DETAILED ACTION
Notice of Pre-AIA or AIA Stat
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 present application claims foreign priority to EP21382593.8, filed on 02 July 2021, and is a 371 of PCT/EP2022/068416, filed on 04 July 2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP21382593.8, filed on 02 July 2021. The effective filing date is 02 July 2021.
Status of Application, Amendments, and/or Claims
Claims 1-15 are the original claims. In the amendment of 02 August 2024, claims 2-15 were amended and claims 16-20 were added. Claims 1-20 are pending and the subject of this office action.
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.
Claims 1-3, 8, 9, 13-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Kumaresan PR, et al. (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5 (herein Kumaresan) in view of Vera J, et al. (2009) The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1506-11 (herein Vera).
In regard to claims 1-3, Kumaresan relates to a study, in which CAR T cells were used to enhance immunity towards opportunistic fungal infections (Abstract). The authors teach that Aspergillus infection is a major concern for immunocompromised patients, with observed Aspergillus-associated mortality rates of 22% or 60-85% for patients receiving solid-organ or hematopoietic stem cell transplants, respectively (Introduction-paragraph 1). Based on the success of CD19 CAR T cell therapies, the authors sought to use a similar methodology in targeting Aspergillus. Towards this end, T cells were genetically engineered to express a chimeric antigen receptor comprising the extracellular domain of Dectin-1, a signal peptide, a transmembrane domain, a CD3[Symbol font/0x7A] signaling domain, and a CD28 co-stimulatory domain (Figure 1 and Results: Generating D-CAR+ Human T cells). The authors state that by modifying the prototypical CAR design (i.e. ligand recognition via the antigen binding domain of antibodies) they were able to achieve carbohydrate recognition by incorporating the pattern-recognition properties of the extracellular portion of Dectin-1 (Introduction-paragraph 3). It is taught that Dectin-1 is a type II transmembrane protein expressed on macrophages, neutrophils, and dendritic cells, and recognizes/binds β-glucans on the cell wall of fungi, such as Aspergillus (Introduction-paragraph 3). The authors demonstrate that these CAR T cells bind specifically to β-glucans, exhibit a central memory phenotype, inhibit the growth of Aspergillus hyphae, and target Aspergillus infection in immunocompromised mice (Introduction-paragraph 4, Results section, and Figures 2-4).
In summary, Kumaresan et al disclose: a chimeric antigen receptor, comprising a non-prototypical CAR binding domain targeted towards β-glucans; cells, comprising the receptor; a pharmaceutical composition, comprising the cells; a method for treating infection, comprising the administration of the composition (Relevant in part to instant claims 1, 8, 11, and 13).
Kumaresan does not teach a chimeric antigen receptor comprising SEQ ID NO:1, and as such does not teach the related cells, composition, or method. Vera teaches these deficiencies.
Vera et al relates to an investigation into the fungal binding capabilities of CD5 (Abstract). Vera teaches that CD5 is a member of the scavenger receptor cysteine-rich domain (SRCR) super family of receptors. CD5, as well as other members of SRCR subgroup B, is characterized by a scaffold, comprising a central core formed by 2 antiparallel β-sheets cradling an α-helix, with substrate specificity being derived by external loops connecting these scaffold-defining elements (Introduction-paragraph 1). It is shown, through direct binding assays, that the extracellular domain of human CD5 binds to various fungal cells (S. pombe, C. albicans, and Cryptococcus neoformans) via any of the three SRCR domains within the extracellular domain (Figure 1 and Results: The Ectodomain of Human CD5 Binds to Fungal Cells). Through a series of competition and fluorescence assays, the fungal cell component bound by CD5 was identified as β-glucan (Results: The CD5 Ectodomain Binds Directly to Conserved Components of Fungal but Not Bacterial Cell Walls). Vera teaches that β-glucans are a cell wall component of yeast and pathogenic fungi, and consist of polymerized β-(1-3)-linked and β-(1-6)-linked β-D-glucopyranosyl units (Discussion-paragraph 2). It is also taught that there is a limited number of receptors capable of recognizing these units (CR3, lactosylceramide, scavenger receptors, and dectin-1). The authors also note that the Kd of the interaction of rshCD5 with soluble (1-3)-β-D-glucan phosphate was 3.7 nM, which is within the range of binding affinities (2.6 mM–2.2 pM) reported for the interaction of dectin-1 with (1-3)-β-D-glucan phosphate from different sources (Discussion-paragraph 3).
It would have been obvious to one skilled in the art, at the time of filing, to combine the teachings of Kumaresan (CAR T cells comprising an extracellular β-glucan binding domain) with Vera (identifying the extracellular domain of CD5 as a β-glucan binder). Kumaresan discloses a chimeric receptor, comprising a signal peptide, a β-glucan binding domain, a transmembrane domain, and intracellular activating domains. The present application claims a chimeric receptor sharing a near identical architecture, in which the β-glucan binding agent is substituted, from the extracellular domain of detrin-1 to the extracellular domain of CD5 (SEQ ID NO:1). In the context of the disclosed chimeric receptors, in which the extracellular domains are separated from their native intracellular domains (i.e. native signaling machinery), the extracellular domains perform the same function (i.e. binding fungal cell walls). Despite differences in receptor family/fold (CD5 being a member of the SRCR family and dectin-1 being a member of C-type lectin-like receptor family), this overlap in function was known in the art, prior to filing date of the application, as evidenced by Vera’s teaching that CD5 and detrin-1 share comparable Kd values towards (1-3)-β-D-glucan phosphate (Discussion-paragraph 3). The resulting receptor, referenced in instant claims 1-3, displays properties, which are entirely predictable, based on the cited prior art, in which the substituted element performs its function in accordance with prior findings.
In regard to claims 8, 9, 16, and 17, Kumaresan and Vera teach CAR receptors, comprising the extracellular domain of CD5 (SEQ ID NO:1), as discussed for the 35 U.S.C. 103 rejections of claims 1-3. Kumaresan teaches αβ CAR T cells, comprising receptors comprising an extracellular domain specific towards β-glucans (Relevant to instant claims 8 and 9) (Results: Generating D-CAR+ Human T Cells). The nature of these cells require that the cells comprise nucleic acid encoding the receptor, thus the limitation of claims 16 and 17 would have been obvious to one skilled in the art.
In regard to claim 13-15, and 20, Kumaresan and Vera teach CAR receptors, comprising the extracellular domain of CD5 (SEQ ID NO:1), as discussed for the 35 U.S.C. 103 rejections of claims 1-3.
Kumaresan also teaches the administration of CAR T cells to immunocompromised mice, infected with Aspergillus (Relevant to instant claims 13-15 and 20) (Results: Targeting Aspergillus Infection in Mice by D-CAR+ T Cells).
Claims 6 is rejected under 35 U.S.C. 103 as being unpatentable over Kumaresan PR, et al. (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5 (herein Kumaresan) in view of Vera J, et al. (2009) The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1506-11 (herein Vera), 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.
In regard to claim 6, Kumaresan and Vera teach CAR receptors, comprising the extracellular domain of CD5 (SEQ ID NO:1), as discussed for the 35 U.S.C. 103 rejections of claims 1-3. The receptors taught by Kumaresan and Vera, embody the limitations of claim 1, as discussed. 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.
Claims 4, 5, 7, 11, 12, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Kumaresan PR, et al. (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5 (herein Kumaresan) and Vera J, et al. (2009) The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1506-11 (herein Vera) in view of EP3696191 A1 (herein Bujan).
In regard to claims 4, 5, and 7, Kumaresan and Vera teach CAR receptors, comprising a signal peptide, a hinge, a transmembrane domain, and one or more intracellular signal transduction domains, as discussed for the 35 U.S.C. 103 rejections of claims 1-3.
Kumaresan and Vera do not teach specific amino acid sequences for chimeric antigen receptor or the individual components of said receptor. Bujan teaches these deficiencies.
Bujan teaches an anti-CD1a chimeric antigen receptor for the treatment of relapsed/refractory T-cell cute lymphoblastic leukemia (Abstract). Bujan discloses a chimeric antigen receptor amino acid sequence (SEQ ID NO: 2), comprising a CD8 signal peptide, a CD8 transmembrane region (SEQ ID NO: 10), a 4-1BB/CD137 co-stimulatory domain (SEQ ID NO: 12), and a CD3[Symbol font/0x7A] intracellular domain (SEQ ID NO: 11). This embodied receptor, encompasses all of the limitations established in instant claims 4 (SEQ ID Nos: 3-5, 7, and 10 of the current application) and 5 (SEQ ID NO: 11 of the instant application), with the exception of comprising SEQ ID NO: 1, the extracellular antigen-binding domain, of the current application, as shown by the annotated amino acid sequences below.
SEQ ID NO:11MALPVTGLLLSLGLLLHAARPRLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMVCSQSWGRSSKQWEDPSQASKVCQRLNCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLGLTCLEPQKTTPPTTRPPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENFLCNNLQCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLALLCSGFQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSVNSYRVLDAGDPTSRGLFCPHQKLSQCHELWERNSYCKKVFVTCQDTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
REF SEQ ID NO:2
MALPVTGLLLSLGLLLHAARPTGQVQLQQSGAELARPGASVKMSCKASGYAFSTYTMHWVKQRPRQGLEWIGYINPNSASTSYNENFKDKATLTADKSSNTAYMHLSSLTSEDSAVYYCARGEYTMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGGGSRDIQMTQSPSSLSASLGGKVTITCQASQDINKYIAWYQFKPGKGPRLLIHYTSTLQPAIPSRFSGSGSGREYSFSISNLEPEDIATYYCLHYDNLPWTFGGGTKLEIKRATTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
CD8 Signal peptide
CD8 hinge
CD8 transmembrane region
4-1BB costimulatory domain
CD3[Symbol font/0x7A] intracellular domain
Extracellular antigen binding domain
It would have been obvious to one skilled in the art to combine the teachings of Vera and Kumaresan with the chimeric antigen receptor template taught by Bujan. Bujan et al demonstrate that the receptor comprising the amino acid corresponding to SEQ ID NO:2 was efficiently expressed, following genomic integration of the corresponding nucleic acid into T cells ([0140]). As a result, the use of this sequence would have been obvious as a template, into which the amino acid sequence for extracellular domain of CD5 (SEQ ID NO:1) could replace the scFv, used in the original design of Bujan. The use of a template, that has previously been shown to be effective, presents a high likelihood of success and as such would have been obvious.
In regard to claim 7, Kumaresan, Vera, and Bujan teach CAR receptors, comprising the chimeric antigen receptor (SEQ ID NO: 11), as discussed for the 35 U.S.C. 103 rejections of claims 4 and 5. Designing a polynucleotide sequence (SEQ ID NO:14) encoding a protein of a specific amino acid sequence (SEQ ID NO: 11), as well optimizing codon 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.
In regard to claim 11, 12, and 19, Kumaresan and Vera teach CAR receptors, comprising a signal peptide, a hinge, a transmembrane domain, and one or more intracellular signal transduction domains, as discussed for the 35 U.S.C. 103 rejections of claims 1-3, and Bujan teaches the limitations referenced in claims 4 and 5, as discussed above.
Bujan also teaches the use of albumin and saline as the pharmaceutically acceptable carrier or diluents in a pharmaceutical composition ([0047] and [0127]). It should be noted that both of these components are well known in the art, and are common components of pharmaceutical compositions, comprising T cells. Additionally, Vera provides additional support for its use, as it is shown that the extracellular domain of CD5 does not bind albumin and is less likely to perturb the desired activity of the cells (Results: The CD5 Ectodomain Binds Directly to Conserved Components of Fungal but Not Bacterial Cell Walls). In regard to the concentration of albumin, the 2.5%, referenced in claim 12, would have been obvious following routine optimization, see MPEP 2144.05 IIa.
Claims 10 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kumaresan PR, et al. (2014) Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10660-5 (herein Kumaresan) and Vera J, et al. (2009) The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1506-11 (herein Vera) in view of Rozenbaum M, et al. (2020) Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia. Front Immunol. 2020 Jul 2;11:1347 (herein Rozenbaum).
Kumaresan and Vera teach chimeric antigen receptors, comprising a CD5 extracellular domain, as well as T cells, pharmaceutical compositions, and methods, comprising the chimeric antigen receptor, as discussed for the 35 U.S.C. 103 rejections of claims 1-3, 8, 9, 11, 13-17.
Kumaresan and Vera do not teach that the cells, comprising the chimeric antigen receptor, are autologous αβT-cells, allogenic γT cells, or NK cells derived from allogenic cord-blood or iPS. Rozenbaum teaches these deficiencies.
Rozenbaum relates to a process for expanding and transducing γδ T cells with nucleic acids encoding an anti-CD19 chimeric antigen receptor (Abstract). The authors demonstrate that these γδ T cells are effectively expanded and transduced, and are effective against CD19+ tumor cells, both in vitro and in vivo (Discussion and Results, and Figures). The authors also discuss the state of the art regarding CAR T therapy, at a point in time slightly before the effective filing date of the current application (Introduction and Discussion). Rozenbaum teaches that autologous CAR T cells, comprising anti-CD19 antigen binding domains, have been shown to produce high remission rates, when used in the treatment of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma (the referenced trials use autologous αβ T cells) (Introduction-paragraph 1). It is also taught that despite the success of autologous treatment, some patient populations experience relapse, through the loss of transferred T cells or alterations in target antigen expression. In addition, autologous CAR T cell therapy is taught to require complex and individualized production. The authors suggest that allogenic γδT CAR cells may address these deficiencies, as they allow for the safe use of allogeneic CARs, due to their lack of allogenicity and their potential to “target minor clones with lower antigen density, which may not be eliminated by the standard CAR T cells” (Introduction-paragraph 4 and Discussion-paragraph 2).
Based on the teachings of Rozenbaum it would have been obvious to one skilled in the art to introduce the chimeric antigen receptor (taught by Vera and Kumaresan), comprising a CD5 extracellular domain, into autologous αβT cells or allogenic γδT cells. Rozenbaum teaches that autologous CAR αβT cells are the standard format for CAR T cell therapy and have proven efficacy in multiple applications (Introduction-paragraph 1). Hence, their use, in the context of the current application, would represent a high likelihood of success. Rozenbaum also teaches the use of allogenic CAR γδT cells, as an alternative, and highlights the unique properties, which render γδT cells an appealing platform for allogenic CAR T cell therapy, namely their lack of allogenicity. The lack of allogenicity provides clear motivation for using γδT cells as a platform for allogenic CAR T therapy, as graft-vs.-host disease is taught to be a concern for allogenic therapy (Introduction-paragraph 2).
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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