DETAILED ACTION
Applicant’s response to the restriction/election of species requirement received on 7/20/26 has been entered. Claims 1-38 are pending in this application. Applicant’s election of the invention of Group I and the species SEQ ID NO:65 as the TCR Vdelta sequence and SEQ ID NO:62 as the TCR Vgamma sequence without traverse is acknowledged.
Claims 9, 11-13, 21, and 35-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/20/26.
Claims 1-8, 10, 14-20, and 22-34 are therefore currently under examination based on the elected species of SEQ ID NO:65 as the TCR Vdelta sequence and SEQ ID NO:62 as the TCR Vgamma sequence. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/31/26 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner and initialed and signed copies of the 1449s are attached to this action.
37 CFR 1.121-1.125
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, Figure 7 and in Figure 8 depict nucleotide sequences that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821 (a)(1) and (a)(2) and which are not identified by SEQ ID NO. Applicant was further encouraged to review the specification for additional sequences which are not identified by SEQ ID NO. It is further noted that the Brief Description of the Drawings present in the specification also does not provide SEQ ID NOS for any of the sequences present in Figures 7 and 8. Compliance with 37 CFR 1.821-1.825 requires that the specification be amended to recite SEQ ID NOS. for each recitation of a sequence in the specification, including the drawings. Therefore, if the sequences are present in the paper and CRF listings, applicant may fully comply with 37 CFR 1.821 by amending the either the drawings or the brief description of the drawings for Figures 7 and 8 to include the appropriate SEQ ID NOS present for the sequences depicted in Figures 7 and 8. If the sequences are not present on the filed paper and CRF listings, then new paper and CRF sequence listings are required as set forth in the attached Notice to Comply.
Claim Rejections - 35 USC § 112
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 1-8, 10, 17-18, 21, 25-30 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 lacks proper antecedent basis for the recitation of “the at least one TCR Vdelta gene segment” in lines 3-4. Lines 1-2 of claim 1 recite at least one TCR “V gene segment”, not a Vdelta gene segment. As such, antecedent basis is lacking the at least on TCR “Vdelta” gene segment which renders the claim indefinite as it is unclear whether claim 1 is intended to be limited to TCR Vdelta gene segments, or whether the claim encompasses any V gene segment. Thus, the metes and bounds of the claim cannot be determined. Claims 2-8 and 10 depend on claim and are therefore included in this rejection.
Claim 5 is further indefinite in that it depends on claim 1 and recites wherein the amino acid sequence of the at least one unarranged human TCR Vdelta gene segment has at least 90% sequence identity with sequence selected from the group consisting of SEQ ID NOS: 65, 66, 67, 68, 69, 70, 71, or 72. It is first noted that claim 5 is indefinite in the recitation of “the amino acid sequence of an unarranged Vdelta gene segment”. Vdelta gene segments are DNA, and while they encode amino acids, they are not themselves amino acid sequences. Further, the recitation that the amino acid sequence of the Vdelta gene segment is 90% identical to a number of sequences is confusing as the recited SEQ ID NOS are amino acid sequences which do not correspond to any known unrearranged Vdelta gene segments. Instead, SEQ ID NOS: 65, 66, 67, 68, 69, 70, 71, or 72, according to the instant specification, are all CDR3 amino acid sequences from rearranged Vdelta variable regions- see for example Figure 20T which include a number of Vdelta CDR sequences derived from rearrangement of a Vdelta1 gene segment whose encoded amino acid sequence comprises SEQ ID NO:65. Furthermore, note that CDR3 sequences are not derived solely from a germline unrearranged V gene segment sequence. Instead they are created through recombination of the V, D, and J gene segments and reflect sequence from the end of V gene segment joined to sequence from the D gene segment joined to sequence from the J gene segment which is further diversified by deletions, and P and N type additions to the sequence which occur during the process of recombination. For this reason, SEQ ID NO:65 is substantially less than 90% identical to any germline Vdelta gene segment. Thus, the limitation of claim 5 is confusing such that the metes and bounds of the claim cannot be determined because it does not appear than any known germline Vdelta gene segment sequence could meet the required 90% identity to the CDR3 sequence of SEQ ID NO:65. Claim 28 includes in part the same limitation as claim 18 and is therefore included in this rejection. Due to the conflicting limitations recited in claim 5 and 28, further examination under 35 U.S.C. 112(a), 35 U.S.C. 102, and 35 U.S.C. 103 is precluded.
Claims 8 and 10 are further indefinite in that claim 8 depends on claim 7, which depends on claim 6, which depends on claim 1, and recites, “wherein the sequence of the complementary determining region 3 (CDR3) of Vdelta1 ….”. Claim 10 has similar dependency and recites, “wherein the CDR3 of Vdelta3..”. Both of claims 8 and 10 lack antecedent basis for these limitations since claim 7 only recites that the animal expresses a humanized TCRdelta variable region and does not limit the rearranged VDJdelta sequence to one derived from an unrearranged Vdelta 1 or Vdelta3 gene segment. Thus, the claim is confusing and the metes and bounds of the claim cannot be determined.
Claim 17 is indefinite in the recitation, “preferably Vgamma9, Vgamma10, and Vgamma11”. The term “preferably”, similar to the phrase "such as", renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In the interests of compact prosecution, claim 17 has not been limited to those following the term “preferably”. Claim 18 depends on claim 17 and thus is included in this rejection.
Claim 18 is further indefinite in that it depends on claim 7, which depends on claim 1, and recites wherein the amino acid sequence of the at least one unrearranged human TCR Vgamma gene segment has at least 90% sequence identity with sequence selected from the group consisting of SEQ ID NOS: 62, 63, or 64. Similar to the rejection of claim 5 above, it is noted that Vgamma gene segments are DNA, and while they encode amino acids, they are not themselves amino acid sequences. Further, the recitation that that the amino acid sequence of the Vgamma gene segment is 90% identical to a number of sequences is confusing as the recited SEQ ID NOS are amino acid sequences which do not correspond to any known unrearranged Vdelta gene segments. Instead, SEQ ID NOS: 62, 63, and 64, according to the instant specification, are all CDR3 amino acid sequences from rearranged Vgamma variable regions. Furthermore, as discussed above, CDR3 sequences are not derived solely from a germline unrearranged V gene segment sequence. Instead they are created through recombination of the V, D, and J gene segments and reflect sequence from the end of V gene segment joined to sequence from the D gene segment joined to sequence from the J gene segment which is further diversified by deletions, and P and N type additions to the sequence which occur during the process of recombination. For this reason, SEQ ID NO:62 is substantially less than 90% identical to any germline Vgamma gene segment. Thus, the limitation of claim 18 is confusing such that the metes and bounds of the claim cannot be determined because it does not appear than any known germline Vgamma gene segment sequence could meet the required 90% identity to the CDR3 sequence of SEQ ID NO:62. Claim 28 includes in part the same limitation as claim 18 and is therefore included in this rejection. Due to the conflicting limitations recited in claim 18 and 28, further examination under 35 U.S.C. 112(a), 35 U.S.C. 102, and 35 U.S.C. 103 is precluded.
Claim 21 is indefinite in that claim 21 depends on claim 20, which depends on claim 19, which depends on claim 14, and recites, “wherein the first four amino acids of CDR3 of Vgamma9”. Claim 21 lacks antecedent basis for this limitation since claim 20 only recites that the animal expresses a humanized TCRgamma variable region and does not limit the rearranged VJ gamma sequence to one derived from an unrearranged Vgamma9 gene segment. Thus, the claim is confusing and the metes and bounds of the claim cannot be determined.
Claims 25 is indefinite in the recitation, “preferably Vgamma9, Vgamma10, and Vgamma11”. The term “preferably”, similar to the phrase "such as", renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In the interests of compact prosecution, claim 25 has not been limited to those following the term “preferably”. Claim 26-27 depend on claim 25 and thus are included in this rejection.
Claims 29 and 30 are indefinite as they recite that the Ddelta (claim 29) or the Jdelta and Jgamma have at least 90% sequence identity with human Ddelta, human Jdelta, and human Jgamma. These claims are confusing because claim 22, upon which both claims depend, recite human Ddelta, human Jdelta, and human Jgamma “gene segments”. It is unclear whether the Ddelta, Jdelta, and Jgamma referred to in claims 29 and 30 are in fact gene segments or something else. In addition, claim 22 already limits the gene segments to human gene segments, and not any Ddelta, Jdelta, or Jgamma gene segments. Finally, there are a number of human Ddelta, Jdelta, and Jgamma gene segments such that it is unclear which sequences are being compared in order to determine 90% sequence identity. Thus, for all of these reasons, the metes and bounds of claims 29 and 30 cannot be determined. In the interests of compact prosecution, claims 29 and 30 have been interpreted as encompassing any human Ddelta, Jdelta, or Jgamma gene segments.
Claim Interpretation
In view of the numerous issues of indefiniteness regarding the claims as set forth in detail in the 112(b) rejections above, and applicant’s election of SEQ ID NOS 62 and 65, the following claim interpretation has been applied. The claims have been given their broadest reasonable interpretation as encompassing a genetically modified non-human animal with the structure recited in independent claims 1, 14, and 22, wherein upon rearrangement, the introduced human TCR delta V, D, and J gene segments, and/or the human TCR gamma V and J gene segments are capable of rearranging to produce TCR delta variable regions and/or TCR gamma variable regions that comprise the CDR3 sequences of SEQ ID NOS 65 and 62 respectively.
Claim Rejections - 35 USC § 103
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.
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 1-4, 6-8, 10, 14-17, 19-20, 22-27, and 29-34 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Application Publication 2022/0386575 (2022), hereafter referred to as Macdonald et al., with an effective filing date of October 28, 2011, in view of IMGT TCR human loci gene segments www.imgt.org/IMGTrepertoire/LocusGenes/listIG_TR /human/TR/Hu_TRgroup.html. accessed 2026, Gene Tables TRDV, TRDD, TRDJ, TRGV, and TRGJ, originally created in either 1995 or 1996.
Macdonald et al. teaches genetically modified non-human animals, particularly mice, whose genome has been modified to comprise unrearranged human TCR delta V, D, and J gene segments, and unrearranged human TCR gamma V and J gene segments. Macdonald et al. teaches genetically modified non-human animals such as mice and rats that comprise in their genome unrearranged human TCR variable region segments (V(D)J segments), wherein the unrearranged human TCR variable region segments replace, at an endogenous non-human TCR variable gene locus such as TCRdelta and TCR gamma endogenous gene loci, the endogenous non-human TCR variable region gene segments (Macdonald et al., paragraphs 76-77). In addition, Macdonald et al. teaches wherein the unrearranged human TCR variable region segments (V(D)J segments), are operably linked to a non-human TCR constant region gene sequence resulting in a humanized TCR locus (Macdonald et al., paragraphs 77-78). More specifically, Macdonald et al. teaches that the non-human animal comprises a complete repertoire of human Vdelta, Ddelta, and Jdelta segments at the unrearranged endogenous locus (Macdonald et al., paragraph 97). Macdonald et al. also teaches that the non-human animal further comprises an unrearranged humanized TCRγ locus, comprising at least one human Vgamma and at least one human Jgamma segments up to a complete repertoire of human Vgamma and human Jgamma variable region segments (Macdonald et al., paragraph 98). Macdonald et al. also references the IMGT database for more details on the TCR delta and TCRgamma loci. Further, Macdonald et l. teaches that the non-human animal comprising the humanized TCRdelta/gamma variable gene loci expresses a humanized delta/gamma T cell receptor comprising a human variable region and a non-human, such as mouse or rat, constant region on a surface of a T cell, and is further capable of expressing a diverse repertoire of humanized T cell receptors that recognize a variety of presented antigens (Macdonald et al., paragraph 99). Macdonald et al. also teaches that the genetically modified non-human animals such as mice express humanized T cell receptors that retain the ability to recruit a variety of endogenous non-human anchor or signaling molecules including CD3 molecules expressed in the T cells (Macdonald et al., paragraph 78).
Macdonald et al., while teaching to replace the endogenous TCR delta and gamma loci with complete human TCR delta and gamma loci gene segments, does not specifically teach all of the individual human TCR delta V, D, and J gene segments or the human TCR gamma V and J gene segments. However, Macdonald et al. does reference the IMGT database. The IMGT database provided sequence information for all of the individual human TCR delta V, D, and J gene segments or the human TCR gamma V and J gene segments- see the IMGT gene Tables. Therefore, based on the teachings of Macdonald et al. to replace the endogenous loci with a complete repertoire of human TCR gamma and delta variable region gene segments, and the teachings of the IMGT database, it would have been prima facie obvious to the skilled artisan at the time of filing to knockin a complete repertoire of human TCR delta V gene segments and complete repertoire of human TCR gamma gene segments into their respective loci in a non-human animal such as a mouse with a reasonable expectation of success. Further, in regards to human delta and gamma CDR3 sequences generated from such mice, since the mice according to Macdonald contain complete gamma and delta variable region gene segments, the skilled artisan would have had a reasonable expectation that CDR3 with the sequences of both SEQ ID NO:62 and 65 could be generated within the mouse during normal rearrangement.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
