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 .
Claims 68-87 are pending.
Applicant’s election without traverse of Group I that read on (A) myelin basic protein epitope as the species of autoimmune disease-associated epitope, (B) a DRB1 polypeptide (SEQ ID NO: 36) as the species of MHC class II beta polypeptide, (C) a DRA polypeptide (SEQ ID NO: 12) as the species of MHC class II alpha polypeptide and (D) PD-L1 (SEQ ID NO: 97) as the species of immunomodulatory polypeptide in the reply filed on November 7, 2025 is acknowledged.
Claims 71-74, 78-81 and 84-87 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 68-70, 75-77, 82 and 83, drawn to a T-cell modulatory multimeric polypeptide (TMMP) that read on (A) myelin basic protein epitope as the species of autoimmune disease-associated epitope, (B) a DRB1 polypeptide (SEQ ID NO: 36) as the species of MHC class II beta polypeptide, (C) a DRA polypeptide (SEQ ID NO: 12) as the species of MHC class II alpha polypeptide and (D) PD-L1 (SEQ ID NO: 97) as the species of immunomodulatory polypeptide, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/076,314, filed September 9, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 7, 2025, June 16, 2025, April 3, 2025, March 3, 2024, December 18, 2024, November 7, 2024, Oct 16, 2024, Oct 15, 2024, September 11, 2024, April 17, 2024, February 16, 2024, January 30, 2024, January 12, 2024, December 12, 2023, November 7, 2023, Oct 5, 2023, September 28, 2023, August 29, 2023, August 25, 2023, July 27, 2023, April 27, 2023, February 10, 2023 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on February 8, 2023 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 69-70, 76-77 and 83 are objected to because of the following informality: “A” should have been “The” for all dependent claims.
Claim 69 is further objected to because of the following informality: the second “ii)” at a1) and a2) should have been “iii)”.
Claim 76 is objected to because of the following informality: “may be joined” should have been “joined”. All claims should be affirmative.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 68-70, 75-77, 82 and 83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 69 encompasses a TMMP of claim 68, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class IIβ polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class IIα polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the second polypeptide optionally may be joined by one or more linkers.
Claim 70 encompasses a TMMP comprising two heterodimers according to claim 69, wherein the heterodimers are covalently linked to each other.
Claim 75 encompasses any T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any autoimmune disease-associated peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) a first major histocompatibility complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is any MHC class II beta polypeptide that comprises a cysteine (Cys),
b) a second polypeptide comprising;
i) one or more immunomodulatory polypeptides, wherein at least one of the one or more immunomodulatory polypeptides is any PD-L1 (elected species) or FasL polypeptide;
ii) a second MHC class II polypeptide, wherein the second MHC class II polypeptide is any MHC class II alpha polypeptide that comprises a Cys; and
iii) any immunoglobulin (Ig) Fc polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the cysteine (Cys) in the MHC class IIβ polypeptide and the Cys in the MHC class IIα polypeptide, and wherein the TMMP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 76 encompasses a TMMP of claim 75, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class II a polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the first and second polypeptide optionally may be joined by one or more linkers.
Claim 77 encompasses a TMMP comprising two heterodimers according to claim 76, wherein the heterodimers are covalently linked to each other.
82. (New) An antigen-presenting polypeptide (APP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) any first major histocompatibility complex (MHC) class II polypeptide; and
b) a second polypeptide comprising a second MHC class II polypeptide, wherein either the first or second polypeptide is any MHC class II alpha chain polypeptide and the other is any MHC class II beta chain polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via at least one disulfide bond,
wherein one or both polypeptides of the heterodimer comprises any immunoglobulin (Ig) Fc polypeptide,
wherein the APP does not include an immunomodulatory polypeptide, and
wherein the APP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 83 encompasses a APP comprising two heterodimers according to claim 82, wherein the heterodimers are covalently linked to each other.
This encompass a huge genus of functionally and structurally distinct autoimmune disease-associated peptide epitopes, major histocompatibility complex class II beta polypeptides, cysteine (Cys) containing linker, PD-L1 polypeptides, MHC class II alpha polypeptides and IgG Fc polypeptides.
Regarding autoimmune disease-associated peptide epitope, the specification discloses:
[0224] As used herein, an “autoimmune disease-associated peptide” is a peptide that, when present in a TMMP of the present disclosure, presents an autoimmune disease-associated epitope capable of being bound by a TCR on the surface of a T cell. An autoimmune disease-associated peptide can have a length of from about 4 amino acids to about 25 amino acids, e.g., the autoimmune disease-associated peptide can have a length of from 4 amino acids (aa) to 10 aa, from 8 aa to 12 aa, from 10 aa to 15 aa, from 12 aa to 20 aa, from 15 aa to 20 aa, from 15 aa to 25 aa, or from 20 aa to 25 aa. For example, an autoimmune disease-associated peptide present in a TMMP of the present disclosure can have a length of 4 amino acids (aa), 5 aa, 6 aa, 7, aa, 8 aa, 9 aa, 10 aa, 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa. In some cases, an autoimmune disease-associated peptide present in a TMMP of the present disclosure has a length of from 5 amino acids to 10 amino acids, e.g., 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa.
[0226] An autoimmune disease-associated peptide can present an epitope associated with or present in a “self” antigen (an autoantigen). Antigens associated with autoimmune disease can be autoantigens associated with autoimmune diseases such as Addison disease (autoimmune adrenalitis, Morbus Addison), alopecia areata, Addison's anemia (Morbus Biermer), autoimmune hemolytic anemia (AIHA), autoimmune hemolytic anemia (AIHA) of the cold type (cold hemagglutinin disease, cold autoimmune hemolytic anemia (AIHA) (cold agglutinin disease), (CHAD)), autoimmune hemolytic anemia (AIHA) of the warm type (warm AIHA, warm autoimmune hemolytic anemia (AIHA)), autoimmune hemolytic Donath-Landsteiner anemia (paroxysmal cold hemoglobinuria), antiphospholipid syndrome (APS), atherosclerosis, autoimmune arthritis, arteriitis temporalis, Takayasu arteriitis (Takayasu's disease, aortic arch disease), temporal arteriitis/giant cell arteriitis, autoimmune chronic gastritis, autoimmune infertility, autoimmune inner ear disease (AIED), Basedow's disease (Morbus Basedow), Bechterew's disease (Morbus Bechterew, ankylosing spondylitis, spondylitis ankylosans), Behcet's syndrome (Morbus Behcet), bowel disease including autoimmune inflammatory bowel disease (including colitis ulcerosa (Morbus Crohn, Crohn's disease), autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (DCM), chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic polyarthritis, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, CREST syndrome (syndrom with Calcinosis cutis, Raynaud phenomenon, motility disorders of the esophagus, sklerodaktylia and teleangiectasia), Crohn's disease (Morbus Crohn, colitis ulcerosa), dermatitis herpetiformis during, dermatologic autoimmune diseases, dermatomyositis, essential mixed cryoglobulinemia, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Goodpasture syndrome (anti-GBM mediated glomerulonephritis), graft versus host disease, Guillain-Barre syndrome (GBM, Polyradikuloneuritis), hematologic autoimmune diseases, Hashimoto thyroiditis, hemophilia, acquired hemophilia, autoimmune hepatitis, idiopathic pulmonary fibrosis (IPF), idiopathic thrombocytopenic purpura, Immuno-thrombocytopenic purpura (Morbus Werlhof, ITP), IgA nephropathy, autoimmune infertility, juvenile rheumatoid arthritis (Morbus Still, Still syndrome), Lambert-Eaton syndrome, systemic lupus erythematosus (SLE), lupus erythematosus (discoid form), Lyme arthritis (Lyme disease, borrelia arthritis), Meniere's disease (Morbus Meniere); mixed connective tissue disease (MCTD), multiple sclerosis (MS, encephalomyelitis disseminate, Charcot's disease), myasthenia gravis (myasthenia, MG), myositis, polymyositis, neural autoimmune diseases, Pemphigus vulgaris, bullous pemphigoid, polyglandular (autoimmune) syndrome (PGA syndrome, Schmidt's syndrome), polymyalgia rheumatica, primary agammaglobulinemia, primary autoimmune cholangitis, progressive systemic sclerosis (PSS), rheumatoid arthritis (RA, chronic polyarthritis, rheumatic disease of the joints, rheumatic fever), sarcoidosis (Morbus Boeck, Besnier-Boeck-Schaumann disease), stiff-man syndrome, Sclerodermia, Scleroderma, Sjögren's syndrome, autoimmune uveiitis, and Wegner's disease (Morbus Wegner, Wegner's granulomatosis).
[0227] In some cases, an autoimmune disease-associated peptide present in a TMMP of the present disclosure is a peptide associated with Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura, bullous pemphigoid, Crohn's disease, Goodpasture's syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave's disease, Hashimoto's thyroiditis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis (MG), pemphigus (e.g., Pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), vasculitis, or vitiligo.
[0228] Autoantigens include, e.g., aggrecan, alanyl-tRNA syntetase (PL-12), alpha beta crystallin, alpha fodrin (Sptan 1), alpha-actinin, α1 antichymotrypsin, α1 antitripsin, α1 microglobulin, aldolase, aminoacyl-tRNA synthetase, an amyloid, an annexin, an apolipoprotein, aquaporin, bactericidal/permeability-increasing protein (BPI), β-globin precursor BP1, β-actin, β-lactoglobulin A, β-2-glycoprotein I, β2-microglobulin, a blood group antigen, C reactive protein (CRP), calmodulin, calreticulin, cardiolipin, catalase, cathepsin B, a centromere protein, chondroitin sulfate, chromatin, collagen, a complement component, cytochrome C, cytochrome P450 2D6, cytokeratins, decorin, dermatan sulfate, DNA topoisomerase I, elastin, Epstein-Barr nuclear antigen 1 (EBNA1), elastin, entaktin, an extractable nuclear antigen, Factor I, Factor P, Factor B, Factor D, Factor H, Factor X, fibrinogen, fibronectin, formiminotransferase cyclodeaminase (LC-1), gp210 nuclear envelope protein, GP2 (major zymogen granule membrane glycoprotein), a glutenin, glycoprotein gpIIb/IIIa, glial fibrillary acidic protein (GFAP), glycated albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), haptoglobin A2, heat shock proteins, hemocyanin, heparin, a histone, histidyl-tRNA synthetase (Jo-1), a hordein, hyaluronidase, immunoglobulins, an integrin, interstitial retinol-binding protein 3, intrinsic factor, Ku (p70/p80), lactate dehydrogenase, laminin, liver cytosol antigen type 1 (LC1), liver/kidney microsomal antigen 1 (LKM1), lysozyme, melanoma differentiation-associated protein 5 (MDAS), Mi-2 (chromodomain helicase DNA binding protein 4), a mitochondrial protein, muscarinic receptors, myelin-associated glycoprotein, myosin, myelin basic protein, myelin proteolipid protein, myelin oligodendrocyte glycoprotein, myeloperoxidase (MPO), rheumatoid factor (IgM anti-IgG), neuron-specific enolase, nicotinic acetylcholine receptor A chain, nucleolin, a nucleoporin, nucleosome antigen, PM/Sc1100, PM/Scl 75, pancreatic β-cell antigen, pepsinogen, peroxiredoxin 1, phosphoglucose isomerase, phospholipids, phosphatidyl inositol, platelet derived growth factors, polymerase beta (POLB), potassium channel KIR4.1, proliferating cell nuclear antigen (PCNA), proteinase-3, proteolipid protein, proteoglycan, prothrombin, recoverin, rhodopsin, ribonuclease, a ribonucleoprotein, ribosomes, a ribosomal phosphoprotein, RNA, an Sm protein, Sp100 nuclear protein, SRP54 (signal recognition particle 54 kDa), a selectin, smooth muscle proteins, sphingomyelin, streptococcal antigens, superoxide dismutase, synovial joint proteins, T1F1 gamma collagen, threonyl-tRNA synthetase (PL-7), tissue transglutaminase, thyroid peroxidase, thyroglobulin, thyroid stimulating hormone receptor, transferrin, triosephosphate isomerase, tubulin, tumor necrosis factor-alpha, topoisomerase, U1-dnRNP 68/70 kDa, U1-snRNP A, U1-snRNP C, U-snRNP B/B′, ubiquitin, vascular endothelial growth factor, vimentin, and vitronectin.
[0230] Autoantigens associated with alopecia areata (autoimmune alopecia) include, e.g., hair follicle keratinocyte polypeptides, melanogenesis-associated autoantigens, and melanocyte polypeptides. An example of a melanocyte autoantigen is tyrosinase. Autoantigens associated with autoimmune alopecia also include trichohyalin (Leung et al. (2010) J. Proteome Res. 9:5153) and keratin 16. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of a hair follicle keratinocyte polypeptide, a melanocyte polypeptide, a melanogenesis-associated polypeptide, tyrosinase, trichohyalin, or keratin 16.
[0231] Autoantigens associated with Addison's disease include, e.g., 21-hydroxylase. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of 21-hydroxylase.
[0232] Autoantigens associated with autoimmune thyroiditis (Hashimoto's thyroiditis) include, e.g., thyroglobulin, thyroid peroxidase, thyroid Stimulating Hormone Receptor (TSH-Receptor), thyroidal iodide transporters Na.sup.+/I-symporter (NIS), pendrin, and the like. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Hashimoto's thyroiditis-associated polypeptides.
[0233] Autoantigens associated with Crohn's disease include, e.g., pancreatic secretory granule membrane glycoprotein-2 (GP2). A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of GP2.
[0234] Autoantigens associated with Goodpasture's disease include, e.g., the α3 chain of type IV collagen, e.g., amino acids 135-145 of the α3 chain of type IV collagen. Penades et al. (1995) Eur. J. Biochem. 229:754; Kalluri et al. (1994) Proc. Natl. Acad. Sci. USA 91:6201. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of the α3 chain of type IV collagen.
[0235] Autoantigens associated with Grave's disease include, for example, thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSH-R). A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Grave's disease-associated antigens.
[0236] Autoantigens associated with mixed connective tissue disease include, e.g., U1 ribonucleoprotein (U1-RNP) polypeptide (also known as snRNP70). Sato et al. (2010) Mol. Cell. Biochem. 106:55. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an autoimmune disease-associated peptide of from 4 amino acids to about 25 amino acids in length of U1-RNP polypeptide.
[0237] Autoantigens associated with multiple sclerosis include, e.g., myelin basic protein, myelin oligodendrocyte glycoprotein, and myelin proteolipid protein. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned multiple sclerosis-associated antigens. As one non-limiting example, the autoimmune disease-associated peptide can comprise the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134). In some cases, a TMMP of the present disclosure comprises a DRB1*15:01 MHC class II β chain; and a peptide epitope of the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134).
However, neither the specification nor the art teaches autoimmune disease-associated peptide epitopes that are less than the length required to span the MHC II peptide binding groove, which generally 9-25 amino acid residues in length depending upon the sequence of the peptide and the particular MHC II peptide binding groove. The specification does not disclose a representative number of such autoimmune disease-associated epitope or peptides for the breadth of the MHC II molecules formed by the generic MHC II beta and alpha polypeptides recited in the TMMP (claims 68-70, 75-77) or APP (claims 82-83) of the instant claims. The specification does not describe sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
Wieczorek (Frontier Immunology 8: 292, 2017; PTO 892) teaches MHC class II proteins usually accommodate peptides of 13–25 residues in length in their open binding groove, with the peptide N-terminus usually extruding from the P1 pocket, see p. 2, left col. in particular. Wieczorek further teaches that [T]he most polymorphic human MHC class I and class II proteins (human leukocyte antigens, HLAs) are each expressed from three gene regions (MHC class I: HLA-A, -B, -C; MHC class II: HLA-DR, -DP, -DQ), which are all highly polymorphic. This allelic variation mainly affects the nature and composition of the peptide-binding groove and thus modulates the peptide repertoire that is presented on the surface by MHC class I or MHC class II proteins for CD8+ or CD4+ T cell recognition, respectively. A good match of the peptide and the MHC binding groove is an important, but certainly not the sole determinant of its presentation. In human alone, with over 10,754 different alleles for human MHC class II, there is significant variation in MHC-II alleles and the peptides they can bind.
Nikolich-Zugich et al (Nature Reviews/Immunology 4: 123-132, 2004; PTO 892) teaches an estimate of how many different peptides with which T cell repertoire could be confronted: “Using the maximal number of combinations for an 11-mer peptide bound to a MHC class II molecule, and minimal restriction on the type of amino acids that are allowed at different positions, Mason calculated the number of antigenic peptides that can potentially be presented by one MHC class II molecule to be - 6 x 1012...and “it remains unclear whether and how structural TCR diversity influences functional diversity”... (see entire reference, especially abstract, introduction, pages 124-125, paragraph spanning columns 1-2 on page 126, paragraph spanning columns 1-2 on page 127, column 1 on page 128 at lines 9-15, and last sentence at column 1 on page 128).
Even assuming the autoimmune-associated peptide epitope is associated with multiple sclerosis (elected species), the specification discloses just one peptide consisting of the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134), see para. [0237]. However, the disclosure of one species is not representative of genus of peptides and MHC class II alpha and beta chains that form the peptide-binding groove encoded by the highly polymorphic MHC allelic genes for CD4+ T cell recognition and antigen presentation for treating all autoimmune diseases in an individual such as a human subject.
Regarding MHC class II β chain, the specification discloses:
[0151] MHC class II beta chains comprise a β1 domain and a β2 domain. In some cases, the β1 domain and the β2 domain present in an antigen-presenting cell are from the same MHC class II β chain polypeptide. In some cases, the β1 domain and the β2 domain present in an antigen-presenting cell are from two different MHC class II β chain polypeptides. In some cases, MHC class II β chain polypeptide suitable for inclusion in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type MHC class II β chain polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys.
[0152] MHC class II beta chains suitable for inclusion in a TMMP of the present disclosure lack a signal peptide. An MHC class II beta chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 210 amino acids; for example, an MHC class II beta chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, from about 180 amino acids to about 200 amino acids, or from about 200 amino acids to about 210 amino acids. An MHC class II β1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC class II β1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids. An MHC class II β2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC class II β2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids.
[0153] In some cases, the MHC class II β chain polypeptide is a variant DRB MHC class II polypeptide that comprises a non-naturally occurring Cys residue. For example, in some cases, the MHC class II β chain polypeptide is a variant DRB1 MHC class II polypeptide that comprises an amino acid substitution selected from the group consisting of PSC, F7C, Q10C, N19C, G20C, H33C, G151C, D152C, and W153C. In some cases, the MHC class II β chain polypeptide is a variant DRB1 polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the following DRB1 amino acid sequence:
[0160] A suitable DRB1 polypeptide can comprise the following amino acid sequence: GDTRPRFLEQVKHECHFFNGTERVRFLDRYFYHQEEYVRFDSDVGEYRAVTELGRPDAEYWNSQKDLLEQKRAAVDTYCRHNYGVGESFTVQRRVYPEVTVYPAKTQPLQHHNLLVCSVNGFYPASIEVRWFRNGQEEKTGVVSTGLIQNCDWTFQTLVMLETVPRSGEVYTCQVEHPSLTSPLTVEWR ARSESAQSKM (SEQ ID NO:36), where G151 is substituted with a Cys (shown in bold text), elected species.
Regarding MHC class II α chain, the specification discloses:
[0113] MHC class II alpha chains suitable for inclusion in a TMMP of the present disclosure lack a signal peptide. An MHC class II alpha chain suitable for inclusion in a multimeric polypeptide of the present disclosure can have a length of from about 60 amino acids to about 190 amino acids; for example, an MHC class II alpha chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, or from about 180 amino acids to about 200 amino acids. An MHC class II α1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC class II α1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids. An MHC class II α2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC class II α2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids.
[0114] In some cases, an MHC class II α chain polypeptide present in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type MHC class II α chain polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys. Such an amino acid substitution can occur between amino acid 55 and 110 of the MHC class II α chain polypeptide. For example, an amino acid substitution that replaces an amino acid other than a Cys with a Cys can be present between amino acids 55 and 60, between amino acids 60 and 65, between amino acids 65 and 70, between amino acids 70 and 75, between amino acids 75 and 80, between amino acids 80 and 85, between amino acids 85 and 90, between amino acids 90 and 95, between amino acids 95 and 100, between amino acids 100 and 105, or between amino acids 105 and 110.
[0117] A “DRA polypeptide” includes allelic variants, e.g., naturally occurring allelic variants. Thus, in some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLEIMTK RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:6, amino acids 26-203 of DRA*01:02:01, see FIG. 6), or an allelic variant thereof. In some cases, the allelic variant is the DRA*01:01:01:01 allelic variant that differs from DRA*01:02:01 by having a valine in place of the leucine at position 242 of the sequence in FIG. 6. In some cases, a DRA polypeptide suitable for inclusion in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type DRA polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys.
[0118] In some cases, a TMMP of the present disclosure comprises a variant DRA polypeptide that comprises a non-naturally occurring Cys residue. For example, in some cases, a TMMP of the present disclosure comprises a variant DRA polypeptide that comprises an amino acid substitution selected from E3C, E4C, F12C, G28C, D29C, I72C, K75C, T80C, P81C, I82C, T93C, N94C, and S95C.
[0119] In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLECMTK RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:7), where amino acid 172 is substituted with a Cys (shown in bold text). In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLEIMTC RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:8), where amino acid K75 is substituted with a Cys (shown in bold text).
[0120] In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:9). In some cases, an amino acid between amino acids 55 and 110 is substituted with a Cys. In some cases, an amino acid between amino acids 70 and 85 is substituted with a Cys.
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGCEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:10), where D29 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLECMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:11), where 172 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTCRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:12), where K75 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTCITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:13), where P81 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPCTNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:14), where 182 is substituted with a Cys (shown in bold text).
However, the specification does not describe where and what amino acids within the full-length sequence of which MHC class II β chain and which MHC class II α chain to be substituted, deleted, added or a combination thereof such that the modified variant having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the unmodified corresponding MHC class II β chain and MHC class II α chain sequences still maintains 3D structure and forming peptide binding groove for the claimed TMMP or APP.
Regarding one or more immunomodulatory polypeptide, the specification discloses:
[0254] As also noted above, the immunomodulatory polypeptide can comprise a wild-type amino acid sequence, or can comprise one or more amino acid substitutions relative to a wild-type amino acid sequence. The immunomodulatory polypeptide can comprise only the extracellular portion of a full-length immunomodulatory polypeptide. Thus, for example, the immunomodulatory polypeptide can in some cases exclude one or more of a signal peptide, a transmembrane domain, and an intracellular domain normally found in a naturally-occurring immunomodulatory polypeptide.
[0255] In some cases, an immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure comprises all or a portion of (e.g., an extracellular portion of) the amino acid sequence of a naturally-occurring immunomodulatory polypeptide. In other instances, an immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure is a variant immunomodulatory polypeptide that comprises at least one amino acid substitution compared to the amino acid sequence of a naturally-occurring immunomodulatory polypeptide. In some instances, a variant immunomodulatory polypeptide exhibits a binding affinity for a co-immunomodulatory polypeptide that is lower than the affinity of a corresponding naturally-occurring immunomodulatory polypeptide (e.g., an immunomodulatory polypeptide not comprising the amino acid substitution(s) present in the variant) for the co-immunomodulatory polypeptide.
[0256] Suitable immunomodulatory domains that exhibit reduced affinity for a co-immunomodulatory domain can have from 1 amino acid (aa) to 20 aa differences from a wild-type immunomodulatory domain For example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure differs in amino acid sequence by 1 aa, 2 aa, 3 aa, 4 aa, 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa, from a corresponding wild-type immunomodulatory polypeptide. As another example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure differs in amino acid sequence by 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, or 20 aa, from a corresponding wild-type immunomodulatory polypeptide. As an example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
[0257] As discussed above, a variant immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure exhibits reduced affinity for a cognate co-immunomodulatory polypeptide, compared to the affinity of a corresponding wild-type immunomodulatory polypeptide for the cognate co-immunomodulatory polypeptide.
Further, the term “modulatory” encompasses stimulating as well as inhibiting, which are mutual exclusive.
The specification exemplifies PD-L1 comprising the amino acid sequence of SEQ ID NO: 97, 98 and 99.
However, the specification does not describe where and what amino acid with the full-length sequence of SEQ ID NO: 97 to be substituted, deleted, added or a combination thereof such that the modified variant having 20 aa difference compared to the wild type correlate with stimulating or inhibiting function.
Regarding immunoglobulin Fc polypeptide, the specification discloses:
[0210] In some cases, the first or the second polypeptide chain of a TMMP of the present disclosure comprises an Fc polypeptide. The Fc polypeptide of a TMMP of the present disclosure can be a human IgG1 Fc, a human IgG2 Fc, a human IgG3 Fc, a human IgG4 Fc, etc. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to an amino acid sequence of an Fc region depicted in FIG. 12A-12G. In some cases, the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG1 Fc polypeptide depicted in FIG. 12A. In some cases, the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%, amino acid sequence identity to the human IgG1 Fc polypeptide depicted in FIG. 12A, and comprises a substitution of N77; e.g., the Fc polypeptide comprises an N77A substitution.
[0211] In some cases, the Ig Fc polypeptide induces cell lysis through activation of complement-dependent cytotoxicity (CDC). In some cases, the Ig Fc polypeptide is a variant that substantially does not induce cell lysis through activation of CDC, e.g., an IgG1 Fc polypeptide comprising L234A and L235A substitutions (L14A and L15A substitution of the amino acid sequence depicted in FIG. 21A). Typically, the TMMPs of this disclosure that employ an Ig Fc polypeptide are meant to engage a target T cell through the MHC-epitope complex and then modulate the activity of a T cell through the immunomodulatory polypeptides, and thus will employ a variant that substantially does not induce cell lysis through activation of CDC.
[0212] In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG2 Fc polypeptide depicted in FIG. 21A; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 99-325 of the human IgG2 Fc polypeptide depicted in FIG. 21A. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG3 Fc polypeptide depicted in FIG. 21A; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 19-246 of the human IgG3 Fc polypeptide depicted in FIG. 21A. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgM Fc polypeptide depicted in FIG. 21B; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-276 to the human IgM Fc polypeptide depicted in FIG. 21B. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgA Fc polypeptide depicted in FIG. 21C; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-234 to the human IgA Fc polypeptide depicted in FIG. 21C.
[0213] In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG4 Fc polypeptide depicted in FIG. 21C. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 100 to 327 of the human IgG4 Fc polypeptide depicted in FIG. 21C.
The specification exemplifies just human IgG1 Fc polypeptide, optionally comprises L234A and L235A substitution (SEQ ID NO: 59), human IgG4 Fc comprising SEQ ID NO: 58.
However, the specification does not teach where and what amino acid sequence within the human IgG1 Fc to be substituted, deleted, added or a combination thereof such that the modified Fc having 70%, 75%, 80%, 85%, 90% or 95% identity to unmodified human IgG1 Fc still maintains FcRn receptor binding, Fcγ receptors binding and/or effector functions. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For example, Moore et al (mAbs 2(2): 181-189, 2010; PTO 892) teaches that the triple mutation Ser267Glu, His268Phe, and serine 324 threonine (Ser324Thr) in the Fc has been found to largely improve CDC at the expense of reduced ADCC and ADCP via increasing the affinity to inhibitory FcγRIIb, see entire document, Table 3, p. 186, right col.
As another example, US 6,737,056 to Presta (PTO 892) provides an extensive list of point mutations within an antibody Fc domain and in Tables 6-9. Presta shows the effect of those mutations, alone or in various combinations, on Fc receptor binding. But, that mutational analysis showed each position can have a different effect and that different amino acid substitutions at any given site can have different effects. Thus, a determination of which mutations will result in a particular modified function is not predictable a prior.
The specification discloses that the covalent linkage of the two MHC II beta and alpha polypeptides is via at least one disulfide bond. In a non-limiting example, the disulfide bond may be present between a cysteine (Cys) present in the first MHC II polypeptide and a Cys present in the second MHC II polypeptide or between a cysteine (Cys) containing linker in the first MHC II polypeptide and a Cys present in the second MHC II polypeptide (para. [0218]).
Vas-Cath Inc, v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Adequate written description requires more than a mere statement that it is part of the invention. Instead, an “adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed.” See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Given the size of the genus of autoimmune disease-associated peptide epitopes, the broad definition of the first and second MHC II beta and alpha polypeptides (natural allelic variants, artificial variants via 60% identity and/or substitution, addition, deletion), immunomodulatory polypeptide such as PD-L1 having one or more amino acid substitutions (up to 20 residues) relative to a wild-type amino acid sequence, immunoglobulin (Ig) Fc variant having 70% identify via substitution, deletion, addition, or a combination thereof and the position/location of the residues that involved in at least one disulfide bond, including cysteine containing potential linkers, the disclosure does not provide a representative number of species of such T-cell modulatory multimeric polypeptide (TMMP) and antigen-presenting polypeptide (APP). One of skill in the art would not immediately envisage the genus of such TMMP and APPs. Thus, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such TMMP and APPs for treating any and all autoimmune disease at the time the instant application was filed.
Claims 68-70, 75-77, 82 and 83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a T-cell modulatory multimeric polypeptide (TMMP) comprising two heterodimers, wherein each heterodimer comprises: a) a first polypeptide comprising i) a basic myelin protein epitope associated with multiple sclerosis wherein the epitope consisting of the amino acid sequence of SE ID NO: 134, ii) a first major histocompatiblity complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is an MHC class II β polypeptide DRB1*0401 comprising the amino acid sequence of SEQ ID NO: 36; and ii) a cysteine (Cys)-containing linker that links the epitope to the MHC class IIβ polypeptide, and b) a second polypeptide comprising i) one or more immunomodulatory polypeptide wherein the one or more immunomodulatory polypeptide is a PD-L1 selected from the group consisting SEQ ID NO 97, 98 and 99, ii) a second MHC class II α polypeptide, wherein the second MHC class II α polypeptide is DRA*01:02 comprising the amino acid sequence of SEQ ID NO 12, and iii) an IgG1 Fc polypeptide, wherein the first and the second polypeptide of the heterodimer covalently linked to one another via a disulfide bond between the Cys in the Cys-containing linker and the Cys in the MHC class IIα polypeptide, and wherein the TMMP presents the epitope and bound by a T cell receptor on a CD4+ T cell, (2) a T-cell modulatory multimeric polypeptide (TMMP) comprising two heterodimers, wherein each heterodimer comprises: a) a first polypeptide comprising i) a basic myelin protein epitope associated with multiple sclerosis wherein the epitope consisting of the amino acid sequence of SE ID NO: 134, ii) a first major histocompatiblity complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is an MHC class II β polypeptide DRB1*0401 comprising the amino acid sequence of SEQ ID NO: 36; and ii) a cysteine (Cys)-containing linker that links the epitope to the MHC class IIβ polypeptide, and b) a second polypeptide comprising i) one or more immunomodulatory polypeptide wherein the one or more immunomodulatory polypeptide is a PD-L1 selected from the group consisting SEQ ID NO 97, 98 and 99, ii) a second MHC class II α polypeptide, wherein the second MHC class II α polypeptide is DRA*01:02 comprising the amino acid sequence of SEQ ID NO 12, and iii) an IgG1 Fc polypeptide, wherein the first and the second polypeptide of the heterodimer covalently linked to one another via a disulfide bond between the Cys in the MHC class II β and the Cys in the MHC class IIα polypeptide, and wherein the TMMP presents the epitope and bound by a T cell receptor on a CD4+ T cell, (3) an antigen-presenting polypeptide (APP) comprising two heterodimers, wherein each heterodimer comprises: a) a first polypeptide comprising i) a basic myelin protein epitope associated with multiple sclerosis wherein the epitope consisting of the amino acid sequence of SE ID NO: 134, ii) a first major histocompatiblity complex (MHC) class II polypeptide, and b) a second polypeptide wherein either the first or the second polypeptide is an MHC class II α polypeptide DRA*01:02 comprising the amino acid sequence of SEQ ID NO 12 or the other is MHC class II β polypeptide DRB1*0401 comprising the amino acid sequence of SEQ ID NO: 36; wherein the first and second polypeptide of the heterodimer are covalently liked to one another via at least one disulfide bond, wherein the APP does not include an immunomodulatory polypeptide (MOD), and wherein the APP presents the epitope by being bound by a T cell receptor on a CD4+ T cell, does not reasonably provide enablement for any T-cell modulatory multimeric polypeptide (TMMP) as set forth in claims 68-70, 75-77 and any antigen-presenting polypeptide (APP) as set forth in claims 82-83. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 68 encompasses any T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising: i) any autoimmune disease-associated peptide epitope that displays an autoimmune disease-associated epitope useful for treating all autoimmune disease other than Type 1 Diabetes (T1D); ii) any first major histocompatibility complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is any MHC class II beta polypeptide; and iii) a cysteine (Cys)-containing linker that links the peptide epitope to the MHC class IIβ polypeptide, and
b) a second polypeptide comprising:
i) one or more immunomodulatory polypeptides, wherein at least one of the one or more immunomodulatory polypeptides is any PD-L1 polypeptide (elected species) or a FasL polypeptide;
ii) a second MHC class II polypeptide, wherein the second MHC class II polypeptide is an MHC class IIa polypeptide that comprises a Cys; and
iii) any immunoglobulin (Ig) Fc polypeptide, wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the Cys in the Cys-containing linker and the Cys in the MHC class IIa polypeptide, and wherein the TMMP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 69 encompasses a TMMP of claim 68, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class IIβ polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class IIα polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the second polypeptide optionally may be joined by one or more linkers.
Claim 70 encompasses a TMMP comprising two heterodimers according to claim 69, wherein the heterodimers are covalently linked to each other.
Claim 75 encompasses any T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any autoimmune disease-associated peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) a first major histocompatibility complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is any MHC class II beta polypeptide that comprises a cysteine (Cys),
b) a second polypeptide comprising;
i) one or more immunomodulatory polypeptides, wherein at least one of the one or more immunomodulatory polypeptides is any PD-L1 (elected species) or FasL polypeptide;
ii) a second MHC class II polypeptide, wherein the second MHC class II polypeptide is any MHC class II alpha polypeptide that comprises a Cys; and
iii) any immunoglobulin (Ig) Fc polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the cysteine (Cys) in the MHC class IIβ polypeptide and the Cys in the MHC class IIα polypeptide, and wherein the TMMP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 76 encompasses a TMMP of claim 75, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class II a polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the first and second polypeptide optionally may be joined by one or more linkers.
Claim 77 encompasses a TMMP comprising two heterodimers according to claim 76, wherein the heterodimers are covalently linked to each other.
82. (New) An antigen-presenting polypeptide (APP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) any first major histocompatibility complex (MHC) class II polypeptide; and
b) a second polypeptide comprising a second MHC class II polypeptide, wherein either the first or second polypeptide is any MHC class II alpha chain polypeptide and the other is any MHC class II beta chain polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via at least one disulfide bond,
wherein one or both polypeptides of the heterodimer comprises any immunoglobulin (Ig) Fc polypeptide,
wherein the APP does not include an immunomodulatory polypeptide, and
wherein the APP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 83 encompasses a APP comprising two heterodimers according to claim 82, wherein the heterodimers are covalently linked to each other.
This encompass a huge genus of functionally and structurally distinct autoimmune disease-associated peptide epitopes, major histocompatibility complex class II beta polypeptides, cysteine (Cys) containing linker, PD-L1 polypeptides, MHC class II alpha polypeptides and IgG Fc polypeptides.
Regarding autoimmune disease-associated peptide epitope, the specification discloses:
[0224] As used herein, an “autoimmune disease-associated peptide” is a peptide that, when present in a TMMP of the present disclosure, presents an autoimmune disease-associated epitope capable of being bound by a TCR on the surface of a T cell. An autoimmune disease-associated peptide can have a length of from about 4 amino acids to about 25 amino acids, e.g., the autoimmune disease-associated peptide can have a length of from 4 amino acids (aa) to 10 aa, from 8 aa to 12 aa, from 10 aa to 15 aa, from 12 aa to 20 aa, from 15 aa to 20 aa, from 15 aa to 25 aa, or from 20 aa to 25 aa. For example, an autoimmune disease-associated peptide present in a TMMP of the present disclosure can have a length of 4 amino acids (aa), 5 aa, 6 aa, 7, aa, 8 aa, 9 aa, 10 aa, 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, 20 aa, 21 aa, 22 aa, 23 aa, 24 aa, or 25 aa. In some cases, an autoimmune disease-associated peptide present in a TMMP of the present disclosure has a length of from 5 amino acids to 10 amino acids, e.g., 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa.
[0226] An autoimmune disease-associated peptide can present an epitope associated with or present in a “self” antigen (an autoantigen). Antigens associated with autoimmune disease can be autoantigens associated with autoimmune diseases such as Addison disease (autoimmune adrenalitis, Morbus Addison), alopecia areata, Addison's anemia (Morbus Biermer), autoimmune hemolytic anemia (AIHA), autoimmune hemolytic anemia (AIHA) of the cold type (cold hemagglutinin disease, cold autoimmune hemolytic anemia (AIHA) (cold agglutinin disease), (CHAD)), autoimmune hemolytic anemia (AIHA) of the warm type (warm AIHA, warm autoimmune hemolytic anemia (AIHA)), autoimmune hemolytic Donath-Landsteiner anemia (paroxysmal cold hemoglobinuria), antiphospholipid syndrome (APS), atherosclerosis, autoimmune arthritis, arteriitis temporalis, Takayasu arteriitis (Takayasu's disease, aortic arch disease), temporal arteriitis/giant cell arteriitis, autoimmune chronic gastritis, autoimmune infertility, autoimmune inner ear disease (AIED), Basedow's disease (Morbus Basedow), Bechterew's disease (Morbus Bechterew, ankylosing spondylitis, spondylitis ankylosans), Behcet's syndrome (Morbus Behcet), bowel disease including autoimmune inflammatory bowel disease (including colitis ulcerosa (Morbus Crohn, Crohn's disease), autoimmune cardiomyopathy, idiopathic dilated cardiomyopathy (DCM), chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIDP), chronic polyarthritis, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, CREST syndrome (syndrom with Calcinosis cutis, Raynaud phenomenon, motility disorders of the esophagus, sklerodaktylia and teleangiectasia), Crohn's disease (Morbus Crohn, colitis ulcerosa), dermatitis herpetiformis during, dermatologic autoimmune diseases, dermatomyositis, essential mixed cryoglobulinemia, essential mixed cryoglobulinemia, fibromyalgia, fibromyositis, Goodpasture syndrome (anti-GBM mediated glomerulonephritis), graft versus host disease, Guillain-Barre syndrome (GBM, Polyradikuloneuritis), hematologic autoimmune diseases, Hashimoto thyroiditis, hemophilia, acquired hemophilia, autoimmune hepatitis, idiopathic pulmonary fibrosis (IPF), idiopathic thrombocytopenic purpura, Immuno-thrombocytopenic purpura (Morbus Werlhof, ITP), IgA nephropathy, autoimmune infertility, juvenile rheumatoid arthritis (Morbus Still, Still syndrome), Lambert-Eaton syndrome, systemic lupus erythematosus (SLE), lupus erythematosus (discoid form), Lyme arthritis (Lyme disease, borrelia arthritis), Meniere's disease (Morbus Meniere); mixed connective tissue disease (MCTD), multiple sclerosis (MS, encephalomyelitis disseminate, Charcot's disease), myasthenia gravis (myasthenia, MG), myositis, polymyositis, neural autoimmune diseases, Pemphigus vulgaris, bullous pemphigoid, polyglandular (autoimmune) syndrome (PGA syndrome, Schmidt's syndrome), polymyalgia rheumatica, primary agammaglobulinemia, primary autoimmune cholangitis, progressive systemic sclerosis (PSS), rheumatoid arthritis (RA, chronic polyarthritis, rheumatic disease of the joints, rheumatic fever), sarcoidosis (Morbus Boeck, Besnier-Boeck-Schaumann disease), stiff-man syndrome, Sclerodermia, Scleroderma, Sjögren's syndrome, autoimmune uveiitis, and Wegner's disease (Morbus Wegner, Wegner's granulomatosis).
[0227] In some cases, an autoimmune disease-associated peptide present in a TMMP of the present disclosure is a peptide associated with Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune-associated infertility, autoimmune thrombocytopenic purpura, bullous pemphigoid, Crohn's disease, Goodpasture's syndrome, glomerulonephritis (e.g., crescentic glomerulonephritis, proliferative glomerulonephritis), Grave's disease, Hashimoto's thyroiditis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis (MG), pemphigus (e.g., Pemphigus vulgaris), pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), vasculitis, or vitiligo.
[0228] Autoantigens include, e.g., aggrecan, alanyl-tRNA syntetase (PL-12), alpha beta crystallin, alpha fodrin (Sptan 1), alpha-actinin, α1 antichymotrypsin, α1 antitripsin, α1 microglobulin, aldolase, aminoacyl-tRNA synthetase, an amyloid, an annexin, an apolipoprotein, aquaporin, bactericidal/permeability-increasing protein (BPI), β-globin precursor BP1, β-actin, β-lactoglobulin A, β-2-glycoprotein I, β2-microglobulin, a blood group antigen, C reactive protein (CRP), calmodulin, calreticulin, cardiolipin, catalase, cathepsin B, a centromere protein, chondroitin sulfate, chromatin, collagen, a complement component, cytochrome C, cytochrome P450 2D6, cytokeratins, decorin, dermatan sulfate, DNA topoisomerase I, elastin, Epstein-Barr nuclear antigen 1 (EBNA1), elastin, entaktin, an extractable nuclear antigen, Factor I, Factor P, Factor B, Factor D, Factor H, Factor X, fibrinogen, fibronectin, formiminotransferase cyclodeaminase (LC-1), gp210 nuclear envelope protein, GP2 (major zymogen granule membrane glycoprotein), a glutenin, glycoprotein gpIIb/IIIa, glial fibrillary acidic protein (GFAP), glycated albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), haptoglobin A2, heat shock proteins, hemocyanin, heparin, a histone, histidyl-tRNA synthetase (Jo-1), a hordein, hyaluronidase, immunoglobulins, an integrin, interstitial retinol-binding protein 3, intrinsic factor, Ku (p70/p80), lactate dehydrogenase, laminin, liver cytosol antigen type 1 (LC1), liver/kidney microsomal antigen 1 (LKM1), lysozyme, melanoma differentiation-associated protein 5 (MDAS), Mi-2 (chromodomain helicase DNA binding protein 4), a mitochondrial protein, muscarinic receptors, myelin-associated glycoprotein, myosin, myelin basic protein, myelin proteolipid protein, myelin oligodendrocyte glycoprotein, myeloperoxidase (MPO), rheumatoid factor (IgM anti-IgG), neuron-specific enolase, nicotinic acetylcholine receptor A chain, nucleolin, a nucleoporin, nucleosome antigen, PM/Sc1100, PM/Scl 75, pancreatic β-cell antigen, pepsinogen, peroxiredoxin 1, phosphoglucose isomerase, phospholipids, phosphatidyl inositol, platelet derived growth factors, polymerase beta (POLB), potassium channel KIR4.1, proliferating cell nuclear antigen (PCNA), proteinase-3, proteolipid protein, proteoglycan, prothrombin, recoverin, rhodopsin, ribonuclease, a ribonucleoprotein, ribosomes, a ribosomal phosphoprotein, RNA, an Sm protein, Sp100 nuclear protein, SRP54 (signal recognition particle 54 kDa), a selectin, smooth muscle proteins, sphingomyelin, streptococcal antigens, superoxide dismutase, synovial joint proteins, T1F1 gamma collagen, threonyl-tRNA synthetase (PL-7), tissue transglutaminase, thyroid peroxidase, thyroglobulin, thyroid stimulating hormone receptor, transferrin, triosephosphate isomerase, tubulin, tumor necrosis factor-alpha, topoisomerase, U1-dnRNP 68/70 kDa, U1-snRNP A, U1-snRNP C, U-snRNP B/B′, ubiquitin, vascular endothelial growth factor, vimentin, and vitronectin.
[0230] Autoantigens associated with alopecia areata (autoimmune alopecia) include, e.g., hair follicle keratinocyte polypeptides, melanogenesis-associated autoantigens, and melanocyte polypeptides. An example of a melanocyte autoantigen is tyrosinase. Autoantigens associated with autoimmune alopecia also include trichohyalin (Leung et al. (2010) J. Proteome Res. 9:5153) and keratin 16. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of a hair follicle keratinocyte polypeptide, a melanocyte polypeptide, a melanogenesis-associated polypeptide, tyrosinase, trichohyalin, or keratin 16.
[0231] Autoantigens associated with Addison's disease include, e.g., 21-hydroxylase. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of 21-hydroxylase.
[0232] Autoantigens associated with autoimmune thyroiditis (Hashimoto's thyroiditis) include, e.g., thyroglobulin, thyroid peroxidase, thyroid Stimulating Hormone Receptor (TSH-Receptor), thyroidal iodide transporters Na.sup.+/I-symporter (NIS), pendrin, and the like. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Hashimoto's thyroiditis-associated polypeptides.
[0233] Autoantigens associated with Crohn's disease include, e.g., pancreatic secretory granule membrane glycoprotein-2 (GP2). A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of GP2.
[0234] Autoantigens associated with Goodpasture's disease include, e.g., the α3 chain of type IV collagen, e.g., amino acids 135-145 of the α3 chain of type IV collagen. Penades et al. (1995) Eur. J. Biochem. 229:754; Kalluri et al. (1994) Proc. Natl. Acad. Sci. USA 91:6201. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of the α3 chain of type IV collagen.
[0235] Autoantigens associated with Grave's disease include, for example, thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSH-R). A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned Grave's disease-associated antigens.
[0236] Autoantigens associated with mixed connective tissue disease include, e.g., U1 ribonucleoprotein (U1-RNP) polypeptide (also known as snRNP70). Sato et al. (2010) Mol. Cell. Biochem. 106:55. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an autoimmune disease-associated peptide of from 4 amino acids to about 25 amino acids in length of U1-RNP polypeptide.
[0237] Autoantigens associated with multiple sclerosis include, e.g., myelin basic protein, myelin oligodendrocyte glycoprotein, and myelin proteolipid protein. A suitable autoimmune disease-associated peptide for inclusion in a TMMP of the present disclosure can be an epitope-presenting peptide of from 4 amino acids to about 25 amino acids in length of any one of the aforementioned multiple sclerosis-associated antigens. As one non-limiting example, the autoimmune disease-associated peptide can comprise the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134). In some cases, a TMMP of the present disclosure comprises a DRB1*15:01 MHC class II β chain; and a peptide epitope of the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134).
However, neither the specification nor the art teaches autoimmune disease-associated peptide epitopes that are less than the length required to span the MHC II peptide binding groove, which generally 13-25 amino acid residues in length depending upon the sequence of the peptide and the particular MHC II peptide binding groove. The specification does not enable one of skilled in the art to make and use the TMMP (claims 68-70, 75-77) or APP (claims 82-83) for treating any and all autoimmune diseases without undue experimentation.
Wieczorek (Frontier Immunology 8: 292, 2017; PTO 892) teaches MHC class II proteins usually accommodate peptides of 13–25 residues in length in their open binding groove, with the peptide N-terminus usually extruding from the P1 pocket, see p. 2, left col. in particular. Wieczorek further teaches that [T]he most polymorphic human MHC class I and class II proteins (human leukocyte antigens, HLAs) are each expressed from three gene regions (MHC class I: HLA-A, -B, -C; MHC class II: HLA-DR, -DP, -DQ), which are all highly polymorphic. This allelic variation mainly affects the nature and composition of the peptide-binding groove and thus modulates the peptide repertoire that is presented on the surface by MHC class I or MHC class II proteins for CD8+ or CD4+ T cell recognition, respectively. A good match of the peptide and the MHC binding groove is an important, but certainly not the sole determinant of its presentation. In human alone, with over 10,754 different alleles for human MHC class II alpha and beta chains, there is significant variation in MHC-II alleles and the peptides they can bind.
Nikolich-Zugich et al (Nature Reviews/Immunology 4: 123-132, 2004; PTO 892) teaches an estimate of how many different peptides with which T cell repertoire could be confronted: “Using the maximal number of combinations for an 11-mer peptide bound to a MHC class II molecule, and minimal restriction on the type of amino acids that are allowed at different positions, Mason calculated the number of antigenic peptides that can potentially be presented by one MHC class II molecule to be — 6 x 1012...and “it remains unclear whether and how structural TCR diversity influences functional diversity”... (see entire reference, especially abstract, introduction, pages 124-125, paragraph spanning columns 1-2 on page 126, paragraph spanning columns 1-2 on page 127, column 1 on page 128 at lines 9-15, and last sentence at column 1 on page 128).
Even assuming the autoimmune-associated peptide epitope is associated with multiple sclerosis (elected species), the specification discloses just one peptide consisting of the amino acid sequence ENPVVHFFKNIVTPR (SEQ ID NO:134), see para. [0237].
However, the disclosure of one species is not representative of genus of peptides and MHC class II alpha and beta chains that form the peptide-binding groove encoded by the highly polymorphic MHC allelic genes for CD4+ T cell recognition and antigen presentation for treating all autoimmune diseases in a human population.
Regarding MHC class II β chain, the specification discloses:
[0151] MHC class II beta chains comprise a β1 domain and a β2 domain. In some cases, the β1 domain and the β2 domain present in an antigen-presenting cell are from the same MHC class II β chain polypeptide. In some cases, the β1 domain and the β2 domain present in an antigen-presenting cell are from two different MHC class II β chain polypeptides. In some cases, MHC class II β chain polypeptide suitable for inclusion in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type MHC class II β chain polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys.
[0152] MHC class II beta chains suitable for inclusion in a TMMP of the present disclosure lack a signal peptide. An MHC class II beta chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 210 amino acids; for example, an MHC class II beta chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, from about 180 amino acids to about 200 amino acids, or from about 200 amino acids to about 210 amino acids. An MHC class II β1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC class II β1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids. An MHC class II β2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 105 amino acids; for example, an MHC class II β2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, from about 90 amino acids to about 95 amino acids, from about 95 amino acids to about 100 amino acids, or from about 100 amino acids to about 105 amino acids.
[0153] In some cases, the MHC class II β chain polypeptide is a variant DRB MHC class II polypeptide that comprises a non-naturally occurring Cys residue. For example, in some cases, the MHC class II β chain polypeptide is a variant DRB1 MHC class II polypeptide that comprises an amino acid substitution selected from the group consisting of PSC, F7C, Q10C, N19C, G20C, H33C, G151C, D152C, and W153C. In some cases, the MHC class II β chain polypeptide is a variant DRB1 polypeptide comprising an amino acid sequence having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the following DRB1 amino acid sequence:
[0160] A suitable DRB1 polypeptide can comprise the following amino acid sequence: GDTRPRFLEQVKHECHFFNGTERVRFLDRYFYHQEEYVRFDSDVGEYRAVTELGRPDAEYWNSQKDLLEQKRAAVDTYCRHNYGVGESFTVQRRVYPEVTVYPAKTQPLQHHNLLVCSVNGFYPASIEVRWFRNGQEEKTGVVSTGLIQNCDWTFQTLVMLETVPRSGEVYTCQVEHPSLTSPLTVEWR ARSESAQSKM (SEQ ID NO:36), where G151 is substituted with a Cys (shown in bold text), elected species.
Regarding MHC class II α chain, the specification discloses:
[0113] MHC class II alpha chains suitable for inclusion in a TMMP of the present disclosure lack a signal peptide. An MHC class II alpha chain suitable for inclusion in a multimeric polypeptide of the present disclosure can have a length of from about 60 amino acids to about 190 amino acids; for example, an MHC class II alpha chain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 60 amino acids to about 80 amino acids, from about 80 amino acids to about 100 amino acids, from about 100 amino acids to about 120 amino acids, from about 120 amino acids to about 140 amino acids, from about 140 amino acids to about 160 amino acids, from about 160 amino acids to about 180 amino acids, or from about 180 amino acids to about 200 amino acids. An MHC class II α1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC class II α1 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids. An MHC class II α2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 95 amino acids; for example, an MHC class II α2 domain suitable for inclusion in a TMMP of the present disclosure can have a length of from about 30 amino acids to about 40 amino acids, from about 40 amino acids to about 50 amino acids, from about 50 amino acids to about 60 amino acids, from about 60 amino acids to about 70 amino acids, from about 70 amino acids to about 80 amino acids, from about 80 amino acids to about 90 amino acids, or from about 90 amino acids to about 95 amino acids.
[0114] In some cases, an MHC class II α chain polypeptide present in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type MHC class II α chain polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys. Such an amino acid substitution can occur between amino acid 55 and 110 of the MHC class II α chain polypeptide. For example, an amino acid substitution that replaces an amino acid other than a Cys with a Cys can be present between amino acids 55 and 60, between amino acids 60 and 65, between amino acids 65 and 70, between amino acids 70 and 75, between amino acids 75 and 80, between amino acids 80 and 85, between amino acids 85 and 90, between amino acids 90 and 95, between amino acids 95 and 100, between amino acids 100 and 105, or between amino acids 105 and 110.
[0117] A “DRA polypeptide” includes allelic variants, e.g., naturally occurring allelic variants. Thus, in some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLEIMTK RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:6, amino acids 26-203 of DRA*01:02:01, see FIG. 6), or an allelic variant thereof. In some cases, the allelic variant is the DRA*01:01:01:01 allelic variant that differs from DRA*01:02:01 by having a valine in place of the leucine at position 242 of the sequence in FIG. 6. In some cases, a DRA polypeptide suitable for inclusion in a TMMP of the present disclosure comprises an amino acid substitution, relative to a wild-type DRA polypeptide, where the amino acid substitution replaces an amino acid (other than a Cys) with a Cys.
[0118] In some cases, a TMMP of the present disclosure comprises a variant DRA polypeptide that comprises a non-naturally occurring Cys residue. For example, in some cases, a TMMP of the present disclosure comprises a variant DRA polypeptide that comprises an amino acid substitution selected from E3C, E4C, F12C, G28C, D29C, I72C, K75C, T80C, P81C, I82C, T93C, N94C, and S95C.
[0119] In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLECMTK RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:7), where amino acid 172 is substituted with a Cys (shown in bold text). In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIAV DKANLEIMTC RSNYTPITNV PPEVTVLTNSPVELREPNVL ICFIDKFTPP VVNVTWLRNG KPVTTGVSET VFLPREDHLF RKFHYLPFLPSTEDVYDCRV EHWGLDEPLL KHW (SEQ ID NO:8), where amino acid K75 is substituted with a Cys (shown in bold text).
[0120] In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:9). In some cases, an amino acid between amino acids 55 and 110 is substituted with a Cys. In some cases, an amino acid between amino acids 70 and 85 is substituted with a Cys.
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGCEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:10), where D29 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLECMTKRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:11), where 172 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTCRSNYTPITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:12), where K75 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTCITNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:13), where P81 is substituted with a Cys (shown in bold text).
In some cases, a suitable DRA polypeptide comprises the following amino acid sequence: IKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVDMAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPCTNVPPEVTVLTNSPVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLPSTEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPET (SEQ ID NO:14), where 182 is substituted with a Cys (shown in bold text).
However, the specification does not teach where and what amino acids within the full-length sequence of which MHC class II β chain and which MHC class II α chain to be substituted, deleted, added or a combination thereof such that the modified variant having at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%, amino acid sequence identity to the unmodified corresponding MHC class II β chain and MHC class II α chain sequences still maintains 3D structure and forming the peptide binding groove for the claimed TMMP or APP. There are no working examples.
Regarding one or more immunomodulatory polypeptide, the specification discloses:
[0253] As noted above, immunomodulatory polypeptides (“MODs”) that are suitable for inclusion in a TMPP of the present disclosure include, but are not limited to, IL-2, TGFβ, CD7, B7-1 (CD80), B7-2 (CD86), PD-L1, PD-L2,4-1BBL, OX40L, Fas ligand (FasL), inducible costimulatory ligand (ICOS-L), intercellular adhesion molecule (ICAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor, 3/TR6, ILT3, ILT4, and HVEM. In some cases, the immunomodulatory polypeptide is selected from an IL-2 polypeptide, a 4-1BBL polypeptide, an ICOS-L polypeptide, an OX-40L polypeptide, a CD80 polypeptide, a CD86 polypeptide, a PD-L1 polypeptide, a FasL polypeptide, a TGFβ polypeptide, and a PD-L2 polypeptide.
[0254] As also noted above, the immunomodulatory polypeptide can comprise a wild-type amino acid sequence, or can comprise one or more amino acid substitutions relative to a wild-type amino acid sequence. The immunomodulatory polypeptide can comprise only the extracellular portion of a full-length immunomodulatory polypeptide. Thus, for example, the immunomodulatory polypeptide can in some cases exclude one or more of a signal peptide, a transmembrane domain, and an intracellular domain normally found in a naturally-occurring immunomodulatory polypeptide.
[0255] In some cases, an immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure comprises all or a portion of (e.g., an extracellular portion of) the amino acid sequence of a naturally-occurring immunomodulatory polypeptide. In other instances, an immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure is a variant immunomodulatory polypeptide that comprises at least one amino acid substitution compared to the amino acid sequence of a naturally-occurring immunomodulatory polypeptide. In some instances, a variant immunomodulatory polypeptide exhibits a binding affinity for a co-immunomodulatory polypeptide that is lower than the affinity of a corresponding naturally-occurring immunomodulatory polypeptide (e.g., an immunomodulatory polypeptide not comprising the amino acid substitution(s) present in the variant) for the co-immunomodulatory polypeptide.
[0256] Suitable immunomodulatory domains that exhibit reduced affinity for a co-immunomodulatory domain can have from 1 amino acid (aa) to 20 aa differences from a wild-type immunomodulatory domain For example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure differs in amino acid sequence by 1 aa, 2 aa, 3 aa, 4 aa, 5 aa, 6 aa, 7 aa, 8 aa, 9 aa, or 10 aa, from a corresponding wild-type immunomodulatory polypeptide. As another example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure differs in amino acid sequence by 11 aa, 12 aa, 13 aa, 14 aa, 15 aa, 16 aa, 17 aa, 18 aa, 19 aa, or 20 aa, from a corresponding wild-type immunomodulatory polypeptide. As an example, in some cases, a variant immunomodulatory polypeptide present in a TMPP of the present disclosure includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, compared to a corresponding reference (e.g., wild-type) immunomodulatory polypeptide.
[0257] As discussed above, a variant immunomodulatory polypeptide suitable for inclusion in a TMPP of the present disclosure exhibits reduced affinity for a cognate co-immunomodulatory polypeptide, compared to the affinity of a corresponding wild-type immunomodulatory polypeptide for the cognate co-immunomodulatory polypeptide.
Further, the term “modulatory” encompasses stimulating as well as inhibiting, which are mutual exclusive.
The specification exemplifies PD-L1 comprising SEQ ID NO: 97, 98 and 99.
However, the specification does not teach where and what amino acid with the full-length sequence of SEQ ID NO: 97 to be substituted, deleted, added or a combination thereof such that the modified variant having 20 aa difference compared to the wild type and correlate which inhibiting or stimulating immune response. There are no working examples.
Regarding immunoglobulin Fc polypeptide, the specification discloses:
[0210] In some cases, the first or the second polypeptide chain of a TMMP of the present disclosure comprises an Fc polypeptide. The Fc polypeptide of a TMMP of the present disclosure can be a human IgG1 Fc, a human IgG2 Fc, a human IgG3 Fc, a human IgG4 Fc, etc. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to an amino acid sequence of an Fc region depicted in FIG. 12A-12G. In some cases, the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG1 Fc polypeptide depicted in FIG. 12A. In some cases, the Fc region comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%, amino acid sequence identity to the human IgG1 Fc polypeptide depicted in FIG. 12A, and comprises a substitution of N77; e.g., the Fc polypeptide comprises an N77A substitution.
[0211] In some cases, the Ig Fc polypeptide induces cell lysis through activation of complement-dependent cytotoxicity (CDC). In some cases, the Ig Fc polypeptide is a variant that substantially does not induce cell lysis through activation of CDC, e.g., an IgG1 Fc polypeptide comprising L234A and L235A substitutions (L14A and L15A substitution of the amino acid sequence depicted in FIG. 21A). Typically, the TMMPs of this disclosure that employ an Ig Fc polypeptide are meant to engage a target T cell through the MHC-epitope complex and then modulate the activity of a T cell through the immunomodulatory polypeptides, and thus will employ a variant that substantially does not induce cell lysis through activation of CDC.
[0212] In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG2 Fc polypeptide depicted in FIG. 21A; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 99-325 of the human IgG2 Fc polypeptide depicted in FIG. 21A. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG3 Fc polypeptide depicted in FIG. 21A; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 19-246 of the human IgG3 Fc polypeptide depicted in FIG. 21A. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgM Fc polypeptide depicted in FIG. 21B; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-276 to the human IgM Fc polypeptide depicted in FIG. 21B. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgA Fc polypeptide depicted in FIG. 21C; e.g., the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 1-234 to the human IgA Fc polypeptide depicted in FIG. 21C.
[0213] In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to the human IgG4 Fc polypeptide depicted in FIG. 21C. In some cases, the Fc polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or 100%, amino acid sequence identity to amino acids 100 to 327 of the human IgG4 Fc polypeptide depicted in FIG. 21C.
The specification exemplifies just human IgG1 Fc polypeptide, optionally comprises L234A and L235A substitution (SEQ ID NO: 59), human IgG4 Fc comprising SEQ ID NO: 58.
Other than the particular L234A and L235A substitution in human IgG1 Fc numbering according to EU as in Kabat, the specification does not teach where and what amino acid sequence within the human IgG1 Fc to be substituted, deleted, added or a combination thereof such that the modified Fc having 70%, 75%, 80%, 85%, 90% or 95% identity to unmodified human IgG1 Fc still maintains FcRn receptor binding, Fcγ receptors binding and effector functions.
For example, Moore et al (mAbs 2(2): 181-189, 2010; PTO 892) teaches that the triple mutation Ser267Glu, His268Phe, and serine 324 threonine (Ser324Thr) in the Fc has been found to largely improve CDC at the expense of reduced ADCC and ADCP via increasing the affinity to inhibitory FcγRIIb, see entire document, Table 3, p. 186, right col.
As another example, US 6,737,056 to Presta (PTO 892) provides an extensive list of point mutations within an antibody Fc domain and in Tables 6-9. Presta shows the effect of those mutations, alone or in various combinations, on Fc receptor binding. But, that mutational analysis showed each position can have a different effect and that different amino acid substitutions at any given site can have different effects. Thus, a determination of which mutations will result in a particular modified function is not predictable a prior.
There are no in vivo working examples of treating any autoimmune disease in the specification as filed.
Given the size of the genus of autoimmune disease-associated peptide epitopes, the broad definition of the first and second MHC II beta and alpha polypeptides (natural allelic variants, artificial variants via 60% identity and/or substitution, addition, deletion), immunomodulatory polypeptide such as PD-L1 having one or more amino acid substitutions (up to 20 residues) relative to a wild-type amino acid sequence, immunoglobulin (Ig) Fc variant having 70% identify via substitution, deletion, addition, or a combination thereof and the position/location of the residues that involved in at least one disulfide bond, including cysteine containing potential linkers, it is unpredictable which undisclosed species of such T-cell modulatory multimeric polypeptide (TMMP) or antigen-presenting polypeptide (APP) is effective for treating all autoimmune disease in an individual such as human at the time of filing.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
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.
Claims 68-70, 75-77, 82 and 83 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019051094, published March 14, 2019 PTO 892) in view of US Patent No. 1,003,065 (issued July 24, 2018; PTO 892).
Claim 68 encompasses any T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising: i) any autoimmune disease-associated peptide epitope that displays an autoimmune disease-associated epitope useful for treating all autoimmune disease other than Type 1 Diabetes (T1D); ii) any first major histocompatibility complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is any MHC class II beta polypeptide; and iii) a cysteine (Cys)-containing linker that links the peptide epitope to the MHC class IIβ polypeptide, and
b) a second polypeptide comprising:
i) one or more immunomodulatory polypeptides, wherein at least one of the one or more immunomodulatory polypeptides is any PD-L1 polypeptide (elected species) or a FasL polypeptide;
ii) a second MHC class II polypeptide, wherein the second MHC class II polypeptide is an MHC class IIa polypeptide that comprises a Cys; and
iii) any immunoglobulin (Ig) Fc polypeptide, wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the Cys in the Cys-containing linker and the Cys in the MHC class IIa polypeptide, and wherein the TMMP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 69 encompasses a TMMP of claim 68, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope;
the Cys-containing linker; and
the MHC class IIβ polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class IIα polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the second polypeptide optionally may be joined by one or more linkers.
Claim 70 encompasses a TMMP comprising two heterodimers according to claim 69, wherein the heterodimers are covalently linked to each other.
Claim 75 encompasses any T-cell modulatory multimeric polypeptide (TMMP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any autoimmune disease-associated peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) a first major histocompatibility complex (MHC) class II polypeptide, wherein the first MHC class II polypeptide is any MHC class II beta polypeptide that comprises a cysteine (Cys),
b) a second polypeptide comprising;
i) one or more immunomodulatory polypeptides, wherein at least one of the one or more immunomodulatory polypeptides is any PD-L1 (elected species) or FasL polypeptide;
ii) a second MHC class II polypeptide, wherein the second MHC class II polypeptide is any MHC class II alpha polypeptide that comprises a Cys; and
iii) any immunoglobulin (Ig) Fc polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the cysteine (Cys) in the MHC class IIβ polypeptide and the Cys in the MHC class IIα polypeptide, and wherein the TMMP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 76 encompasses a TMMP of claim 75, wherein
a1) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b1) the second polypeptide comprises, in order from N-terminus to C-terminus:
the one or more immunomodulatory polypeptides;
the MHC class IIa polypeptide; and
the Ig Fc polypeptide, or
a2) the first polypeptide comprises, in order from N-terminus to C-terminus:
the peptide epitope; and
the MHC class II
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polypeptide; and
b2) the second polypeptide comprises, in order from N-terminus to C-terminus:
the MHC class II a polypeptide; and
the Ig Fc polypeptide; and
the one or more immunomodulatory polypeptides, and wherein, in either of the above TMMPs, the components of the first and second polypeptide optionally may be joined by one or more linkers.
Claim 77 encompasses a TMMP comprising two heterodimers according to claim 76, wherein the heterodimers are covalently linked to each other.
82. (New) An antigen-presenting polypeptide (APP) comprising at least one heterodimer, wherein each heterodimer comprises:
a) a first polypeptide comprising:
i) any peptide epitope that displays any autoimmune disease-associated epitope useful for treating any and all autoimmune disease other than Type 1 Diabetes (T1D); and
ii) any first major histocompatibility complex (MHC) class II polypeptide; and
b) a second polypeptide comprising a second MHC class II polypeptide, wherein either the first or second polypeptide is any MHC class II alpha chain polypeptide and the other is any MHC class II beta chain polypeptide,
wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via at least one disulfide bond,
wherein one or both polypeptides of the heterodimer comprises any immunoglobulin (Ig) Fc polypeptide,
wherein the APP does not include an immunomodulatory polypeptide, and
wherein the APP presents an autoimmune disease-associated epitope capable of being bound by a T-cell receptor on a CD4+ T cell.
Claim 83 encompasses a APP comprising two heterodimers according to claim 82, wherein the heterodimers are covalently linked to each other.
Regarding claims 68 and 75, WO2019051094 A1 teaches a multimeric T-cell modulatory polypeptide (TMAPP) comprising first polypeptide comprising, in order from N- to C-terminus, an epitope associated with autoimmune antigen, e.g., myeline basic protein (para. [0167]) that is recognized by TCR, a MHC class II beta chain polypeptide comprising beta 1/beta 2 (extracellular region), and a second polypeptide comprising, in order from N- to C-terminus, one or more immunomodulatory polypeptide (MOD), e.g., PD-L1 (para. [0174], p. 42, [00210], p. 73, [00241], p. 80), a MHC class II alpha chain polypeptide comprising alpha 1/alpha 2 and an Ig Fc (e.g., [0071], [0074]), Fig. 22C), and the two polypeptide chains are covalently linked to one another, for example, by a disulfide bond, [0073], [0074].
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WO2019051094 A1 teaches that a linker polypeptide present in an APP (antigen presenting polypeptide) includes a cysteine residue that can form a disulfide bond with a cysteine residue present in a second polypeptide of the APP ([00154], p. 35, p. 43, p. 47).
WO2019051094 A1 teaches that suitable epitopes from 4 to about 25 amino acids in length of any antigen associated with any autoimmune disease, e.g., Grave’s disease include, for example, thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSH-R) for treating Grave's disease (see para. [00163], aka other than Type 1 Diabetes (T1D)), or antigens associated with multiple sclerosis include, e.g., myelin basic protein, see para. [00167]. The two polypeptide chains are covalently linked to one another, e.g., via a disulfide bond, see para. [0073].
Regarding claims 69 a2/b2, WO2019051094 A1 teaches that the order of the components in the polypeptides may alternatively be: in the first polypeptide, the epitope-MHC class II alpha 1 domain/alpha 2 domain; and the second polypeptide comprises a MHC class II beta 1 domain/beta 2 domain and an Ig Fc polypeptide (with an immunomodulatory domain at the N-terminus of the second polypeptide chain).
Regarding claim 82, WO2019051094 A1 further teaches multimeric antigen-presenting polypeptides (APPs), see entire document, para. [0070], the APP comprises at least one heterodimer each comprises a) a first polypeptide comprising an epitope and ii) a first major histocompatibility complex (MHC) class II beta chain (para. [00107] to [00108]) and an immunomodulatory polypeptide (MOM), and a second polypeptide comprising a second MHC class II alpha chain (para. [0065], [0081] to [0082]) and an Fc (para. [0026], [0074]), without immunomodulatory polypeptide (MOD) and wherein the first and second polypeptide dimerized to form a heterodimer, see para. [0074] to [0075], FIG. 22A below. The epitope is recognized by a TCR, see para. [0075]. The term “comprising” is open ended. It expands the first polypeptide to include MOD at the C-terminus, see FIG. 22A.
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The linker, e.g., GCGASGGGGSGGGGS (SEQ ID NO: 77) present in the first polypeptides of the APP includes a cysteine residue that can form a disulfide bond with a cysteine present in a second polypeptide of the APP, (see para. [00154]). The two polypeptide chains are covalently linked to one another, e.g., via a disulfide bond, see para. [0073]. Suitable epitopes from 4 to about 25 amino acids in length of any antigen associated with any autoimmune disease, e.g., Grave’s disease include, for example, thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSH-R) for treating Grave's disease (see para. [00163], aka other than Type 1 Diabetes (T1D)), or antigens associated with multiple sclerosis include, e.g., myelin basic protein, see para. [00167].
WO2019051094 A1 does not teach wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the Cys in the Cys-containing linker and the Cys in the MHC class II alpha chain polypeptide as per claim 68, or wherein the first and the second polypeptide of the heterodimer are covalently linked to one another via a disulfide bond between the Cys in the MHC class II beta polypeptide and the cysteine in the MHC class II alpha polypeptide as per claim 75.
However, the ‘065 patent teaches MHC class II complexes can be increased by covalent modification of the protein, e.g., introduce one or more cysteine residues by amino acid exchange at the COOH-terminal of both alpha-chain and beta-chain to create disulfide bridges between the two chains upon assembly of the MHC complex, see entire document, col. 40, line 61-65, in particular. The ‘065 patent also teaches the MHC molecule construct can comprise one or more biologically active molecule, e.g., PD-L1, see col. 32, line 11, in particular. The ‘065 patent teaches that linker can be comprised a disulfide bridge connecting amino acids from both polypeptides, see col. 25, lines 25-26. MHC complex, through association of a linker molecule comprising the reactive group, e.g., SH, see col. 24, lines 27-28.
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have introduced one or more cysteine residues in one or both MHC class II beta chain and MHC class II alpha chain to covalently linked one another, e.g., via a disulfide bond as taught by the ‘065 patent in the multimeric T-cell modulatory polypeptide (TMAPP) taught by the primary reference WO2019051094 A1.
One of ordinary skill in the art would have been motivated to do this in order to create disulfide bridges between the two polypeptide chains upon assembly of the MHC class II complex to arrive at the claimed heterodimer covalently linked to one another via a disulfide bond between the Cys in the MHC class II beta chain and the Cys in the MHC class II alpha chain as per claims 75-77, 82-83.
Claims 68 and 70 are included in this rejection because one of ordinary skill in the art was aware that the SH group of the cysteine containing linker in the first polypeptide can form disulfide bond with the SH group in the cysteine in the second polypeptide comprising MHC class II alpha chain of the WO2019051094 A1 to arrive at the claimed heterodimer covalently linked to one another via a disulfide bond between the Cys in the Cys-containing linker and the Cys in the MHC class II alpha chain.
“The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 {2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
SEQ ID NO: 36, 12 are free of prior art.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641