Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 45 and 56-74 are pending.
Claims 60-64, 66, 68-74 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 45, 56-62, 65 and 67, drawn to a method for producing an antibody, are being acted upon 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 26, 2026 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Specification
The amendment to the specification filed on January 26, 2026 has been entered.
Rejection Withdrawn
The new matter rejection of claims 45, 49, 55-62 and 64 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the claim amendment.
Claim Rejections - 35 USC § 112
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.
Claims 45 and 56-74 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
The recitation of “more strongly” in claim 45 is indefinite because the metes and bounds of what would constitute a “more strongly” cannot be determined. The term "more strongly" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 45 recites “at one or more of the following Kabat numbering positions VH positions 27, 31, 32, 33, 35, 50, 52, 57, 58, 59, 61, 62, 98, 99, 100b, 102 and 107, and VL positions 27, 28, 31, 32, 50, 53, 54, 56, 89, 90, 91, 92, 93 and 94”. The language is ambiguous because it is unclear if the claim requires a selection of at one or more from either the VH or VL positions, or if at one or more positions in both VH and VL must be occupied by histidine residue.
Claims 56-74 are included in the rejection because they are dependent on rejected claim and do not correct the deficiency of the claim from which they depend.
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 45 and 56-74 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 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).
The claims are drawn to a method for producing any antibody, the method comprising
screening a library of polypeptides, each of which comprises an antigen-binding domain comprising a heavy chain variable domain (VH) sequence and a light chain variable domain (VL) sequence, to select an antigen-binding domain that binds to an antigen with an antigen- binding activity that is lower at acidic pH than at neutral pH, wherein the acidic pH is a pH in the range of pH 4.0 to 6.5 and the neutral pH is a pH in the range of pH 6.7 to 10.0, and wherein the selected antigen-binding domain comprises a histidine residue at one or more of the following Kabat numbering positions: VH positions 27, 31, 32, 33, 35, 50, 52, 57, 58, 59, 61, 62, 98, 99, 100b, 102, and 107, and VL positions 27, 28, 31, 32, 50, 53, 54, 56, 89, 90, 91, 92, 93, and 94; and
producing an antibody comprising (1) an antigen-binding domain comprising the VH and VL sequences of the selected antigen-binding domain and (2) a non-native Fc region that in which EU numbering position 238 is Asp or EU numbering position 328 is Glu, wherein the non- native Fc region (a) binds to a human FcRn at pH 7.0 more strongly than a native human IgG1 Fc region binds to the human FcRn, so that a KD value of binding to the human FcRn can be measured, and (b)
comprises one of the following combinations of substitutions, wherein each position number is according to EU numbering: P238D/E233D, P238D/S267A, P238D/S267Q, P238D/S267V, P238D/H268D, P238D/H268E, P238D/H268N, P238D/P271G, P238D/Y296D, P238D/V323I, P238D/V323L, P238D/V323M, P238D/K326A, P238D/K326D, P238D/K326E, P238D/K326L, P238D/K326M, P238D/K326N, P238D/K326Q, P238D/K326S, P238D/K326T, P238D/A330K, P238D/A33 OM, P238D/A330R, E233D/P238D/V323M, E233D/P238D/Y296D, E233D/P238D/A3 30K, P238D/Y296D/A3 30K, P238D/V323M/A330K, G237D/P238D/A3 30K, P238D/K326A/A330K, L234Y/P238D/A3 30K,G237D/P238D/K326A/A330K, L234Y/P238D/K326A/A3 30K, E233D/P238D/Y296D/A3 30K, E233D/P238D/V323M/A330K, E233D/G237D/P238D/A3 30K, E233D/P238D/K326A/A330K, E233D/L234Y/P238D/A330K, L234Y/P238D/K326A, G237D/P238D/K326A, L234Y/G237D/P238D,L234Y/G237D/P238D/K326A,L234Y/G237D/P238D/K326A/A3 30K,E233D/L324Y/G237D/P238D/K326A/A3 30K,E233D/L234Y/G237D/P238D/Y296D/K326A/A3 30K,L234Y/G237D/P238D/K326A/A33 OR,E233D/L234Y/G237D/P238D/K326A/A33 OR,E233D/L234Y/G237D/P238D/Y296D/K326A/A33 OR,E233D/P238D/K326D/A330K,E233D/L234Y/G237D/P238D/P271 G/K326D/A3 30K,E233D/G237D/P238D/P271 G/A3 30K, G237D/P238D/P271 G/K326A/A3 30K,G237D/P238D/P271G/A330K,E233D/P238D/P271 G/K326A/A3 30K, E233D/P238D/P271 G/Y296D/A3 30K,E233D/L234Y/P238D/P271 G/K326A/A3 30K,E233D/P238D/P271 G/A3 30K,E233D/L234Y/G237D/P238D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/P271 G/Y296D/K326A/A3 30K,L234Y/P238D/P271 G/K326A/A3 30K,E233D/G237D/P238D/H268D/P271 G/A3 30K, G237D/P238D/H268D/P271 G/K326A/A3 30K,G237D/P238D/H268D/P271 G/A3 30K,E233D/P238D/H268D/P271 G/K326A/A3 30K, E233D/P238D/H268D/P271 G/Y296D/A3 30K,E233D/P238D/H268D/P271 G/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/Y296D/K326A/A3 30K,L234Y/P238D/H268D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/Y296D/K326D/A3 30K,E233D/L234Y/P238D/H268D/P271 G/K326A/A3 30K,E233D/P238D/K326D/A330R,E233D/L234Y/G237D/P238D/P271 G/K326D/A33 OR,E233D/G237D/P238D/P271 G/A33 OR, G237D/P238D/P271 G/K326A/A33 OR,G237D/P238D/P271G/A330R,E233D/P238D/P271 G/K326A/A33 OR, E233D/P238D/P271 G/Y296D/A33 OR,E233D/P238D/P271 G/A33 OR,E233D/P238D/A33 OR,E233D/G237D/P238D/H268D/P271 G/A33 OR, G237D/P238D/H268D/P271 G/K326A/A33 OR,G237D/P238D/H268D/P271 G/A33 OR,E233D/P238D/H268D/P271 G/K326A/A33 OR, E233D/P238D/H268D/P271 G/Y296D/A33 OR,E233D/P238D/H268D/P271G/A330R, or E233D/L234Y/G237D/P238D/Y296D/K326D/A330K.
The specification discloses a method of producing Human IL-6 Receptor-Binding Human Antibodies.
[0094] FIG. 1 is a diagram showing effects on a soluble antigen of an existing neutralizing antibody and an antibody that binds to an antigen in a pH-dependent manner and exhibits augmented FcRn binding under a neutral condition.
[0095] FIG. 2 is a graph showing a plasma concentration time course after intravenous or subcutaneous administration of Fv4-IgG1 or Fv4-IgG1-F1 to normal mice.
[0096] FIG. 3 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to human FcγRIa.
[0097] FIG. 4 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to human FcγRIIa(R).
[0098] FIG. 5 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to human FcγRIIa(H).
[0099] FIG. 6 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to human FcγRIIb.
[0100] FIG. 7 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to human FcγRIIIa(F).
[0101] FIG. 8 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to mouse FcγRI.
[0102] FIG. 9 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to mouse FcγRIIb.
[0103] FIG. 10 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to mouse FcγRIII.
[0104] FIG. 11 is a graph demonstrating that in a human FcRn-bound state, Fv4-IgG1-F157 binds to mouse FcγRIV.
[0105] FIG. 12 is a graph demonstrating that in a mouse FcRn-bound state, Fv4-IgG1-F20 binds to mouse FcγRI, mouse FcγRIIb, mouse FcγRIII, and mouse FcγRIV.
[0106] FIG. 13 is a graph demonstrating that in a mouse FcRn-bound state, mPM1-mIgG1-mF3 binds to mouse FcγRIIb and mouse FcγRIII.
[0107] FIG. 14 is a graph showing a plasma concentration time course of Fv4-IgG1-F21, Fv4-IgG1-F140, Fv4-IgG1-F157, and Fv4-IgG1-F424 in human FcRn transgenic mice.
[0108] FIG. 15 is a graph showing a plasma concentration time course of Fv4-IgG1 and Fv4-IgG1-F760 in human FcRn transgenic mice.
[0109] FIG. 16 is a graph showing a plasma concentration time course of Fv4-IgG1-F11, Fv4-IgG1-F890, Fv4-IgG1-F947, Fv4-IgG1-F821, Fv4-IgG1-F939, and Fv4-IgG1-F1009 in human FcRn transgenic mice.
[0110] FIG. 17 is a graph showing a plasma concentration time course of mPM1-mIgG1-mF14, mPM1-mIgG1-mF38, mPM1-mIgG1-mF39, and mPM1-mIgG1-mF40 in normal mice.
[0111] FIG. 18 is a diagram showing the result of immunogenicity assessment using Fv4-IgG1-F21 and Fv4-IgG1-F140.
[0112] FIG. 19 is a diagram showing the result of immunogenicity assessment using hA33-IgG1-F21 and hA33-IgG1-F140.
[0113] FIG. 20 is a diagram showing the result of immunogenicity assessment using hA33-IgG1-F698 and hA33-IgG1-F699.
[0114] FIG. 21 is a diagram showing the result of immunogenicity assessment using hA33-IgG1-F698 and hA33-IgG1-F763.
[0115] FIG. 22 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F11, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice.
[0116] FIG. 23 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F821, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice.
[0117] FIG. 24 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F890, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice. B is an enlargement of A
[0118] FIG. 25 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F939, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice.
[0119] FIG. 26 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F947, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice.
[0120] FIG. 27 is a graph showing titers of mouse antibody produced against Fv4-IgG1-F1009, 3, 7, 14, 21, and 28 days after administration to human FcRn transgenic mice.
[0121] FIG. 28 is a graph showing titers of mouse antibody produced against mPM1-IgG1-mF14, 14, 21, and 28 days after administration to normal mice.
[0122] FIG. 29 is a graph showing titers of mouse antibody produced against mPM1-IgG1-mF39, 14, 21, and 28 days after administration to normal mice.
[0123] FIG. 30 is a graph showing titers of mouse antibody produced against mPM1-IgG1-mF38, 14, 21, and 28 days after administration to normal mice.
[0124] FIG. 31 is a graph showing titers of mouse antibody produced against mPM1-IgG1-mF40, 14, 21, and 28 days after administration to normal mice.
[0125] FIG. 32 is a graph showing the plasma antibody concentrations for Fv4-IgG1-F947 and Fv4-IgG1-FA6a/FB4a 15 minutes, seven hours, one, two, three, four, and seven days after administration to human FcRn transgenic mice.
[0126] FIG. 33 is a diagram showing variance in the binding of each B3 mutant to FcγRIIb and FcγRIa.
[0127] FIG. 34 is a diagram showing variance in the binding of each B3 mutant to FcγRIIb and FcγRIIa(H).
[0128] FIG. 35 is a diagram showing variance in the binding of each B3 mutant to FcγRIIb and FcγRIIa(R).
[0129] FIG. 36 is a diagram showing variance in the binding of each B3 mutant to FcγRIIb and FcγRIIIa.
[0130] FIG. 37 is a graph showing the plasma kinetics of a soluble human IL-6 receptor in normal mice and the antibody titer of mouse antibody against the soluble human IL-6 receptor in mouse plasma.
[0131] FIG. 38 is a graph showing the plasma kinetics of a soluble human IL-6 receptor in normal mice administered with an anti-mouse CD4 antibody and the antibody titer of mouse antibody against the soluble human IL-6 receptor in mouse plasma.
[0132] FIG. 39 is a graph showing the plasma kinetics of an anti-IL-6 receptor antibody in normal mice.
[0133] FIG. 40 is a graph showing a time course of soluble human IL-6 receptor concentration after co-administration of a soluble human IL-6 receptor and an anti-IL-6 receptor antibody to human FcRn transgenic mice.
[0134] FIG. 41 is a diagram showing the structure of the Fab fragment heavy-chain CDR3 of antibody 6RL #9 determined by X-ray crystallography.
[0135] FIG. 42 is a graph showing a plasma antibody concentration time course for H54/L28-IgG1, 6RL #9-IgG1, and FH4-IgG1 in normal mice.
[0136] FIG. 43 is a graph showing a time course of plasma soluble human IL-6 receptor concentration in normal mice administered with H54/L28-IgG1, 6RL #9-IgG1, or FH4-IgG1.
[0137] FIG. 44 is a graph showing a time course of the plasma antibody concentrations of H54/L28-N434W, 6RL #9-N434W, and FH4-N434W in normal mice.
[0138] FIG. 45 is a graph showing a time course of plasma soluble human IL-6 receptor concentration in normal mice administered with H54/L28-N434W, 6RL #9-N434W, or FH4-N434W.
[0139] FIG. 46 is an ion-exchange chromatogram for an antibody comprising a human Vk5-2 sequence and an antibody comprising an h Vk5-2_L65 sequence which has a modified glycosylation sequence of the human Vk5-2 sequence. The solid line represents a chromatogram for the antibody comprising the human Vk5-2 sequence (heavy chain: CIM_H., SEQ ID NO: 108; and light chain: hVk5-2, SEQ ID NO: 4). The broken line represents a chromatogram for the antibody comprising the hVk5-2_L65 sequence (heavy chain: CIM_H (SEQ ID NO: 108); and light chain: hVk5-2_L65 (SEQ ID NO: 107)).
[0140] FIG. 47 is a diagram showing an alignment of the constant region sequences of IgG1, IgG2, IgG3, and IgG4, which are numbered according to the EU numbering system.
[0141] FIG. 48 is a schematic diagram showing the formation of a tetramer complex consisting of one molecule of an Fc region that has FcRn-binding activity in a neutral pH range, two molecules of FcRn, and one molecule of FcγR.
[0142] FIG. 49 is a schematic diagram showing the interaction of two FcRn molecules and one FcγR molecule with an Fc region that has FcRn-binding activity in a neutral pH range and a lower binding activity to activating FcγR than that of a native Fc region.
[0143] FIG. 50 is a schematic diagram showing the interaction of two FcRn molecules and one FcγR molecule with an Fc region that has FcRn-binding activity in a neutral pH range and selective binding activity to inhibitory FcγR.
[0144] FIG. 51 is a schematic diagram showing the interaction of two FcRn molecules and one FcγR molecule with an Fc region in which only one of the two polypeptides of FcRn-binding domain has FcRn-binding activity in a neutral pH range and the other does not have FcRn-binding activity in a neutral pH range.
[0145] FIG. 52 is a graph showing the relationship of a designed amino acid distribution (indicated as Design) to the amino acid distribution (indicated as Library) for the sequence information on 290 clones isolated from E. coli introduced with a gene library of antibodies that bind to antigens in a Ca-dependent manner. The horizontal axis indicates amino acid positions in the Kabat numbering system. The vertical axis indicates % amino acid distribution.
[0146] FIG. 53 is a graph showing the relationship of a designed amino acid distribution (indicated as Design) to the amino acid distribution (indicated as Library) for the sequence information on 132 clones isolated from E. coli introduced with a gene library of antibodies that bind to antigens in a pH-dependent manner. The horizontal axis indicates amino acid positions in the Kabat numbering system. The vertical axis indicates % amino acid distribution.
[0147] FIG. 54 is a graph showing a plasma concentration time course of Fv4-IgG1-F947 and Fv4-IgG1-F1326 in human FcRn transgenic mice administered with Fv4-IgG1-F947 or Fv4-IgG1-F1326.
[0148] FIG. 55 shows a graph in which the horizontal axis shows the relative value of FcγRIIb-binding activity of each PD variant, and the vertical axis shows the relative value of FcγRIIa type R-binding activity of each PD variant. The value for the amount of binding of each PD variant to each FcγR was divided by the value for the amount of binding of IL6R-F652, which is a control antibody prior to introduction of the alteration (altered Fc with substitution of Pro at position 238 (indicated by EU numbering) with Asp), to each FcγR; and then the obtained value was multiplied by 100, and used as the relative binding activity value for each PD variant to each FcγR. The F652 plot in the figure shows the value for IL6R-F652.
[0149] FIG. 56 shows a graph in which the vertical axis shows the relative value of FcγRIIb-binding activity of variants produced by introducing each alteration into GpH7-B3 which does not have the P238D alteration, and the horizontal axis shows the relative value of FcγRIIb-binding activity of variants produced by introducing each alteration into IL6R-F652 which has the P238D alteration. The value for the amount of FcγRIIb binding of each variant was divided by the value for the amount of FcγRIIb binding of the pre-altered antibody; and then the obtained value was multiplied by 100, and used as the value of relative binding activity. Here, region A contains alterations that exhibit the effect of enhancing FcγRIIb binding in both cases where an alteration is introduced into GpH7-B3 which does not have P238D and where an alteration is introduced into IL6R-F652 which has P238D. Region B contains alterations that exhibit the effect of enhancing FcγRIIb binding when introduced into GpH7-B3 which does not have P238D, but do not exhibit the effect of enhancing FcγRIIb binding when introduced into IL6R-F652 which has P238D.
[0150] FIG. 57 shows a crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex.
[0151] FIG. 58 shows an image of superimposing the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex and the model structure of the Fc(WT)/FcγRIIb extracellular region complex, with respect to the FcγRIIb extracellular region and the Fc CH2 domain A by the least squares fitting based on the Ca atom pair distances.
[0152] FIG. 59 shows comparison of the detailed structure around P238D after superimposing the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex and the model structure of the Fc(WT)/FcγRIIb extracellular region complex with respect to the only Fc CH2 domain A or the only Fc CH2 domain B by the least squares fitting based on the Ca atom pair distances.
[0153] FIG. 60 shows that a hydrogen bond can be found between the main chain of Gly at position 237 (indicated by EU numbering) in Fc CH2 domain A, and Tyr at position 160 in FcγRIIb in the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex.
[0154] FIG. 61 shows that an electrostatic interaction can be found between Asp at position 270 (indicated by EU numbering) in Fc CH2 domain B, and Arg at position 131 in FcγRIIb in the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex.
[0155] FIG. 62 shows a graph in which the horizontal axis shows the relative value of FcγRIIb-binding activity of each 2B variant, and the vertical axis shows the relative value of FcγRIIa type R-binding activity of each 2B variant. The value for the amount of binding of each 2B variant to each FcγR was divided by the value for the amount of binding of a control antibody prior to alteration (altered Fc with substitution of Pro at position 238 (indicated by EU numbering) with Asp) to each FcγR; and then the obtained value was multiplied by 100, and used as the value of relative binding activity of each 2B variant towards each FcγR.
[0156] FIG. 63 shows Glu at position 233 (indicated by EU numbering) in Fc Chain A and the surrounding residues in the extracellular region of FcγRIIb in the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex.
[0157] FIG. 64 shows Ala at position 330 (indicated by EU numbering) in Fc Chain A and the surrounding residues in the extracellular region of FcγRIIb in the crystal structure of the Fc(P238D)/FcγRIIb extracellular region complex.
[0158] FIG. 65 shows the structures of Pro at position 271 (EU numbering) of Fc Chain B after superimposing the crystal structures of the Fc(P238D)/FcγRIIb extracellular region complex and the Fc(WT)/FcγRIIIa extracellular region complex by the least squares fitting based on the Ca atom pair distances with respect to Fc Chain B.
Regarding screening library and selecting any antigen-binding domain that binds to any antigen (claim 45), the specification discloses screening a library and selecting a pH-dependent antibody that binds to human IL-6R antigen in a pH-dependent manner, see FIG. 1, 53.
However, the specification does not teach selecting any antigen binding domain comprises a histidine residue at one or more positions in VH and/or VL.
Regarding antigen-binding activity that is lower at acidic pH than at neutral pH, wherein the acidic pH is a pH in the range of pH 4.0 to 6.5 and the neutral pH is a pH in the range of pH 6.7 to 10, the specification discloses that the antigen binding is measured using just BIACORE where the dissociation constant (KD) for antigen-binding is weaker at acidic pH, e.g., 5.8 than at a neutral pH, e.g., 7.4, at 25˚C, which is the value of KD (pH5.8) / KD (pH7.4), see specification at p. 77.
The specification does not teach selecting antigen-binding domain whose antigen binding activity that is lower at acidic pH, e.g., pH 4.0 to 6.5 than neutral pH, e.g., 8.0 to 10.0.
It is known in the art that pure water is neutral at pH 7.0 at 25˚C. However, a pH of greater than 8.0 is considered basic, not neutral. For example, sea water has a pH of 8.0, baking soda has a pH of 9.5 and ammonia solution has a pH of 10.5 to 11.5.
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Regarding producing an antibody comprising an antigen-binding domain comprising any VH and VL sequences selected from screening library above and any non-native Fc region that binds to a human FcRn at pH 7.0 more strongly than a native human IgG1 Fc region that binds to the human FcRn, and the Fc has any one of the combination of substitution in claim 45, the specification discloses a method of producing a pH dependent human IL-6 receptor binding-antibody (see p. 284) wherein the
[0564] Binding activity (dissociation constant KD) to human FcRn at pH 7.0 and binding activity to mouse FcγR at pH 7.4 of antibodies containing the produced VH3-IgG1-F21, VH3-IgG1-F140, VH3-IgG1-F157 or VH3-IgG1-F424 for the heavy chain and L(WT)-CK for the light chain were measured using the method shown below.
(4-3) Kinetic Analysis of Binding to Human FcRn
[0565] A kinetic analysis of binding between human FcRn and the aforementioned antibodies was carried out using the BIACORE™ T100 or T200 surface plasmon resonance system (GE Healthcare). The antibodies being tested were captured on the CM4 Sensor Chip (GE Healthcare) on which a suitable amount of Protein L (ACTIGEN® protein (Alltech)) was suitably immobilized by amine coupling. Next, diluted human FcRn and a running buffer used as a blank were injected to allow the human FcRn to interact with the antibody captured on the sensor chip. A buffer consisting of 50 mmol/L sodium phosphate, 150 mmol/L NaCl and 0.05% (w/v) polysorbate 20 (Tween 20®) (pH 7.0 or pH 7.4) was used for the running buffer, and each buffer was also used to dilute the human FcRn. 10 mmol/L glycine-HCl (pH 1.5) was used to regenerate the sensor chip. All measurements of binding were carried out at 25° C. The K.sub.D(M) of each antibody to human FcRn was calculated based on kinetics parameters, i.e., the association rate constant ka (1/Ms) and the dissociation rate constant kd (1/s) calculated from a sensorgram obtained by the measurement. The BIACORE™ T100 or T200 Evaluation Software (GE Healthcare) was used to calculate each parameter.
(7-2) Evaluation of Binding Activity to Human FcγR
[0613] The binding activities of VH3/L(WT)-IgG1, VH3/L(WT)-IgG1-F21 and VH3/L(WT)-IgG1-F140 to human FcγR at pH 7.4 were measured using the method shown below.
[0614] Binding activity between the antibodies and human FcγRIa, FcγRIIa(H), FcγRIIa(R), FcγRIIb and FcγRIIIa(F) (hereinafter referred to as human FcγRs) was evaluated using the BIACORE™ T100 or T200 surface plasmon resonance system (GE Healthcare). The antibodies being tested were captured by Protein L (ACTIGEN® protein (Alltech)) that was immobilized in suitable amounts on the CM4 Sensor Chip (GE Healthcare) by amine coupling. Next, the diluted human FcγRs and a running buffer used as a blank were injected to allow interaction with the antibodies captured on the sensor chip. A buffer consisting of 20 mmol/L N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), 150 mmol/L NaCl and 0.05% (w/v) polysorbate 20 (Tween 20®) (pH 7.4) was used for the running buffer, and this buffer was also used to dilute the human FcγRs. 10 mmol/L glycine-HCl (pH 1.5) was used to regenerate the sensor chip. All measurements were carried out at 25° C.
[0615] Binding activity to human FcγRs can be represented by the relative binding activity to human FcγRs. Antibody was captured by Protein L, and the amount of change in a sensorgram before and after the antibody was captured was defined as X1. Next, human FcγRs were allowed to interact with the antibody, and the value obtained by subtracting binding activity of human FcγRs represented as the amount of change in a sensorgram before and after allowing the running buffer to interact with antibody captured by Protein L (ΔA2) from the value obtained by multiplying by 1500 the value obtained by dividing the binding activity of human FcγRs represented as the amount of change in a sensorgram before and after that interaction (ΔA1) by the captured amount (X) of each antibody, was divided by the captured amount of each antibody (X) followed by multiplying by 1500 to obtain the binding activity of the human FcγRs (Y) (Equation 2).
Binding activity of human FcγRs(Y)=(ΔA1−ΔA2)/X×1500 [Equation 2]
[0616] The results are shown in Table 14 below.
TABLE-US-00015 TABLE 14 BINDING AMOUNT (RU) hFcgRIa hFcgRIIa(R) hFcgRIIa(H) hFcgRIIb hFcgRIIIa(F) IgG1 399.6 158.9 158.7 81.4 143.8 IgG1-F21 403.0 145.2 153.6 63.4 146.7 IgG1-F140 335.1 7.6 8.8 2.2 1.8
[0617] According to the results of Table 14, Fv4-IgG1-F140 demonstrated a decrease in binding to each human FcγR without affecting the binding activity to human FcRn in comparison with Fv4-IgG1-F21.
(8-2) Production of an A33-Binding Antibody Having Binding Activity to Human FcRn Under Conditions of the Neutral pH Region
[0627] Since the produced hA33-IgG1 is a human antibody having a naturally-occurring human Fc region, it does not have binding activity to human FcRn under conditions of the neutral pH region. Therefore, an amino acid modification was introduced into the heavy chain constant region of hA33-IgG1 in order to impart the ability to bind to human FcRn under conditions of the neutral pH region.
[0628] More specifically, hA33H-IgG1-F21 (SEQ ID NO: 65) was produced by substituting Tyr for Met at position 252 (EU numbering), substituting Pro for Val at position 308 (EU numbering) and substituting Tyr for Asn at position 434 (EU numbering) in the heavy chain constant region of hA33-IgG1 in the form of hA33H-IgG1. Using the method of Reference Example 2, an A33-binding antibody having binding activity to human FcRn under conditions of the neutral pH region was produced in the form of hA33-IgG1-F21 containing hA33H-IgG1-F21 for the heavy chain and hA33L-k0 for the light chain.
(8-3) Production of an A33-Binding Antibody Containing an FcγR-Binding Domain Whose Binding Activity to Human FcγR Under Conditions of the Neutral pH Region is Lower than the Binding Activity of a Native FcγR-Binding Domain
[0629] hA33H-IgG1-F140 (SEQ ID NO: 66) was produced in which Lys is substituted for Ser at position 239 (EU numbering) in the amino acid sequence of hA33H-IgG1-F21 in order to lower the binding activity of hA33-IgG1-F21 to human FcγR.
However, the specification does not teach which combination of modification, e.g., substitutions, deletions, additions or a combination thereof in the human IgG1 Fc that binds to human FcRn at pH 7.0 more strongly than a native human IgG1 Fc (claim 45), presumably the pH dependent antibody has increased human FcRn-binding than FcRn-binding than that of intact human IgG1, that would improve antigen elimination from plasma. The specification discloses antibody plasma retention is known to worsen as a result of binding to FcRn under neutral conditions. If an antibody ends up bound to FcRn under neutral conditions, even if the antibody returns to the cell surface by binding to FcRn under acidic conditions in endosomes, an IgG antibody is not recycled to the plasma unless the IgG antibody dissociates from FcRn in the plasma under neutral conditions, thereby conversely causing plasma retention to be impaired.
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Regarding antibody in claims 60-63, 68-74, the specification discloses pH dependent antibodies that binds to just human IL-6 receptor.
However, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Such claims are often referred to as “reach-through” claims, where an applicant attempts to obtain patent protection on an invention not yet discovered. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In this case, the specification does not describe the amino acid sequences of heavy and light chain variable regions encompassed by the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed antibodies themselves.
The specification does not disclose a representative number of species of such antibody that is produced by the claimed method, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function (i.e., a correlation between the primary sequence of the antibody heavy chain variable region and light chain variable region and specific binding to any and all antigen.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Antibodies that bind to human IL-6 receptor do not bind to other protein or different epitope from the same protein.
At the time the invention was made, one of skill in the art was aware that the number and sequence of antibodies that bind to a single protein is a very large and structurally diverse genus (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes), as is evidenced below.
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 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., 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).
Khan and Salunke (J. Immunol. 192: 5398-5405, 2014; PTO 892) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences.
Poosarla et al (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.)
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.
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 that bind to just human IL-6 receptor, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to any and all antigen (as held in Abbvie).
In AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014), a claim drawn to a genus of antibodies having a recited binding affinity and binding specificity to a fully characterized antigen was found to be invalid for lack of written description such that it was not infringed by a subsequently disclosed antibody having all of the recited functional characteristics but a completely different structure (amino acid sequence). The Court held:
“It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date... The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara®, whereas the patents do not describe representative examples to support the full scope of the claims. (AbbVie, 759 F.3d at 1298; 111 USPQ2d at 1791) (emphasis added).
Since the disclosure does not describe the common attributes or structural characteristics that identify members of the genus, and because the genus is highly variant, the binding of antibody to human FcRn at pH 7.0 whose antigen-binding activity is lower at acidic pH than at neutral pH is insufficient to describe the genus of antibodies produced by the claimed method. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus at the time the invention was made.
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, there is insufficient written description for genus of the antibodies broadly encompassed by the claims, other than the pH dependent human IL-6 receptor binding antibodies produced by the claimed method described in the specification as filed under the written description provision of 35 USC 112, first paragraph.
Applicants’ arguments filed January 26, 2026 have been fully considered but are not found persuasive.
Applicants’ position is that the present amendment to claim 45 deletes VL position 24, 52 and 55, but not VH position 33. Applicant points out that VH position 33 is specified trice in Table 43. Further, applicant has added four more VH positions to claim 45 (VH positions 52, 57, 98 and 107), all of which are supported by Table 43.
The Office action at pages 10 to 11 helpfully describes a scope that the Office deems to have sufficient written description support. This scope includes a limitation referencing Tables 49 to 51 of the specification. Those tables list combinations of substitutions that enhance binding to human FcγRIIb compared to an activating Fcγ receptor. The Office action says at page 12 that applicant's prior argument regarding the claim 45 limitation about increased Fc binding to FcRn at neutral pH 7.4 "is moot," which applicant understands to mean that applicant's prior argument overcame the rejection as to that particular functional limitation.
Without acquiescing in this ground of rejection, applicant has amended claim 45 as suggested by the Examiner, i.e., to remove the functional limitation regarding enhanced binding toward human FcγRIIb compared to an activating Fcγ receptor and instead specify structure, i.e., that the non-native Fc region comprises a combination of substitutions derived from the combinations listed in Tables 49 and 51 (the combinations listed in Table 50 being identical to those listed in Table 49). Because each of the combinations now listed in claim 45 includes Asp at EU numbering position 238, the separate limitation in the claim specifying Asp at position 238 is deleted as redundant. The claim language approved by the Examiner does not specify particular substitutions that increase Fc binding to FcRn at neutral pH, so applicant assumes that the Examiner is satisfied that the 1000+ species disclosed in Table 27 are considered to provide sufficient written description support for that functional limitation.
In response, the amendment to claim 45 is acknowledged. The new matter rejection is mooted as the rejection has been withdrawn.
Claim 45 encompasses a method for producing any antibody, the method comprising
screening a library of polypeptides, each of which comprises an antigen-binding domain comprising a heavy chain variable domain (VH) sequence and a light chain variable domain (VL) sequence, to select an antigen-binding domain that binds to an antigen with an antigen- binding activity that is lower at acidic pH than at neutral pH, wherein the acidic pH is a pH in the range of pH 4.0 to 6.5 and the neutral pH is a pH in the range of pH 6.7 to 10.0, and wherein the selected antigen-binding domain comprises a histidine residue at one or more of the following Kabat numbering positions: VH positions 27, 31, 32, 33, 35, 50, 52, 57, 58, 59, 61, 62, 98, 99, 100b, 102, and 107, and VL positions 27, 28, 31, 32, 50, 53, 54, 56, 89, 90, 91, 92, 93, and 94; and
producing an antibody comprising (1) an antigen-binding domain comprising the VH and VL sequences of the selected antigen-binding domain and (2) a non-native Fc region that in which EU numbering position 238 is Asp or EU numbering position 328 is Glu, wherein the non- native Fc region (a) binds to a human FcRn at pH 7.0 more strongly than a native human IgG1 Fc region binds to the human FcRn, so that a KD value of binding to the human FcRn can be measured, and (b)
comprises one of the following combinations of substitutions, wherein each position number is according to EU numbering: P238D/E233D, P238D/S267A, P238D/S267Q, P238D/S267V, P238D/H268D, P238D/H268E, P238D/H268N, P238D/P271G, P238D/Y296D, P238D/V323I, P238D/V323L, P238D/V323M, P238D/K326A, P238D/K326D, P238D/K326E, P238D/K326L, P238D/K326M, P238D/K326N, P238D/K326Q, P238D/K326S, P238D/K326T, P238D/A330K, P238D/A33 OM, P238D/A330R, E233D/P238D/V323M, E233D/P238D/Y296D, E233D/P238D/A3 30K, P238D/Y296D/A3 30K, P238D/V323M/A330K, G237D/P238D/A3 30K, P238D/K326A/A330K, L234Y/P238D/A3 30K,G237D/P238D/K326A/A330K, L234Y/P238D/K326A/A3 30K, E233D/P238D/Y296D/A3 30K, E233D/P238D/V323M/A330K, E233D/G237D/P238D/A3 30K, E233D/P238D/K326A/A330K, E233D/L234Y/P238D/A330K, L234Y/P238D/K326A, G237D/P238D/K326A, L234Y/G237D/P238D,L234Y/G237D/P238D/K326A,L234Y/G237D/P238D/K326A/A3 30K,E233D/L324Y/G237D/P238D/K326A/A3 30K,E233D/L234Y/G237D/P238D/Y296D/K326A/A3 30K,L234Y/G237D/P238D/K326A/A33 OR,E233D/L234Y/G237D/P238D/K326A/A33 OR,E233D/L234Y/G237D/P238D/Y296D/K326A/A33 OR,E233D/P238D/K326D/A330K,E233D/L234Y/G237D/P238D/P271 G/K326D/A3 30K,E233D/G237D/P238D/P271 G/A3 30K, G237D/P238D/P271 G/K326A/A3 30K,G237D/P238D/P271G/A330K,E233D/P238D/P271 G/K326A/A3 30K, E233D/P238D/P271 G/Y296D/A3 30K,E233D/L234Y/P238D/P271 G/K326A/A3 30K,E233D/P238D/P271 G/A3 30K,E233D/L234Y/G237D/P238D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/P271 G/Y296D/K326A/A3 30K,L234Y/P238D/P271 G/K326A/A3 30K,E233D/G237D/P238D/H268D/P271 G/A3 30K, G237D/P238D/H268D/P271 G/K326A/A3 30K,G237D/P238D/H268D/P271 G/A3 30K,E233D/P238D/H268D/P271 G/K326A/A3 30K, E233D/P238D/H268D/P271 G/Y296D/A3 30K,E233D/P238D/H268D/P271 G/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/Y296D/K326A/A3 30K,L234Y/P238D/H268D/P271 G/K326A/A3 30K,E233D/L234Y/G237D/P238D/H268D/P271 G/Y296D/K326D/A3 30K,E233D/L234Y/P238D/H268D/P271 G/K326A/A3 30K,E233D/P238D/K326D/A330R,E233D/L234Y/G237D/P238D/P271 G/K326D/A33 OR,E233D/G237D/P238D/P271 G/A33 OR, G237D/P238D/P271 G/K326A/A33 OR,G237D/P238D/P271G/A330R,E233D/P238D/P271 G/K326A/A33 OR, E233D/P238D/P271 G/Y296D/A33 OR,E233D/P238D/P271 G/A33 OR,E233D/P238D/A33 OR,E233D/G237D/P238D/H268D/P271 G/A33 OR, G237D/P238D/H268D/P271 G/K326A/A33 OR,G237D/P238D/H268D/P271 G/A33 OR,E233D/P238D/H268D/P271 G/K326A/A33 OR, E233D/P238D/H268D/P271 G/Y296D/A33 OR,E233D/P238D/H268D/P271G/A330R, or E233D/L234Y/G237D/P238D/Y296D/K326D/A330K.
Regarding screening library and selecting any antigen-binding domain that binds to any antigen (claim 45), the specification discloses screening a library and selecting a pH-dependent antibody that binds to human IL-6R antigen in a pH-dependent manner, see FIG. 1, 53.
However, the specification does not teach selecting any antigen binding domain comprises a histidine residue at one or more positions in VH and/or VL.
Regarding antigen-binding activity that is lower at acidic pH than at neutral pH, wherein the acidic pH is a pH in the range of pH 4.0 to 6.5 and the neutral pH is a pH in the range of pH 6.7 to 10, the specification discloses that the antigen binding is measured using just BIACORE where the dissociation constant (KD) for antigen-binding is weaker at acidic pH, e.g., 5.8 than at a neutral pH, e.g., 7.4, at 25˚C, which is the value of KD (pH5.8) / KD (pH7.4), see specification at p. 77.
The specification does not teach selecting antigen-binding domain whose antigen binding activity that is lower at acidic pH, e.g., pH 4.0 to 6.5 than neutral pH, e.g., 8.0 to 10.0.
It is known in the art that pure water is neutral at pH 7.0 at 25˚C. However, a pH of greater than 8.0 is considered basic, NOT neutral. For example, sea water has a pH of 8.0, baking soda has a pH of 9.5 and ammonia solution has a pH of 10.5 to 11.5.
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Regarding producing an antibody comprising an antigen-binding domain comprising any VH and VL sequences selected from screening library above and any non-native Fc region that binds to a human FcRn at pH 7.0 more strongly than a native human IgG1 Fc region that binds to the human FcRn, and the Fc has any one of the combination of substitution in claim 45, the specification discloses a method of producing a pH dependent human IL-6 receptor binding-antibody (see p. 284) wherein the
[0564] Binding activity (dissociation constant KD) to human FcRn at pH 7.0 and binding activity to mouse FcγR at pH 7.4 of antibodies containing the produced VH3-IgG1-F21, VH3-IgG1-F140, VH3-IgG1-F157 or VH3-IgG1-F424 for the heavy chain and L(WT)-CK for the light chain were measured using the method shown below.
(4-3) Kinetic Analysis of Binding to Human FcRn
[0565] A kinetic analysis of binding between human FcRn and the aforementioned antibodies was carried out using the BIACORE™ T100 or T200 surface plasmon resonance system (GE Healthcare). The antibodies being tested were captured on the CM4 Sensor Chip (GE Healthcare) on which a suitable amount of Protein L (ACTIGEN® protein (Alltech)) was suitably immobilized by amine coupling. Next, diluted human FcRn and a running buffer used as a blank were injected to allow the human FcRn to interact with the antibody captured on the sensor chip. A buffer consisting of 50 mmol/L sodium phosphate, 150 mmol/L NaCl and 0.05% (w/v) polysorbate 20 (Tween 20®) (pH 7.0 or pH 7.4) was used for the running buffer, and each buffer was also used to dilute the human FcRn. 10 mmol/L glycine-HCl (pH 1.5) was used to regenerate the sensor chip. All measurements of binding were carried out at 25° C. The K.sub.D(M) of each antibody to human FcRn was calculated based on kinetics parameters, i.e., the association rate constant ka (1/Ms) and the dissociation rate constant kd (1/s) calculated from a sensorgram obtained by the measurement. The BIACORE™ T100 or T200 Evaluation Software (GE Healthcare) was used to calculate each parameter.
(7-2) Evaluation of Binding Activity to Human FcγR
[0613] The binding activities of VH3/L(WT)-IgG1, VH3/L(WT)-IgG1-F21 and VH3/L(WT)-IgG1-F140 to human FcγR at pH 7.4 were measured using the method shown below.
[0614] Binding activity between the antibodies and human FcγRIa, FcγRIIa(H), FcγRIIa(R), FcγRIIb and FcγRIIIa(F) (hereinafter referred to as human FcγRs) was evaluated using the BIACORE™ T100 or T200 surface plasmon resonance system (GE Healthcare). The antibodies being tested were captured by Protein L (ACTIGEN® protein (Alltech)) that was immobilized in suitable amounts on the CM4 Sensor Chip (GE Healthcare) by amine coupling. Next, the diluted human FcγRs and a running buffer used as a blank were injected to allow interaction with the antibodies captured on the sensor chip. A buffer consisting of 20 mmol/L N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), 150 mmol/L NaCl and 0.05% (w/v) polysorbate 20 (Tween 20®) (pH 7.4) was used for the running buffer, and this buffer was also used to dilute the human FcγRs. 10 mmol/L glycine-HCl (pH 1.5) was used to regenerate the sensor chip. All measurements were carried out at 25° C.
[0615] Binding activity to human FcγRs can be represented by the relative binding activity to human FcγRs. Antibody was captured by Protein L, and the amount of change in a sensorgram before and after the antibody was captured was defined as X1. Next, human FcγRs were allowed to interact with the antibody, and the value obtained by subtracting binding activity of human FcγRs represented as the amount of change in a sensorgram before and after allowing the running buffer to interact with antibody captured by Protein L (ΔA2) from the value obtained by multiplying by 1500 the value obtained by dividing the binding activity of human FcγRs represented as the amount of change in a sensorgram before and after that interaction (ΔA1) by the captured amount (X) of each antibody, was divided by the captured amount of each antibody (X) followed by multiplying by 1500 to obtain the binding activity of the human FcγRs (Y) (Equation 2).
Binding activity of human FcγRs(Y)=(ΔA1−ΔA2)/X×1500 [Equation 2]
[0616] The results are shown in Table 14 below.
TABLE-US-00015 TABLE 14 BINDING AMOUNT (RU) hFcgRIa hFcgRIIa(R) hFcgRIIa(H) hFcgRIIb hFcgRIIIa(F) IgG1 399.6 158.9 158.7 81.4 143.8 IgG1-F21 403.0 145.2 153.6 63.4 146.7 IgG1-F140 335.1 7.6 8.8 2.2 1.8
[0617] According to the results of Table 14, Fv4-IgG1-F140 demonstrated a decrease in binding to each human FcγR without affecting the binding activity to human FcRn in comparison with Fv4-IgG1-F21.
(8-2) Production of an A33-Binding Antibody Having Binding Activity to Human FcRn Under Conditions of the Neutral pH Region
[0627] Since the produced hA33-IgG1 is a human antibody having a naturally-occurring human Fc region, it does not have binding activity to human FcRn under conditions of the neutral pH region. Therefore, an amino acid modification was introduced into the heavy chain constant region of hA33-IgG1 in order to impart the ability to bind to human FcRn under conditions of the neutral pH region.
[0628] More specifically, hA33H-IgG1-F21 (SEQ ID NO: 65) was produced by substituting Tyr for Met at position 252 (EU numbering), substituting Pro for Val at position 308 (EU numbering) and substituting Tyr for Asn at position 434 (EU numbering) in the heavy chain constant region of hA33-IgG1 in the form of hA33H-IgG1. Using the method of Reference Example 2, an A33-binding antibody having binding activity to human FcRn under conditions of the neutral pH region was produced in the form of hA33-IgG1-F21 containing hA33H-IgG1-F21 for the heavy chain and hA33L-k0 for the light chain.
(8-3) Production of an A33-Binding Antibody Containing an FcγR-Binding Domain Whose Binding Activity to Human FcγR Under Conditions of the Neutral pH Region is Lower than the Binding Activity of a Native FcγR-Binding Domain
[0629] hA33H-IgG1-F140 (SEQ ID NO: 66) was produced in which Lys is substituted for Ser at position 239 (EU numbering) in the amino acid sequence of hA33H-IgG1-F21 in order to lower the binding activity of hA33-IgG1-F21 to human FcγR.
However, the specification does not teach which any combination of modification, e.g., substitutions, deletions, additions or a combination thereof in the human IgG1 Fc that binds to human FcRn at pH 7.0 more strongly than a native human IgG1 Fc (claim 45), presumably the pH dependent antibody has increased human FcRn-binding than FcRn-binding than that of intact human IgG1, that would improve antigen elimination from plasma. The specification discloses antibody plasma retention is known to worsen as a result of binding to FcRn under neutral conditions. If an antibody ends up bound to FcRn under neutral conditions, even if the antibody returns to the cell surface by binding to FcRn under acidic conditions in endosomes, an IgG antibody is not recycled to the plasma unless the IgG antibody dissociates from FcRn in the plasma under neutral conditions, thereby conversely causing plasma retention to be impaired.
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Regarding antibody in claims 60-63, 68-74, the specification discloses pH dependent antibodies that binds to just human IL-6 receptor.
However, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Such claims are often referred to as “reach-through” claims, where an applicant attempts to obtain patent protection on an invention not yet discovered. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In this case, the specification does not describe the amino acid sequences of heavy and light chain variable regions encompassed by the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed antibodies themselves.
The specification does not disclose a representative number of species of such antibody that is produced by the claimed method, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function (i.e., a correlation between the primary sequence of the antibody heavy chain variable region and light chain variable region and specific binding to any and all antigen.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Antibodies that bind to human IL-6 receptor do not bind to other protein or different epitope from the same protein.
At the time the invention was made, one of skill in the art was aware that the number and sequence of antibodies that bind to a single protein is a very large and structurally diverse genus (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes), as is evidenced below.
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 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., 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).
Khan and Salunke (J. Immunol. 192: 5398-5405, 2014; PTO 892) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences.
Poosarla et al (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.)
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.
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 that bind to just human IL-6 receptor, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to any and all antigen (as held in Abbvie).
In AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014), a claim drawn to a genus of antibodies having a recited binding affinity and binding specificity to a fully characterized antigen was found to be invalid for lack of written description such that it was not infringed by a subsequently disclosed antibody having all of the recited functional characteristics but a completely different structure (amino acid sequence). The Court held:
“It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date... The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara®, whereas the patents do not describe representative examples to support the full scope of the claims. (AbbVie, 759 F.3d at 1298; 111 USPQ2d at 1791) (emphasis added).
Since the disclosure does not describe the common attributes or structural characteristics that identify members of the genus, and because the genus is highly variant, the binding of antibody to human FcRn at pH 7.0 whose antigen-binding activity is lower at acidic pH than at neutral pH is insufficient to describe the genus of antibodies produced by the claimed method. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus at the time the invention was made.
Therefore, there is insufficient written description for genus of the antibodies broadly encompassed by the claims, other than the pH dependent human IL-6 receptor binding antibodies produced by the claimed method described in the specification as filed under the written description provision of 35 USC 112, first paragraph.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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