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 .
Status of Claims
Claims 1-3, 7-9, 12-13, and 16 are pending.
Priority
Claims 1-3, 7-9, 12-13, and 16 have priority to PRO 63/383,213 filed on November 10, 2022, and to PRO 63/376,706 filed on September 22, 2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on May 28, 2024, and on June 1, 2026, and on June 4, 2026, were filed before the mailing of the First Office Action on August 22, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Election/Restrictions
Applicant’s election of group I, drawn to a mouse model in which T cells contain TCR γ gene segments that undergo rearrangement to produce functional TCR γ chain where the mouse generates CD3+T cells expressing functional humanized T cell receptors on their surface, in the reply filed on May 29, 2026, is acknowledged. The election was made without traverse.
Claims 4-6 and 10-11 of group II, claims 21-23 of group III, claim 24 of group IV, claim 38 of group V, claim 39 of group VI, claims 40 and 52 of group VII, claim 41 of group VIII, claim 42 of group IX, claim 43 of group X, claim 44 of group XI, claim 45 of group XII, and claims 53-56 of group XIII are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groupings.
Furthermore, claims 40 and 52 of group VII, claim 41 of group VIII, and claim 45 of group XII are related as being drawn to a product and to a process of using the product will be rejoined pursuant to MPEP §821.04(b) upon identification of allowable subject matter for Group I. Thus, claims 40, 41, 45, and 52 will be rejoined upon the identification of allowable subject matter in Group I.
Claims 1-3, 7-9, 12-13, and 16 are considered herein.
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.
Claims 1-3, 7-9, 12, and 16 are rejected under 35 U.S.C. §103 as being unpatentable over Macdonald et al. [US 2013 109053 A1], in view of Vavassori et al. [Butryophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells, Nature Immunology, 2013], in view of Naik et al. [Specification of Vδ and Vα usage by Tcra/Tcrd locus V gene segment promoters, J Immunol., 2016], in view of Peng Dong et al. [Global characterization of differential gene expression profiles in mouse Vγ1+ and Vγ4+ γδ T cells, PLoS One, 2014].
Regarding claim 1, Macdonald teaches a genetically modified mouse comprising an unrearranged humanized TCR γ locus having an unrearranged human TCR Vγ segment and an unrearranged human TCR Jγ segment [¶ 0002]. Macdonald et al. further teaches that the human Vγ and Jγ segments are capable of rearranging in T cells of the mouse to generate a rearranged human Vγ/Jγ variable region sequence [¶ 0009, 0098]. However, Macdonald does not teach the TCR γ region being operably linked to a TCR γ constant region. For this limitation, Vavassori et al. discloses a transgenic expression of a human Vγ9Vδ2 T cell receptor showing that the human Vγ9Vδ2 TCR is functional in a mouse T-cell environment [Results ¶ 2]. This demonstrates that a human TCR γ polypeptide can be expressed as part of a function TCR on the surface of mouse T cells. Additionally, Macdonald et al. discloses the humanized TCR γ locus is present in an unrearranged configuration and undergoes V γ/J γ rearrangement during T-cell development showing the progression of immature T cell development to mature T cell development, i.e. CD3- to CD3+ [¶ 0112]. Given this, it would have been prima facie obvious prior to the filing of the claimed invention to modify the systems and methods of Macdonald et al. where it disclosed genetically modified T cell receptors in mice that contained a rearranged human variable region with the teachings of Vavossori et al. where the authors disclosed that a human variable region sequence, such as the one recited in Macdonald et al., could be operably linked to a human TCR constant region sequence to encode a human TCR γ polypeptide resulting in a CD3+ mouse T cell expressing a functional TCR comprising the human TCR γ polypeptide. Furthermore, there would have been a reasonable expectation of success for a person of ordinary skill in the art to recognize that the resulting configuration as disclosed in Vavassori et al. combined with the teachings of Macdonald et al. where Vavassori et al. demonstrated human Vγ9Vδ2 TCR could be functionally expressed in a mouse T cell environment resulting in a predictable use of human TCRγ constant region sequence with a humanized Vγ/Jγ locus taught by Macdonald et al.
For claim 2, Macdonald et al., similar to claim 1 rejection, teaches a genetically modified mouse model comprising an unrearranged humanized TCRγ variable region locus containing human TCR Vγ and Jγ segments where these segments rearrange during T cell development in the mouse to form a rearranged human Vγ/Jγ variable region sequence [¶ 0009, 0098]. Furthermore, Vavassori et al. teaches that a transgenic expression of a human Vγ9Vδ2 T cell receptor showing that the human Vγ9Vδ2 TCR is functional in a mouse T-cell environment [Results ¶ 2]. This demonstrates that a human TCR γ polypeptide can be expressed as part of a function TCR on the surface of mouse T cells. Additionally, Macdonald et al. discloses the humanized TCR γ locus is present in an unrearranged configuration and undergoes V γ/J γ rearrangement during T-cell development showing the progression of immature T cell development to mature T cell development. Vavassori et al. further teaches the use of human TCR Vδ, Dδ, Jδ, and constant region sequences to produce a human TCRδ polypeptide together with a TCRγ chain [Vγ9Vδ2 transgenic mice]. Although Vavassori et al. does not expressly disclose the unrearranged transgenic human Vδ, Dδ, Jδ, genomic configuration, the Vavassori et al. demonstrates that human γ and δ TCR chains can be functionally expressed together in mouse T cells. Here, a person of ordinary skill in the art would have been motivated to apply the human TCR δ chain structure found in Vavossori et al. to a humanized TCR mouse as taught by Macdonald et al. that would have included Vδ, Dδ, Jδ segments capable of rearrangement during T cell development.
For claim 3, Macdonald et al., similar to claims 1 and 2 rejections, teach a genetically modified mouse comprising humanized TCR variable loci containing unrearranged human TCR variable region segments that rearrange during T cell development [¶ 0009, 0098]. Macdonald et al. further teaches unrearranged V, D, and J segments in the TCR loci, rearrangement of the segments in developing mouse T cells, and the resulting expression of TCRs by CD3+ T cells [¶ 0171]. In addition, Vavassori et al. teaches a transgenic expression of a human Vγ9Vδ2 T cell receptor showing that the human Vγ9Vδ2 TCR is functional in a mouse T-cell environment [Results ¶ 2]. However, neither of these references teach an unrearranged human TCR Vα segment positioned upstream of unrearranged human TCR Dδ and Jδ segments where the Vα, Dδ, and Jδ segments rearrange to form a rearranged Vα/Dδ/Jδ variable region sequence that is operably linked to a human TCR δ constant region gene sequence. However, Naik et al. does teach that a human TCRα/TCRδ locus contains V gene segments having overlapping Vα and Vδ usage and that V/Dδ/Jδ rearrangement occurs in immature CD4/CD8 thrombocytes [Abstract]. Naik et al. further teaches that TRAV15/DV6 family contribute to Tcra and Tcrd repertoires [Id.]. This establishes that a V segment associated with a TCRα locus can participate in V/Dδ/Jδ rearrangement and contribute to formation of a TCRδ variable region [Fig. 1, Discussion].
For claim 7, the same analysis as applied to claim 1 part (A) is applied here. Furthermore, Macdonald et al. is directed to replacing endogenous mouse TCR sequences with corresponding human sequences [¶ 0002].
For claim 8, Macdonald et al. specifically states the replacement of endogenous TCRα variable gene locus results in a replacement of at least one non-human Vδ segment with a human Vδ segment. Macdonald et al. further states in other embodiments, the non-human animal of the invention comprises a complete repertoire of human Vδ, Dδ, and Jδ segments at the unrearranged humanized TCRα locus [¶ 0097]. Macdonald et al. also goes on to state that the non-human animal can comprise a complete unrearranged human TCRδ locus [Id.].
Regarding claim 9, Macdonald teaches a genetically modified mouse in which endogenous mouse TCR gene segments are replaced with corresponding human TCR gene segments to provide humanized TCR loci [¶ 0002]. Macdonald et al. also teaches humanized TCRγ and TCRδ loci comprising human V, D, and J segments, including complete repertoires of the corresponding human variable region segments, and teaches the rearrangement of the human loci during T cell development to generate functional TCRs [¶ 0009]. Macdonald et al. further teaches of TCRα and TCRβ loci that includes replacement of endogenous mouse TCR segments with corresponding human TCR segments [Id.] providing a mouse having a humanized TCRαβ and a TCRγδ gene configurations. Although, Macdonald et al. does not specifically disclose replacing every endogenous V, D, J and constant region segments across each of the γ, δ, α, and β loci in the exact comprehensive configuration recited by claim 9, it would have been prima facie obvious to a person of ordinary skill prior to the filing of the claimed invention to modify the systems and methods of Macdonald et al. to include the complete corresponding human TCR gene segment repertoires in order to provide the mouse with a full human TCR repertoire. Additionally, Vavassori et al., as stated above, teaches that human TCRγ and TCRδ polypeptides can be expressed together mouse T cells as a functional human Vγ9Vδ2 TCR [Abstract]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of the Macdonald et al. where a genetically modified mouse’s TCR sequences were replaced with corresponding human sequences resulting in CD3+ T cells capable of expressing a functional human γδ TCR with the additional teachings of Vavassori et al. showing that human TCRγ and TCRδ proteins can be expressed together in mouse T cells to form a functional TCR. Given this, there is a reasonable expectation of success for a person of ordinary skill in the art to apply these teachings to TCRα and TCRβ as well. Furthermore, a person of ordinary skill would have been able to reasonably infer that replacing endogenous TRCγ, δ, α, and β gene segments with corresponding human TCR sequences would produce mouse T cells expressing functional human or humanized TCR segments.
For claim 16 where the mouse comprises γδ T cells in the thymus, spleen, skin, or gut mucosa, Peng Dong et al. teaches that γδ T cells are found in the mouse spleen [Figure 1]. Here, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Macdonald et al. and Vavassori et al. with the additional teachings of Peng Dong et al. given that γδ T cells are present in the spleen of healthy mice and comprise approximately 1-2% of total splenocytes. Given this, there is a reasonable expectation of success that a person of ordinary skill would have combined the teachings where Macdonald et al. discloses a genetically modified mouse model comprising an unrearranged humanized TCRγ variable region locus containing human TCR Vγ and Jγ segments where these segments rearrange during T cell development in the mouse to form a rearranged human Vγ/Jγ variable region sequence [¶ 0009, 0098]. Furthermore, Vavassori et al. teaches that a transgenic expression of a human Vγ9Vδ2 T cell receptor showing that the human Vγ9Vδ2 TCR is functional in a mouse T-cell environment [Results ¶ 2]. This demonstrates that a human TCR γ polypeptide can be expressed as part of a function TCR on the surface of mouse T cells. Additionally, Macdonald et al. discloses the humanized TCR γ locus is present in an unrearranged configuration and undergoes V γ/J γ rearrangement during T-cell development showing the progression of immature T cell development to mature T cell development. Vavassori et al. further teaches the use of human TCR Vδ, Dδ, Jδ, and constant region sequences to produce a human TCRδ polypeptide together with a TCRγ chain [Vγ9Vδ2 transgenic mice]. Although Vavassori et al. does not expressly disclose the unrearranged transgenic human Vδ, Dδ, Jδ, genomic configuration, the Vavassori et al. demonstrates that human γ and δ TCR chains can be functionally expressed together in mouse T cells. Here, a person of ordinary skill in the art would have been motivated to apply the human TCR δ chain structure found in Vavossori et al. to a humanized TCR mouse as taught by Macdonald et al. that would have included Vδ, Dδ, Jδ segments capable of rearrangement during T cell development with the further teachings of Peng Dong et al. teaching that γδ T cells are present in the spleen of healthy mice and comprise approximately 1-2% of total splenocytes.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims Free of the Art
Claim 13 is free of the art. The art does not teach various full repertoire of TCR segments in addition to a nucleotide sequence comprising D1, D2, and D3 domains of a human polypeptide that is operably linked to D4 as well as part (G) wherein the chimeric human/mouse MHC II α polypeptide comprises all the elements listed in part (G).
Conclusion
No claims allowed.
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/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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