FINAL ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment filed June 4, 2025 is acknowledged. Claims 1, 16, 34, 39, 57 have been amended. Claims 66-74 are new. Claims 2-15, 17-33, 35-38, 40-56, 58-65 have been canceled. Claims 1, 16, 34, 39, 57 and 66-74 are pending and under examination.
Specification Objection
The specification objection, page 3 of the Nonfinal Office action Mailed January 16, 2025 has been withdrawn based on Applicant’s amendment to the specification.
Rejections Withdrawn
In view of Applicant’s amendments, the rejection of claim 1 rejected under 102(a)(1) as being anticipated by Yamamoto et al., page 18 of the Nonfinal Office Action mailed January 16, 2025 is withdrawn.
In view of Applicant’s amendments, the rejection of claim 16 rejected under 102(a)(1) as being anticipated by Ring et al., page 19 of the Nonfinal Office Action mailed January 16, 2025 is withdrawn.
In view of Applicant’s amendments, the rejection of claim 39 rejected under 102(a)(1) as being anticipated by Ring et al., page 19 of the Nonfinal Office Action mailed January 16, 2025 is withdrawn.
Rejection Maintained
The rejection of claims 1, 16, 34, 39, 57 and newly submitted claims 66-74 is maintained under 35 U.S.C. 112(a) (written description).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 1, 16, 34, 39, 57 and newly submitted claims 66-74 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or 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 the Applicants were in possession of the claimed genus.
Claim 1. A composition comprising a variant human IL18 protein, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions selected from the group consisting of E6, S7, of SEQ ID NO: 1 or SEQ ID NO: 2.
Claim 16. A monovalent Fc fusion protein comprising:(a) a first monomer comprising from N-terminus to C-terminus: a variant human IL-18 protein and a first Fc domain of human IgG, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions selected from the group consisting of E6, S7, S10, V11, N14, L15, Q18, D23, R27, P28, L29, M33, R39, R44, I46, I49, S50, D54, A61, V62, T63, S65, K67, E69, 171, 180, 181, N87, P88, D90, K93, T95, K96, S97, S119, A126, D132, L136, L138, K139, E141, L144, D146, R147, 1149, M150,E156, and D157, as compared to wildtype human IL18 of SEQ ID NO: 1 or SEQ ID NO: 2; and(b) a second monomer comprising a second Fc domain of human IgG.
Claim 34. A monovalent Fc fusion protein comprising:(a) a first monomer comprising from N-terminus to C-terminus: a variant human IL-18 protein and a first Fc domain of human IgG, wherein the variant human IL[[-]] 18 protein comprises amino acid substitutions 4CS/E6Q/S10C/K53D/N111T/N155C as compared to wildtype human IL18 of SEQ ID NO: 1 or SEQ ID NO: 2, and wherein the variant human IL-18 protein is covalently attached to the N-terminus of the first Fe domain; and(b) a second monomer comprising a second Fe domain of human IgG, wherein the first Fe domain comprises amino acid substitutions C220S/PVA/S267K/L368D/K370S/M428L/N434S, and the second Fe domain comprises amino acid substitutions PVA/S267K/S364K/E357Q/M428L/N434S, according to EU numbering.
Claim 39. A Fab-Fc fusion protein comprising:(a) a first monomer comprising from N-terminus to C-terminus: a variable heavy (VH) chain and a first Fc domain of human IgG;(b) a second monomer comprising from N-terminus to C-terminus: a variant human IL-18 protein and a second Fc domain of human IgG, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions selected from the group consisting of E6, S7, S10, V11, N14, L15, Q18, D23, R27, P28, L29, M33, R39, R44, I46, I49, S50, D54, A61, V62, T63, S65, K67, E69, 171, 180, 181, N87, P88, D90, K93, T95, K96, S97, S119, A126, D132, L136, L138, K139, E141, L144, D146, R147, 1149, M150, E156, and D157, as compared to wildtype human IL18 of SEQ ID NO: 1 or SEQ ID NO: 2; and(c) a third monomer comprising a variable light (VL) chain, wherein the VH and VL form an antigen binding fragment (Fab).
Claim 57. A Fab-Fc fusion protein comprising:(a) a first monomer comprising from N-terminus to C-terminus: a variable heavy (VH) chain and a first Fc domain of human IgG;(b) a second monomer comprising from N-terminus to C-terminus: a variant human IL-18 protein and a second Fc domain of human IgG, wherein the variant human IL-18 protein comprises amino acid substitutions 4CS/E6Q/S10C/K53D/N111T/N155C as compared to wildtype human IL18 of SEQ ID NO: 1 or SEQ ID NO: 2; and(c) a third monomer comprising a variable light (VL) chain, wherein the VH and VL form an antigen binding fragment (Fab), wherein the first Fe domain comprises amino acid substitutions C220S/PVA_/S267K/L368D/K370S/M428L/N434S, and the second Fe domain comprises amino acid substitutions PVA/S267K/S364K/E357Q/M428L/N434S, according to EU numbering.
Claim 66. The composition of claim 1, wherein the variant human IL18 protein comprises one or more amino acid substitutions selected from the group consisting of:E6A, E6Q, S7C, S7P, K8Y, K8Q, K8E, S10C, V11I, N14C, N14W, L15C, Q18L, D23N, D23S, R27Q, P28C, L29V, M33C, T34P, R39T, R39S, E42A, R44Q, I46V, I49C, S50C,S50Y, K53N, K53R, K53H, K53M, K53E, K53Q, K53A, K53S, K53G, K53T, K53I, K53L, K53D, K53V, K53Y, K53F, D54C, Q56I, Q56L, A61C, V62C, T63C, S65C, K67Q, E69K, I71M, E77K, I80T, I81V, I81L, N87S, P88C, D90E, K93D, K93N, T95E, K96G, K96Q, S97N, Q103C, Q103E, Q1031, Q103L, S119L, A126C, D132Q, D132E, L136C, L138C, K139C, E141K, E141Q, L144N, D146Y, D146L, D146F, R147C, R147K, 1149V, M150F, M150T, N155C, E156Q, and D157N.
Claim 67. The composition of claim 1, wherein the variant human IL18 protein comprises amino acid substitutions selected from the group consisting of:4CS/E6A, 4CS/E6Q, 4CS/S10C/E31Q/I49C, 4CS/L15C/E31Q/R147C, 4CS/P28C/E31Q/L136C, 4CS/E31Q/S50C/P88C, 4CS/E31Q/T63C/P88C, 4CS/E31Q/V62C/Q103C, 4CS/S10C/E31Q/N155C, 4CS/E31Q/S65C/P88C, 4CS/S7C/E31Q/S50C, 4CS/E31Q/D54C/A61C, 4CS/E31Q/A126C/K139C, 4CS/N14W/E31Q, 4CS/E31 Q/D 146Y, 4CS/E31 Q/D 146L, 4CS/E31 Q/D 146F, 4CS/E31 Q/M150F, 4CS/Q 18L/E31Q, 4CS/S7P/E31Q, 4CS/V 11I/E31Q, 4CS/D23N/E31Q, 4CS/D23 S/E31Q, 4CS/R27Q/E31Q, 4CS/L29V/E31Q, 4CS/E31 Q/R39T, 4CS/E31 Q/R39S, 4CS/E31 Q/R44Q, 4CS/E31Q/I46V, 4CS/E31 Q/S50Y, 4CS/E31 Q/K67Q, 4CS/E31 Q/E69K, 4CS/E31Q/17iM, 4CS/E31Q/I80T, 4CS/E31Q/I81 V, 4CS/E31Q/I81 L, 4CS/E31 Q/N87S, 4CS/E31 Q/D90E, 4CS/E31 Q/K93D/T95E, 4CS/E31 Q/K93N/T95E, 4CS/E31 Q/T95E, 4CS/E31 Q/K96G,4CS/E31 Q/S97N, 4CS/E31 Q/S 119L, 4CS/E31Q/L 144N, 4CS/E31 Q/R147K, 4CS/E31Q/I149V, 4CS/E31 Q/M150T, 4CS/E31 Q/E 156Q/D 157N, 4CS/D23N/E31Q/R27Q, 4CS/E31 Q/Q56L/T95E, 4CS/E31 Q/K96Q/S 119L, 4CS/E31 Q/E 141K/I149V, 4CS/E31Q/E141Q/I149V, 4CS/S7P/E31Q/S50Y, 4CS/S10C/D35E/N155C, 4CS/S10C/S36D/N155C, 4CS/S10C/S36N/N155C, 4CS/S10C/K53V/N155C, 4CS/S10C/K53Y/N155C, 4CS/S10C/K53F/N155C, 4CS/S10C/M51R/N155C, 4CS/S10C/M51L/N155C, 4CS/S10C/M51H/N155C, 4CS/S10C/M51F/N155C, 4CS/S10C/M51Y/N155C, 4CS/S10C/S55D/N155C, 4CS/S10C/S55E/N155C, 4CS/S10C/S55T/N155C, 4CS/S10C/P57Q/N155C, 4CS/S10C/P57D/N155C, 4CS/S10C/P57Y/N155C, 4CS/S10C/P57N/N155C, 4CS/S10C/M60Y/N155C, 4CS/S10C/M60F/N155C, 4CS/S10C/D110Q/N155C, 4CS/S10C/D110R/N155C, 4CS/S10C/N111D/N155C, 4CS/S10C/N111S/N155C, 4CS/S10C/N111T/N155C, 4CS/S10C/N111E/N155C, 4CS/S10C/D132Q/N155C, 4CS/S10C/D132E/N155C, 4CS/E6Q/S10C/K53D/N155C, 4CS/E6Q/S10C/M51K/K53D/N155C, 4CS/S10C/E31Q/D35N/N41Q/K53A/N155C, 4CS/S10C/E31Q/N41Q/K53A/N155C, 4CS/S10C/E31Q/K53A/N155C, 4CS/S10C/K53T/N155C, 4CS/S10C/P57A/N155C, 4CS/S10C/N155C, 4CS/S10C/M51K/K53D/N155C, 4CS/S10C/K53D/N155C, 4CS/S10C/E31Q/N41Q/N155C, 4CS/S10C/M51L/K53D/N155C, 4CS/S10C/K53D/D110R/N155C, 4CS/S10C/K53D/N111T/N155C, 4CS/S10C/K53D/S55T/N155C, 4CS/S10C/K53D/S55T/D110R/N155C, 4CS/S1OC/M51L/K53D/S55T/D110R/N 111 T/N155C, 4CS/S10C/M51L/K53D/S55T/D110R/N155C, 4CS/S10C/K53D/S55T/D110R/N111T/N155C, 4CS/S10C/K53D/S55T/N111T/N155C, 4CS/S10C/E31Q/D35N/N155C, 4CS/S10C/N41Q/N155C, 4CS/S10C/D35N/N155C, 4CS/S10C/D37N/N155C, 4CS/S10C/E31Q/D37N/N155C, 4CS/S10C/D35N/D37N/N155C, 4CS/S10C/D37N/K53D/N155C, and 4CS/E6Q/S10C/K53D/N111T/N155C, wherein 4CS comprises the amino acid substitutions C38S/C68S/C76S/C172S.
Claim 68. The composition of claim 1, wherein the variant human IL18 protein comprises amino acid substitutions 4CS/E6Q/S10C/K53D/N111T/N155C. 69. (New) The monovalent Fe fusion protein of claim 16, wherein the variant human IL18 protein comprises one or more amino acid substitutions selected from the group consisting of:E6A, E6Q, S7C, S7P, K8Y, K8Q, K8E, S10C, V11I, N14C, N14W, L15C, Q18L, D23N, D23S, R27Q, P28C, L29V, M33C, T34P, R39T, R39S, E42A, R44Q, I46V, I49C, S5OC,S5OY, K53N, K53R, K53H, K53M, K53E, K53Q, K53A, K53S, K53G, K53T, K53I, K53L, K53D, K53V, K53Y, K53F, D54C, Q56I, Q56L, A61C, V62C, T63C, S65C, K67Q, E69K, I71M, E77K, I80T, I81V, I81L, N87S, P88C, D90E, K93D, K93N, T95E, K96G, K96Q, S97N, Q103C, Q103E, Q103I, Q103L, S119L, A126C, D132Q, D132E, L136C, L138C, K139C, E141K, E141Q, L144N, D146Y, D146L, D146F, R147C, R147K, I149V, M150F, M150T, N155C, E156Q, and D157N.
Claim 70. The monovalent Fc fusion protein of claim 16, wherein the variant human IL18 protein comprises amino acid substitutions selected from the group consisting of:4CS/E6A, 4CS/E6Q, 4CS/S10C/E31Q/I49C, 4CS/L15C/E31Q/R147C, 4CS/P28C/E31Q/L136C, 4CS/E31Q/S5OC/P88C, 4CS/E31Q/T63C/P88C, 4CS/E31Q/V62C/Q103C, 4CS/S10C/E31Q/N155C, 4CS/E31Q/S65C/P88C, 4CS/S7C/E31Q/S5OC, 4CS/E31Q/D54C/A61C, 4CS/E31Q/A126C/K139C, 4CS/N14W/E31Q, 4CS/E31 Q/D 146Y, 4CS/E31 Q/D 146L, 4CS/E31 Q/D 146F, 4CS/E31 Q/M150F, 4CS/Q 18L/E31Q, 4CS/S7P/E31Q, 4CS/V 11IE31Q, 4CS/D23N/E31Q, 4CS/D23S/E31Q, 4CS/R27Q/E31Q, 4CS/L29V/E31Q, 4CS/E31 Q/R39T, 4CS/E31 Q/R39S, 4CS/E31 Q/R44Q, 4CS/E31Q/I46V, 4CS/E31Q/S5OY, 4CS/E31Q/K67Q, 4CS/E31Q/E69K, 4CS/E31Q/I71M, 4CS/E31Q/I80T, 4CS/E31Q/I81 V, 4CS/E31Q/I81 L, 4CS/E31 Q/N87S, 4CS/E31 Q/D90E, 4CS/E31 Q/K93D/T95E, 4CS/E31 Q/K93N/T95E, 4CS/E31 Q/T95E, 4CS/E31 Q/K96G, 4CS/E31 Q/S97N, 4CS/E31 Q/S 119L, 4CS/E31Q/L 144N, 4CS/E31 Q/R147K, 4CS/E31Q/I149V, 4CS/E31 Q/M150T, 4CS/E31 Q/E 156Q/D 157N, 4CS/D23N/E31Q/R27Q, 4CS/E31 Q/Q56L/T95E, 4CS/E31 Q/K96Q/S 119L, 4CS/E31 Q/E 141K/I149V, 4CS/E31Q/E141Q/I149V, 4CS/S7P/E31Q/S5OY, , 4CS/S10C/D35E/N155C, 4CS/S10C/S36D/N155C, 4CS/S10C/S36N/N155C, 4CS/S10C/K53V/N155C, 4CS/S10C/K53Y/N155C, 4CS/S10C/K53F/N155C, 4CS/S10C/M51R/N155C, 4CS/S10C/M51L/N155C, 4CS/S10C/M51H/N155C, 4CS/S10C/M51F/N155C, 4CS/S10C/M51Y/N155C, 4CS/S10C/S55D/N155C, 4CS/S10C/S55E/N155C, 4CS/S10C/S55T/N155C, 4CS/S10C/P57Q/N155C, 4CS/S10C/P57D/N155C, 4144-1821-2187.1 64CS/S10C/P57Y/N155C, 4CS/S10C/P57N/N155C, 4CS/S10C/M60Y/N155C, 4CS/S10C/M60F/N155C, 4CS/S10C/D110Q/N155C, 4CS/S10C/D110R/N155C, 4CS/S10C/N111D/N155C, 4CS/S10C/N111S/N155C, 4CS/S10C/N111T/N155C, 4CS/S10C/N111E/N155C, 4CS/S10C/D132Q/N155C, 4CS/S10C/D132E/N155C, 4CS/E6Q/S10C/K53D/N155C, 4CS/E6Q/S10C/M51K/K53D/N155C, 4CS/S10C/E31Q/D35N/N41Q/K53A/N155C, 4CS/S10C/E31Q/N41Q/K53A/N155C, 4CS/S10C/E31Q/K53A/N155C, 4CS/S10C/K53T/N155C, 4CS/S10C/P57A/N155C, 4CS/S10C/N155C, 4CS/S10C/M51K/K53D/N155C, 4CS/S10C/K53D/N155C, 4CS/S10C/E31Q/N41Q/N155C, 4CS/S10C/M51L/K53D/N155C, 4CS/S10C/K53D/D110R/N155C, 4CS/S10C/K53D/N111T/N155C, 4CS/S10C/K53D/S55T/N155C, 4CS/S10C/K53D/S55T/D110R/N155C, 4CS/S1OC/M51L/K53D/S55T/D110R/N 111 T/N155C, 4CS/S10C/M51L/K53D/S55T/D110R/N155C, 4CS/S10C/K53D/S55T/D110R/N111T/N155C, 4CS/S10C/K53D/S55T/N111T/N155C, 4CS/S10C/E31Q/D35N/N155C, 4CS/S10C/N41Q/N155C, 4CS/S10C/D35N/N155C, 4CS/S10C/D37N/N155C, 4CS/S10C/E31Q/D37N/N155C, 4CS/S10C/D35N/D37N/N155C, 4CS/S10C/D37N/K53D/N155C, and 4CS/E6Q/S10C/K53D/N111T/N155C, wherein 4CS comprises the amino acid substitutions C38S/C68S/C76S/C172S.
Claim 71. The monovalent Fc fusion protein of claim 70, wherein the variant human IL18 protein comprises amino acid substitutions 4CS/E6Q/S10C/K53D/N111T/N155C.
Claim 72. The Fab-Fc fusion protein of claim 39, wherein the variant human IL18 protein comprises one or more amino acid substitutions selected from the group consisting of:E6A, E6Q, S7C, S7P, K8Y, K8Q, K8E, S10C, V11I, N14C, N14W, L15C, Q18L, D23N, D23S, R27Q, P28C, L29V, M33C, T34P, R39T, R39S, E42A, R44Q, I46V, I49C, S5OC,S5OY, K53N, K53R, K53H, K53M, K53E, K53Q, K53A, K53S, K53G, K53T, K53I, K53L, K53D, K53V, K53Y, K53F, D54C, Q56I, Q56L, A61C, V62C, T63C, S65C, K67Q, E69K, I71M, E77K, I80T, I81V, I81L, N87S, P88C, D90E, K93D, K93N, T95E, K96G, K96Q, S97N, Q103C, Q103E, Q103I, Q103L, S119L, A126C, D132Q, D132E, L136C, L138C, K139C, E141K, E141Q, L144N, D146Y, D146L, D146F, R147C, R147K, I149V, M150F, M150T, N155C, E156Q, and D157N.
Claim 73. The Fab-Fc fusion protein of claim 39, wherein the variant human IL18 protein comprises amino acid substitutions selected from the group consisting of:4CS/E6A, 4CS/E6Q, 4CS/S10C/E31Q/I49C, 4CS/L15C/E31Q/R147C, 4CS/P28C/E31Q/L136C, 4CS/E31Q/S5OC/P88C, 4CS/E31Q/T63C/P88C, 4CS/E31Q/V62C/Q103C, 4CS/S10C/E31Q/N155C, 4CS/E31Q/S65C/P88C, 4CS/S7C/E31Q/S5OC, 4CS/E31Q/D54C/A61C, 4CS/E31Q/A126C/K139C, 4CS/N14W/E31Q, 4CS/E31 Q/D 146Y, 4CS/E31 Q/D 146L, 4CS/E31 Q/D 146F, 4CS/E31 Q/M150F, 4CS/Q 18L/E31Q, 4CS/S7P/E31Q, 4CS/V 11IE31Q, 4CS/D23N/E31Q, 4CS/D23 S/E31Q, 4CS/R27Q/E31Q, 4CS/L29V/E31Q, 4CS/E31 Q/R39T, 4CS/E31 Q/R39S, 4CS/E31 Q/R44Q, 4CS/E31Q/I46V, 4CS/E31Q/S5OY, 4CS/E31Q/K67Q, 4CS/E31Q/E69K, 4CS/E31Q/I71M, 4CS/E31Q/I80T, 4CS/E31Q/I81 V, 4CS/E31Q/I81 L, 4CS/E31 Q/N87S, 4CS/E31 Q/D90E, 4CS/E31 Q/K93D/T95E, 4CS/E31 Q/K93N/T95E, 4CS/E31 Q/T95E, 4CS/E31 Q/K96G, 4CS/E31 Q/S97N, 4CS/E31 Q/S 119L, 4CS/E31Q/L 144N, 4CS/E31 Q/R147K, 4CS/E31Q/I149V, 4CS/E31 Q/M150T, 4CS/E31 Q/E 156Q/D 157N, 4CS/D23N/E31Q/R27Q, 4CS/E31 Q/Q56L/T95E, 4CS/E31 Q/K96Q/S 119L, 4CS/E31 Q/E 141K/I149V, 4CS/E31Q/E141Q/I149V, 4CS/S7P/E31Q/S5OY, 4CS/S10C/D35E/N155C, 4CS/S10C/S36D/N155C, 4CS/S10C/S36N/N155C, 4CS/S10C/K53V/N155C, 4CS/S10C/K53Y/N155C, 4CS/S10C/K53F/N155C, 4CS/S10C/M51R/N155C, 4CS/S10C/M51L/N155C, 4CS/S10C/M51H/N155C, 4CS/S10C/M51F/N155C, 4CS/S10C/M51Y/N155C, 4CS/S10C/S55D/N155C, 4CS/S10C/S55E/N155C, 4CS/S10C/S55T/N155C, 4CS/S10C/P57Q/N155C, 4CS/S10C/P57D/N155C, 4CS/S10C/P57Y/N155C, 4CS/S10C/P57N/N155C, 4CS/S10C/M60Y/N155C, 4CS/S10C/M60F/N155C, 4CS/S10C/D110Q/N155C, 4CS/S10C/D110R/N155C, 4CS/S10C/N111D/N155C, 4CS/S10C/N111S/N155C, 4CS/S10C/N111T/N155C, 4CS/S10C/N111E/N155C, 4CS/S10C/D132Q/N155C, 4CS/S10C/D132E/N155C, 4CS/E6Q/S10C/K53D/N155C, 4CS/E6Q/S10C/M51K/K53D/N155C, 4CS/S10C/E31Q/D35N/N41Q/K53A/N155C, 4CS/S10C/E31Q/N41Q/K53A/N155C, 4CS/S10C/E31Q/K53A/N155C, 4CS/S10C/K53T/N155C, 4CS/S10C/P57A/N155C, 4CS/S10C/N155C, 4CS/S10C/M51K/K53D/N155C, 4CS/S10C/K53D/N155C, 4CS/S10C/E31Q/N41Q/N155C, 4CS/S10C/M51L/K53D/N155C, 4CS/S10C/K53D/D110R/N155C, 4CS/S10C/K53D/N111T/N155C,4CS/S10C/K53D/S55T/N155C, 4CS/S10C/K53D/S55T/D110R/N155C, 4CS/S1OC/M51L/K53D/S55T/D110R/N 111 T/N155C, 4CS/S10C/M51L/K53D/S55T/D110R/N155C, 4CS/S10C/K53D/S55T/D110R/N111T/N155C, 4CS/S10C/K53D/S55T/N111T/N155C, 4CS/S10C/E31Q/D35N/N155C, 4CS/S10C/N41Q/N155C, 4CS/S10C/D35N/N155C, 4CS/S10C/D37N/N155C, 4CS/S10C/E31Q/D37N/N155C, 4CS/S10C/D35N/D37N/N155C, 4CS/S10C/D37N/K53D/N155C, and 4CS/E6Q/S10C/K53D/N111T/N155C, wherein 4CS comprises the amino acid substitutions C38S/C68S/C76S/C172S.
Claim 74. The Fab-Fc fusion protein of claim 73, wherein the variant human IL18 protein comprises amino acid substitutions 4CS/E6Q/S10C/K53D/N111T/N155C.
The claims broadly encompass a genus of variant human IL18 proteins, monovalent Fc fusion proteins comprising the IL-18 variants, and Fab-Fc fusion proteins that are not adequately described.
With regard to the IL-18 variants and fusion proteins comprising variant IL-18 proteins, although the claims are inclusive of the fully described IL-18 variants and IL-18 fusion proteins disclosed in the specification, the claims also encompass (i) IL-18 variants in which the IL-18 protein comprises a modification at one and up to 75 of the amino acid positions recited in the claims compared to the parent protein, and (ii) IL-18 fusion proteins in which the IL-18 protein comprises at least one modification at any amino acid position compared to the parent protein. The modifications that produce the required functions are not defined, which means that essentially any of the recited amino acid positions can be substituted with any of the 20 naturally occurring amino acids. Further, there is no limitation that the substitution, for example, must be conservative. Moreover, the modification can be an addition, deletion, or substitution. As a result, there are potentially thousands of variant permutations that could be made. However, the specification fails to provide sufficient correlation between the structure of the IL-18 variants and the required functional characteristics (i.e., improved production and/or reduced binding affinity and/or improved stability and/or improved potency). The specification does not correlate any particular structure to a defined function, which is emphasized in the specification. Applicant has only provided a few structurally very similar proteins, which does not demonstrate the breadth of the genus sufficiently for one of skill in the art to immediately envisage the alternative proteins that have the required functions. These proteins have no correlation between their structure and function.
With regard to the Fc portion of the fusion proteins, the claims do not specify any particular Fc domain, and encompass any known Fc domain in the art. The specification teaches that “Fc” or “Fc region” or “Fc domain” refers to the polypeptide comprising the constant region of an antibody, in some instances, excluding all of the first constant region immunoglobulin domain (e.g., CH1) or a portion thereof, and in some cases, optionally including all or part of the hinge. The specification teaches that for IgG, the Fc domain comprises immunoglobulin domains CH2 and CH3 (Cy2 and Cy3), and optionally all or a portion of the hinge region between CH1 (Cγ1) and CH2 (Cy2). The specification teaches that in some cases, the Fc domain includes, from N- to C-terminus, CH2-CH3 and hinge-CH2-CH3. The specification teaches that in some embodiments, the Fc domain is that from IgG1, IgG2, IgG3 or IgG4, with IgG1 hinge-CH2-CH3 and IgG4 hinge-CH2-CH3 finding particular use in many embodiments. The specification teaches that wherein the Fc domain is a human IgG1 Fc domain, the hinge includes a C220S amino acid substitution. The specification teaches that in some embodiments where the Fc domain is a human IgG4 Fc domain, the hinge includes a S228P amino acid substitution. Thus, the claims broadly encompass IL-18 fusion proteins comprising any number of IL-18 variants and any number of Fc domains. Although, the specification describes specific fusion proteins comprising specific Fc domains, the claims encompass far more than the few species disclosed. Thus, the Fc fusion proteins are described only in terms of their function, and the specification fails to disclose a structure function correlation for the fusion proteins.
With regard to the Fab-Fc fusion proteins, the claims do not specify the structure of the variable chain, first Fc domain, variable light chain, or second Fc domain. The heavy and light chain must form an antigen binding fragment; however, there is no guidance regarding the heavy and light chain sequence such that one would know which heavy and light chains pair to form a functional antigen binding fragment. Thus, the Fab-Fc fusions are described only in terms of their function, and the specification fails to disclose a structure function correlation for the fusion proteins. These proteins have no correlation between their structure and function.
The claims recite the phrase “as compared to wildtype IL-18”. This is merely and comparison and no sequence is required. It cannot be determined whether the claims are referring to the sequences of SEQ ID Nos. 1 and 2.
Furthermore, Application has not shown possession of a represented number of species that have the claimed function(s). While the specification sets forth a correlation between the IL-18 variants and fusion proteins comprising the variants specifically described in the specification, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed Il-18 variants and IL-18 fusion protein sequences disclosed, and broadly encompass IL-18 variants with modifications at up to 75 positions, and in some embodiments, IL-18 variants comprising one or more modifications at any amino acid residue of the parent sequence. Further, the Fc fusions encompass any number of Fc domains, and the Fab-Fc fusions encompass any heavy chain and light chain variable region that forms an antigen binding site. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus.
There are substantial variations with species correlation, because of the numerous alternative species, and there is limited description of the species. While the specification clearly sets forth a correlation between variant human IL-18 variants and variant IL-18 proteins specifically disclosed by sequence in the specification, this correlation does not appear to be clearly present in the breadth of the claims. The claims are not limited to the disclosed variant human IL18 and variant IL18 protein sequences and broadly encompass IL18 variants with up to 75 amino acid substitutions and variant IL18 proteins. However, the genus of variant human IL18 and variants IL18 proteins has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure of each species, in common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be a representative number of species in the breadth of the genus. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genu[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous heterodimers had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of heterodimers claimed only by a partial structure and functional characteristic(s).
Vas-Cath Inc. v. Mahurkar, 19 U5PQ2d 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.)
With the exception of the variant human IL-18 protein, wherein the variant IL18 described proteins set forth in the specification, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. 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. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, 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.
`University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d
1565,1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("The description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
In Ariad Pharrns., Inc. v. Eh Lilly & Co., 598 F.3d 1336,1351 (Fed. Cir. 2010), the court held that 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." Ariad, 598 F. Bd at 1350.
An adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” Id. Although “functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genu and showing that one has invented a genus and not just a species.”Id.
Tsutsumi et al. (“The structural for receptor recognition of the human interlukin-18. Nat Commun 5, 5340 p 2-4, Figure 2, Figure 3 (2014)) teach IL18, a proinflammatory cytokine which is secreted by various types of cells and strongly augments IFN-y production in type-1 helper T (Th1) cells and natural killer (NK) cells following activation of NK cell cytotoxicity. Tsutsumi et al. teaches the structures and associated biochemical and cellular data should aid in developing novel drugs (Tsutsumi et al See p 2).
Ring et al. (US2021/0015891 A1 publication date 21 January 2021) teach the various structural additions of one or more modifications, will have a more complex functional / structural, certain positions on sequences are critical for structural / functional relationship. The position in the protein’s sequence where such modifications and/or amino acid substitutions can be made with reasonable expectation of maintaining function in the claim, all the substitutions in the claims and modifications in the specification teaches, will be convoluted. (Ring et al, See paragraph [0071]).
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three-dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138,1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252,1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue falls. Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of assigning a function to an amino acid sequence based upon similarity as taught by Whisstock, the claimed proteins could not be predicted. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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). In view of all of the above, the rejection is maintained.
Applicant’s Arguments
Applicant urges that they have amended the claims to recite “an amino acid substitution”. “ as compared to wildtype human IL18 of SEQ ID NO:1 or SEQ ID NO.2” and “a first Fc domain of human IgG”.
Applicant argues that they disagree with the Office’s assertion that the claims contain subject matter which has not been described in the specification in a way to reasonably convey to one skilled in the relevant art that the inventor…at the time of filing was in possession of the claimed invention.
Applicant argues that the specification provides sequences of the claimed proteins in the sequence listings, figures and presents experimental observation based on the sequences including figures.
Response to Applicant’s Arguments
The Office acknowledges Applicant’s amendments. However, due to the recitation of the claim language “as compared to wild type human n IL18” the claims, the claims do not positively recite a reference sequence.
Applicant's arguments filed June 4, 2025 have been fully considered but they are not persuasive. The claims are drawn to a composition comprising an amino acid substitution mutants as compared to wildtype human IL18 of SEQ ID No:1 or SEQ ID No.2. The claim language as presented compare the mutants with the SEQ ID Nos. 1 or 2. It does not require that the sequences are definite in the claims. The claims require amino acid substitutions at one or more amino acid positions across the sequence. Therefore, Applicant is not in possession of claimed invention.
There are substantial variations with species correlation, because of the numerous alternative species, and there is limited description of the species. While the specification clearly sets forth a correlation between variant human IL-18 variants and variant IL-18 proteins specifically disclosed by sequence in the specification, this correlation does not appear to be clearly present in the breadth of the claims.
The rejection of claims 1, 16, 34, 39, 57 and newly submitted claims 66-74 is maintained under 35 U.S.C. 112(b).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1, 16, 34, 39, 57and newly amended claims 66-74 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), the second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to a pre -AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims are drawn to composition and fc fusion proteins comprising a variant human IL18 protein, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions. However, the claims do not provide reference sequence such that one of skill in the art would know which variant human IL18 the recited amino acid modification would work. The specification recites the IL-18 has the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2; however, these limitations are not in the claims. Applicant can overcome the rejection by amending the claim to recite a reference sequence for IL-18. Clarification and/or correction is required.
Applicant’s Arguments
Applicant argues that the claims have been amended to clarify the issue.
Response to Applicant’s Arguments
The claims recite “as compared to wild type human IL18”. However, the claims do not provide reference sequence such that one of skill in the art would know which variant human IL18 the recited amino acid modification would work. The specification recites the IL-18 has the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 2; however, these limitations are not positively recited in the claims. Only a comparison is required. Applicant can overcome the rejection by amending the claims to positively recite a reference sequence for IL-18. Clarification and/or correction is required.
New Grounds of Rejection Necessitated by Applicant’s Amendment
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jirakrit et al. (PLOS One, August 2, 2016).
Claim 1. A composition comprising a variant human IL18 protein, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions selected from the group consisting of E6, S7,
Jirakrit et al. teach compositions comprising IL18 variants E6K and T63A (See the Abstract). Jirakrit et al. anticipate the claimed invention.
Claim 1 and 66 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou et al. (Nature 2020 July; 583(7817): 609-614).
Claim 1. A composition comprising a variant human IL18 protein, wherein the variant human IL18 protein comprises an amino acid substitution at one or more amino acid positions selected from the group consisting of E6, S7, of SEQ ID NO: 1 or SEQ ID NO: 2.
Claim 66. The composition of claim 1, wherein the variant human IL18 protein comprises one or more amino acid substitutions selected from the group consisting of:E6A, E6Q, S7C, S7P, K8Y, K8Q, K8E, S10C, V11I, N14C, N14W, L15C, Q18L, D23N, D23S, R27Q, P28C, L29V, M33C, T34P, R39T, R39S, E42A, R44Q, I46V, I49C, S50C,S50Y, K53N, K53R, K53H, K53M, K53E, K53Q, K53A, K53S, K53G, K53T, K53I, K53L, K53D, K53V, K53Y, K53F, D54C, Q56I, Q56L, A61C, V62C, T63C, S65C, K67Q, E69K, I71M, E77K, I80T, I81V, I81L, N87S, P88C, D90E, K93D, K93N, T95E, K96G, K96Q, S97N, Q103C, Q103E, Q1031, Q103L, S119L, A126C, D132Q, D132E, L136C, L138C, K139C, E141K, E141Q, L144N, D146Y, D146L, D146F, R147C, R147K, 1149V, M150F, M150T, N155C, E156Q, and D157N.
Zhou et al teach compositions comprising IL18 variants E6A and K53A (under subheading engineering a “decoy-resistant” IL-18 (DR-18)). Zhou et al. anticipate the claimed invention.
Status of Claims
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Patricia Mallari whose telephone number is 571.272.4729. The examiner can normally be reached Monday to Friday 9:00 -5:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa L Ford can be reached at 571.272.0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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