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 .
DETAILED ACTION
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 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.
Election/Restrictions
Applicant’s election without traverse of Invention I, claims 1-10 and 19, in the reply filed on May 7, 2026 is acknowledged.
Based on the results of the search, the species election requirement between the species of Groups 1 and 2 has been withdrawn.
Claims 1-19 remain pending in the current application, claims 11-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
The requirement for the restriction of Inventions I-IV is still deemed proper and is therefore made FINAL.
Claims 1-10 and 19 have been considered on the merits.
Status of the Claims
Claims 1-19 are currently pending.
Claims 11-18 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 1-10 and 19 have been considered on the merits.
Specification
The disclosure is objected to because of the following informalities: the use of trademarks.
The use of the terms Plasma-Lyte® A on pg. 13 line 2, pg. 91 lines 10-11; CryoStor® CS10 on pg. 13 line 2, pg. 80 line 11; CellBanker® on pg. 80 line 11; CryoMACs™ Freezing Bag on pg. 91 lines 5-6; Miltenyi® on pg. 107 lines 19-20; TexMACS™ on pg. 107 line 22, pg. 108 lines 19-21, pg. 113 lines 1-2, 17, 22 and 33; Lonza® X-unit on pg. 107 line 30; Tween®-20 on pg. 108 line 20; Attune™ NxT Flow Cytometer on pg. 108 line 27, pg. 109 line 1; FlowJo® on pg. 108 line 27, on pg. 109 line 2, pg. 113 lines 13, 15, and 32, pg. 114 line 9; FCS Express® on pg. 109 line 2; eBioscience® Fixable Viability Dye eFluor® 780 on pg. 1113 line 10; ThermoFisher® Attune™ on pg. 113 line 13 and 31, pg. 114 line 9; BD® Stain Buffer on pg. 113 line 24, which are a trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
The disclosure is objected to because of the following informalities: minor grammatical error in claims.
Claims 1 and 7 are objected to because of the following informalities: the first time an acronym is utilized in a claim-set, said acronym should be spelled out in its entirety followed by said acronym in parenthesis (e.g. transforming growth factor-beta receptor 2 (TGFβRII); T cell receptor alpha chain (TRAC) locus; T cell receptor beta chain (TRBC) locus).
Appropriate corrections are appreciated.
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.
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 1-4, 6, 8-10 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Melchiori et al. (WO 2020/109616 A1) as evidenced by Srinivasan et al. (Frontiers in Immunology, 2024) in view of Tang et al. (JCI Insight, Feb. 27, 2020).
With respect to claims 1 and 10, Melchiori teaches a modified T cell containing a heterologous recombinant (exogenous) T cell receptor (TCR) and a heterologous recombinant (exogenous) CD8 co-receptor for use in cancer treatment (abstract and pg. 3 lines 11-15).
With respect to claim 2 and claim 4 a) and b), Melchiori teaches the heterologous recombinant (exogenous) CD8 co-receptor is a CD8α homodimer or a CD8α/CD8β heterodimer (a first monomer and a second monomer) (pg. 2 lines 22-32, pg. 3 lines 11-12 and 38-40).
Although Mechiori does not explicitly teach the first monomer and the second monomer comprise a signal peptide, an extracellular domain, a transmembrane domain, and an intracellular domain as recited in claims 3 and 4, these domains are inherent to the peptide monomers as evidenced by Srinivasan. Srinivasan reports that CD8 is a dimeric receptor that contains an ectodomain (extracellular) domain, a transmembrane domain, and cytoplasmic tail an intracellular domain) (pg. 2 Col. 1 para. 1)
With respect to claim 8, Mechiori teaches the exogenous TCR is a patient derived TCR and/or wherein the exogenous TCR recognizes a patient derived cancer antigen (pg. 12 lines 1-4 and pg. 17 line 38 to pg. 18 line 7).
Although Melchiori does not explicitly teach that the cancer antigen is a neoantigen or a private antigen as recited in claim 9, Melchiori teaches heterologous TCRs that identified for a specific cancer patient which is considered a neoantigen since it is specific that patient (pg. 17 line 38 to pg. 18 line 7).
With respect to claim 10, Melchiori teaches the immune cell is a T cell (abstract and pg. 3 lines 11-15).
Melchiori does not teach the cells with a gene disruption of a TGFβRII locus as recited in claim 1 c). Similarly, Melchiori does not teach the gene disruption of a TGFβRII locus generates a knockout or a knockdown of the TGFβRII gene expression as recited in claim 6.
However, Tang teaches knocking out the endogenous TGF-β receptor II (TGFβR2 or TGFβRII) in CAR T cells reduces the induced Treg conversion (reprogramming of T cells into an immunosuppressive Regulatory T cell) and prevents exhaustion of CAR T cells (abstract). Tang teaches TGFβR2 edited CAR T cells had better in vivo tumor elimination efficacy (abstract and pg. 2 para. 2). Tang further teaches that “gene editing of multiple genes in CAR T cells to avoid the combined inhibitory effects of multiple immune factors might provide a more targeted and effective therapy for different cancer patients” (pg. 13 para. 1).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the immune cell or T cells of Melchiori to include a gene disruption of a TGFβRII locus for the benefit of reducing the reprogramming of T cells into an immunosuppressive regulatory T cells, preventing the exhaustion of the T cells, and improving tumor elimination efficacy as taught by Tang. It would have been obvious to one of ordinary skill in the art to make such a modification to Melchiori, since Tang teaches multiple modifications can be made to T cells for therapy to improve the therapy for different cancer patients by providing a targeted cell and avoiding inhibitory effects of multiple immune factors as taught by Tang. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Melchiori, since Tang teaches a similar immune cell, CAR T cell, that successfully contains a gene disruption of a TGFβRII locus.
Although, neither Melchiori or Tang teach the immune cell in a kit, It would be obvious to put the cells in a kit as recited in claim 19. Additionally, there are no other components to the kit so art reciting the cells would read on the kit.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103(a) as being unpatentable over Melchiori as evidence by Srinivasan in view of Tang (as applied to claims 1-4, 6, 8-10 and 19 above), and further in view of Kley et al. (US 2020/0231674 A1) as evidenced by BLASTP alignments (Alignment: SEQ ID NOs: 9-12 and 13-16, with SEQ ID NOs: 4-5, respectively of US 20200231674 A1, Date: Jun. 24, 2026).
The teachings of Melchiori and Tang can be found in the previous rejection above.
Melchiori does not teach the monomers or heterodimers where the extracellular, transmembrane and intracellular domains have the particular sequences of claim 5 a) and b).
However, Kley teaches CD8 homodimeric form can comprise of two CD8 α chains and the heterodimeric form can comprise of one CD8 α chain and one CD8 β chain (0021). Kley teaches a human CD8 α chain with SEQ ID NO: 1 which shares 100% identity with SEQ ID NOs: 9-12 as evidenced by BLASTP alignments (0022). Kley teaches a human CD8 β chain with SEQ ID NO: 4 which shares 100% identity with SEQ ID NOs: 13-16 as evidenced by BLASTP alignments (0025).
One of ordinary skill in the art would be motivated to use the sequences taught by Kley encoding human TCR amino acid sequences because human sequences would be useful for modified T cells. It would be obvious to one of ordinary skill in the art to use known sequences of CD8 α and β. Additionally, one ordinary skill in the art would have had a reasonable expectation of success in the modifying the T cells of Melchiori so that the CD8 receptor monomers have the claimed sequences of claim 5 a) and b), since these are known human sequences for CD8 α and β as taught by Kley.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claim 7 is rejected under 35 U.S.C. 103(a) as being unpatentable over Melchiori as evidence by Srinivasan in view of Tang (as applied to claims 1-4, 6, 8-10 and 19 above), and further in view of Legut et al. (Blood, The Journal of the American Society of Hematology, 2018).
The teachings of Melchiori and Tang can be found in the previous rejection above.
Neither Melchiori or Tang teach the immune cell has a gene disruption of a TRAC locus and a TRBC locus as recited in claim 7.
However, Legut teaches a major issue with transducing T cells with a transgenic TCR is the preexisting expression of TCRs in the recipient cells, since the endogenous TCRs compete with the transgenic TCR for surface expression and allow mixed dimer formation (abstract and pg. 317 last para.). Legut further teaches that the mixed dimers formed by mispairing between the endogenous an transgenic TCRs may have autoreactive specificities (abstract). Legut teaches that knocking out the endogenous TCR-β from the recipient cells resulted in a stronger and more polyfunctional response of the engineered T cells to their target cancer cells and the engineered T cells were up to a thousand fold more sensitive to antigens than the standard TCR-transduced T cells (abstract). Additionally, Legut teaches that knocking out the both endogenous α and β TCR resulted in more efficient redirection of CD4+ and CD8+ T cells against cancer compared to the standard TCR transfer (abstract and pg. 312 Col. 1 para. 3).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the immune cell or T cells of Melchiori to include a gene disruption of a TRAC locus and a TRBC locus for the benefit of preventing the combining of the endogenous TCRs with the exogenous TCRs as taught by Legut. It would have been obvious to one of ordinary skill in the art to make such a modification to Melchiori, since Legut teaches the disadvantages of the presence of the endogenous TCRs in engineered T cells and the benefits of disrupting the endogenous genes include improved response of the engineered cells. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Melchiori, since Legut teaches a similar immune cell, T cell, that successfully contains a gene disruption of a gene disruption of a TRAC locus and a TRBC locus and has an improved response to target cancer cells and increased sensitive to antigens compared to engineered T cells without disruption of these genes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Allowable Subject Matter
The exogenous CD8 receptors disclosed in claim 4 c) and d) and claim 5 c) and d) appear to be free of the art. The closest prior art does not teach exogenous CD8 receptors containing an CD8α extracellular and transmembrane domain coupled with either a CD8β intracellular domain or CD4 intracellular domain.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
Prosecution Insights