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 1-18, 21-36 and 38-52 are pending.
Claims 1-17, 21-36 and 48-51 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 18, 38-47 and 52, drawn to a method for preventing and/or treating that read on (A) CD3 as the second binding site, (B) heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14; and (C) autoimmune disease as the species of disease, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Specification
The substitute specification filed on January 14, 2026 has been entered.
Objection and Rejection Withdrawn
The objection to the specification is withdrawn in view of the amendment filed January 14, 2026.
The objection to the title is hereby withdrawn in view of the amendment to the title filed December 17, 2025.
The rejection of claims 37 and 38 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment filed December 17, 2025.
The rejection of claims 18 and 44 under 35 U.S.C. 102 (a)(2) as being anticipated by Walker (of record, US20200190189 A1, filed May 8, 2018, which is now US Patent No. 11,542,330, claimed earliest priority to 62/503,315, filed May 8, 2017; PTO 892) is withdrawn in view of the claim amendment filed December 17, 2025.
The rejection of claims 18 and 44 under 35 U.S.C. 102 (a)(1)as being anticipated by Lowman (US20150079088, published March 19, 2015; PTO 892) is withdrawn in view of the claim amendment.
The rejection of claims 18, 40, 44 and 45-47 under 35 U.S.C. 103 as being unpatentable over Walker (of record, US20200190189 A1, filed May 8, 2018, claimed earliest priority to 62/503,315, filed May 8, 2017; PTO 892) or Lowman (US20150079088, published March 19, 2015; PTO 892) each in view of Sentman (US20180085400, published March 29, 2018; PTO 892) is withdrawn in view of the claim amendment. The addition of Sentman does not cure the deficiency of Walker or Lowman.
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 18 and 38-40, 44-47 and 52 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 18 is drawn to a method for treating any autoimmune disease (elected species), an allergic disease, or a graft-versus-host disease in any subject in need thereof, the method comprising: administering an effective amount of any bispecific molecule or a pharmaceutical composition comprising the bispecific molecule, to the subject, wherein the bispecific molecule comprises a first binding site that specifically binds to any lymphocyte activation gene 3 (LAG3) and a second binding site that specifically binds to an extracellular region of a cluster of differentiation 3 (CD3) or an extracellular region of a cluster of differentiation 8 (CD8).
Claim 38 is drawn to the method according to claim 18, wherein the first binding site binds to one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse of LAG3 having the amino acid sequence of SEQ ID NO: 2.
Claim 39 is drawn to the method according to claim 18, wherein the first binding site binds to a region of the LAG3, said region comprising one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61, and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2.
Claim 40 is drawn to the method according to claim 18, wherein the first binding site comprises a heavy chain variable region and a light chain variable region of any anti-LAG3 antibody.
Claim 41 is drawn to the method according to claim 40, wherein the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14.
Claim 42 is drawn to the method according to claim 40, wherein the heavy chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 8.
Claim 43 is drawn to the method according to claim 18, wherein the first binding site competes, for binding to LAG3, with an anti-LAG3 antibody that comprises:
a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or
(ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
Claim 44 is drawn to the method according to claim 18, wherein the second binding site specifically binds to any CD3.
Claim 45 is drawn to the method according to claim 44, wherein the second binding site comprises a heavy chain variable region and a light chain variable region of any anti-CD3 antibody.
Claim 46 is drawn to the method according to claim 45, wherein the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22.
Claim 47 is drawn to the method according to claim 45, wherein the heavy chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 15; and wherein the light chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 16.
Claim 52 is drawn to the method according to claim 18, wherein the bispecific molecule suppresses activation of a T cell co-expressing LAG3 and CD3 or CD8.
Regarding autoimmune diseases, the specification discloses:
[0251] Examples of the disease characterized by enhanced immunity include autoimmune diseases, allergic diseases and graft-versus-host diseases. Examples of the autoimmune disease include Behcet's disease, systemic lupus erythematosus, multiple sclerosis (systemic sclerosis, progressive systemic sclerosis), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa, microscopic polyangiitis), aortitis syndrome (Takayasu's arteritis), malignant rheumatoid arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, Wegener's granulomatosis, mixed connective tissue disease, Sjogren's syndrome, Adult-onset Still's disease, allergic granulomatous angiitis, hypersensitivity vasculitis, Cogan's syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica, fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related diseases (e.g., primary sclerosing cholangitis, autoimmune pancreatitis), Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, aortitis syndrome, Goodpasture syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow's disease (hyperthyroidism), Hashimoto disease, autoimmune adrenal insufficiency, primary hypothyroidism, idiopathic Addison disease (chronic hypoadreno corticism), type I diabetes, slowly progressive type I diabetes (latent autoimmune diabetes in adults), chronic discoid lupus erythematosus, circumscribed scleroderma, psoriasis, psoriatic arthritis, pemphigus, pemphigoid, gestational herpes, linear IgA bullous dermatosis, acquired epidermolysis bullosa, alopecia areata, white spots, vitiligo vulgaris, atopic dermatitis, neuromyelitis optica, Chronic inflammatory demyelinating polyneuropathy, sarcoidosis, bullous pemphigoid, giant cell arteritis, amyotrophic lateral sclerosis, eosinophilic granulomatosis with polyangiitis, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, habitual abortion, inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), and celiac disease. In a certain embodiment, the autoimmune disease is type I diabetes, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In a certain embodiment, the autoimmune disease is multiple sclerosis. Examples of the allergic disease include asthma, atopic dermatitis, rhinitis, conjunctivitis, and hay fever.
The specification exemplifies:
Example 1
Production of Bispecific Molecules 2C11xTKB58 and TKB58x2C11 Binding to LAG3 and CD3ϵ
[0445] A nucleic acid encoding the heavy and light chain variable regions of an anti-mouse LAG3 antibody (TKB58) and an anti-mouse CD3ε antibody (2C11) was synthesized, amplified by PCR, and was cloned into an expression plasmid vector produced by modifying pEBMulti-Neo (Wako) or pSecTag2/Hygro (Thermo Fisher Scientific), whereby expression plasmids of bispecific molecules 2C11xTKB58 (SEQ ID NO: 31) and TKB58x2C11 (SEQ ID NO: 32) recognizing mouse LAG3 and mouse CDR were produced. The expression plasmid was transfected into PlatE cells using Avalanche-Omni Transfection Reagent (EZ Biosystems), and the culture supernatant was collected after 48 hours. BW5147, DO11.10, and DO11.10-mLAG3 cells were stained using the culture supernatant.
[0446] The results are shown in FIG. 1. Binding to DO11.10 cells expressing mouse CD3ϵ but not mouse LAG3 was confirmed, from which it was confirmed that the bispecific molecule had a binding ability to mouse CD3ϵ. In addition, as compared with DO11.10 cells, the bispecific molecule strongly bound to DO11.10-mLAG3 cells in which mouse LAG3 was forcibly expressed, from which it was also confirmed that the bispecific molecule had a binding ability to mouse LAG3. On the other hand, no binding was observed to BW5147 cells that do not express mouse CD3ϵ and mouse LAG3, from which it was confirmed that the binding is specific to both molecules. A stronger binding was observed with 2C11xTKB58, as compared to TKB58x2C11.
Example 2
Bispecific Molecules 2C11xTKB58 and TKB58x2C11 Suppress Antigen-Specific Activation of T Cells in LAG3 Dependent Manner
Example 2-1
Experiments with Antigen-Presenting Cells Strongly Inducing Suppression by LAG3
[0447] DO11.10 cells are known to recognize an OVA-derived peptide (pOVA323-339, ISQAVHAAHAEINEAGR) presented on the mouse MHC class II molecule I-A.sup.d and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing I-A.sup.d were pulsed with pOVA323-339 to stimulate DO11.10 cells (mock), production of IL-2 was observed, but neither TKB58x2C11 nor 2C11xTKB58 affected IL-2 production (FIG. 2). This confirmed that these bispecific molecules did not affect antigen-specific activation of T cells not expressing LAG3.
[0448] In addition, DO11.10-mLAG3 cells (mLAG3 WT) obtained by causing mouse LAG3 to be forcibly expressed in DO11.10 cells were similarly antigen-stimulated (FIG. 2). The production of IL-2 was strongly suppressed in a LAG3 dependent manner. The addition of anti-mouse LAG3 antibody TKB58 inhibited the function of mouse LAG3 and restored the production of IL-2. On the other hand, the addition of TKB58x2C11 or 2C11xTKB58 did not inhibit the suppression of IL-2 production by LAG3.
Example 2-2
Experiments with Antigen-Presenting Cells that do not Induce Suppression by LAG3 Too Strongly
[0449] LAG3 selectively binds to a stable peptide MHCII complex and does not bind to an unstable peptide MHCII complex. When pOVA323-339 is pulsed into BW5147-mCD86/I-A.sup.d cells obtained by forcibly expressing I-A.sup.d in BW5147-mCD86 cells, pOVA323-339 does not bind to mouse LAG3, because pOVA323-339, with an unstable structure, is presented to I-A.sup.d, resulting in that inhibition via mouse LAG3 hardly functions.
[0450] In this stimulation condition, when TKB58x2C 11 or 2C11xTKB58 was added, the production of IL-2 was strongly suppressed only when DO11.10 cells expressing LAG3 (mLAG3WT) were used (FIG. 3). In the cell binding experiment (FIG. 1), similarly to the result that 2C11xTKB58 bound to the target cells more strongly than TKB58x2C11, 2C11xTKB58 showed a stronger inhibitory effect than TKB58x2C11.
Example 2-3
Experiments with MHC Class I-Restricted Cells in Which LAG3 Hardly Exhibits an Inhibitory Effect
[0451] B3Z cells are known to recognize an OVA-derived peptide (pOVA257-264, SIINFEKL) presented on the mouse MHC class I molecule H-2K.sup.b and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing H-2Kb were pulsed with the OVA peptide to stimulate B3Z cells (mock), production of IL-2 was observed, but the expression of mouse LAG3 (mLAG3WT) did not inhibit the production of IL-2 (FIG. 4). This is because LAG3 cannot exert the inhibitory function in the MHCI class I-restricted B3Z cells. The addition of TKB58x2C11 or 2C11xTKB58 strongly suppressed the production of IL-2 only when B3Z cells expressed mouse LAG3. These results indicate that TKB58x2C 11 and 2C11xTKB58 suppress antigen-specific activation of LAG3 expressing cells, even in MHC class I-restricted CD8 positive cells.
Example 2-4
Experiments with LAG3 Mutant Without Ligand Binding Ability
[0452] An amino acid mutant of LAG3, LAG3-P111A, lacks the ability to bind to pMHCII, and thus does not exert a T cell suppressive function even when it is antigen-stimulated. Using this mutant, the same experiment as in Example 2-1 was carried out. The results are shown in FIG. 5. When TKB58x2C11 or 2C11xTKB58 was added under this stimulation condition, the production of IL-2 was strongly suppressed in a LAG3-P111A-dependent manner. Therefore, it was revealed that TKB58x2C11 and 2C11xTKB58 suppress antigen-specific activation of LAG3-expressing cells even under conditions where LAG3 does not bind to pMHCII as a ligand. These results indicate that TKB58x2C11 and 2C11xTKB58 activate LAG3 and suppress TCR even in situations where LAG3 cannot bind to MHCII.
Example 3
Evaluation of Bispecific Molecule Using Experimental Autoimmune Encephalomyelitis (EAE)
[0453] In vivo effects of 2C11xTKB58 were evaluated in an EAE model using C57BL/6 mice. Killed tuberculosis bacteria H37Ra (BD Biosciences, model number 231141) and incomplete Freund's adjuvant (BD Biosciences, model number 263910) were mixed so that complete Freund's adjuvant (CFA) containing 4 mg/mL of killed tuberculosis bacteria H37Ra was prepared. One mg/mL of MOG peptide (ANASPEC, model number AS-60130) and an equal amount of CFA were mixed so that an emulsion was prepared, and was used as an inducer of an EAE model. 200 μl of the inducer was subcutaneously administered to a base of the tail of a C57BL/6 mouse, and 200 μl of 1 μg/mL 100 day tussive toxin (SIGMA-ALDRICH, model number P7208) was intravenously administered on the day of immunization and day 2 of the immunization. C57BL/6 mice were then intraperitoneally administered with 2C11xTKB58 once daily at a dosage of 0.3 mg/kg each from day 6 to day 10 of immunization. After the day of immunization, the neurological symptoms were evaluated according to the method of Onuki et al. (Onuki M, et al., Microsc Res Tech 2001; 52: 731-9.), and the neurological symptom score was recorded (normal: score 0; tail relaxation: score 1; partial hind limb paralysis: score 2; post limb paralysis: score 3; forelimb paralysis: score 4; moribund or dead: score 5). When a plurality of neurological symptoms were observed, a high value was adopted as the neurological symptom score of the evaluation date. The evaluation results (average value +standard error) are shown in FIG. 6. The bispecific molecule 2C11xTKB58 alleviated the symptoms of experimental autoimmune encephalomyelitis (EAE).
Example 4
Experiments of Binding of Mouse LAG3 Soluble Protein to IIA1.6 Cells in Presence of Bispecific Molecule
[0454] A mouse LAG3 soluble protein was obtained as follows. cDNA fragments encoding D1 to D4 (LAG3-EC) of mouse LAG3 were amplified by PCR. A five-stranded coiled coil domain of a cartilage oligomer substrate protein (COMP) with a DYKDDDDK-tag, a TEV cleavage site, and a PA-tag was added to the C-terminus of LAG3-EC. The chimeric cDNA was cloned into an expression vector modified from pEBMulti-Neo (Wako). Plat-E cells were transfected with the plasmid using Avalanche-Omni Transfection Reagent (EZ Biosystems) and the culture supernatant was collected after 48 hours.
[0455] IIA1.6 cells expressing pMHCII, a ligand of mouse LAG3, were treated with TKB58x2C11, 2C11xTKB58, or a TKB58 antibody as a full-form anti-mouse LAG3 antibody, and thereafter, the cells were stained with a mouse LAG3 soluble protein. The results are shown in FIG. 7. The full-form TKB58 antibody completely inhibited the binding of the mouse LAG3 soluble protein to IIA1.6 cells, while TKB58x2C11 and 2C11xTKB58 did not.
Example 5
Production of Bispecific Molecule TKB58xYTS 169 Binding to LAG3 and CD8
[0456] A nucleic acid encoding the heavy and light chain variable regions of an anti-mouse LAG3 antibody (TKB58) and an anti-mouse CD8 antibody (YTS169) was synthesized, amplified by PCR, and was cloned into an expression plasmid vector produced by modifying pEBMulti-Neo (Wako), whereby an expression plasmid of a bispecific molecule TKB58xYTS169 (SEQ ID NO: 33) recognizing mouse LAG3 and mouse CD8 was produced. The expression plasmid was transfected into PlatE cells using Avalanche-Omni Transfection Reagent (EZ Biosystems), and the culture supernatant was collected after 48 hours. DO11.10, DO11.10-mLAG3, B3Z, and B3Z-mLAG3 cells were stained using the culture supernatant.
[0457] The results are shown in FIG. 8. Binding to DO11.10 cells (expressing mouse LAG3 and not expressing mouse CD8) and B3Z cells (expressing mouse CD8 and not expressing mouse LAG3) was confirmed, which proves that TKB58xYTS169 had the binding ability to mouse CD8 and mouse LAG3. In addition, the bispecific molecule TKB58xYTS169 more strongly bound to B3Z-mLAG3 cells expressing mouse CD8 and mouse LAG3, which suggests that the bispecific molecule TKB58xYTS169 bound to mouse CD8 and mouse LAG3 on the same cells. On the other hand, binding to DO11.10 cells expressing neither of the foregoing molecules was not observed, with which it was confirmed that the binding was specific to both of the foregoing molecules.
Example 6
Evaluation of Bispecific Molecule TKB58xYTS169 for Antigen-Specific Activation of T Cells
[0458] B3Z cells are known to recognize an OVA-derived peptide (pOVA257-264, SIINFEKL) presented on the mouse MHC class I molecule H-2K.sup.b and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing H-2Kb were pulsed with pOVA257-264 to stimulate B3Z cells, production of IL-2 was observed, but the expression of mouse LAG3 did not inhibit the production of IL-2 (FIG. 9). This is because LAG3 cannot exert the inhibitory function in the MHCI class I-restricted B3Z cells, even if IIA1.6 cells express a ligand of LAG3. The addition of TKB58xYTS169 strongly suppressed the production of IL-2 only when B3Z cells expressed mouse LAG3. This revealed that TKB58xYTS169 suppressed antigen-specific activation of LAG3-expressing cells.
Example 7
Binding of Anti-Mouse LAG3 Antibody TKB58 to LAG3 Mutants
Example 7-1
Mouse LAG3 Recognition Region of Anti-Mouse LAG3 Antibody TKB58
[0459] Mouse LAG3 has four Ig-like domains (D1, D2, D3, D4) in the extracellular region. Chimeric molecules in which the Ig-like domains were substituted with the corresponding human Ig-like domains, respectively, were produced and were forcibly expressed in DO11.10 cells. Briefly, each cDNA fragment was amplified by PCR and cloned into a retrovirus expression plasmid vector modified from pFB-ires-Neo (Agilent). Mouse and human LAG3 chimeric cDNAs were produced by overlap extension PCR. Plasmids were introduced into Plat-E cells (D'MEM, supplemented with high glucose (Gibco), 20% (v/v) FBS, 100 U/ml penicillin and 100 μg/ml streptomycin) using FuGENE HD (Promega). Using virus-containing supernatant, the genes were introduced into the target cells. Infected cells were selected by G418 (Wako), puromycin (Sigma-Aldrich), or cell sorting. The cells were stained using an anti-mouse LAG3 antibody (TKB58) and analyzed by flow cytometry. The results are shown in FIG. 10. TKB58 did not bind to the chimeric molecule in which mouse D1 was substituted with human DI, which reveals that TKB58 recognizes D1 of mouse LAG3.
However, the specification does not describe the structure, e.g., amino acid sequence of the heavy and light chain variable domains of the bispecific antibody that correlated with binding to an extracellular region of any lymphocyte activation gene 3 (LAG3), such as one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 (claim 38) and an extracellular region of any cluster of differentiation 3 (CD3) such as any region comprising one or more amino acids corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claims 18, 38, 39, 40, 44, 45). There is no limitation on the structure or function of the bispecific antibody, or the epitope to which it binds of LAG3 and CD3. There is no information in the specification how much variation is permissible for it still binds LAG3 and CD3. The specification does not describe the structure, e.g., amino acid sequence of the heavy and light chain variable regions of all bispecific antibody comprising a binding site that binds a region comprising one or more amino acids corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claim 39) encompassed by the claimed method.
Regarding number of species, the specification fails to disclose a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the claimed bispecific antibody that bind to any portion include D1 region of any LAG3 and CD3 themselves encompassed by the claimed method. A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech. Ill USPQ2d 1780, 1790 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc, v. Abbott Labs.. 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 8 (claim 42), the specification does not describe where and what amino acid within the full-length sequence of SEQ ID NO: 7 or SEQ ID NO: 8 to be substituted, deleted, added or a combination thereof such that the modified antibody stills maintains structural conformation and binding specifically to LAG3.
Even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Wu et al (J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all 11-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Thus, one of skill in the art would reasonably conclude that the disclosure of just one anti-LAG3 comprises a heavy chain region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 does not provide a representative number of species of all antibodies that specifically bind any LAG3 that would be sufficient to describe the claimed genus for the claimed method. Thus, the specification does not disclose a representative number of species of bispecific antibodies that are effective for treating any autoimmune disease in any subject.
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 and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a method of treating autoimmune disease in a subject in needed thereof comprising administering the subject a bispecific antibody comprises a first binding site that specifically binds to lymphocyte activation gene 3 (LAG3) and a second binding site that specifically binds to CD3 wherein the first binding site comprises: (i) a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or (ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and wherein the second binding site comprises the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22 or wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 15; and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 16, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicant’s arguments and the declaration of Taku Okazaki under 37 C.F.R. § 1.132 filed December 17, 2025 have been carefully considered but are not found persuasive.
Applicant’s position is that claim 18 has been amended.
The reasons for the traversal are set forth in the Declaration by Dr. Taku Okazaki, a co- inventor of the presently claimed methods, submitted herewith. The contents of the Declaration are also set forth below for the Examiner's convenience.
The present claims are directed to methods for treating conditions in which immunity is enhanced, namely autoimmune diseases, allergic diseases, or graft-versus-host disease, by physically bringing LAG3 and the TCR complex (composed of TCRα chain, β chain, CD3, and CD8 (or CD4)) into close proximity on the same T cell by crosslinking LAG3 and CD3 or CD8 on the same T cell. This allows LAG-3 to suppress signals transmitted from the TCR complex, thereby reducing T cell activity, suppressing immunity, and treating the aforementioned conditions. The characteristic of immunosuppression in the presently claimed methods lies in enabling LAG-3 to suppress signals transmitted from the TCR complex by physically bringing LAG3 and the TCR complex into close proximity, and does not depend on the agonist function of the first binding site that specifically binds to LAG3 alone. In other words, it is sufficient for the first binding site to bind to the extracellular domain of LAG3 as recited in the claims. Similarly, for the second binding site that specifically binds to CD3 or CD8, it is not necessary to directly alter the activity of CD3 or CD8; binding to the extracellular domain as recited in the claims is sufficient to achieve the effect of the presently claimed methods.
The present specification describes specific embodiments of the bispecific molecule supporting the claims:
- Using cells expressing LAG3 and CD3 or CD8 on the same cell, it was demonstrated that the bispecific molecules 2C11xTKB58 and TKB58x2C11, which bind to LAG3 and CD3, and TKB58xYTS 169, which binds to LAG3 and CD8, are capable of binding to LAG3 and CD3 or CD8 on the same cell (Example 1, Fig. 1; Example 5, Fig. 8).
- A T cell stimulation assay system capable of evaluating the function of bispecific antibodies was established, and it was demonstrated that the above bispecific molecules suppress antigen-specific activation of T cells expressing LAG3, whereas they do not suppress activation of T cells lacking LAG3 expression. (Example 2, Figs. 2-5; Example 6, Fig. 9). In other words, as described in the specification, it was experimentally confirmed that the bispecific molecules suppress T cell activation only when the T cells co-express LAG3 and CD3 or CD8.
- 2C11xTKB58, which binds to LAG3 and CD3, alleviated symptoms in an experimental autoimmune encephalomyelitis (EAE) model, a model of multiple sclerosis (Example 3, Fig. 6). Since CD8 is a molecule that constitutes the TCR complex together with CD3, and bispecific molecules binding to LAG3 and CD8 showed equivalent results in vitro to those binding to
LAG3 and CD3, it is highly probable that they are also effective in vivo. Thus, Applicants demonstrated that the bispecific molecules of the present claims can suppress immunity in vivo.
Furthermore, the first binding site of the bispecific molecules used in the Examples provided in the specification is derived from TKB58, an anti-LAG3 antibody. It has been reported that TKB58 inhibits the function of LAG3 in suppressing T cell activation (See Maeda TK et al., J. Biol. Chem. (2019) 294(15) 6017-6026; submitted with the Declaration as Exhibit Al), and thus, unlike the bispecific molecules of the present claims, is an antibody that activates immunity. Similarly, in the Examples provided in the specification, the antigen-binding site derived from the anti-CD3 antibody 2C11 was used as the second binding site, and it has been reported that 2C11 enhances the production of IFNy (See W02017004563, Example 7, Fig. 38; submitted with the Declaration as Exhibit B), and thus, unlike the bispecific molecules of the present claims, is an antibody that activates immunity.
This supports that the immunosuppressive mechanism of the presently claimed methods does not depend on the inherent function of each antibody. That is, the first binding site only needs to bind to the extracellular region of LAG3, and similarly, the second binding site that specifically binds to CD3 or CD8 only needs to bind to the extracellular region of CD3 or CD8.
Therefore, as the first binding site that binds to LAG3, known anti-LAG3 antibodies described in paragraph [0042] of the specification as filed, such as BMS-986016, LAG525, MK- 4280, 11E3, 17B4, 3DS223H, REA351, REA776, 11C3C65, 7H2C65, C9B7W, or 631501, can be used. As the second binding site that binds to CD3, known anti-CD3 antibodies described in paragraph [0055] of the specification as filed can be used, and as the second binding site that binds to CD8, known anti-CD8 antibodies described in PCT application paragraph [0068] can be used.
In response, the amendment to claims 18, 38 is acknowledged.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
The claims encompass a method for treating any autoimmune disease (elected species), an allergic disease, or a graft-versus-host disease in any subject in need thereof, the method comprising: administering an effective amount of any bispecific molecule or a pharmaceutical composition comprising the bispecific molecule, to the subject, wherein the bispecific molecule comprises a first binding site that specifically binds to any lymphocyte activation gene 3 (LAG3) from any species and a second binding site that specifically binds to an extracellular region of any cluster of differentiation 3 (CD3) from any species or an extracellular region of a cluster of differentiation 8 (CD8).
Here, applicant is claiming a method of treating any autoimmune disease (elected species), an allergic disease, or a graft-versus-host disease in any mammalian subject by the antigens, e.g., extracellular domain of any lymphocyte activation gene 3 (LAG3) and extracellular domain of any cluster of differentiation 3 (CD3) to which the bispecific antibody binds but does not describe the structure-identifying information about the claimed bispecific antibodies, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual bispecific antibodies themselves encompassed by the claims.
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Further, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Thus antibody structure cannot be determined from a recited antibody function, e.g., binding ECD of LAG-3 and ECD of CD3. See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
As such, it is submitted that a skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus of bispecific antibody that exhibit this functional properties, e.g., binds an extracellular region of lymphocyte activation gene 3 (LAG3) and an extracellular region of a CD3 or CD8 (claim 18) or one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 (claim 38) or a region of the LAG3 comprising one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61, and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claim 39) or CD3 (claim 44) encompassed by the claimed method.
In response to the argument that the first binding site that binds to LAG3 described in paragraph [0042] of the specification as filed, such as BMS-986016, LAG525, MK- 4280, 11E3, 17B4, 3DS223H, REA351, REA776, 11C3C65, 7H2C65, C9B7W, or 631501, and second binding site that binds to CD3, described in paragraph [0055] of the specification as filed can be used, it is noted that the specification discloses:
[0052] In the present disclosure, LAG3, CD3 and CD8 may be of any species, and are typically mammalian (for example, human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like), for example, mouse or human, particularly human. The amino acid sequences of LAG3, CD3, and CD8 derived from various species are readily available using known databases. In the present disclosure, LAG3, CD3, and CD8 encompass the products of their naturally occurring alleles.
The phrases “for example” and “the like” are not limited to the ones that disclose. It is not clear the binding sites from antibodies disclosed in paragraphs [0042] and [0055] bind to the ECD of LAG3 and ECD of CD3 from any mammalian species, e.g., human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like, let alone the particular one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claim 39). The specification does not describe the structure, e.g. amino acid sequence of the VH and VL of antibody that correlated with binding to such discontinued or conformational epitope in SEQ ID NO: 2 for the claimed method to demonstrate possession of the invention at the time of filing.
For example, even assuming the first binding site that binds to the extracellular domain of LAG-3 is from an anti-mouse LAG-3 monoclonal antibody TKB58 (the same antibody discloses in the specification), Maeda (Exhibit A, J Biol Chem 294(15): 6017-6026, 2019) teaches recognition of mouse LAG-3 D1, D4,and D2 by TKB58,TKB27,and C9B7W clones of anti-mouse LAG-3 Abs. C9B7W antibody recognized D2 of mouse LAG-3 because it failed to recognize the chimeric molecule with human D2 (Fig. 1A). TBK58 and TBK27 recognized D1 and D4 of mouse LAG-3, respectively (Fig. 1A).
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As such, it is clear that depending on the epitope to which the antibody binds, e.g., D1 versus D2, D3 and/or D4 in the extracellular domain of mouse LAG-3 from which species, the activity, e.g., IL-2 production (Fig C) and the capacity of anti-mouse LAG-3 Abs to block LAG-3function (Fig 1E) are different.
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Further, bispecific antibody that binds to ECD of mouse LAG-3 and mouse CD3 may not bind to ECD of LAG-3 and CD3 from human, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like, in turn, effective for treating any autoimmune disease in species.
In response to the argument that the bispecific molecule suppress T cell activation only when binds to LAG3 and CD3 or CD8 on the same cell or bispecific molecule suppress T cell activation only when the T cells co-express LAG3 and CD3 or CD8, nowhere in any of the rejected claims recite the bispecific antibody binds to LAG3 and CD3 on the same T cell or the activated T cells co-express LAG3 and CD3 or CD8. Maeda teaches that LAG-3 is not expressed on naive T cells but inducibly expressed on T cells upon activation; cell surface expression level of LAG-3 is also regulated by shedding of the EC region by two transmembrane metalloproteases, ADAM10 and ADAM17, see p. 6021, Discussion, in particular.
The argument with respect to preventing any autoimmune disease is moot as claim 18 has been amended.
For these reasons, the rejection is maintained.
Claims 18 and 38-40, 44-47 and 52 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 a method of treating autoimmune disease in a subject in needed thereof comprising administering the subject a bispecific antibody comprises a first binding site that specifically binds to lymphocyte activation gene 3 (LAG3) and a second binding site that specifically binds to CD3 wherein the first binding site comprises: (i) a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or (ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and wherein the second binding site comprises the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22 or wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 15; and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 16, does not reasonably provide enablement for a method for treating any autoimmune disease as set forth in claims 18 and 38-47 and 52. 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 18 is drawn to a method for treating any autoimmune disease (elected species), an allergic disease, or a graft-versus-host disease in any subject in need thereof, the method comprising: administering an effective amount of any bispecific molecule or a pharmaceutical composition comprising the bispecific molecule, to the subject, wherein the bispecific molecule comprises a first binding site that specifically binds to any lymphocyte activation gene 3 (LAG3) and a second binding site that specifically binds to an extracellular region of a cluster of differentiation 3 (CD3) or an extracellular region of a cluster of differentiation 8 (CD8).
Claim 38 is drawn to the method according to claim 18, wherein the first binding site binds to one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse of LAG3 having the amino acid sequence of SEQ ID NO: 2.
Claim 39 is drawn to the method according to claim 18, wherein the first binding site binds to a region of the LAG3, said region comprising one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61, and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2.
Claim 40 is drawn to the method according to claim 18, wherein the first binding site comprises a heavy chain variable region and a light chain variable region of any anti-LAG3 antibody.
Claim 41 is drawn to the method according to claim 40, wherein the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14.
Claim 42 is drawn to the method according to claim 40, wherein the heavy chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 7; and wherein the light chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 8.
Claim 43 is drawn to the method according to claim 18, wherein the first binding site competes, for binding to LAG3, with an anti-LAG3 antibody that comprises:
a heavy chain variable region comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 10, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 11; and a light chain variable region comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 13 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 14, or
(ii) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
Claim 44 is drawn to the method according to claim 18, wherein the second binding site specifically binds to any CD3.
Claim 45 is drawn to the method according to claim 44, wherein the second binding site comprises a heavy chain variable region and a light chain variable region of any anti-CD3 antibody.
Claim 46 is drawn to the method according to claim 45, wherein the heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and wherein the light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22.
Claim 47 is drawn to the method according to claim 45, wherein the heavy chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 15; and wherein the light chain variable region comprises an amino acid sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 16.
Claim 52 is drawn to the method according to claim 18, wherein the bispecific molecule suppresses activation of a T cell co-expressing LAG3 and CD3 or CD8.
Regarding autoimmune diseases, the specification discloses:
[0251] Examples of the disease characterized by enhanced immunity include autoimmune diseases, allergic diseases and graft-versus-host diseases. Examples of the autoimmune disease include Behcet's disease, systemic lupus erythematosus, multiple sclerosis (systemic sclerosis, progressive systemic sclerosis), scleroderma, polymyositis, dermatomyositis, periarteritis nodosa (polyarteritis nodosa, microscopic polyangiitis), aortitis syndrome (Takayasu's arteritis), malignant rheumatoid arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, Wegener's granulomatosis, mixed connective tissue disease, Sjogren's syndrome, Adult-onset Still's disease, allergic granulomatous angiitis, hypersensitivity vasculitis, Cogan's syndrome, RS3PE syndrome, temporal arteritis, polymyalgia rheumatica, fibromyalgia, antiphospholipid antibody syndrome, eosinophilic fasciitis, IgG4-related diseases (e.g., primary sclerosing cholangitis, autoimmune pancreatitis), Guillain-Barre syndrome, myasthenia gravis, chronic atrophic gastritis, autoimmune hepatitis, primary biliary cirrhosis, aortitis syndrome, Goodpasture syndrome, rapidly progressive glomerulonephritis, megaloblastic anemia, autoimmune hemolytic anemia, autoimmune neutropenia, idiopathic thrombocytopenic purpura, Basedow's disease (hyperthyroidism), Hashimoto disease, autoimmune adrenal insufficiency, primary hypothyroidism, idiopathic Addison disease (chronic hypoadreno corticism), type I diabetes, slowly progressive type I diabetes (latent autoimmune diabetes in adults), chronic discoid lupus erythematosus, circumscribed scleroderma, psoriasis, psoriatic arthritis, pemphigus, pemphigoid, gestational herpes, linear IgA bullous dermatosis, acquired epidermolysis bullosa, alopecia areata, white spots, vitiligo vulgaris, atopic dermatitis, neuromyelitis optica, Chronic inflammatory demyelinating polyneuropathy, sarcoidosis, bullous pemphigoid, giant cell arteritis, amyotrophic lateral sclerosis, eosinophilic granulomatosis with polyangiitis, Harada disease, autoimmune optic neuropathy, idiopathic azoospermia, habitual abortion, inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), and celiac disease. In a certain embodiment, the autoimmune disease is type I diabetes, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In a certain embodiment, the autoimmune disease is multiple sclerosis. Examples of the allergic disease include asthma, atopic dermatitis, rhinitis, conjunctivitis, and hay fever.
The specification exemplifies:
Example 1
Production of Bispecific Molecules 2C11xTKB58 and TKB58x2C11 Binding to LAG3 and CD3ϵ
[0445] A nucleic acid encoding the heavy and light chain variable regions of an anti-mouse LAG3 antibody (TKB58) and an anti-mouse CD3e antibody (2C11) was synthesized, amplified by PCR, and was cloned into an expression plasmid vector produced by modifying pEBMulti-Neo (Wako) or pSecTag2/Hygro (Thermo Fisher Scientific), whereby expression plasmids of bispecific molecules 2C11xTKB58 (SEQ ID NO: 31) and TKB58x2C11 (SEQ ID NO: 32) recognizing mouse LAG3 and mouse CDR were produced. The expression plasmid was transfected into PlatE cells using Avalanche-Omni Transfection Reagent (EZ Biosystems), and the culture supernatant was collected after 48 hours. BW5147, DO11.10, and DO11.10-mLAG3 cells were stained using the culture supernatant.
[0446] The results are shown in FIG. 1. Binding to DO11.10 cells expressing mouse CD3ϵ but not mouse LAG3 was confirmed, from which it was confirmed that the bispecific molecule had a binding ability to mouse CD3ϵ. In addition, as compared with DO11.10 cells, the bispecific molecule strongly bound to DO11.10-mLAG3 cells in which mouse LAG3 was forcibly expressed, from which it was also confirmed that the bispecific molecule had a binding ability to mouse LAG3. On the other hand, no binding was observed to BW5147 cells that do not express mouse CD3ϵ and mouse LAG3, from which it was confirmed that the binding is specific to both molecules. A stronger binding was observed with 2C11xTKB58, as compared to TKB58x2C11.
Example 2
Bispecific Molecules 2C11xTKB58 and TKB58x2C11 Suppress Antigen-Specific Activation of T Cells in LAG3 Dependent Manner
Example 2-1
Experiments with Antigen-Presenting Cells Strongly Inducing Suppression by LAG3
[0447] DO11.10 cells are known to recognize an OVA-derived peptide (pOVA323-339, ISQAVHAAHAEINEAGR) presented on the mouse MHC class II molecule I-A.sup.d and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing I-A.sup.d were pulsed with pOVA323-339 to stimulate DO11.10 cells (mock), production of IL-2 was observed, but neither TKB58x2C11 nor 2C11xTKB58 affected IL-2 production (FIG. 2). This confirmed that these bispecific molecules did not affect antigen-specific activation of T cells not expressing LAG3.
[0448] In addition, DO11.10-mLAG3 cells (mLAG3 WT) obtained by causing mouse LAG3 to be forcibly expressed in DO11.10 cells were similarly antigen-stimulated (FIG. 2). The production of IL-2 was strongly suppressed in a LAG3 dependent manner. The addition of anti-mouse LAG3 antibody TKB58 inhibited the function of mouse LAG3 and restored the production of IL-2. On the other hand, the addition of TKB58x2C11 or 2C11xTKB58 did not inhibit the suppression of IL-2 production by LAG3.
Example 2-2
Experiments with Antigen-Presenting Cells that do not Induce Suppression by LAG3 Too Strongly
[0449] LAG3 selectively binds to a stable peptide MHCII complex and does not bind to an unstable peptide MHCII complex. When pOVA323-339 is pulsed into BW5147-mCD86/I-A.sup.d cells obtained by forcibly expressing I-A.sup.d in BW5147-mCD86 cells, pOVA323-339 does not bind to mouse LAG3, because pOVA323-339, with an unstable structure, is presented to I-A.sup.d, resulting in that inhibition via mouse LAG3 hardly functions.
[0450] In this stimulation condition, when TKB58x2C 11 or 2C11xTKB58 was added, the production of IL-2 was strongly suppressed only when DO11.10 cells expressing LAG3 (mLAG3WT) were used (FIG. 3). In the cell binding experiment (FIG. 1), similarly to the result that 2C11xTKB58 bound to the target cells more strongly than TKB58x2C11, 2C11xTKB58 showed a stronger inhibitory effect than TKB58x2C11.
Example 2-3
Experiments with MHC Class I-Restricted Cells in Which LAG3 Hardly Exhibits an Inhibitory Effect
[0451] B3Z cells are known to recognize an OVA-derived peptide (pOVA257-264, SIINFEKL) presented on the mouse MHC class I molecule H-2K.sup.b and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing H-2Kb were pulsed with the OVA peptide to stimulate B3Z cells (mock), production of IL-2 was observed, but the expression of mouse LAG3 (mLAG3WT) did not inhibit the production of IL-2 (FIG. 4). This is because LAG3 cannot exert the inhibitory function in the MHCI class I-restricted B3Z cells. The addition of TKB58x2C11 or 2C11xTKB58 strongly suppressed the production of IL-2 only when B3Z cells expressed mouse LAG3. These results indicate that TKB58x2C 11 and 2C11xTKB58 suppress antigen-specific activation of LAG3 expressing cells, even in MHC class I-restricted CD8 positive cells.
Example 2-4
Experiments with LAG3 Mutant Without Ligand Binding Ability
[0452] An amino acid mutant of LAG3, LAG3-P111A, lacks the ability to bind to pMHCII, and thus does not exert a T cell suppressive function even when it is antigen-stimulated. Using this mutant, the same experiment as in Example 2-1 was carried out. The results are shown in FIG. 5. When TKB58x2C11 or 2C11xTKB58 was added under this stimulation condition, the production of IL-2 was strongly suppressed in a LAG3-P111A-dependent manner. Therefore, it was revealed that TKB58x2C11 and 2C11xTKB58 suppress antigen-specific activation of LAG3-expressing cells even under conditions where LAG3 does not bind to pMHCII as a ligand. These results indicate that TKB58x2C11 and 2C11xTKB58 activate LAG3 and suppress TCR even in situations where LAG3 cannot bind to MHCII.
Example 3
Evaluation of Bispecific Molecule Using Experimental Autoimmune Encephalomyelitis (EAE)
[0453] In vivo effects of 2C11xTKB58 were evaluated in an EAE model using C57BL/6 mice. Killed tuberculosis bacteria H37Ra (BD Biosciences, model number 231141) and incomplete Freund's adjuvant (BD Biosciences, model number 263910) were mixed so that complete Freund's adjuvant (CFA) containing 4 mg/mL of killed tuberculosis bacteria H37Ra was prepared. One mg/mL of MOG peptide (ANASPEC, model number AS-60130) and an equal amount of CFA were mixed so that an emulsion was prepared, and was used as an inducer of an EAE model. 200 μl of the inducer was subcutaneously administered to a base of the tail of a C57BL/6 mouse, and 200 μl of 1 μg/mL 100 day tussive toxin (SIGMA-ALDRICH, model number P7208) was intravenously administered on the day of immunization and day 2 of the immunization. C57BL/6 mice were then intraperitoneally administered with 2C11xTKB58 once daily at a dosage of 0.3 mg/kg each from day 6 to day 10 of immunization. After the day of immunization, the neurological symptoms were evaluated according to the method of Onuki et al. (Onuki M, et al., Microsc Res Tech 2001; 52: 731-9.), and the neurological symptom score was recorded (normal: score 0; tail relaxation: score 1; partial hind limb paralysis: score 2; post limb paralysis: score 3; forelimb paralysis: score 4; moribund or dead: score 5). When a plurality of neurological symptoms were observed, a high value was adopted as the neurological symptom score of the evaluation date. The evaluation results (average value +standard error) are shown in FIG. 6. The bispecific molecule 2C11xTKB58 alleviated the symptoms of experimental autoimmune encephalomyelitis (EAE).
Example 4
Experiments of Binding of Mouse LAG3 Soluble Protein to IIA1.6 Cells in Presence of Bispecific Molecule
[0454] A mouse LAG3 soluble protein was obtained as follows. cDNA fragments encoding D1 to D4 (LAG3-EC) of mouse LAG3 were amplified by PCR. A five-stranded coiled coil domain of a cartilage oligomer substrate protein (COMP) with a DYKDDDDK-tag, a TEV cleavage site, and a PA-tag was added to the C-terminus of LAG3-EC. The chimeric cDNA was cloned into an expression vector modified from pEBMulti-Neo (Wako). Plat-E cells were transfected with the plasmid using Avalanche-Omni Transfection Reagent (EZ Biosystems) and the culture supernatant was collected after 48 hours.
[0455] IIA1.6 cells expressing pMHCII, a ligand of mouse LAG3, were treated with TKB58x2C11, 2C11xTKB58, or a TKB58 antibody as a full-form anti-mouse LAG3 antibody, and thereafter, the cells were stained with a mouse LAG3 soluble protein. The results are shown in FIG. 7. The full-form TKB58 antibody completely inhibited the binding of the mouse LAG3 soluble protein to IIA1.6 cells, while TKB58x2C11 and 2C11xTKB58 did not.
Example 5
Production of Bispecific Molecule TKB58xYTS 169 Binding to LAG3 and CD8
[0456] A nucleic acid encoding the heavy and light chain variable regions of an anti-mouse LAG3 antibody (TKB58) and an anti-mouse CD8 antibody (YTS169) was synthesized, amplified by PCR, and was cloned into an expression plasmid vector produced by modifying pEBMulti-Neo (Wako), whereby an expression plasmid of a bispecific molecule TKB58xYTS169 (SEQ ID NO: 33) recognizing mouse LAG3 and mouse CD8 was produced. The expression plasmid was transfected into PlatE cells using Avalanche-Omni Transfection Reagent (EZ Biosystems), and the culture supernatant was collected after 48 hours. DO11.10, DO11.10-mLAG3, B3Z, and B3Z-mLAG3 cells were stained using the culture supernatant.
[0457] The results are shown in FIG. 8. Binding to DO11.10 cells (expressing mouse LAG3 and not expressing mouse CD8) and B3Z cells (expressing mouse CD8 and not expressing mouse LAG3) was confirmed, which proves that TKB58xYTS169 had the binding ability to mouse CD8 and mouse LAG3. In addition, the bispecific molecule TKB58xYTS169 more strongly bound to B3Z-mLAG3 cells expressing mouse CD8 and mouse LAG3, which suggests that the bispecific molecule TKB58xYTS169 bound to mouse CD8 and mouse LAG3 on the same cells. On the other hand, binding to DO11.10 cells expressing neither of the foregoing molecules was not observed, with which it was confirmed that the binding was specific to both of the foregoing molecules.
Example 6
Evaluation of Bispecific Molecule TKB58xYTS169 for Antigen-Specific Activation of T Cells
[0458] B3Z cells are known to recognize an OVA-derived peptide (pOVA257-264, SIINFEKL) presented on the mouse MHC class I molecule H-2K.sup.b and produce IL-2 depending on the amount of an antigenic peptide. When IIA1.6 cells expressing H-2Kb were pulsed with pOVA257-264 to stimulate B3Z cells, production of IL-2 was observed, but the expression of mouse LAG3 did not inhibit the production of IL-2 (FIG. 9). This is because LAG3 cannot exert the inhibitory function in the MHCI class I-restricted B3Z cells, even if IIA1.6 cells express a ligand of LAG3. The addition of TKB58xYTS169 strongly suppressed the production of IL-2 only when B3Z cells expressed mouse LAG3. This revealed that TKB58xYTS169 suppressed antigen-specific activation of LAG3-expressing cells.
Example 7
Binding of Anti-Mouse LAG3 Antibody TKB58 to LAG3 Mutants
Example 7-1
Mouse LAG3 Recognition Region of Anti-Mouse LAG3 Antibody TKB58
[0459] Mouse LAG3 has four Ig-like domains (D1, D2, D3, D4) in the extracellular region. Chimeric molecules in which the Ig-like domains were substituted with the corresponding human Ig-like domains, respectively, were produced and were forcibly expressed in DO11.10 cells. Briefly, each cDNA fragment was amplified by PCR and cloned into a retrovirus expression plasmid vector modified from pFB-ires-Neo (Agilent). Mouse and human LAG3 chimeric cDNAs were produced by overlap extension PCR. Plasmids were introduced into Plat-E cells (D'MEM, supplemented with high glucose (Gibco), 20% (v/v) FBS, 100 U/ml penicillin and 100 μg/ml streptomycin) using FuGENE HD (Promega). Using virus-containing supernatant, the genes were introduced into the target cells. Infected cells were selected by G418 (Wako), puromycin (Sigma-Aldrich), or cell sorting. The cells were stained using an anti-mouse LAG3 antibody (TKB58) and analyzed by flow cytometry. The results are shown in FIG. 10. TKB58 did not bind to the chimeric molecule in which mouse D1 was substituted with human DI, which reveals that TKB58 recognizes D1 of mouse LAG3.
However, enablement is not commensurate in scope with treating any and all autoimmune diseases in any subject. Notably, the specification does not teach the structure, e.g., amino acid sequence of the heavy and light chain variable domains of the bispecific antibody that correlated with binding to an extracellular region of any lymphocyte activation gene 3 (LAG3), such as one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 (claim 38) and an extracellular region of any cluster of differentiation 3 (CD3) such as any region comprising one or more amino acids corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claims 18, 38, 39, 40, 44, 45) effective for treating all autoimmune diseases. There are insufficient in vivo working examples.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Regarding sequence having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 8 (claim 42), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 7 or SEQ ID NO: 8 to be substituted, deleted, added or a combination thereof such that the modified antibody having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 7 and SEQ ID NO: 8 stills maintains structural conformation and binding specifically to LAG3. Likewise, the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 15 or SEQ ID NO: 16 (claim 47) to be substituted, deleted, added or a combination thereof such that the modified antibody having an identity of 90% or more with the amino acid sequence of SEQ ID NO: 15 and SEQ ID NO: 16 stills maintains structural conformation and binding specifically to CD3.
Even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Wu et al (of record, J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher. 166 USPQ 19 24 (CCPA 1970). Without such guidance, the method is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc, v. Chuqai Pharmaceutical Co. Ltd.. 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman. 230 USPQ 546 (BPAI 1986).
Accordingly, it would require undue experimentation of one skilled in the art to practice the claimed invention. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
Applicant’s arguments and the declaration of Taku Okazaki under 37 C.F.R. § 1.132 filed December 17, 2025 have been carefully considered but are not found persuasive.
Applicant’s position is that the full scope of the claims is enabled for at least the reasons set forth above.
Similarly to the written description requirement, in determining whether the claims are enabled, the level of skill in the art and state of the prior art must be considered. MPEP 2164.01
As explained above, Applicants demonstrated that the effect of treating the diseases recited in the claims is achieved by crosslinking LAG3 and CD3 or CD8, even without depending on specific sequences. The specification provides several examples demonstrating that bispecific molecules which bind to LAG3 and CD3 or CD8 on the same cell suppress antigen-specific activation of T cells can suppress immunity in vivo. Antibodies binding to LAG3, CD3 and CD8 and methods of their production are known in the art.
Therefore, Applicants respectfully submit that the specification in combination with the knowledge in the art provides sufficient guidance to practice the full scope of the claims.
In response, the amendment to claims 18, 38 is acknowledged.
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 18 is drawn to a method for treating any autoimmune disease (elected species), an allergic disease, or a graft-versus-host disease in any subject in need thereof, the method comprising: administering an effective amount of any bispecific molecule or a pharmaceutical composition comprising the bispecific molecule, to the subject, wherein the bispecific molecule comprises a first binding site that specifically binds to any lymphocyte activation gene 3 (LAG3) and a second binding site that specifically binds to an extracellular region of a cluster of differentiation 3 (CD3) or an extracellular region of a cluster of differentiation 8 (CD8).
Claim 38 is drawn to the method according to claim 18, wherein the first binding site binds to one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse of LAG3 having the amino acid sequence of SEQ ID NO: 2.
Claim 39 is drawn to the method according to claim 18, wherein the first binding site binds to a region of the LAG3, said region comprising one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61, and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2.
Enablement is not commensurate in scope with the claims because the specification discloses just treating Autoimmune Encephalomyelitis (EAE) by administering bispecific antibody 2C11xTKB58 that binds to ECD of mouse LAG-3 and mouse CD3, see Example 3.
However, the specification does not teach the structure, e.g., amino acid sequence of the heavy and light chain variable domains of the bispecific antibody that correlated with binding to an extracellular region of any lymphocyte activation gene 3 (LAG3), such as one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 (claim 38) and an extracellular region of any cluster of differentiation 3 (CD3) such as any region comprising one or more amino acids corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claims 18, 38, 39, 40, 44, 45) effective for treating all autoimmune diseases. There are insufficient in vivo working examples.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.) Thus antibody structure cannot be determined from a recited antibody function, e.g., binding ECD of LAG-3 and ECD of CD3.
As such, it is submitted that a skilled artisan cannot predict which bispecific antibody out of the universe that exhibit this functional properties, e.g., binds an extracellular region (ECD) of lymphocyte activation gene 3 (LAG3) and CD3 or CD8 (claim 18) or one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 (claim 38) or a region of the LAG3 comprising one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61, and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claim 39) or CD3 (claim 44), in turn, effective to treat autoimmune disease in any and all subject as claimed.
In response to the argument that the first binding site that binds to LAG3 described in paragraph [0042] of the specification as filed, such as BMS-986016, LAG525, MK- 4280, 11E3, 17B4, 3DS223H, REA351, REA776, 11C3C65, 7H2C65, C9B7W, or 631501, and second binding site that binds to CD3, described in paragraph [0055] of the specification as filed can be used, it is noted that the specification discloses:
[0052] In the present disclosure, LAG3, CD3 and CD8 may be of any species, and are typically mammalian (for example, human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like), for example, mouse or human, particularly human. The amino acid sequences of LAG3, CD3, and CD8 derived from various species are readily available using known databases. In the present disclosure, LAG3, CD3, and CD8 encompass the products of their naturally occurring alleles.
The phrases “for example” and “the like” are not limited to the ones that disclose. It is not clear the binding sites from antibodies disclosed in paragraphs [0042] and [0055] bind to the ECD of LAG3 and ECD of CD3 from any mammalian species, e.g., human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like, let alone the particular one or more amino acid residues corresponding to asparagine at position 54, phenylalanine at position 55, valine at position 61 and/or isoleucine at position 62 of the amino acid sequence of SEQ ID NO: 2 (claim 39). The specification does not teach the structure, e.g. amino acid sequence of the VH and VL of antibody that correlated with binding to such discontinued or conformational epitope in SEQ ID NO: 2 to enable one of skill in the art to make and use without undue experimentation.
For example, even assuming the first binding site that binds to the extracellular domain of LAG-3 is from an anti-mouse LAG-3 monoclonal antibody TKB58 (the same antibody discloses in the specification), Maeda (Exhibit A, J Biol Chem 294(15): 6017-6026, 2019) teaches recognition of mouse LAG-3 D1, D4, and D2 by TKB58,TKB27,and C9B7W clones of anti-mouse LAG-3 Abs. C9B7W antibody recognized D2 of mouse LAG-3 because it failed to recognize the chimeric molecule with human D2 (Fig. 1A). TBK58 and TBK27 recognized D1 and D4 of mouse LAG-3, respectively (Fig. 1A).
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As such, it is clear that depending on the epitope to which the antibody binds, e.g., D1 versus D2, D3 and/or D4 in the extracellular domain of mouse LAG-3 from which species, the activity, e.g., IL-2 production (Fig C) and the capacity of anti-mouse LAG-3 Abs to block LAG-3function (Fig 1E) are different.
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Further, bispecific antibody that binds to ECD of mouse LAG-3 and CD3 may not bind to ECD of LAG-3 and CD3 from human, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, and the like, in turn, effective for treating any autoimmune disease in species.
In response to the argument that the bispecific molecule suppress T cell activation only when binds to LAG3 and CD3 or CD8 on the same cell or bispecific molecule suppress T cell activation only when the T cells co-express LAG3 and CD3 or CD8, nowhere in any of the rejected claims recite the bispecific antibody binds to LAG3 and CD3 on the same T cell or the activated T cells co-express LAG3 and CD3 or CD8. Maeda teaches that LAG-3 is not expressed on naive T cells but inducibly expressed on T cells upon activation; cell surface expression level of LAG-3 is also regulated by shedding of the EC region by two transmembrane metalloproteases, ADAM10 and ADAM17, see p. 6021, Discussion, in particular.
The argument with respect to preventing any autoimmune disease is moot as claim 18 has been amended.
For these reasons, the rejection is maintained.
New Ground of Rejection Necessitated by Claim Amendment filed December 17, 2025
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 18 and 44 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by et al (US20190153112, published May 23, 2019; PTO 892).
Claims 18 and 44 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by Wang et al (US Patent No. 11,390,679, claimed earliest priority to US62/551927, filed August 30, 2017; PTO 892).
Regarding claims 18 and 44, Wang teaches a method of treating an autoimmune disorder (abstract) comprising administering to a subject, e.g., mouse or human (col. 10, line 64 to col. 11, line 2) in need a bispecific antibody that binds to a first epitope located on extracellular domain (ECD) of lymphocyte activation gene-3 (LAG-3, Examples 1, 5, 6) and the second epitope on CD3 (see col. 15, lines 5-35) comprising a binding domain that binds to CD3 and a second binding domain that binds to LAG-3 (lymphocyte activation gene-3), see para. [0070].
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 18, 40, 44 and 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US Patent No. 11,390,679, claimed earliest priority to US62/551927, filed August 30, 2017; PTO 892) in view of Sentman (of record, US20180085400, published March 29, 2018; PTO 892).
Regarding claims 18 and 40, Wang et al (US Patent No. 11,390,679, claimed earliest priority to US62/551927, filed August 30, 2017; PTO 892).
Regarding claims 18 and 44, Wang teaches a method of treating an autoimmune disorder (abstract) comprising administering to a subject, e.g., mouse or human (col. 10, line 64 to col. 11, line 2) in need a bispecific antibody (reference claim 10) comprising a first binding site (VH and VL) that binds to a first epitope located on extracellular domain (ECD) of lymphocyte activation gene-3 (LAG-3, Examples 1, 5, 6, 7) and a second binding site that binds to a second epitope on CD3 (see col. 15, lines 5-35) comprising a binding domain that binds to CD3 and a second binding domain that binds to LAG-3 (lymphocyte activation gene-3), see para. [0070].
Regarding claim 40, Wang teaches that the first binding site comprises a heavy chain variable region and a light chain variable region of any one of the anti-LAG3 antibody, see VH and VL sequences in Table 11, in particular.
Wang does not teach the second binding site that specifically binds to an extracellular region of CD3 as per claims 18, 44 and 45, wherein the second binding site comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 15 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 16 as per claim 47.
However, Sentman teaches bispecific antibody comprising a first antigen binding site comprising a heavy chain variable region and a light chain variable region of an anti-CD3 antibody and a second antigen binding site that binds to MICA antigen. The reference CD3 binding site comprises a heavy chain variable domain and a light chain variable domain wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 11, which is 100% identical to the claimed SEQ ID NO: 15, see sequence alignment below, the 3 CDRS are in bold, Table 3, in particular.
Query Match 100.0%; Score 609; Length 259;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 EVQLVESGGGLVQPGKSLKLSCEASGFTFSGYGMHWVRQAPGRGLESVAYITSSSINIKY 81
Qy 61 ADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 82 ADAVKGRFTVSRDNAKNLLFLQMNILKSEDTAMYYCARFDWDKNYWGQGTMVTVSS 137
And a light chain variable domain wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 12, which is 100% identical to the claimed SEQ ID NO: 16, see sequence alignment below, 3 CDRs are in bold:
Query Match 100.0%; Score 573; Length 110;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 3 DIQMTQSPSSLPASLGDRVTINCQASQDISNYLNWYQQKPGKAPKLLIYYTNKLADGVPS 62
Qy 61 RFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 63 RFSGSGSGRDSSFTISSLESEDIGSYYCQQYYNYPWTFGPGTKLEIK 109
Product of identical structure is expected to bind to the extracellular domain of CD3. The bispecific antibody (para. [0148], reference claim 5) is useful for treating autoimmune disease, e.g., rheumatoid arthritis (RA), see para. [0166], reference claim 53-54.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Wang and Sentman to treat autoimmune disease such as rheumatoid arthritis by substituting the CD3 binding domain of Wang for the CD3 binding domain that binds to ECD of CD3 as taught by Sentman to arrive at the claimed invention with a reasonable expectation success, i.e., Bispecific T-cell engagers to treat various autoimmune disorders.
One of ordinary skill in the art would have been motivated to do so because Sentman teaches that the bispecific antibody can reduce or alleviate one or more signs or symptoms of the autoimmune disorder, see para. [0127].
One having ordinary skill in the art would have been motivated with the expectation of success to make bispecific antibody that binds to different antigens such as LAG3 and CD3 because Wang teaches that bispecific antibody that binds to LAG-3 and CD3 can be used to treat autoimmune disorder, see Abstract.
One having ordinary skill in the art would have been motivated with the expectation of success to make bispecific antibody that binds to different antigens such as LAG3 and CD3 because the bispecific antibody that binds to ECD of LAG3 and ECD of CD3 is useful for treating autoimmune disorder and Sentman teaches that bispecific antibodies being able to bind to different antigens simultaneously are known in the art, see para. [0150] to [0152].
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 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.
Claims 38 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US Patent No. 11,390,679, claimed earliest priority to 62/551927, filed August 30, 2017; PTO 892) in view of Sentman (of record, US20180085400, published March 29, 2018; PTO 892) as applied to claims 18, 40, 44 and 45, and 47 mentioned above and further in view of Triebel (US20190153112, published May 23, 2019; PTO 892) and Grandal et al (WO2018069500 publication, published; PTO 892).
The teachings of Wang and Sentman have been discussed supra.
The references do not that the first binding site binds to one or more amino acids in a region corresponding to a region ranging from serine at position 23 to isoleucine at position 168 of mouse LAG3 having the amino acid sequence of SEQ ID NO: 2 as per claim 38 or suppresses activation of T cell co-expressing LAG3 and CD3 or CD8 as per claim 52.
However, Triebel teaches the amino acid sequence of human LAG-3 (SEQ ID NO: 27) and murine LAG-3 protein (SEQ ID NO: ). The amino acid sequences of the four extracellular Ig superfamily domains (D1, D2, D3, and D4) of human LAG-3 are at amino acid residues: 1-149 (D1) (SEQ ID NO:28); 150-239 (D2) (SEQ ID NO:29); 240-330 (D3) (SEQ ID NO:39); and 331-412 (D4) (SEQ ID NO:51). Triebel further teaches anti-LAG-3 antibody that binds to LAG-3 D1 domain, see para. [0047], [0049]. Triebel teaches that the antibodies that specifically deplete activated T cells present a promising therapeutic strategy to prevent and/or treat autoimmune disorders, see para. [0007] to [0009]. The anti-LAG-3 antibody inhibits antigen-induced CD4+ and/or CD8+ T cells proliferation, or antigen-induced T cell activation as per claim 52, see para. [0014], [0017], [0018].
Grandal teaches human LAG-3 receptor (CD223) is a 525 amino acid (AA) transmembrane protein that comprises an extracellular domain (ECD) of 427 amino acids (residues 23 -450) followed by a transmembrane domain (residues 451 - 471) and a cytoplasmic domain (residues 472 - 525). LAG-3 ECD contains 4 immunoglobulin domains (D1-D4) where the first domain, an IgV-type domain, is involved in ligand binding (MHCII binding) and the remaining three domains are lgC2 type domains. The first two N-terminal domains alone (D1-D2) are sufficient for ligand binding, and D2 has been shown to be required for correct receptor presentation. Domain 1 contains an additional unique stretch of 30 amino acids (extra loop) that is not found in other IgV-domains and that has been shown to be essential for ligand binding. The mouse LAG-3 comprises SEQ ID NO: 72, which is identical to the claimed SEQ ID NO: 2, see sequence alignment below.
Query Match 100.0%; Score 2764; Length 521;
Best Local Similarity 100.0%;
Matches 521; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MREDLLLGFLLLGLLWEAPVVSSGPGKELPVVWAQEGAPVHLPCSLKSPNLDPNFLRRGG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MREDLLLGFLLLGLLWEAPVVSSGPGKELPVVWAQEGAPVHLPCSLKSPNLDPNFLRRGG 60
Qy 61 VIWQHQPDSGQPTPIPALDLHQGMPSPRQPAPGRYTVLSVAPGGLRSGRQPLHPHVQLEE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VIWQHQPDSGQPTPIPALDLHQGMPSPRQPAPGRYTVLSVAPGGLRSGRQPLHPHVQLEE 120
Qy 121 RGLQRGDFSLWLRPALRTDAGEYHATVRLPNRALSCSLRLRVGQASMIASPSGVLKLSDW 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RGLQRGDFSLWLRPALRTDAGEYHATVRLPNRALSCSLRLRVGQASMIASPSGVLKLSDW 180
Qy 181 VLLNCSFSRPDRPVSVHWFQGQNRVPVYNSPRHFLAETFLLLPQVSPLDSGTWGCVLTYR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VLLNCSFSRPDRPVSVHWFQGQNRVPVYNSPRHFLAETFLLLPQVSPLDSGTWGCVLTYR 240
Qy 241 DGFNVSITYNLKVLGLEPVAPLTVYAAEGSRVELPCHLPPGVGTPSLLIAKWTPPGGGPE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DGFNVSITYNLKVLGLEPVAPLTVYAAEGSRVELPCHLPPGVGTPSLLIAKWTPPGGGPE 300
Qy 301 LPVAGKSGNFTLHLEAVGLAQAGTYTCSIHLQGQQLNATVTLAVITVTPKSFGLPGSRGK 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LPVAGKSGNFTLHLEAVGLAQAGTYTCSIHLQGQQLNATVTLAVITVTPKSFGLPGSRGK 360
Qy 361 LLCEVTPASGKERFVWRPLNNLSRSCPGPVLEIQEARLLAERWQCQLYEGQRLLGATVYA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LLCEVTPASGKERFVWRPLNNLSRSCPGPVLEIQEARLLAERWQCQLYEGQRLLGATVYA 420
Qy 421 AESSSGAHSARRISGDLKGGHLVLVLILGALSLFLLVAGAFGFHWWRKQLLLRRFSALEH 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 AESSSGAHSARRISGDLKGGHLVLVLILGALSLFLLVAGAFGFHWWRKQLLLRRFSALEH 480
Qy 481 GIQPFPAQRKIEELERELETEMGQEPEPEPEPQLEPEPRQL 521
|||||||||||||||||||||||||||||||||||||||||
Db 481 GIQPFPAQRKIEELERELETEMGQEPEPEPEPQLEPEPRQL 521
The term “having” is open ended. It expands the claimed sequence of SEQ ID NO: 2 to include the signal peptide.
Grandal further teaches various antibodies 15532, 15431, 15572, 15011 that binds to ECD of mouse LAG-3, see Table 3, para. [0258], in particular. The anti-LAG-3 antibodies of the invention are able to block the interaction of LAG-3 with its putative ligands such as MHCII, which is mediated by D1, see para. [0082]. The bispecific antibody or anti-LAG-3 that block the interaction between LAG-3 and its ligand such as MHC class II (MHCII) is useful for treating various diseases including autoimmune disease such as psoriasis (see p. 42, line 2), systemic lupus erythematosus, MLS (sclerosis), Crohn’s disease, diabetes mellitus, and/or colitis ulcerotis, see p. 47, para. [0190].
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Wang, Sentman in view of Triebel and Grandal by substituting the binding domain that binds to the LAG-3 in the bispecific antibody for another, e.g., any one of the binding domain that binds to the extracellular domain (ECD), e.g., D1 of mouse LAG-3 comprising the amino acid sequence of SEQ ID NO: 72 as taught by Grandal or Triebel to arrive at the claimed invention with a reasonable expectation success, i.e., treating autoimmune disease, such as rheumatoid arthritis by administering a Bispecific antibody that binds to the ECD of mouse LAG-3 and ECD of CD3.
One of ordinary skill in the art would have been motivated to and had a reasonable expectation of success to do so because Triebel teaches that the antibodies that specifically deplete activated T cells present a promising therapeutic strategy to prevent and/or treat autoimmune disorders, see para. [0007] to [0009] and Grandal teaches that bispecific antibody or anti-LAG-3 antibodies that binds to the domain 1 of ECD of mouse LAG-3 are able to block the interaction of LAG-3 with its putative ligands such as MHCII, see para. [0082].
One having ordinary skill in the art would have been motivated with the expectation of success to make bispecific antibody that binds to domain 1 in the ECD of murine LAG3 and the ECD of CD3 each of which is useful for sample purpose. In this case, Wang teaches that bispecific antibody that binds to LAG-3 and CD3 can be used to treat autoimmune disorder (see Abstract), Triebel teaches that the LAG-3 binding antibodies that specifically deplete activated T cells present a promising therapeutic strategy to prevent and/or treat autoimmune disorders (see para. [0007] to [0009]) and Grandal teaches that bispecific antibody or anti-LAG-3 that block the interaction between LAG-3 and its ligand such as MHC class II (MHCII) is useful for treating various diseases including autoimmune disease such as psoriasis (see p. 42, line 2), systemic lupus erythematosus, MLS (sclerosis), Crohn’s disease, diabetes mellitus, and/or colitis ulcerotis (see p. 47, para. [0190]) would have motivated one of skilled in the art to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 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: 9-11, 12-14, 7 and 8 are free of prior art.
Claims 41-43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641