DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response filed 02/20/2026 has been received and considered entered. This is a response to amendments and arguments filed 02/20/2026.
Election/Restrictions
Applicant’s election without traverse of a spacer sequence of SEQ ID NO:5955, an endonuclease of SEQ ID NO:421, a RuvCIII domain of SEQ ID NO:2242, an HNH domain of SEQ ID NO:4056, and a gRNA of SEQ ID NO:5466 in the reply filed on 09/09/2025 was acknowledged in the non-final rejection mailed 11/06/2025.
Claims Status
Claims 1-104 is/are cancelled. Claims 105-132 is/are currently pending. Claims 105-132 is/are under examination.
Claim Rejections - 35 USC § 112
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.
Written Description:
Claims 105-130 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. This rejection is maintained and amended as necessitated by claim amendments.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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 Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claims 105 and 116 recite spacer sequences at least 85% identical to SEQ ID NOs:5955 or 5963; claims 105, 107, and 128 recite RNA-guided endonucleases having sequences at least 88%, 90%, or 95% identical to SEQ ID NOs:421 or 423; claims 108, 124-125 recite RuvCIII domains comprising sequences at least 75%, 90%, or 95% identical to SEQ ID NOs:2242 or 2244; claims 110 and 127 recite HNH domains comprising sequences at least 80% or 90% identical to SEQ ID NOs:4056 or 4063, and claim 109 recites HNH domains of any sequence; claim 112 recites sequences configured to bind an RNA-guided endonuclease at least 80% identical to SEQ ID NOs:5466 or 6304, and claim 111 recites RNA sequences of any sequence which are “configured to bind said RNA-guided endonuclease”. These claims thus create enormous genera of sequences.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In this case, only sequences 100% identical to SEQ IDNOs:421, 423, 2242, 2244, 4056, 4063, 5466, 6304, 5955, and 5963 are disclosed. While the genera encompass large numbers of variants and molecules that have the same activity (targeting of a TRAC locus, SEQ ID NOs: 5955 and 5963; RNA-guided endonuclease activity, SEQ ID NOs:421 and 423; endonuclease activity, SEQ ID NOs:2242, 2244, 4056, 4063; ability to bind an RNA-guided endonuclease, SEQ ID NOs:5466, 6304), the genus encompasses a large number of variants and molecules that have distinct and different structures, and the specification does not describe the complete structure of a representative number of species of the large genera of spacer sequences, RNA-guided endonuclease sequences, RuvCIII and HNH domain sequences, and guide RNA sequences “configured to bind said RNA-guided endonuclease”, or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genera of modified spacer sequences, RNA-guided endonuclease sequences, RuvCIII and HNH domain sequences, and guide RNA or tracrRNA sequences.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than nucleotide or amino acid sequence), such as specific features or functional attributes, which would distinguish different members of the claimed genus. In the instant case, the only other characteristics are: the ability of the spacer sequences to hybridize with a TRAC gene sequence (claim 105); endonuclease activity of RuvCIII and HNH domains paragraphs [00270]-[00271]); ability of an RNA-guided endonuclease to bind and be guided by RNA (claim 105); and ability of a guiding RNA to bind to an RNA-guided endonuclease (claims 105, 111-112). Such functional limitations cannot be identifying characteristics for the claimed diverse genera of molecules since by Applicant’s definitions of spacer sequences targeting a TRAC locus, RNA-guided endonucleases, RuvCIII domains, HNH domains, and RNA which bind to RNA-guided endonucleases, or functional equivalents thereof, all members of the claimed genera will have the corresponding functional characteristic. Further, no identifying characteristics of the modified nucleic acids and polypeptides are disclosed.
The inventions of claims 105-132 require the use of the inventions of claims 105-112, 116-117, 124-125, 127-129 and therefore are likewise rejected under 35 USC 112(a) as failing to comply with the written description requirement.
Response to Arguments
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Applicant argues that “claim 105 recites species of RNA-guided endonucleases and associated spacer sequences that have been sufficiently described in the Specification at least at Example 22 and Fig. 58 such that one skilled in the art would reasonably conclude that the inventor had possession of the claimed invention” (page 12). Given that endonucleases of SEQ ID NOs:421 and 423 are not known in the prior art, their respective structure-function relationships cannot be reasonably assumed by an artisan—in other words, an artisan would not be able to assume which amino acid residues, protein domains, or sequence elements could be altered or must be preserved in order for their function as RNA-guided endonucleases to be preserved. The disclosure does not provide a description of such a structure-function relationship, or a description of which sequence elements or domains of SEQ ID NOs:421 or 423 can be altered or must be preserved while still preserving desired function. Likewise, the structural elements of protein domain sequences SEQ ID NOs:2242, 2244, 4056, and 4063 which can be altered or must be preserved are not described by the disclosure or the prior art.
Spacer sequences at least 90% identical to SEQ ID NOs:5955 and 5963 are sufficiently described, as a mismatch of up to two nucleotides of a spacer sequence and a target sequence were known to be tolerated by different class 2 Type II Cas endonucleases (see Anderson, 2015). As claim 117 requires an endonuclease at least 88% identical to SEQ ID NOs:421 or 423, however, claim 117 lacks sufficient written description. Moreover, as the disclosure does not provide a description of spacer sequences less than 90% identical to SEQ ID NOs:5955 and 5963 which retain the required function of binding a target sequence (in claim 105, the target sequence is a TRAC locus), nor a description of which nucleotides may be changed or must be preserved in order to maintain the desired targeting function, spacer sequences less than 90% identical to SEQ ID NOs:5955 and 5963 are not sufficiently described.
Sequences less than 100% identical to SEQ ID NOs:5466 and 6304 which retain the function of binding an RNA-guided endonuclease are not described in the disclosure, and the disclosure does not describe which nucleotides or sequence elements may be changed or must be preserved of the 104 defined nucleotides of SEQ ID NO:6304 or the 88 defined nucleotides of SEQ ID NO:5466 (both comprise an additional 22 nucleotides which can be any nucleotide) in order for these sequences to retain the function of binding the RNA-guided endonucleases of SEQ ID NOs:421 or 423. As such, sequences less than 100% identical to SEQ ID NOs:5466 and 6304 are not sufficiently described.
Limitations not Found in Prior Art
A search of SEQ ID NOs:421 and 423 did not show any teaching or suggestion in the prior art of endonucleases having amino acid sequences at least 88% identical to SEQ ID NOs:421 or 423. As this limitation is required by independent claim 105, the pending claims are not anticipated or rendered obvious by the prior art.
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.
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18668543:
Claims 105-132 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18668543 in view of Welstead (WO2015161276A2). This rejection is maintained.
The copending application recites all the required limitations of the pending claims, except for the limitations that the gRNA comprise a spacer sequence targeting a TRAC locus and comprising one of SEQ ID NOs:5950-5965 and that nucleic acids encoding the RNA-guided endonuclease, guide RNA, and donor repair DNA sequence are in an AAV vector. The sequences recited by the copending application have the same sequence identifiers as the pending claims (e.g., SEQ ID NO:421 of the copending application is 100% identical to instant SEQ ID NO:421).
Welstead teaches a method of editing a TRAC locus in a cell using a CRISPR system, and teaches that nucleic acids can be introduced into T cells using AAV vectors or transfection.
Regarding claims 105 and 116-117, Welstead teaches a method of editing a TRAC locus in a cell, comprising contacting to said cell: (a) an RNA-guided endonuclease (Cas9) or a nucleic acid encoding the RNA-guided endonuclease; and (b) an engineered guide RNA or a nucleic acid encoding the engineered guide RNA, wherein the engineered guide RNA forms a complex with the RNA-guided endonuclease and comprises a spacer sequence of SEQ ID NO:49479, which hybridizes to a region of the TRAC locus (SEQ ID NO: 49479 is 100% identical to instant SEQ ID NO:5955, see alignment below, required by claims 105 and 116-117) (claims 1-2, 5, 18, 36-37, 41-44, 59, 74-75, 79-80, 136, 139-140, 156-160; Table 25C, page 215 teaches SEQ ID NO:49479 is a gRNA spacer sequence targeting a TRAC gene).
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Regarding claims 115 and 120, Welstead teaches that the method comprises a step of transfecting the cell with the nucleic acid encoding the RNA-guided endonuclease and the gRNA (Figs. 13-14; Table 800, pages 336-338; page 341 lines 24-29).
Regarding claim 118, Welstead teaches that the T cell is “engineered to express a TCR or a CAR at the same time as inducing a T cell target position mutation in one or more of the…TRAC…gene” (claim 184) or after inducing the mutation in the TRAC gene (claim 183).
Regarding claims 121-123, Welstead teaches that the nucleic acid encoding the Cas endonuclease and gRNA is delivered to cells encoded in an AAV vector (page 37 lines 17-32; Table 800, pages 336-338; page 340 lines 15-23).
The copending application does not specify the target nucleic acid to which the guide RNA hybridizes and to which the donor DNA comprises homology arms, nor does note copending application recite methods for introducing nucleic acids into the recited cell. Welstead teaches a similar system for gene editing, targeting a TRAC locus and introducing the components of the gene editing system into a cell using transfection methods or AAV. It would be obvious to an artisan that the method recited by the copending claims could be used to target any gene, including the TRAC gene locus as taught by Welstead, and that the nucleic acids of the copending method could be introduced to the recited cell through transfection or using an AAV vector, as taught by Welstead.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
Applicant argues that “Welstead fails to verify the function of said gRNA with an endonuclease using said gRNA. Instead, FIGs. 13 and 14 of Welstead show that different gRNAs exhibit significant variability in function. One of ordinary skill in the art could not have predicted the function of the spacer sequence as recited in amended claim 105 based on the disclosure of Welstead” (page 18). However, because Welstead teaches that some gRNAs targeting a TRAC locus have higher efficacy and some have lower or negligible efficacy (as shown in Figs. 13 and 14), it would be obvious for an artisan to try any of the untested guide RNAs targeting a TRAC locus taught by Welstead, including the gRNA of SEQ ID NO:49479.
Conclusion
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).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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