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 .
Priority
The application claims priority to provisional application 63/253266, filed on 07 October 2021, provisional application 63/399889, filed on 22 August 2022, and is a 371 of PCT/US2022/077696, filed on 06 October 2022. The effective filing date is 07 October 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 13 March 2024 was considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-28 are the original claims. In the preliminary amendment of 13 March 2024, claims 3, 8, and 10-15 were cancelled, and claims 5, 6, 18, 21, and 26 were amended. Claims 1, 2, 4-7, 9, and 16-28 are pending and the subject to of this office action.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4, 5, 6, 16, 19, 21, 24, and 26, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2021/142302 A1 (herein Getts).
In regard to claims 1, 16, and 24, Getts teaches recombinant nucleic acids encoding T cell receptor fusion proteins (TFPs), modified human immune cells, expressing the encoded molecules, and methods of use for the treatment of diseases, including autoimmune diseases (Abstract). Getts teaches TFPs, also referred to as TRuCs, comprising a configuration illustrated in Figure 1 of the reference, as shown below:
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The overall structure of the TFPs is summarized in claim 1, as detailed below:
(TCR) fusion protein (TFP) comprising:
(i) a TCR-integrating subunit comprising:
(1) an extracellular domain,
(2) a TCR transmembrane domain, and
(3) a TCR intracellular domain comprising a stimulatory domain from an
intracellular signaling domain;
(ii) a binding domain.
It is taught that the binding domain may comprise a scFv (including VH and VL chains) that is specific to an exogenous antigen, such as FVIII ([0010]). In an exemplary embodiment (SEQ ID NO: 52), the scFv is fused to N-terminus of a CD3 epsilon subunit (Relevant to instant claim 2) (Page 105). It is also taught that the TCR intracellular and transmembrane domains may comprise that of CD3 epsilon ([0013-0016]). In addition to the TFPs, described above, recombinant nucleic acids molecules, encoding said TFPs, are taught ([0017]). It is further taught that pharmaceutical compositions, comprising Treg cells, which comprise the above-mentioned nucleic acid molecules, may be used in a method to treat a disease or disorder ([0041]). In certain embodiments, the method may be used to treat an autoantibody-mediated autoimmune disease or allergic reactions, and as mentioned previously it is taught that the TFP may comprise a binding domain specific to an exogenous antigen (i.e. therapeutic macromolecules like FVIII) (Relevant to instant claims 5, 19, and 26) ([0021] and [0028]).
In regard to claim 4, Getts teaches that the modified cells may be autologous with respect to the recipient ([0416]).
In regard to claims 6 and 21, Getts teaches that the extracellular region of the TFP can be attached to the binding domain via a hinge, with that of human CD8 being a provided example ([0179]).
In regard to claims 17 and 27, Getts teaches that the modified TFP-expressing cells can further comprise additional inhibitory agents, with PD-L1 being a provided example ([0192]).
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.
Claim 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/142302 A1 (herein Getts) in view of Kim YU, et al. (2017) Enforced Expression of CXCR5 Drives T Follicular Regulatory-Like Features in Foxp3+ T Cells. Biomol Ther (Seoul). 2017 Mar 1;25(2):130-139 (herein Kim).
Getts teaches recombinant nucleic acids encoding T cell receptor fusion proteins (TFPs), modified human immune cells, expressing the encoded molecules, and methods of use for the treatment of diseases, including autoimmune diseases (Abstract). Getts further teaches that a TFP, comprising a binding domain comprised of a FVIII-specific scFv, a CD3 epsilon intracellular domain, and in certain embodiments cells, expressing the TFPs, may additionally express additional inhibitory agents.
Getts does not teach that that the method comprises engineered Treg cells further express a gene encoding the chemokine receptor CXCR5. Kim teaches this deficiency.
Kim relates to a study investigating the effect of enforced CXCR5 expression in Foxp3+ Treg cells (Abstract). Kim teaches that CXCR5+ T follicular helper T cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune disease, such as lupus. It is also taught that a specialized subset of CXCR5+ Foxp3+ Treg cells (Tfr), when adoptively transferred into a BXD2 lupus mouse model, ameliorates lupus development (Introduction-paragraph 3). Kim et al demonstrate that CXCR5 transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment (Abstract). The transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells (Abstract and Results: Cxcr5-transduced Treg cells efficiently migrate toward the CXCL13 gradient and suppress antibody production from B cell). Therefore, it is hypothesized CXCR5 transduced cells might represent a promising therapeutic approach to the treatment of autoimmunity associated with increased autoantibodies (Abstract and Discussion).
It would have been obvious to one skilled in the art, at the time of filing, to combine the teachings of Kim (CXCR5 enforced expression in Treg cells) with the teachings of Getts (Treg cell engineered to comprise TFPs, comprising FVIII-targeted binding domains, for use in a method to treat autoantibody-mediated autoimmune diseases). As noted in the 35 U.S.C. 102(a)(1) rejections of 1, 2, 4, 5, 6, 16, 19, 21, 24, and 26, Getts teaches a method, aimed at treating autoantibody-mediated autoimmune diseases and teaches that the method may comprise additional inhibitory agents. Based on the teachings of Kim, it would have been obvious to further modify the Tregs cells, described above, to express CXCR5, as it is shown that this modification leads to suppression of antibody production from B cells stimulated with Tfh cells, a major cause of autoantibody-mediated autoimmune diseases (Introduction, Abstract and Results: Cxcr5-transduced Treg cells efficiently migrate toward the CXCL13 gradient and suppress antibody production from B cell). Furthermore, the teachings of Kim suggest that this modification is of use for the treatment of autoantibody-mediated autoimmune diseases (Abstract).
Claims 9, 20, 22, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/142302 A1 (herein Getts) in view of US 2011/0010786 A1 (herein Saint-Remy) and Szymczak AL, Vignali DA. (2005) Development of 2A peptide-based strategies in the design of multicistronic vectors. Expert Opin Biol Ther. 2005 May;5(5):627-38 (herein Szymczak).
In regard to claims 9, 22, and 25, Getts teaches recombinant nucleic acids encoding T cell receptor fusion proteins (TFPs), modified human immune cells, expressing the encoded molecules, and methods of use for the treatment of diseases, including autoimmune diseases (Abstract). Getts further teaches that a TFP, comprising a binding domain comprised of a FVIII-specific scFv and a CD3 epsilon domain, and in certain embodiments cells, expressing the TFPs, may additionally express additional inhibitory agent, such as PD-L1. Getts does not explicitly provide the amino acid or nucleotide sequences corresponding to these TFPs, namely the amino acid sequence corresponding to the FVIII-specific binding domain or the means by which PD-L1 is expressed. Saint-Remy and Szymczak teach these deficiencies.
Saint-Remy relates to non-human transgenic mammal containing in its genome a DNA construct expressing a B cell antigen receptor specific for factor VIII of the coagulation pathway (Abstract). In this disclosure an scFv anti-FVIII antibody, 2C11 scFv, is taught to comprise heavy and light chains, that share 100% sequence identity with those of scFv used in the current application, as shown below ([0052]). This antibody is taught to be representative of inhibitory and C2-specific antibodies (binding, developed by patients undergoing FVIII replacement therapy ([0050]). The epitope targeted by this antibody, C2, corresponds to residues 2250-2253, 2197-2203, 2222, and 2223 (Relevant to instant claim 20) ([0050]). Additionally, it is taught that this antibody is cross-reactive with mouse FVIII.
Light Chain:
scFv(Instant SEQ ID Nos:2/4) EIALTQSPGTLSLSPGERATLSCRASQSFSSSYLAWYQQKPGQAPRLLIYGASTRATGIP 60
Ref (SEQ ID NO:2) EIALTQSPGTLSLSPGERATLSCRASQSFSSSYLAWYQQKPGQAPRLLIYGASTRATGIP 60
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scFv(Instant SEQ ID Nos:2/4) DRFSGSGSGTDFTLTISRLEPEDFAVYYCQKYGTSAITFGQGTRLEIK 108
Ref (SEQ ID NO:2) DRFSGSGSGTDFTLTISRLEPEDFAVYYCQKYGTSAITFGQGTRLEIK 108
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Heavy Chain:
scFv(Instant SEQ ID Nos:2/4) QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELPVHWVRQAPGKGLEWVGSFDPESGESIY 60
Ref (SEQ ID NO:2) QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELPVHWVRQAPGKGLEWVGSFDPESGESIY 60
************************************************************
scFv(Instant SEQ ID Nos:2/4) AREFQGSVTMTADTSTDIAYMELSSLRSDDTAVYYCAVPDPDAFDIWGQGTMVTVSS 117
Ref (SEQ ID NO:2) AREFQGSVTMTADTSTDIAYMELSSLRSDDTAVYYCAVPDPDAFDIWGQGTMVTVSS 117
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Szymczak et al provide a review discussing techniques allowing for the expression of multiple genes from one vector (Abstract). It is taught that there exists a number of limitations present in the field of gene therapy or genetic engineering, regarding the size of inserted genetic material and the means for expressing more than one exogenous gene (Introduction-paragraph 2). Methods for increasing the size limit of insert are still in their initial stages of development, but there are multiple strategies for the expression of more than one gene (Introduction-paragraph 3). One the methods discussed is the use of 2A peptide sequences (Section 2.3). This method allows for the expression of multiple proteins from a single transcript. By designing a vector encoding two target proteins, separated by a 2A peptide sequence (examples provided in Table 2), one is able to a produce a polyprotein, that is able to “cleave” itself, without the need for additional cellular machinery (i.e. exogenous proteases) (Section 2.3-paragraph 2). The authors list numerous advantages associated with the 2A peptide strategy, compared to more tradition techniques, such as the use of IRES, which include the relatively small size of 2A peptide (18-22 amino acids) and the inert nature of the resulting 2A peptide fused to the C-terminus of the N-terminal polyprotein, following “cleavage” (Section 2.3-paragraph 3). It should be noted that Table 2 discloses the PTV1 2A-peptide sequence, which shares 100% sequence identity with the 2A peptide sequence used in SEQ ID NO:4.
It would have been obvious to combine the teachings of Saint-Remy (the use of the anti-FVIII antibody 2C11 scFv) and Szymczak (the 2A peptide to express multiple proteins from a single transcript) with the teachings of Getts (cells comprising T cell receptor fusion proteins comprising binding domains specific for FVIII). The use of 2C11 would have been obvious, in the context of the teachings of Getts, due to its cross-species reactivity, which would allow for its use in both mice models and human models, and the fact that it is taught to be a representative of inhibitory and C2-specific antibodies, developed in response to FVIII replacement therapy ([0050]). Thus, there is ample motivation to use this antibody, specifically in the scFv format, in the method comprising administration of cells comprising a TFP, taught by Getts, for the treatment of autoantibody-mediated autoimmune disease or allergic reactions, as it has been shown to be associated with the mechanism, that Gett’s method is intended to treat ([0021] and [0028]). The use of a 2A peptide to embody the TFP, taught by Getts, comprising PD-L1 as an additional inhibitory agent, would have been obvious, based on the teachings of Szymczak, which state that the small and well-tolerated 2A peptide self-cleaves and presents a high likelihood of success, when used as a method for multigene expression.
Furthermore, the amino acid (SEQ ID NO: 2 and 4) and nucleotide sequences (SEQ ID NO: 1 and 3) would have been obvious, following the combination of these teachings.
In regard to SEQ ID NO: 2, Getts provides example TFP constructs encoding TFPs, comprising binding domains (either anti-HLA-A2 scFv or anti-MLSN) linked to CD3 epsilon using a (G4S)3 linker ([0429] and SEQ ID NO:52). Using this template, the anti-FVIII scFv, taught by Saint-Remy, and the mouse sequence for CD3 epsilon and the CD3 epsilon signal peptide, as opposed to the human forms shown in SEQ ID NO:52, one would arrive at SEQ ID NO:2 of the current application, as shown below. The use of the mouse form of CD3 epsilon would have been obvious for use in a mouse model, as evidenced by Getts’ use of human CD3 epsilon components, when applying the TFP to humanized mouse models ([0461]). This in turn relates to instant claim 23, in which an amino acid sequence corresponding to a human equivalent of SEQ ID NO: 4 is claimed.
Getts SEQ ID NO:52MLLLVTSLLLCELPHPAFLLIPEVQLVESGGGLVQPGGSLRLSCAASGGDWSANFMYWYRQAPGKQRELVARISGRGVVDYVESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVASYWGQGTLVTVSSAAAGGGGSGGGGSGGGGSLEDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI
SEQ ID NO: 2 of the current application
MRWNTFWGILCLSLLAVGTCQDEIALTQSPGTLSLSPGERATLSCRASQSFSSSYLAWYQQKPGQAPRLLIYGASTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQKYGTSAITFGQGTRLEIKGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKVSGYTLTELPVHWVRQAPGKGLEWVGSFDPESGESIYAREFQGSVTMTADTSTDIAYMELSSLRSDDTAVYYCAVPDPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDAENIEYKVSISGTSVELTCPLDSDENLKWEKNGQELPQKHDKHLVLQDFSEVEDSGYYVCYTPASNKNTYLYLKARVCEYCVEVDLTAVAIIIIVDICITLGLLMVIYYWSKNRKAKAKPVTRGTGAGSRPRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRAV
CD3 Epsilon Signal Peptide
Binding domain
(G4S)3 spacer
CD3 Epsilon
In regard to SEQ ID NO:4, the scFv and CD3 epsilon components of the sequence would have been obvious to based on the teachings of Saint-Remy and Getts, as discussed above in regard to SEQ ID NO:2. Furthermore, when incorporating the teachings of Szymczak, in order to allow for the expression of PD-L1, the use of a 2A peptide sequence would result in the sequence defined by SEQ ID NO:4, as shown below. It should be noted that following the C-terminal end of the CD3 epsilon, there exists a GSG spacer sequence, that is neither part of CD3 or the 2A peptide sequence. This spacer is taught by Getts, as Getts also uses 2A sequences in certain embodiments, such as SEQ ID NO: 55, in which a GSG spacer is used to link the Foxp3 sequence with the 2A sequence.
MRWNTFWGILCLSLLAVGTCQDEIALTQSPGTLSLSPGERATLSCRASQSFSSSYLAWYQQKPGQAPRLLIYGASTRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQKYGTSAITFGQGTRLEIKGGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKVSGYTLTELPVHWVRQAPGKGLEWVGSFDPESGESIYAREFQGSVTMTADTSTDIAYMELSSLRSDDTAVYYCAVPDPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSDAENIEYKVSISGTSVELTCPLDSDENLKWEKNGQELPQKHDKHLVLQDFSEVEDSGYYVCYTPASNKNTYLYLKARVCEYCVEVDLTAVAIIIIVDICITLGLLMVIYYWSKNRKAKAKPVTRGTGAGSRPRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRAVGSGATNFSLLKQAGDVEENPGPMRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYWEKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCCIISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDHQPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPELPATHPPQNRTHWVLLGSILLFLIVVSTVLLFLRKQVRMLDVEKCGVEDTSSKNRNDTQFEET
Signal Peptide (mouse)
Binding domain
(G4S)3 spacer
CD3 Epsilon (mouse)
2A peptide
PD-L1
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/142302 A1 (herein Getts), US 2011/0010786 A1 (herein Saint-Remy) and Szymczak AL, Vignali DA. (2005) Development of 2A peptide-based strategies in the design of multicistronic vectors. Expert Opin Biol Ther. 2005 May;5(5):627-38 (herein Szymczak) with Gustafsson C, et al. (2004) Codon bias and heterologous protein expression. Trends Biotechnol. 2004 Jul;22(7):346-53 (herein Gustafsson) providing additional evidentiary value.
Getts, Saint-Remy, and Szymczak teach T cell receptor fusion proteins (comprising SEQ ID Nos: 2 and 4), modified human immune cells, expressing the encoded molecules, and methods of use for the treatment of diseases, including autoimmune diseases, as discussed above. Designing a polynucleotide sequence encoding a protein of a specific amino acid sequence, as well optimizing codon usage for its intended expression system is routine in the field and would have been obvious to one skilled in the art, at the time of filing. Gustafsson et al provide a review discussing the codon bias in relation to the expression of heterologous proteins. In this review, the authors provide a general strategy for de novo gene design, this strategy considers the multiple variables that determine transgene expression (i.e. codon usage, unfavorable codon pairs, GC content, elimination of repetitive sequences, avoidance of unfavorable mRNA secondary structure, avoidance of restriction sites, etc), and provides a procedure for codon optimization (Gene design considerations and Box 1). In addition to the art cited, for de novo transgene design, there exists many alternative tools for codon optimization, that were available prior to the effective filing date of the current application.
Conclusion
No claims allowed.
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/MATTHEW CURRAN METCALF/ Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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