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 .
Election/Restriction
Applicant’s election without traverse of Group I (claims 1-13) in the reply filed on 06/24/2025 is acknowledged. Applicant’s election of species in the reply filed on 06/24/2025 is as follows:
a single scFv sequence Seq ID NO:71 (which includes Seq ID Nos 1-6 as the CDRs and Seq ID Nos 19 and 20 as VH and VL domains, respectively);
a single cytoplasmic domain: 4-1BB;
a single CAR polypeptide formula: SP-CD83-HG-TM-CSR-ISD.
Claims Status
Claim 14 is newly canceled, and claims 1-13 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 01/02/2026 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 10/02/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
Claim Rejections - 35 USC § 103 (new)
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Davila et al (WO 2018/053463 A1; cited previously) in view of Pilipow et al (Cancer Res (2015) 75:24;1-13) and Zhang et al (J Immunol (2007) 179:1;1-18).
Regarding claims 1-4: The claim recites the intended use statement “for producing regulatory T (Treg) cells”.
MPEP (2111.02 II) states “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim”.
The intended use phrase of claim 1 does not impart or imply any active steps on the claimed method.
Example 1 of Davila teach a method for producing T cells comprising (a) isolating PBMCs from a donor and (b) isolating T cells from the PBMCs; peripheral circulating cells (PBMCs) are collected from a patient by leukapheresis and T cells are isolated (p10 ln 29-30).
Davila also teach cell-based artificial antigen presenting cells (aAPCs) which are NIH-3T3 cells (a cell line) that express membrane bound anti-CD3 scFV and membrane bound anti-CD28 scFV (p11 ln 9-10; Fig 4). Davila teach scFV is single chain antibodies (p1 ln 24-25).
Davila teach human T cells are added to the aAPCs (p10 ln 10-15). This reads on contacting the T cells with artificial antigen presenting cells expressing on its outer membrane an anti-CD3 scFv and an anti-CD28 scFv.
Example 1 of Davila does not explicitly teach the cell-based artificial antigen presenting cell expresses a 41BB ligand or an IL-15 receptor on its outer membrane.
Davila also teach a method for producing T cells comprising providing a substrate comprising an antigen recognition domain that selectively binds an antigen on immune effector cells in which the substrate can comprise a cell based artificial antigen presenting cell or a non-cell substrate (claims 1-4 and 8, p14).
Claim 14 of Davila teaches the antigen recognition domain of the substrate binds IL15. The antigen recognition domain is disposed on the surface of the substrate. This reads on an IL-15 receptor per the interpretation discussed supra.
Claim 13 of Davila teaches the antigen recognition domain of the substrate binds 41BB. The antigen recognition domain is disposed on the surface of the substrate.
While Davila teach an artificial antigen presenting cell comprising a 41BBL and an IL15R on the surface of the substrate, Davila do not explicitly teach the artificial antigen presenting cell comprises an outer membrane on which 41BBL and IL15R are expressed.
Zhang teach an aAPC cell line generated by transfecting K562 cells with 41BBL (p2 ¶5). Zhang further teach 41BBL could serve as an effective costimulatory molecule for ex vivo expansion of CD8+ T cells (p4 ¶4). Zhang also teach cell-based aAPCs with 41BBL induce greater T cell expansion than non-cell (bead based) aAPCs (p4 ¶5).
Pilipow teach IL-15 induces the activation, the proliferation and the survival of T cells (p2 ¶2).
It would have been obvious to one of ordinary skill in the art to modify the AAPC expressing a 41BB ligand and IL-15 receptor as taught by Zhang et al. and Pilipow with a reasonable expectation of success.
One of ordinary skill in the art would have been motivated to modify the aAPC of Davila to express 41BBL and/or IL15R because Davila also teach a non-cellular aAPC which includes 41BB ligand an IL15R and both the 41BB ligand and IL-15 (presented by an IL-15 receptor) are well known in the art for survival and expansion of T cells; Zhang teach 41BBL is a costimulatory molecule for ex vivo expansion of T cells and Pilipow teach IL15 (which is presented when bound to the IL15R) induces activation, proliferation and survival of T cells.
One would be further motived to express the molecules on a cell surface instead of a non-cell based antigen presenting cell (such as a bead) because Zhang teach cell-based aAPCs with 41BBL are more effective than non-cell (bead based) aAPCs (p4 ¶5).
One would have a reasonable expectation of success because Zhang teach cell based artificial antigen presenting cells are effective.
Regarding claim 4: Davila also teach co-culturing immune effector cells and viral vectors encoding chimeric antigen receptors (claim 1b). Example 1 teaches T cells are expanded and transduced with CAR genes (p9 ln25-30).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Davila et al, in view of Pilipow et al and Zhang et al, as applied to claims 1-4 above, and further in view of Juillerat et al (WO 2018/073394 A1; cited previously) and Casey et al (WO 2016/061617 A1; cited previously).
Regarding claims 5-6: Regarding claims 5 and 6: The teachings of Davila, Pilipow and Zhang are discussed supra. Davila do not teach the CAR polypeptide comprises a CD83 antigen binding domain, a transmembrane domain, an intracellular signaling domain and a co-stimulatory signaling region.
Juillerat teach chimeric antigen receptors (CARs) and an engineered immune cell expressing at its surface the CAR (abstract).
Juillerat further teach the extracellular ligand-binding domain is specific for the CD83 antigen (claim 111). Juillerat also teach the CAR is a single chain CAR, which reads on a scFv of an antibody that specifically binds CD83 (claim 113).
Casey teach CD83 is an attractive target for immunotherapy due to its preferential expression on mature dendritic cells (p2 ln5-15).
It would have been obvious to one of ordinary skill in the art to adapt the method of Davila drawn to a method of generating Treg cells comprising aAPCs by using a T cells comprising a CAR with a CD83 antigen binding domain as taught by Juillerat. Casey disclose CD83 is an attractive target for immunotherapy and that targeting CD83 expressing cells depletes immune cells to modulate aberrant or unwanted immune responses in, for example, inflammatory and/or autoimmune conditions or diseases (p49 ln20-25).
Accordingly, one of ordinary skill in the art would have been motivated to modify the method taught by Davila, Pilipow and Zhang by using a CAR directed to CD83, as taught by Juillerat for the purposes of using CART cells targeted to CD83 expressing cells to for the purposes of modulating unwanted immune responses, as taught by Casey.
One would have had a reasonable expectation of success because Davila teach T cell immunotherapy offers a promising strategy for specifically targeting and CART cells can be engineered to express receptors specific for tumor antigens, and that additional antigens (e.g. immune cell antigens such as CD83) could also be targeted (p1 ln5-15).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Davila et al in view of Pilipow et al and Zhang et al, as applied to claims 1-4 above, and further in view of Diehl et al (US 9,562,097 B2; cited previously).
Regarding claim 7-9: The teachings of Davila, Pilipow and Zhang are discussed supra. Davila do not teach the anti-CD83 scFv comprises a variable heavy (VH) domain comprising seq ID NO:19 of the instant application or that the anti-CD83 scFv VL domain comprises Seq ID NO: 20 of the instant application. Seq ID NOs: 19 and 20 comprise Seq ID NOs:1-6 of the instant application, and thus art that reads on Seq ID NOs: 19 and 20 also read on Seq ID NOs: 1-6.
Diehl teach methods of treating autoimmune disorders with anti-CD83 antibodies (abstract). Diehl disclose Sequences 30 and 35, which have 100% identity with Seq ID NOs: 19 and 20 of the instant application.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Davila, Pilipow and Zhang drawn to a CAR by using an scFv comprising variable heavy and light chains of Seq IDs 30 and 35 directed against CD83 as taught by Diehl. Diehl disclose treating mice in an inflammatory bowel disease model with antibodies targeted to CD83 have reduced histology scores, demonstrating the efficacy of the CD83 scFv in vivo.
Accordingly, one of ordinary skill in the art would have been motivated to modify the CAR as taught by Davila with the variable heavy and light chains as taught by Diehl to for the purposes of targeting CD83.
One would have had a reasonable expectation of success because Diehl disclose the anti-CD83 variable light and heavy chains target CD83 and are efficacious in mice and one of ordinary skill in the art would understand that scFv sequences that recognize the target receptor in mice are likely functional are likely to recognize the target receptor as the scFv when incorporated into a CAR.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Davila et al, Pilipow et al and Zhang et al, and as evidenced by Shankaran et al and NCBI MeSH as applied to claims 1-4 above, and further in view of Tokarew et al (BJC(2018)120;26-37; cited previously), Chen et al (Adv Drug Deliv Rev(2013)65:10;1-32; cited previously) and Arai et al (Protein Engineering(2001)14;8:1-4; cited previously).
Regarding claim 10: The claim is drawn to Seq ID NO: 71, which comprises the sequences of the variable light and heavy chains disclosed by Seq ID NOs:19 and 20 of the instant application, which are known in the art as discussed supra. A 15 amino acid residue comprising (GGGS)4 links the variable light and heavy chain sequences of Seq ID NOs:19 and 20.
The teachings of Davila, Pilipow and Zhang and Diehl are discussed supra. Diehl disclose the variable light and heavy chain sequences of Seq ID NOs: 19 and 20, as discussed supra, but do not do not teach the anti-CD83 scFv comprises the entire amino acid sequence of Seq ID NO: 71 including the glycine rich linker sequence between the variable light and heavy chains. The 15 residue linker sequence is the only part of Seq ID NO: 71 that is not taught by Diehl.
Tokarew teach the extracellular structure of a fifth-generation CAR, which comprises an scFv domain (p27 col1 para2, Fig1b). Tokarew further teach the variable light and heavy chains of an scFv CAR domain are predominantly composed of the variable light and heavy chain regions of an antigen-specific immunoglobulin separated by a flexible linker (p27 col1 para2).
Chen teach the successful construction of a recombinant fusion protein requires two indispensable elements: the component proteins and the linkers (p1 para2). Chen teach flexible linkers are usually applied when the joined domains required movement or interaction, and are generally composed of small non-polar (e.g. Gly) or polar (e.g. Ser) amino acids (p4 para2). Chen teach (Gly-Gly-Gly-Gly-Ser)n, wherein the “n” indicates the copy number, is an example of the most widely used linker (p4 para3).
Arai teach the design of the linkers which effectively separate domains of a bifunctional fusion protein (title). Arai teach the flexible linker FL4, which comprises (GGGS)4.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Davila drawn to a CAR with variable heavy and light chains linked by a flexible linker, as taught by Tokarew, wherein the flexible linker comprises (GGGS)4, as taught by Arai. Tokarew discloses the scFv of a CAR comprises a variable heavy chain and a variable light chain linked by a flexible linker (Fig 1). Chen teach that GGGS is the most widely used flexible linker and Arai discloses the (GGGS)4 linker effectively separates components of a bifunctional protein.
Accordingly, one of ordinary skill in the art would have been motivated to modify the CAR as taught by Davila to for the purposes of having a CAR with bifunctional components (VH and VL) that were flexibly linked in order to perform their function.
One would have had a reasonable expectation of success because Chen and Arai disclose the GGGS linker is one of the most widely used linkers and one of ordinary skill in the art would understand that a widely used linker would be well characterized and likely to function as expected.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Davila et al, Pilipow et al and Zhang et al, and as evidenced by Shankaran et al and NCBI MeSH as applied to claims 1-4 above, and further in view of Long et al (Nat Med(2015)21:6;1-27; cited previously).
Regarding claim 11: The teachings of Davila, Pilipow and Zhang are discussed supra. Davila do not teach the CAR comprises the costimulatory molecule 41BB.
Long teach T cell exhaustion is a major factor limiting the T cell response in the setting of chronic antigen exposure, and that early T cell exhaustion is a primary factor limiting the efficacy of CAR T cells (p2 para2/3). Long further teach that 41BB costimulation ameliorates exhaustion induced by persistent CAR signaling (abstract).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Davila drawn to a CART cell by using a 41BB costimulatory molecule as taught by Long. Long discloses costimulation of a CAR using a 41BB costimulation molecule ameliorates T cell exhaustion.
Accordingly, one of ordinary skill in the art would have been motivated to modify the CART as taught by Davila to for the purposes of generating a CART cell that would be less likely to exhibit early T cell exhaustion and thus be a more effective therapy.
One would have had a reasonable expectation of success because Long discloses known CAR costimulatory components and one of ordinary skill in the art would understand standard molecular biology methods can be used to generate CARs with different costimulatory regions.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Davila et al, Pilipow et al and Zhang et al, and as evidenced by Shankaran et al and NCBI MeSH as applied to claims 1-4 above, as evidenced by Zhang et al (Biomarker Research(2017)5:22;1-6; cited previously; hereafter referred to as Zhang(2017) and further in view of Tokarew et al (BJC(2018)120;26-37; cited previously).
Regarding claim 12: The teachings of Davila, Pilipow and Zhang are discussed supra. Davila also teach the CAR comprises CD28-HBD-TM-ID, wherein "CD28" comprises a CD28-antigen recognition domain, wherein "HBD" comprises a heparin binding domain, wherein "TM" comprises a transmembrane domain, and wherein "ID" comprises an optional intracellular domain, and wherein"-" represents a peptide linker (claim 18). Davila(463) is silent on if the CAR polypeptide comprises a signal peptide.
Zhang(2017) teach CARs include three parts: an extracellular antigen recognition domain (ectodomain), a transmembrane domain, and an intracellular T cell activation domain (p1 col1 para1). Zhang(2017) further teach that the scFv serves as the signal peptide of the ectodomain in a CAR (p1 col2 para1).
Thus one of ordinary skill in the art would recognize that, absent of evidence to the contrary, the CAR taught by Davila comprises a signal peptide, as evidenced by Zhang(2017), because the CAR of Davila comprises an scFv.
Davila is silent on if the linker is a bivalent linker, however because the linker connects two domains it must have two chemically active sites to link the two domains, and therefore is a bivalent linker.
Davila do not explicitly teach the CAR polypeptide is defined by the specific formula SP-CD83-HG-TM-CSR-ISD.
Tokarew teach the scFv of the CAR is tethered to the transmembrane domain through the spacer (hinge region) (p27 col1 para2). Tokarew also teach fifth-generation CAR comprise an intracellular domain which comprises a costimulatory domain (CM1) between the TM and the ISD (Fig 1). One of ordinary skill in the art would understand that when designing a CAR with multiple functional domains, one would use a bivalent linker between the domains to provide steric freedom for the domains to interact with their functional components.
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to combine the CAR taught by Davila with structure taught by Tokarew because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Combining the CAR taught by Davila with structure of a fifth-generation CAR as taught by Tokarew would have led to predictable results with a reasonable expectation of success because both inventions are drawn to CARs with typical CAR domain organization.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Davila et al, Pilipow et al and Zhang et al, and as evidenced by Shankaran et al and NCBI MeSH as applied to claims 1-4 above, and further in view of Tokarew et al (BJC(2018)120;26-37; cited previously).
Regarding claim 13: The teachings of Davila, Pilipow and Zhang are discussed supra. Davila do not teach the intracellular signaling domain of the CAR comprises a CD3 zeta signaling domain.
Tokarew teach the intracellular domain of the T cell co-receptor CD3 zeta is the core component of most CARs (p27 col1 para2).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Davila drawn to a CAR by doing using a CD3 zeta signaling domain as taught by Tokarew because Tokarew disclose the CD3 zeta domain is the core component of most CARs.
Accordingly, one of ordinary skill in the art would have been motivated to modify the CAR as taught by Davila with the CD3 zeta signaling domain as taught by Tokarew for the purposes of having a well characterized CAR functional domain.
One would have had a reasonable expectation of success because Tokarew discloses the CD3 signaling domain is the core component of most CARs and one of ordinary skill in the art would understand that a signaling domain that is part of most CARs and thus likely to function effectively in the CAR.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
The responses are directed to the Arguments filed 01/02/2026.
Regarding Arguments directed to 35 USC § 102:
Applicant's arguments filed on 01/02/2026 have been fully considered and they are persuasive. Davila disclose cell-cell based artificial antigen presenting cells comprising the claimed components, but do not disclose the antigen presenting cell comprising all of the components in a single embodiment.
The rejection is withdrawn.
Regarding Arguments directed to 35 USC § 103:
Applicant's arguments filed on 01/02/2026 have been fully considered and they are persuasive. Applicant submits the secondary references do not cure the deficiencies of Davila. The arguments against the secondary references are addressed in the new rejection above where expression of IL15R and 14BBL for a cell based aAPC is discussed.
The rejection is withdrawn.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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