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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/02/2026 has been entered.
Election/Restrictions
Applicant’s election of Group I (i.e., an engineered Cas protein) in the reply filed on September 16, 2024 is acknowledged.
Claim18-21, 23-31, and 33-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Amendments Received
Amendments to the claims were received and entered on 01/02/2026.
Status of Claims
Claims 10 and 12 are cancelled; claim 44 has been newly added.
Claims 1, 7-9, 13-16, 18-21, 23-31, and 33-44 are currently pending.
Claims 1, 7-9, 13-16, and 41-44 are under consideration, as claims 18-21, 23-31, and 33-40 are withdrawn.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2020/033855 filed on May 20, 2020. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 63/000,293, filed on March 26, 2020 and Provisional application No. 62/850,516, filed on May 20, 2019. The present application and all claims are being examined with an effective filing date of May 20, 2019. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Objections
In view of Applicant’s amendments, the objection to claim 43 is hereby withdrawn.
Withdrawn Rejections
In view of Applicant’s cancellation of claims 10 and 12, all rejections of claims 10 and 12 are now moot and are hereby withdrawn.
In view of Applicant’s amendments, rejection of claims 14-15 under 35 USC § 112(b) is hereby withdrawn.
Claim Interpretation
Claim 1 recites an engineered Cas protein “lacking a REC1 domain a REC2 domain”. For examination purposes, this limitation is interpreted as requiring the absence of both a REC1 domain and a REC2 domain. The specification provides guidance as to the meaning of “lacking” a Rec domain. In particular, the specification discloses that a Cas protein may “lack or substantially lack” a Rec domain, may lack “a portion” or a “substantial portion” of a Rec domain, or may lack a domain having “structural similarity” to a Rec domain (see, e.g., para 0065–0066). The specification further describes embodiments in which Rec domains are partially deleted, structurally disrupted, or no longer retain recognizable domain features. In view of these disclosures, the claim term “lacking a REC1 domain and a REC2 domain” is interpreted under the broadest reasonable interpretation as encompassing proteins in which the REC1 and REC2 domains are not structurally or functionally present as recognizable domains, including embodiments in which such domains are substantially deleted or disrupted, and does not require complete removal of every amino acid residue corresponding to those domains.
Claim Objections
Claim 1 is objected to because of the following informalities:
The recitation of “lacking a Rec1 a Rec2 domain” contains a minor drafting error. In view of applicant’s remarks indicating that both domains are intended be absent, it is suggested that the claim be amended to recite “lacking a Rec1 and a Rec2 domain” or “lacking a Rec1 domain and a Rec2 domain”.
Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 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.
Claim 15 depends from claim 14, which recites an engineered Cas protein comprising both an HNH nuclease domain and a RuvC nuclease domain, and further comprising an additional nuclease domain. Thus, the protein of claim 14 includes at least three nuclease domains.
Claim 15 is indefinite due to the recitation of “wherein both nuclease domains are catalytically inactive”, as it is unclear which two nuclease domains are being referred to by the phrase “both nuclease domains,”. Accordingly, the scope of the claim is unclear. For examination purposes, it cannot be determined whether the limitation refers to (i) the HNH and RuvC nuclease domains or (ii) one of these domains and the additional nuclease domain.
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 14-16 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.
Claim 14 has been broadly interpreted as directed to an engineered Cas protein comprising: (i) both an HNH nuclease domain and a RuvC nuclease domain; (ii) lacking both a REC1 domain and a REC2 domain; (iii) having a length of 750 amino acids or less; and (iv) further comprising an additional nuclease domain.
The written description requirement of 35 U.S.C. §112(a) is not satisfied unless the specification reasonably conveys to one of ordinary skill in the art that the inventor had possession of the claimed invention at the time of filing (MPEP §2163; MPEP §2111.01).
In the instant case, the specification describes each of the above-recited features individually. For example, the specification discloses Cas proteins comprising HNH and RuvC nuclease domains, Cas proteins lacking REC1 and/or REC2 domains, and Cas proteins having reduced size, including proteins of 800 amino acids or less. The specification further discloses, in a general manner, that Cas proteins may be fused to additional functional domains, including domains having nuclease activity. However, the specification fails to describe an engineered Cas protein that combines all of these limitations in a single embodiment. In particular, the specification does not identify any specific Cas protein sequence or construct that (i) retains both HNH and RuvC domains, (ii) lacks both REC1 and REC2 domains, (iii) has a length of 750 amino acids or less, and (iv) includes an additional nuclease domain. Moreover, while the specification broadly suggests that functional domains may be fused to Cas proteins, it does not provide sufficient guidance or examples demonstrating how an additional nuclease domain may be incorporated into a reduced-size Cas protein (≤750 amino acids) while retaining both HNH and RuvC domains and lacking REC1 and REC2 domains. The disclosure of such functional domains is generic and does not reasonably convey possession of the specific claimed combination.
Accordingly, the specification fails to demonstrate possession of the full scope of claim 14, and the written description requirement is not met.
Dependent claim 15 is rejected for the same reasons, as they do not remedy the above-noted deficiencies.
Claim 16 has been broadly interpreted as directed to a genus of engineered Cas proteins as recited in claim 1, having at least 80% amino acid sequence identity to ISCB. Accordingly, the claim encompasses a genus of Cas proteins having substantial sequence variation within the ISCB region while maintaining the structural limitations of claim 1, including a length of 750 amino acids or less and lacking REC1 and REC2 domains.
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) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person 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’ depends on whether one of skill in the art would recognize that the 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 which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
In the instant case, while the specification identifies ISCB and may disclose specific sequences corresponding thereto, the specification does not provide a representative number of species or sufficient guidance to demonstrate possession of the full scope of variants encompassed by the 80% identity limitation. In particular, the specification does not disclose which residues within the ISCB region may be varied while preserving the structural and functional characteristics required by claim 1, nor does it provide examples spanning the breadth of the claimed identity range within the recited protein architecture. The specification and cited disclosures (e.g., Kapitonov et al., cited in the IDS) describe ISCB proteins as evolutionarily related to Cas proteins and sharing certain structural features. However, such general characterization does not provide a representative number of species or sufficient guidance to demonstrate possession of the full scope of variants encompassed by the claimed 80% identity limitation. In particular, the disclosure reflects diversity among ISCB-related sequences rather than defining a limited set of permissible variations within the claimed range.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the full scope of the invention of claim 16. Therefore, claim 16 is rejected under 35 U.S.C. §112(a) for lack of written description.
Maintained/Modified Rejections Necessitated by Amendment
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.
Claim 43 is 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 43 has been broadly interpreted as encompassing a genus of Cas proteins comprising either or both nuclease domains HNH and RuvC, ranging from 600 to 750 amino acids in lengths, and lacking both Rec1 and Rec2 domains, and having at least 92% sequence identity to the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 9, 11, 13, 15, and 17.
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) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person 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’ depends on whether one of skill in the art would recognize that the 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 which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The specification does not provide representative species across the full scope of “at least 92% identity” variants to each of the eight recited sequences. The specification provides a limited number of expressly described embodiments and discloses the structural features recited in claim 1, namely the lacking a Rec1 and/or Rec2 domain, as being critical for increasing exposure of the DNA-RNA duplex and enabling functional domains to act efficiently, but such disclosure does not provide guidance as to how sequence variation within the claimed 92% identity range affects the structure or function of the engineered Cas protein. As drafted, the claim encompasses a large genus of potential variants (all sequences ≥92% identical to each of eight different SEQ IDs), and there is insufficient guidance regarding which amino acid residues may be altered while still retaining the recited function and structural features. Therefore, the disclosure does not convey to one of ordinary skill in the art that the inventors had possession of the entire scope of the genus, i.e., all engineered Cas proteins at least 92% identical to the recited sequences and meeting the structural limitations of claim 1, at the time of filing.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the full scope of the invention of claim 43. Therefore, claim 43 is rejected under 35 U.S.C. §112(a) for lack of written description.
Response to Arguments for Rejections under 35 USC § 112(a)
In the response filed on 01/02/2026, Applicant argues that amendment of claim 43 to require at least 92% sequence identity limits the claim to minor variants of the disclosed sequences and that one of ordinary skill in the art would recognize that such closely related variants were possessed by the inventors. Applicant further asserts that the specification provides a structure-function correlation regarding deletion of REC1 and/or REC2 domains sufficient to support the claimed scope. Applicant’s arguments have been considered in full and are not persuasive.
While the amendment to 92% identity narrows the scope relative to the previously rejected claim, the claim nonetheless encompasses a genus of sequences defined by sequence identity rather than by specific structural features. The specification does not provide a representative number of species spanning the full scope of variants encompassed by the 92% identity limitation, nor does it provide guidance as to which amino acid residues may be varied while maintaining the required structure and function. Furthermore, the cited structure-function relationship relates to deletion of REC domains (it is noted that the claim already requires that the protein lacks Rec1 and Rec2) and does not address how sequence variation within the claimed identity range affects protein structure or function. The disclosed relationship therefore does not demonstrate possession of the full scope of sequence variants encompassed by the claim.
Accordingly, the amendment does not overcome the written description rejection.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 7-9, 13, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al. (WO 2018/074979, cited in the IDS), as evidenced by Makarova et al. (Annotation and Classification of CRISPR-Cas Systems", Methods in Molecular Biology, Vol. 1311, 2015, 27 pages, cited in the IDS) and Kapitonov, et al., ("ISC, a Novel Group of Bacterial and Archaeal DNA Transposons That Encode Cas9 Homologs", J Bacteriol., doi: 10.1128/JB.00783-15, Vol. 198, No. 5, December 28, 2015, pp. 797-807, cited in the IDS).
Regarding claims 1 and 41, Tan et al. teaches that despite the potential of CRISPR-Cas for genome engineering, the system suffers from certain shortcomings, including the large size of Cas9 proteins in particular, which adversely affects delivery both in vitro and in vivo. Tan et al. further teaches that due to its large size, and the packaging limitations of commonly used delivery vectors such as adeno-associated virus (AAV), there is little capacity for incorporating Cas9 into delivery systems, thereby motivating the development of smaller, truncated variants. Tan et al. teaches engineered CRISPR-Cas proteins, wherein the polypeptide has at least 50% sequence identity to Streptococcus pyogenes Cas9 (also called SpCas9 when the source is S. pyogenes) having the amino acid sequence set forth in SEQ ID NO: 1 over its entire length, wherein said polypeptide comprises at least one deletion selected from the group consisting of ΔΗΝΗ (Δ775-909), ΔRuvCIII-b (Δ1002-1074), ΔREC1 -a (Δ510-655), ΔREC1 - b (Δ525-587), ΔREC1 -C (Δ662-710), ΔREC2 (Δ180-308), ΔREC2-a (Δ212-244), ΔREC2-b (Δ244-276), ΔREC2-C (Δ276-308), ΔREC2-d (Δ199-283), ΔREC2-e (Δ198-257), ΔREC2-f (Δ235- 286), ΔREC2-g (Δ217-266), ΔREC3 (Δ498-712) and combinations thereof, wherein the position numbering is in accordance with SEQ ID NO:1, and wherein the polypeptide has DNA-binding activity (Specification, pg. 1, lines 17-18 and pg. 2, lines 33-41). Tan et al. additionally teaches that the resulting polypeptide(s) may be truncated to a length of at least 500 aa (i.e., amino acids), preferably up to 600, 700, 800…” (pg. 9, lines 15-16). It is noted that Tan et al. explicitly demonstrates that REC domains are amenable to substantial deletion while retaining function. For example, Tan et al. discloses constructs (e.g., SEQ ID NO: 26) in which the REC2 domain is deleted and substantial portions of the REC1 domain are also removed, while maintaining DNA-binding activity. Thus, Tan et al. demonstrates that REC domains need not remain intact and may be progressively reduced or structurally disrupted.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the invention, Tan et al. expressly teaches that one or more domains of SpCas9 may be deleted, including deletions within REC-associated regions, and that such deletions may be combined to generate compact variants while retaining DNA-binding activity. Tan et al. further identifies protein size as a limiting factor for delivery (e.g., AAV packaging) and teaches that truncated polypeptides may be reduced to as small as approximately 500 amino acids, with preferred sizes including 600 and 700 amino acids. In view of these teachings, a person of ordinary skill in the art would have been motivated to reduce Cas9 protein size through combinations of domain deletions in order to meet delivery constraints, including generating variants within the claimed size range of 600 to 750 amino acids, as protein length is a result-effective variable subject to routine optimization. Additionally, Tan et al. demonstrates that Cas9 tolerates multiple deletions across domains, including deletion of REC2 and substantial portions of REC1, while retaining DNA-binding activity, thereby evidencing that REC domains need not remain intact. Given Tan et al.’s teachings of combinatorial deletions, functional tolerance to truncation, and achievable sizes down to approximately 500 amino acids, such modifications would have been routine protein engineering design choices, and a person of ordinary skill in the art would have had a reasonable expectation of success in obtaining a truncated Cas protein within the claimed size range and domain configuration. 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.
Regarding claim 7, Tan et al. teaches that SpCas9 comprises a RuvC nuclease domain (see, e.g., Fig. 1), which is structurally organized into multiple subdomains, including RuvC-I, RuvC-II, and RuvC-III. Tan et al. further teaches that deletions may be made within certain regions of the protein, including a portion of the RuvC domain (ΔRuvCIII-b), while retaining overall nuclease domain structure and DNA-binding activity. Accordingly, Tan et al. teaches a RuvC nuclease domain comprising at least RuvCI and RuvCII, and depending on the extent of deletion, may further include RuvCIII or substantial portions thereof. Therefore, the limitation of claim 7 is met. Additionally, it is noted that claim 7 recites wherein the RUVC nuclease domain comprises RUVCI, RUVCII and/or RUVCIII. Under this interpretation, the presence of RuvCIII is not required to satisfy the claim.
Regarding claims 8-9, Tan et al. teaches Cas9 proteins based on S. pyogenes Cas9, which “binds to a target genomic locus and catalyzes DNA cleavage”. Tan et al. further teaches that “enzymatic action by Cas9 derived from Streptococcus pyogenes or any closely related Cas9 generates double stranded breaks at target site sequences” (pg. 28., lines 21-24).
Regarding claim 13, as evidenced by Makarova et al., the SpCas9 proteins taught by Tan et al., are Class 2, Type II CRISPR-Cas proteins (pg. 2, 3rd para).
Response to Arguments for Prior Art Rejections under 35 USC § 103
In the response filed on 01/02/2026, Applicant argues that Tan et al. teaches away from the claimed invention because its working examples retain at least one REC domain and do not disclose a functional Cas protein lacking both REC1 and REC2 domains. Applicant further contends that Tan provides no guidance for achieving proteins within the claimed size range of 600–750 amino acids lacking both REC domains, and that the Examiner’s position relies on improper hindsight. These arguments have been considered in full and are not persuasive.
With respect to teaching away, a reference teaches away only when it criticizes, discredits, or otherwise discourages the claimed modification. Tan et al. does not contain any such teaching. Rather, Tan et al. expressly teaches that multiple domain deletions may be introduced into Cas9 proteins, including deletions of REC2, substantial portions of REC1, and other domains, and that such deletions may be combined while retaining DNA-binding activity. The disclosure therefore reflects a framework of progressive and combinatorial domain deletion, not a teaching that any particular domain must be retained. The mere absence of an example in which both REC1 and REC2 are entirely removed does not constitute a teaching away.
Applicant’s argument that all functional examples in Tan retain at least one “complete” REC domain is also not dispositive. Tan et al. demonstrates that REC domains are not required to remain intact, as it discloses constructs in which REC2 is deleted and substantial portions of REC1 are removed while retaining function. For example, Tan et al. teaches constructs (e.g., SEQ ID NO: 26) in which REC2 is deleted and substantial portions of REC1 are also removed, thereby evidencing that REC domains may be progressively reduced and structurally disrupted without abolishing activity. This disclosure undermines Applicant’s assertion that the art of record requires retention of a complete REC domain for functionality.
Furthermore, in view of the specification, which defines “lacking” a REC domain to include embodiments in which the domain is substantially deleted or no longer structurally recognizable. Therefore, under the broadest reasonable interpretation in light of the specification, the claimed limitation does not require complete removal of all residues corresponding to REC1 and REC2. Accordingly, Tan et al.’s disclosure of constructs with substantial deletions in REC domains would have suggested proteins lacking REC domains within the meaning of the claim.
Applicant also argues that Tan provides no guidance for achieving proteins within the claimed size range of 600–750 amino acids. However, Tan et al. explicitly identifies protein size as a limiting factor for delivery, particularly in the context of AAV packaging, and teaches that truncated Cas proteins may be as small as 500 amino acids, with preferred sizes including 600 and 700 amino acids. This disclosure provides express guidance that protein length is a result-effective variable and that further reduction in size is both contemplated and desirable. In view of this teaching, a person of ordinary skill in the art would have been motivated to generate smaller variants, including within the claimed size range, through additional combinations of domain deletions, as taught by Tan et al. Applicant’s characterization of Tan’s size disclosure as “speculative” is not persuasive. Tan et al. provides both working examples of truncated proteins and an express teaching that further size reduction to approximately 500 amino acids is achievable. When considered together with its teaching of combinatorial deletions across multiple domains, this constitutes sufficient guidance for further size optimization.
Applicant also argues that, in light of Tan’s disclosure, the claimed invention represents a “substantial functional leap”. This argument is not persuasive. Tan et al. demonstrates that Cas9 proteins tolerate multiple domain deletions, including deletion of REC2 and substantial portions of REC1, while retaining DNA-binding activity. This progressive reduction of domain content indicates that REC domains are not required to remain intact and supports a reasonable expectation that further reductions could be made. The fact that Tan et al. does not expressly disclose a construct lacking both REC1 and REC2 domains in whole does not negate the reasonable expectation of success arising from its demonstrated tolerance to multiple deletions and its express teaching that proteins may be reduced to as small as 500 amino acids.
Accordingly, Tan et al. does not teach away from the claimed invention, but rather provides motivation and a reasonable expectation of success for generating truncated Cas proteins with reduced domain content and size, including proteins lacking REC domains within the meaning of the claim. Therefore, rejections under 35 USC 103 over Tan et al. above have been maintained.
Allowable Subject Matter
Claims 42 and 44 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Relevant Art
Guilinger et al. (Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. (2014) Nat Biotechnol 32, 577–582, cited in PTO-892) teaches engineered CRISPR-Cas systems in which a catalytically inactive Cas9 (dCas9) is fused to a heterologous nuclease domain, such as the FokI nuclease, to create a chimeric protein capable of targeted DNA cleavage. Guilinger et al. teaches that the Cas9 component provides sequence-specific DNA binding, while the fused nuclease domain supplies the cleavage activity, thereby demonstrating the modularity of Cas proteins and the feasibility of incorporating additional nuclease domains. Guilinger et al. further teaches that such fusion constructs can be used to improve genome editing specificity through engineered multi-domain architectures.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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