic DNA, is a highly promising approach for the study of gene function and has the potential to provide new therapies for human genetic diseases by effecting a specific nucleotide change at a specific location in the genome. Liu further teaches that programmable cleavage can result in mutation of the DNA at the cleavage site via non-homologous end joining (NHEJ) or replacement of the DNA surrounding the cleavage site via homology-directed repair (HDR) (Specification, para 0001). However, “both NHEJ and HDR are stochastic processes that typically result in modest gene editing efficiencies as well as unwanted gene alterations that can compete with the desired alteration”. Accordingly, Liu teaches nucleic acid programmable DNA binding proteins (napDNAbp), including dCas9 (catalytically inactive) and Cas9 nickase (cleaving one strand of double stranded DNA), fused to a cytidine deaminase, via a linker for deaminating target cytidine residues., and a uracil glycosylase inhibitor (UGI) domain (Specification, para 0003-0008). Liu teaches that base editing (e.g., deaminating target cytidine residues) can be reversed by endogenous DNA repair mechanisms – “Uracil DNA glycosylase (UDG) catalyzes removal of U from DNA in cells, which may initiate base excision repair, with reversion of the U:G pair to a C:G pair as the most common outcome. As demonstrated herein, Uracil DNA Glycosylase Inhibitor (UGI) may inhibit human UDG activity” (para 0023). Liu teaches that these fusion proteins “generate less indels and more efficiently deaminate target nucleic acids than other base editors, such as base editors without a UGI domain” (para 0006). Therefore, the inclusion of an UGI would improve efficiency of deaminating target nucleotides. Liu discloses a UGI set forth in SEQ ID NO: 178 having 100% sequence identity to instant SEQ ID NO: 18, and a cytidine deaminase set forth in SEQ ID NO: 168 having 100% sequence identity to instant SEQ ID NO: 9 (see sequence alignments below). It is noted that Liu teaches point mutations can be introduced into Cas9 to abolish nuclease activity, resulting in dCas9 (para 0004). More specifically, Liu teaches that mutations within the HNH or RuVC subdomains “can silence the nuclease activity of Cas9”, such as D10A and H840A, which “completely inactivate the nuclease activity of S. pyogenes Cas9” (para 00214 and para 0008).
In view of claim 116 of application ‘135 which discloses an engineered nucleic acid editing system comprising a type II Cas endonuclease together with an engineered guide ribonucleic acid structure to direct the endonuclease to target a DNA sequence and a tracr sequence to bind said endonuclease, and Liu’s disclosure of nucleobase editor fusion proteins comprising programmable DNA binding proteins (including dCas9 and Cas9 nickase) linked to cytidine deaminase (SEQ ID NO: 168), for more precision editing compared to programmable cleavage that may result in unwanted gene alterations, a person of ordinary skill in the art would have been motivated to incorporate a base editor, such as SEQ ID NO: 168 into the system disclosed by application ‘135 in order to enable direct conversion of target nucleotides at specific genomic loci using sequence specific targeting, because Liu teaches the potential for treating diseases by effecting a specific nucleotide change at a specific location in the genome. Said practitioner would further be motivated to modify the endonuclease of application ‘135 in view of Liu’s disclosure of catalytically inactive Cas9 proteins, obtained by mutations in the RuvC domain of Cas9, because reduction or elimination of nuclease cleavage activity avoids formation of double strand DNA breaks and thereby reduces undesired insertions and deletions associated with cleavage based genome editing while maintaining programmable DNA binding capability. Because Liu expressly demonstrates programmable DNA-binding proteins operating in combination with deaminase editors, nickase or catalytically inactive variants, to perform targeted nucleobase editing, a person of ordinary skill in the art would have had a reasonable expectation of success in combining these teachings with the engineered CRISPR system of application ‘135 to arrive at the claimed engineered nucleic acid editing system. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is in condition for allowance.
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 NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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