DETAILED ACTION
Status of claim rejections
The rejections of record under 112(a) written description is modified in view of Applicant’s amendments in the response filed 01/27/2026.
The rejections of record under 35 USC 103 is maintained and modified in view of Applicant’s amendments to the claims/arguments in the response filed 01/27/2026.
The double patenting rejections of record are maintained in view of Applicant’s amendments in the response filed 01/27/2026.
This Action is Final, as necessitated by Applicant’s amendments.
New 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.
Claims 1-5, 12-13, 16, 20, 22-27, 29, 32 and 35-41 are 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 1 recites the limitation "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 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 and wherein said fusion endonuclease is a class 2, type II Cas endonuclease.” It is unclear how the claimed junction between the N-terminal and C-terminal sequences occurs within a RuvC-III domain of the C-terminal sequence, because the C-terminal sequence as instantly claimed does not require a RuvC-III domain. It only requires either a WED domain, TOPO domain, or CTD domain (see claim 1). Thus, the claim is indefinite. For the purposes of compact patent prosecution, the examiner is interpreting the junction to occur between the N-terminal RuvC-III (e.g., SEQ ID NO: 696 as instantly claimed) and the C-terminal sequence (i.e., either SEQ ID NO: 706 or 708 as instantly claimed), e.g., either directly or through a linker. Please note that the dependent claims are also indefinite due to dependency on indefinite claim 1.
New Claim Rejections - 35 USC § 112(a) New Matter
Claims 1-5, 12-13, 16, 20, 22-27, 29, 32 and 35-41 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 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 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 “junction . . . occur[ing] within a RuvC-III domain of said N-terminal sequence and a RuvC-III domain of said C-terminal sequence”. 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 a RuvC-III domain of said N-terminal sequence and a RuvC-III domain of said C-terminal sequence”.
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.
Modified 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 and 20 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 any one of SEQ ID NOs: 28-45 or 605-610.
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 any one of SEQ ID NOs: 28-45 or 605-610, 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 NOs: 28-45 and 605-610, 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 NOs 28-45 and 605-610. 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 any of SEQ Nos: 28-45 and 605-610 could be modified to a minimum 90% sequence identity and still possess its desired activity for use in a 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 Nos: 28-45 and 605-610.
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.
Response to Arguments
Applicant's arguments filed 01/27/2026 have been fully considered but they are not persuasive.
On pg. 7-8 of the remarks, Applicant argues claim 16 as amended is directed to engineered guide RNA structures which the specification adequately described and reduced to practice. Applicant also argues that example 4 provides clear description of protein specific single guide RNAs. Applicant also points to Fig. 11B and examples 11-18 for structural portions of the guide RNAs and how to achieve hybridization of the structures with an array of targeting sequences.
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 (SEQ ID NOs: 28-45 and 605-610), the claim as amended now requires nucleases with at least 90% sequence identity to SEQ ID NOs 28-45 and 605-610. 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 any of SEQ Nos: 28-45 and 605-610 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 those sequences. 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: 28-45 and 605-610.
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 35-41 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).
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-II 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.
Response to Arguments
Applicant's arguments filed 01/27/2026 have been fully considered but they are not persuasive.
On pg. 8-11 of the remarks, Applicant argues the references do not teach the claim as amended, and does not teach or suggest for one of ordinary skill in the art to generate a fusion endonuclease comprising 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 with a reasonable expectation of success. Applicant argues that the N-terminal sequence of the claimed fusion endonuclease (SEQ ID NO: 696) spans from the N-terminus to within the RuvC-III domain of SEQ ID NO: 421 of Thomas and the C-terminal sequence of the claimed endonuclease (e.g., SEQ ID NO: 708) spans from within the RuvC-III domain to the C-terminus of SEQ ID NO: 423 of Thomas such that an endonuclease of SEQ ID NO: 696 and 706 or 708 represents distinct sequences with breakpoints within the RuvC-III domain and represent more than a single element. Applicant also argues the Doudna reference for the same reason.
In response, the examiner disagrees. First, as discussed in the above 112(b) rejection, the examiner is interpreting the junction to occur between the N-terminal RuvC-III (e.g., SEQ ID NO: 696 as instantly claimed) and the C-terminal sequence (i.e., either SEQ ID NO: 706 or 708 as instantly claimed), e.g., either directly or through a linker. Second, the claim is drawn to a fusion endonuclease comprising the claimed sequences. Thomas teaches both and Applicant seems to be arguing that the sequences of Thomas (SEQ ID NO: 421 and 423) each contain the RuvC-III domains as instantly claimed. 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 fusion endonuclease. As such, the rejections are maintained as set forth above.
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, 32-33, and 36-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 1202472 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, 32-33, and 36-41 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 01/27/2026 have been fully considered but they are not persuasive.
On pg. 11-13 of the remarks, Applicant argues that claim 1 is patentably distinct from the ‘183 application because the ;173 application 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 rejection against 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 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.
Examiner Note
The examiner performed a search of Applicant’s claimed SEQ ID NOs: 28-45 and 605-610, which are noted in the specification to be nucleotide sequences of sgRNAs engineered to function with an MG3-6 chimeric nuclease (see paragraph 0064). The examiner notes that the prior art does not teach or suggest the sequences as claimed.
Conclusion
NO CLAIMS ALLOWED.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672