DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/22/2026 has been entered.
Status of claim rejections
The rejections of record under 35 USC 112(b) are withdrawn in view of Applicant’s amendments in the response filed 06/22/2026.
The rejection of record under 35 USC 112(a) new matter is maintained in view of Applicant’s arguments/amendments in the response filed 06/22/2026.
The rejection of record under 356 USC 112(a) written description is modified maintained in view of Applicant’s arguments/amendments in the response filed 06/22/2026.
The rejections of record under 35 USC 103 are maintained in view of Applicant’s arguments/amendments in the response filed 06/22/2026. Please note that the rejection is modified to include newly added claim 42.
Maintained Claim Rejection - 35 USC § 112(a) New Matter
Claims 1-5, 12-13, 16, 20, 22-27, 29, 32, and 35-38 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.
Instant claim 1 has been amended to recite "A fusion endonuclease comprising: (a) an N-terminal sequence comprising a RuvC domain, a recognition (REC) domain, or an HNH domain, wherein said N-terminal sequence comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 696; and(b) a C-terminal sequence comprising a wedge (WED) domain, a topoisomerase-homology (TOPO) domain, or a C-terminal (CTD) domain, wherein said C-terminal sequence comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NOs: 706 or 708, wherein said N-terminal sequence and said C-terminal sequence do not naturally occur together in a same reading frame, wherein said fusion endonuclease comprises a RuvC-III domain, wherein a junction between said N-terminal sequence and said C-terminal sequence of said fusion endonuclease occurs within said RuvC-III domain and wherein said fusion endonuclease is a class 2, type II Cas endonuclease” (emphasis added). Neither the instant specification nor the originally filed claims appear to provide support for this limitation.
The instant specification provides support for the use of, for example, MG3-6 N-terminus (SEQ ID NO: 696) and MG3-8 C-terminus (SEQ ID NO: 708) to create chimeric fusion endonuclease (see SEQ ID NO:12; pg. 45-48 of the specification, including Table 1). Furthermore, the specification merely speculates that any “junctions” are found in paragraph 00133 which states: “Junctions between fragments or domains from different nucleases or species can occur in stretches of unstructured regions. Unstructured regions may include regions which are exposed within a protein structure or are not conserved within various nuclease orthologs” However, there is no recitation anywhere in the instant specification that provides support for the claimed “a junction between said N-terminal sequence and said C-terminal sequence of said fusion endonuclease occurs within said RuvC-III domain”. Mere recitation of this structure in the claims and use of a chimeric fusion endonuclease of SEQ ID NO: 12 is not enough to support the recitation of a “a junction between said N-terminal sequence and said C-terminal sequence of said fusion endonuclease occurs within said RuvC-III domain”.
Thus, such a recitation constitutes NEW MATTER. In response to this rejection, Applicant is required to point to support for the recitation of “a junction between said N-terminal sequence and said C-terminal sequence of said fusion endonuclease occurs within a RuvC-III domain of said N-terminal sequence and a RuvC-III domain of said C-terminal sequence” or to cancel the new matter.
New 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 16, 20, and 42 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.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) (“[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 (‘[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.’ (internal quotation marks omitted).”).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
The Specification does not sufficiently describe an engineered guide ribonucleic acid structure configured to form a complex with the fusion endonuclease of claim 1 comprising a guide ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence nor a guide ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence wherein the gRNA structure has at least 90% sequence identity to non-degenerate nucleotides of SEQ ID NO: 35.
Instant claim 16 has been amended to require an engineered nuclease system, comprising: (a) said fusion endonuclease of claim 1; and (b) an engineered guide ribonucleic acid structure configured to form a complex with said fusion endonuclease comprising: a guide ribonucleic acid sequence configured to hybridize to a target nucleic acid sequence, wherein said engineered guide ribonucleic acid structure comprises a sequence having at least 90% sequence identity to non-degenerate nucleotides of SEQ ID No: 35, and wherein said engineered guide ribonucleic acid structure further comprises a trans-activating CRISPR (tracr) ribonucleic acid sequence configured to bind said fusion endonuclease.
The Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to endonuclease activity, let alone binding to virtually any engineered guide ribonucleic acid structure.
It is noted that the instant claims encompass a massive genus of guide ribonucleic acid (gRNA) sequences configured to hybridize to virtually any target nucleic acid (e.g., RNA or DNA) sequence as well as tracr RNA sequences configured to bind to the vast genus of the endonucleases encompassed by the broad scope of the instant claims. However, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to gRNA-endonuclease binding. For example, the Specification fails to describe any motifs, domains, secondary structures, etc. that must be retained by the gRNA and/or endonucleases to allow for formation of a complex.
Likewise, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to hybridization to virtually any target DNA acid sequence in, e.g., the genome of virtually any organism. Liu et al (Comp. Struct. Biotech. J., 18:35-44 (2020), hereinafter “Liu”) teaches that, the CRISPR/Cas protein scans the PAM sequence, and sgRNA [recognizes] target loci and activates endonuclease activity to cleave specific sites (page 36, § 2). However, cleavage efficiency varies greatly among different target sites and/or cell lines, suggesting that several features may influence the binding and cutting efficacy of the sgRNA Cas complex (page 36, § 2). Numerous studies have revealed that gRNA sequence features (sequence composition, nucleotide position, GC content), genetic and epigenetic features (chromatin accessibility, gene expression) and energetics properties (RNA secondary structure, melting temperature, free energy) all contribute to gRNA efficacy (page 36, § 2). As such, ability of a gRNA sequence to hybridize to a target RNA or DNA sequence is unpredictable and cannot be established by sequence homology alone.
It is noted that complex formation with the fusion endonuclease and hybridization to RNA or DNA sequence are indications of what the genus does, rather than what it is. Moreover, the Specification has only adequately described and successfully reduced to practice gRNAs engineered to function with specific chimeric nucleases (see e.g., SEQ ID No: 35), which are sgRNAs engineered to function with an MG3-6 chimeric nuclease). The claim as amended now requires nucleases with at least 90% sequence identity to SEQ ID No: 35. Applicant has not provided information as to what parts of the recited nucleases are important for the claimed activity or what modifications could be made that would allow any of the nucleases to retain a desired range of functionality when used in the engineered guide ribonucleic acid structure. There is no disclosure or examples in the specification that exemplify the use of sequences at 90% sequence identity to the claimed sequences.
The specification also fails to disclose how SEQ No: 35 could be modified to a minimum 90% sequence identity and still possess its desired activity for use in an engineered guide RNA. Even with knowledge in the art regarding modification of sequences, one of ordinary skill would not know what sequence features are required for the outcome of having nuclease that still retains enough functional capacity to form a complex with the fusion endonuclease and to hybridize to a target nucleic acid sequence without a recognized correlation between structure and function. As such, those of ordinary skill would not be able to identify, without further testing, which gene sequences that have at least 90% sequence identity to SEQ ID No: 35.
The Specification does not sufficiently describe an engineered fusion nuclease comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 10 or 12.
The claims have been amended to include new claim 42, which recites “An engineered fusion endonuclease comprising: (a) an N-terminal sequence comprising a RuvC domain, a REC domain, or an HNH domain of an endonuclease; and(b) a C-terminal sequence comprising a WED domain, a TOPO domain, or a CTD domain of an endonuclease, wherein said engineered fusion nuclease comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 10 or 12, and wherein said N-terminal sequence and said C-terminal sequence do not naturally occur together in a same reading frame. In the instant case, the specification has failed to sufficiently describe the structural features that must be retained by members of the claimed genus to establish structure-function relationship with respect to endonuclease activity. SEQ ID NO: 10 and 12 are each 1134 amino acids long. A protein sharing only 90% identity relative to SEQ ID NO: 10 or 12 could have anywhere between 1-113 substitutions, deletions, or additions in any combination along the sequences’ length. Thus, an enormous genus (20226 = 1 x 10294) comprising trillions upon trillions of sequences is encompassed by the tremendously broad scope of the instant claims.
However, while the claims are drawn to a genus that comprises countless sequences, the Specification has only adequately described and successfully reduced to practice a fusion endonuclease comprising the full-length of SEQ ID NO: 696 (MG3-6) and SEQ ID NO: 708 (MG3-8) corresponding to SEQ ID NO: 12. This is not representative of the extremely large genus of sequences claimed, since no variants of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 696 and/or SEQ ID NO: 708 are demonstrated to have endonuclease activity. At best, the Specification contemplates the use of BLAST to identify functional homologs based on sequence homology. However, this is not sufficient to describe members of the claimed genus because such methods access online databases that are continually being updated as sequencing technology improves. As a result, they are not a static source of information. Thus, one of skill in the art would readily appreciate that relying on a non-patent source that is continuously subject to change as a means to identify members of the claimed genus does not sufficiently meet the written description requirement.
Moreover, Friedberg (Brief Bioinformatics, 7: 225-242 (2006)) teaches that homology-based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub-regions is critical to functional annotation, and that often addition, deletion, or re-shuffling
of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg teaches that sequence-based tools are just not sensitive enough to identify functional protein similarity as databases get larger, and diversity of sequences gets larger (page 228, first full paragraph).
Thorton et al. (Nature Struct. Biol, Struct. Genom. Suppl. Nov., 991-994 (2000), hereinafter “Thorton”) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton further describes examples of little correlation between specific enzyme function and overall protein structure (page 992, right column, at lines 2-10). Thus, when taken with the teachings of Friedberg and Thorton, one of skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function.
In the absence of a representative number of examples, the Specification must at least describe the structural features that are required for the claimed function, in this case endonuclease activity. However, as discussed above, the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to endonuclease activity. Instead, Applicant merely offers a cursory statement that any polypeptide having endonuclease activity will work.
Accordingly, the claims as currently written are not adequately described and one of skill
in the art would readily appreciate that Applicant was not in possession of the claimed genus at the time of filing.
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 (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 1-5, 12-13, 16, 20, 22-27, 29, 32 and 35-38, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Thomas et al (US 2020/0332273, IDS-US, prior art of record; hereinafter “Thomas”) in view of Doudna et al (WO 2015/103153, prior art of record; hereinafter “Doudna”).
It is noted that Thomas and the instant application share a common applicant, but list different inventors. As such, Thomas, published October 22, 2020, constitutes prior art under 35 U.S.C. §§ 102(a)(1) and 102(a)(2).
Please also note that the instant rejection has been recast to include new claim 42.
Thomas teaches a Cas endonuclease, MG3-6, having 100% sequence identity to instant SEQ ID NO: 696 (SEQ ID NO: 421, see Sequence Search US-18-056-629A-696, database: Issued_Patents_AA, run February 12, 2024, Result 1 for sequence alignment). Thomas teaches a second Cas endonuclease, MG3-8, from a different organism, having 100% sequence identity to instant SEQ ID NO: 708 (SEQ ID NO: 423, see Sequence Search US-18-056-629A-708, database: Issued_Patents_AA, run February 1, 2024, Result 1 for sequence alignment). Thomas teaches that the endonucleases have an RuvC-III domain and an HNH domain (¶ 0004; as in claim 1). Since, MG3-8 has 100% sequence identity to instant SEQ ID NO: 708, the endonuclease would, absent evidence to the contrary, inherently contain at least a WED domain, a TOPO domain, or a CTD domain, as claimed.
Thomas further teaches an engineered nuclease system comprising, (a) an engineered guide ribonucleic acid structure comprising: (i) a guide ribonucleic acid sequence configured to hybridize to a target deoxyribonucleic acid sequence; and (ii) a tracr ribonucleic acid sequence configured to bind to an endonuclease; (b) a class 2, type II Cas endonuclease configured to bind to the engineered guide ribonucleic acid (¶ 0008). Thomas teaches the guide RNA, MG3-6 sgRNA (SEQ ID NO: 5466), has 100% sequence identity to SEQ ID NO: 35 (see Sequence Search US-18-056-629A-35, database: Issued_Patents_AA, run February 1, 2024, Result 1 for sequence alignment).
Thomas does not explicitly teach a fusion endonuclease comprising an N-terminal sequence comprising at least part of a RuvC domain, a REC domain, or an HNH domain of a first endonuclease; and a C-terminal sequence comprising a WED domain, a TOPO domain, or a CTD domain of a second endonuclease, as claimed.
However, Doudna teaches that domains or motifs within Cas endonucleases may be substituted or exchanged with orthologous domains or motifs from related CRISPR-Cas polypeptides (¶ 00106). Doudna teaches that such substitutions may have utility for altering the overall performance characteristics of a particular Cas, such as increasing or decreasing binding affinity, processivity, etc. (¶ 00106). Doudna further teaches that such substitutions may also have utility for exchanging the activity of one species of Cas with another by exchanging domains or motifs, e.g., exchanging protospacer adjacent motif (PAM) recognition domains, PAM-binding loops, catalytic domains, nuclease domains, DNA binding domains, crRNA binding domains, tracrRNA binding domains, RuvC-I domains, RuvC-II domains, RuvC-III domains, Arginine rich domains, alpha-helical lobes, beta-hairpin domains, HNH domains, Topo (Topoisomerase) domains, C-terminal domains (CTDs), N-terminal domains, etc. (¶ 00106).
As it relates to creation of chimeric (i.e., fusion) polypeptides, Doudna explicitly teaches that chimeric polypeptides may be derived in many ways; e.g., through the fusion of two or more amino acid sequences end-to-end (i.e., fused directly), or e.g., through the insertion of one or more amino acid sequences into another amino acid sequence, or e.g., through the mutation or removal of individual amino acid residues in a polypeptide such that motifs or domains within the polypeptide more similarly resemble motifs or domains within a different polypeptide (see paragraph 0053). As such, Doudna also teaches that fusion polypeptides can contain a “junction” as instantly claimed (e.g, joining directly or through a linker; see claim interpretation in above 112(b) rejection).
One of ordinary skill in the art would have been motivated to combine the N- and C-terminal sequences of MG3-6 and MG3-8, respectively, in order to advantageously screen for improved overall performance characteristics with a reasonable expectation of success. Doudna provides a clear teaching, suggestion, and motivation to substitute or exchange domains, motifs, etc. between different Cas endonucleases, and the instant claims constitute a simple substitution of one known element for another, i.e., N- or C-terminal sequences of an endonuclease, to a obtain predictable result of an endonuclease.
As such, it would have been prima facie obvious at the time of filing to combine the N-terminal sequence of MG3-6 and the C-terminal sequence of MG3-8, which would yield a fusion endonuclease having 100% sequence identity to SEQ ID NO: 12 with a reasonable expectation of success of producing a fusion endonuclease. In this regard, it would have been prima facie obvious to further include an N-terminal RuvC-I domain and/or RuvC-III domain as well as a C-terminal CTD in the fusion endonuclease taught by Thomas and Doudna since Doudna further teaches that these domains modulate the overall performance of CRISPR-Cas9 activity (¶ 00106).
Moreover, given that Thomas teaches Cas endonucleases with 100% sequence identity to the claimed sequences, absent evidence to the contrary, the fusion endonuclease taught by Thomas and Doudna would have an amino acid sequence having less than 86% sequence identity to a SpyCas9, i.e., a Streptococcus pyogenes Cas9 endonuclease and would be a class 2, type II Cas endonuclease.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
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.
First rejection
Claims 1, 3-5, 12-13, 16, 20, 25, 27, 29, 32, and 36-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12024727 B2 in view of Thomas and Doudna. Although the claims at issue are not identical, they are not patentably distinct from each other.
It is noted for the purposes of this rejection, shares identical sequence numbering.
The conflicting claims are drawn to an engineered composition comprising:
(a) an endonuclease comprising a RuvC-III domain and an HNH domain, wherein said
endonuclease comprises a sequence having at least 90% sequence identity to SEQ ID NO: 421; and (b) an engineered guide ribonucleic acid structure configured to form a complex with said endonuclease comprising: i) a guide ribonucleic acid sequence configured to hybridize to a target deoxyribonucleic acid (DNA) sequence; and ii) a tracr ribonucleic acid sequence configured to form a complex with said endonuclease claim 1).
As discussed above, SEQ ID NO: 421, i.e., MG3-6, shares 100% sequence identity with instant SEQ ID NO: 696 (see Sequence Search US-18-056-629A-696, database: Issued_Patents_AA, run February 12, 2024, Result 1 for sequence alignment). The conflicting claims do not teach a fusion endonuclease, as claimed.
However, Thomas teaches SEQ ID NO 423, i.e., MG3-8, shares 100% sequence identity with instant SEQ ID NO: 708 (see Sequence Search US-18-056-629A-708, database: Issued_Patents_AA, run February 1, 2024, Result 1 for sequence alignment). Since MG3-8 has 100% sequence identity to instant SEQ ID NO: 708, the endonuclease would, absent evidence to the contrary, inherently contain at least a C-terminal WED domain, a TOPO domain, or a CTD domain.
Moreover, Doudna teaches that domains or motifs within Cas endonucleases may be substituted or exchanged with orthologous domains or motifs from related CRISPR-Cas polypeptides (¶ 00106). Doudna teaches that such substitutions may have utility for altering the overall performance characteristics of a particular Cas, such as increasing or decreasing binding affinity, processivity, etc. (¶ 00106). Doudna further teaches that such substitutions may also have utility for exchanging the activity of one species of Cas with another by exchanging domains or motifs, e.g., exchanging protospacer adjacent motif (PAM) recognition domains, PAM-binding loops, catalytic domains, nuclease domains, DNA binding domains, crRNA binding domains, tracrRNA binding domains, RuvC-I domains, RuvC-II domains, RuvC-III domains, Arginine rich domains, alpha-helical lobes, beta-hairpin domains, HNH domains, Topo (Topoisomerase) domains, C-terminal domains (CTTs), N-terminal domains, etc. (¶ 00106).
As it relates to creation of chimeric (i.e., fusion) polypeptides, Doudna explicitly teaches that chimeric polypeptides may be derived in many ways; e.g., through the fusion of two or more amino acid sequences end-to-end (i.e., fused directly), or e.g., through the insertion of one or more amino acid sequences into another amino acid sequence, or e.g., through the mutation or removal of individual amino acid residues in a polypeptide such that motifs or domains within the polypeptide more similarly resemble motifs or domains within a different polypeptide. As such, Doudna also teaches that fusion polypeptides can contain a “junction” as instantly claimed (i.e., joined directly or through a linker; see claim interpretation in 112(b) rejection above).
One of ordinary skill in the art would have been motivated to combine the N- and C-terminal sequences of the conflicting claims and MG3-8, respectively, in order to advantageously screen for improved overall performance characteristics with a reasonable expectation of success. Doudna provides a clear teaching, suggestion, and motivation to substitute, include or exchange domains, motifs, etc. between different Cas endonuclease, and the instant claims constitute a simple substitution of one known element for another, i.e., N- or C-terminal sequences of an endonuclease, to a obtain predictable result of a fusion endonuclease.
As such, it would have been prima facie obvious at the time of filing to combine the N-terminal sequence of the conflicting claims and the C-terminal sequence of MG3-8, which would yield a fusion endonuclease having at least 90% sequence identity to SEQ ID NO: 12 with a reasonable expectation of success of producing a fusion endonuclease. In this regard, it would have prima facie obvious to further include an N-terminal RuvC-I domain and/or RuvC-II domain as well as a C-terminal CTD in the fusion endonuclease taught by the conflicting claims since Doudna further teaches that these domains modulate the overall performance of CRISPR-Cas9 activity (¶ 00106).
Moreover, given the high sequence identity to the claimed sequences, absent evidence to the contrary, the fusion endonuclease taught by the conflicting claims, MG3-8, and Doudna would have an amino acid sequence having less than 86% sequence identity to a SpyCas9, i.e., a Streptococcus pyogenes Cas9 endonuclease.
Second rejection
Claims 1, 3-5, 12-13, 16, 20, 25, 27, 29, 32, and 36-42 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10,913,941 in view of Thomas and Doudna.
It is noted that, for purposes of this rejection, the ’941 patent shares identical sequence numbering as U.S. Patent No. 10,982,200 (application no.: 16/917,837).
The conflicting claims are drawn to an engineered nuclease composition comprising: (a) an endonuclease comprising a RuvC-III domain comprising a sequence having at least 90% sequence identity to SEQ ID NO: 2242; and (b) an engineered guide ribonucleic acid structure configured to form a complex with said endonuclease comprising: (i) a guide ribonucleic acid sequence configured to hybridize to a target deoxyribonucleic acid sequence; and (ii) a tracr ribonucleic acid sequence configured to bind to said endonuclease wherein said endonuclease comprises a sequence having at least 90% sequence identity to SEQ ID NO: 421 (claim 1). The conflicting claims teach that the endonuclease further comprises an HNH domain (claim 2).
As discussed above, SEQ ID NO: 421, i.e., MG3-6, shares 100% sequence identity with instant SEQ ID NO: 696 (see Sequence Search US-18-056-629A-696, database: Issued_Patents_AA, run February 12, 2024, Result 1 for sequence alignment). The conflicting claims do not teach a fusion endonuclease, as claimed.
However, Thomas teaches SEQ ID NO 423, i.e., MG3-8, shares 100% sequence identity with instant SEQ ID NO: 708 (see Sequence Search US-18-056-629A-708, database: Issued_Patents_AA, run February 1, 2024, Result 1 for sequence alignment).
Moreover, Doudna teaches that domains or motifs within Cas endonucleases may be substituted or exchanged with orthologous domains or motifs from related CRISPR-Cas polypeptides (¶ 00106). Doudna teaches that such substitutions may have utility for altering the overall performance characteristics of a particular Cas, such as increasing or decreasing binding affinity, processivity, etc. (¶ 00106). Doudna further teaches that such substitutions may also have utility for exchanging the activity of one species of Cas with another by exchanging domains or motifs, e.g., exchanging protospacer adjacent motif (PAM) recognition domains, PAM-binding loops, catalytic domains, nuclease domains, DNA binding domains, crRNA binding domains, tracrRNA binding domains, RuvC-I domains, RuvC-II domains, RuvC-III domains, Arginine rich domains, alpha-helical lobes, beta-hairpin domains, HNH domains, Topo (Topoisomerase) domains, C-terminal domains (CTDs), N-terminal domains, etc. (¶ 00106).
As it relates to creation of chimeric (i.e., fusion) polypeptides, Doudna explicitly teaches that chimeric polypeptides may be derived in many ways; e.g., through the fusion of two or more amino acid sequences end-to-end (i.e., fused directly), or e.g., through the insertion of one or more amino acid sequences into another amino acid sequence, or e.g., through the mutation or removal of individual amino acid residues in a polypeptide such that motifs or domains within the polypeptide more similarly resemble motifs or domains within a different polypeptide. As such, Doudna also teaches that fusion polypeptides can contain a “junction” as instantly claimed (i.e., joined directly or through a linker; see claim interpretation in 112(b) rejection above).
One of ordinary skill in the art would have been motivated to combine the N- and C-terminal sequences of the conflicting claims and MG3-8, respectively, in order to advantageously screen for improved overall performance characteristics with a reasonable expectation of success. Doudna provides a clear teaching, suggestion, and motivation to substitute or exchange domains, motifs, etc. between different Cas endonuclease, and the instant claims constitute a simple substitution of one known element for another, i.e., N- or C-terminal sequences of an endonuclease, to a obtain predictable result of an endonuclease.
As such, it would have been prima facie obvious at the time of filing to combine the N-terminal sequence of the conflicting claims and the C-terminal sequence of NW4, which would yield a fusion endonuclease having at least 90% sequence identity to SEQ ID NO: 12 with a reasonable expectation of success of producing a fusion endonuclease. In this regard, it would have prima facie obvious to further include an N-terminal RuvC-I domain and/or RuvC-II domain as well as a C-terminal CTD in the fusion endonuclease taught by the conflicting claims since Doudna further teaches that these domains modulate the overall performance of CRISPR-Cas9 activity (¶ 00106).
Moreover, given the high sequence identity to the claimed sequences, absent evidence to the contrary, the fusion endonuclease taught by the conflicting claims, Thomas, and Doudna would have an amino acid sequence having less than 86% sequence identity to a SpyCas9, i.e., a Streptococcus pyogenes Cas9 endonuclease.
Accordingly, the instant and conflicting claims are drawn to obvious variations of overlapping subject matter.
Response to Arguments
Applicant's arguments filed 06/22/2026 have been fully considered but they are not persuasive.
On pg. 9-10 of the remarks, Applicant argues the new matter rejection under 112(a), specifically that claim 1 is fully supported by paragraph 0037, 00133, and 00135, Table 1, and Figs. 3A and 3B. Applicant argues that the figures provide exemplary chimeric compositions including the amino acid positions of an N-terminus of MG3-6 and C terminus of MG3-8 and MG3-4, the alignment of multiple sequences to guide determination of optimal breakpoint for swapping, and the specification guides one of ordinary skill in the art to determine optimal breakpoints for domain swapping and recombination.
In response, the examiner disagrees. As set forth in the rejection above, at most, Applicant’s specification (including the figures as argued above) provides speculation that any “junctions” are found in paragraph 00133 which states: “Junctions between fragments or domains from different nucleases or species can occur in stretches of unstructured regions. Unstructured regions may include regions which are exposed within a protein structure or are not conserved within various nuclease orthologs” Mere recitation of this structure in the claims and use of a chimeric fusion endonuclease of SEQ ID NO: 12 is not enough to support the recitation of a “a junction between said N-terminal sequence and said C-terminal sequence of said fusion endonuclease occurs within said RuvC-III domain”. Thus, the rejection is maintained as set forth above.
On pg. 10-12, Applicant argues the written description rejection. Specifically, Applicant argues that the amendment to the claim to recite “90% identity to non-degenerate nucleotides of SEQ ID NO: 35” is sufficient to overcome the rejection. Applicant argues that example 3 and Fig, 4-5 describe active protein complexes comprising fusion endonuclease as set forth in claim 1 compatible with an engineered gRNA structure and example 4 provides description of protein-specific sgRNA structure developed for use with the claimed endonuclease. Applicant argues that Fig. 11B depicts structural portions of sgRNA structures and examples 11-189 detail how to achieve hybridization such that the rejection should be withdrawn.
In response, the examiner disagrees. As discussed above, while the specification reduces to practice the to practice gRNAs engineered to function with specific chimeric nucleases (e.g., SEQ ID No: 35), the claim as amended now requires nucleases with at least 90% sequence identity to SEQ ID No: 35. Applicant has not provided information as to what parts of the recited nucleases are important for the claimed activity or what modifications could be made that would allow those nucleases within the genus to retain a desired range of functionality when used in the engineered guide ribonucleic acid structure. There is no disclosure or examples in the specification that exemplify the use of sequences at 90% sequence identity to the claimed sequences.
The specification also fails to disclose how the sequence could be modified to a minimum 90% sequence identity and still possess its desired activity for use in an engineered guide RNA. Even with knowledge in the art regarding modification of sequences, one of ordinary skill would not know what sequence features are required for the outcome of having nuclease that still retains enough functional capacity to form a complex with the fusion endonuclease and to hybridize to a target nucleic acid sequence without a recognized correlation between structure and function. As such, those of ordinary skill would not be able to identify, without further testing, which sequences that have at least 90% sequence identity to SEQ ID NO: 35. Thus, the rejection is maintained as set forth above. The examiner notes that it may be sufficient to overcome the rejection by amending the claim to recite 95% sequence identity to SEQ IDs NO: 35.
On pg. 12-14, Applicant argues a PHOSITA would have had no motivation or reasonable expectation of success to arrive at a functional fusion endonuclease with the claimed components. Specifically, Applicant argues that the Douda reference (combined with the Thomas reference), does not provide a teaching, suggestion, or motivation for generating a functional fusion endonuclease with the claimed domains and the claimed junction. Applicant argues that Doudna teaches exchanging whole domains but does not contemplate the fusion endonuclease claimed having substitutions or exchanges within domains. Applicant then argues no structural or functional guidance on amino acid sequences to be substituted or exchanged from the polypeptides, no working examples for generating a functional fusion endonuclease. Applicant further argues that the recitation of the limitations of new claim 42 are not met.
In response, the examiner disagrees. The claim is drawn to a fusion endonuclease comprising the claimed sequences. The claims do not require any substitution or exchange of domain motifs. As it relates to creation of chimeric (i.e., fusion) polypeptides, Doudna explicitly teaches that chimeric polypeptides may be derived in many ways; e.g., through the fusion of two or more amino acid sequences end-to-end (i.e., fused directly), or e.g., through the insertion of one or more amino acid sequences into another amino acid sequence, or e.g., through the mutation or removal of individual amino acid residues in a polypeptide such that motifs or domains within the polypeptide more similarly resemble motifs or domains within a different polypeptide (see paragraph 0053). As such, Doudna also teaches that fusion polypeptides can contain a “junction” as instantly claimed (i.e., joined directly or through a linker; see claim interpretation above). Considering the sequences of Thomas are 100% identical to the ones claimed, absent evidence to the contrary, the “breakpoints” (see pg. 10-11 of the arguments) within the RuvC-III domains are also within the sequences of Thomas, absent evidence to the contrary. Doudna then provides the explicit teaching, suggestion, and motivation to combine each endonuclease (with the RuvC-III breakpoints) to create a chimera (i.e., fusion) with a reasonable expectation of success of producing a functional fusion endonuclease. Second, the structural guidance of the particular amino acids as instantly claimed was provided by the Thomas reference (see rejection above), as Thomas teaches sequences with 100% identity to both claimed sequences. Doudna provides one of ordinary skill the teaching, suggestion, and motivation to substitute or exchange domains, motifs, etc. between different Cas endonucleases, and the instant claims constitute a simple substitution of one known element for another, i.e., N- or C-terminal sequences of an endonuclease, to a obtain predictable result of an endonuclease. As such, the rejections are maintained as set forth above.
On pg. 14-16, Applicant argues the claimed fusion endonuclease represents an unpredictable result. Applicant argues neither reference discloses the surprising or unexpected result of the claimed fusion endonuclease. Applicant argues that the identification of functional fusion endonuclease is highly unpredictable and the claimed endonucleases are unexpected. Applicant argues that the PAM enrichment assays and points to Fig. 4 and 6 of the specification showing that when the N-terminal of SEQ ID NO: 696 was fused to C-terminal of other endonucleases, none of the resulting fusion endonucleases were functional or less than 15% of total fusion endonucleases in the PAM enrichment assays were functional. Applicant argues that the claimed fusion endonuclease does have endonuclease function. Applicant urges that this demonstrates a high degree of unpredictability in arriving at a functional endonuclease and none of the references contemplate the fusion protein of claim 1 or it unexpected results.
In response, the examiner disagrees. While the examiner appreciates Applicant pointing to the figures in the specification, the invention requires a fusion endonuclease comprising the components recited in instant claim 1, which are taught by the combination of Thomas and Doudna. In this case, Thomas teaches the requisite parts (sequences with 100% sequence identity to SEQ ID NO: 696 and 708) as instantly claimed. Doudna (as outlined above) provides a clear teaching, suggestion, and motivation to one of ordinary skill to substitute or exchange domains, motifs, (i.e., RuvC domain, a WED domain, a TOPO domain, CTD domain, etc.) between different Cas endonucleases and have a “junction” as instantly claimed and combine the sequences of Thomas to create a functional fusion endonuclease with a reasonable expectation of success.
Furthermore, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Thus, the claims remain rejected as set forth above.
On pg. 16-18, Applicant argues Applicant argues that claim 1 is patentably distinct from the ‘727 application because the ‘727 patent requires an endonuclease with 90% sequence identity to SEQ ID NO: 421. Applicant argues that neither Thomas nor Doudna teach, disclose, or suggest the claimed endonuclease. Applicant argues much of the same for the ‘941 patent.
In response, the examiner disagrees for much of the same reasons as set forth above. Thomas teaches both claimed sequences and Applicant concedes on record (see previous remarks from the Non-Final Office action 10/29/2025) that the sequences of Thomas each contain the claimed RuvC-III domains. Doudna then provides the explicit teaching, suggestion, and motivation to combine each endonuclease to create a chimera (i.e., fusion) with a reasonable expectation of success of producing a fusion endonuclease. As such, the rejections are maintained as set forth above.
Conclusion
NO CLAIMS ALLOWED.
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/G.C.R./Examiner, Art Unit 1651 /THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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