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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-17 are the original claims filed 9/30/2022. In the preliminary amendment of 9/30/2022, claims 1, 3, 5-12, and 14-16 are amended and new claims 18-20 are added. Claims 1-20 are all the claims.
Election/Restrictions
2. Applicant’s election without traverse of Group I in the reply filed on 10/10/2025 is acknowledged.
3. Claims 13, 15 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/10/2025. The transformant of Group II set forth below is defined in the specification as an “animal individual” and encompass transgenic animals:
[0777] When the transformant is an animal individual or a plant individual, the individual is raised or cultivated according to a conventional method to produce and accumulate the IgG half-molecule, and the IgG half-molecule can be collected from the animal individual or the plant individual.
[0561] The human antibody originally refers to an antibody that can be naturally present in the human body or an antibody composed of an amino acid sequence encoded by a human gene, but also includes antibodies that are obtained from human antibody phage libraries, cloning of immortalized human peripheral blood lymphocytes, or human antibody-producing transgenic animals, which are produced by recent advancement of genetic engineering, cellular engineering, and developmental engineering technologies, and the like.
A transgenic human is specifically disclaimed in the specification at
[0567] As for a method for producing a human antibody from a human antibody-producing transgenic animal, a human antibody-producing hybridoma is obtained by a general method for producing a hybridoma performed for mammals other than humans, and cultured, whereby human antibody can be produced and accumulated in the culture.
4. Claims 1-12, 14 and 16-19 are all the claims under examination.
Priority
5. USAN 17/916,275, filed 09/30/2022, is a National Stage entry of PCT/JP2021/014181, International Filing Date: 04/01/2021, claims foreign priority to JP 2020-066313, filed 04/01/2020, and claims foreign priority to JP 2020-181493, filed 10/29/2020.
Information Disclosure Statement
6. As of 12/21/2025, a total of two (2) IDS are filed: 9/30/2022 and 9/30/2022. The corresponding initialed and dated 1449 is considered and of record. The submissions are in compliance with the provisions of 37 CFR 1.97.
7. The listing of references in the specification ([0019-0020]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered
Objections
Specification
8. The disclosure is objected to because of the following informalities:
a) The use of the term, ATCC, Sepharose, Tris, AlphaLISA, In-Fusion, LabChip, NanoDrop, Superdex, BIGDYE, QIAquick, GeneAmp, PrimeStar, NanoTemper, BioLC, DIAION, EX-CELL, RNeasy, BiaCore, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
9. Claim(s) 1, 9, 10 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chugai I/II (WO2013/002362; US 9890218 (IDS 9/30/2022) and WO2014/104165; US 10766960 (IDS 9/30/2022)) and in view of Genentech (JP 2008511337 (4/17/2008 (IDS 9/30/2022)), Chugai III (WO 2016/159213; US 11142587
(10/6/2016 ((IDS 9/30/2022)), Niwa et al (US 20210380684 (PTO 892)) and Lakatos et al (WO 2021/232162).
(a) As regards claim 1, 9 and 10, Claim 1 is drawn to "first polypeptide” and a "second polypeptide" that correspond to the "first IgG halfmer" and the "second IgG halfmer", claim 9 is drawn to a 1st half-molecule corresponding to claim 1, and claim 10 is drawn to a 2nd half-molecule corresponding to claim 1.
1. An antibody composition, which is an antibody composition against a first antigen and a second antigen that are different from each other, comprising a first IgG half-molecule and a second IgG half-molecule, wherein the following (IA) to (6A) are satisfied:
(IA) each of the first IgG half-molecule and the second IgG half-molecule is composed of one immunoglobulin light chain (hereinafter abbreviated as L chain) and one immunoglobulin heavy chain (hereinafter abbreviated as H chain), and the H chain includes an H chain variable region, a hinge domain, a CHI domain, a CH2 domain, and a CH3 domain, and has a first Fcy receptor IIIA (hereinafter CD16a)-binding domain and a second CD16a-binding domain that are different from each other in the CH2 domain,
(2A) each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of C226A and C229A numbered according to the EU index,
(3A) the first IgG half-molecule includes an antigen-binding domain that binds to the first antigen, and includes an amino acid residue substitution of D265A numbered according to the EU index in the first CD16a-binding domain,
(4A) the second IgG half-molecule includes an antigen-binding domain that binds to the second antigen, and includes an amino acid residue substitution of P329Y numbered according to the EU index in the second CD16a-binding domain,
(5A) each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (a) S239D and K326T numbered according to the EU index, or each of the first IgG half-molecule and the second IgG half-molecule includes amino acid residue substitutions of (b) S239D, S298A, E333A, L242C, and K334C numbered according to the EU index, and
(6A) at least one of the first IgG half-molecule and the second IgG half-molecule includes an amino acid residue substitution in the CH3 domain as an alteration for attenuating an inter-CH3 domain interaction as compared with an inter-CH3 domain interaction of the IgGI subclass.
NOTE: claims 9, 10 and 14 comprise elements (1B)-(7B), (1C)-(7C) and (1D-7D), respectively. Elements (1B), (1C) and (1D) comprise the limitation that the half molecules bind different antigens from each other and that is otherwise provided in the preamble of claim 1. Elements 2B-7B, 2C-7C and 2D-7D correspond to elements 1A-6A of claim 1.
Chugai I/II teaches the Fc region being constituted from a heterodimer including the first polypeptide and the second polypeptide against different antigens, the polypeptides being characterized comprising an Fc region, wherein the Fc region is characterized by the properties (1A)-(6A):
(1A) an altered heterodimeric Fc region that each comprises the CD16A binding domain. Chugai teaches
In the present invention, Fcγ receptor (which may be described as Fcγ receptor, FcγR or FcgR in the present specification) refers to a receptor that can bind to the Fc region of IgG1, IgG2, IgG3, or IgG4. By any member of the family of proteins encoded by the Fcγ receptor gene. In humans, this family includes FcγRI (CD64), including isoforms FcγRIa, FcγRIb and FcγRIc; isoforms FcγRIIa (including allotypes H131 (H) and R131 (R)), FcγRIIb (FcγRIIb-1 and FcγRIIb- 2) and FcγRII (CD32) including FcγRIIc; and FcγRIII (CD16) including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2) and any undiscovered Human FcγRs or FcγR isoforms or allotypes, but are not limited to these. FcγR includes, but is not limited to, those derived from human, mouse, rat, rabbit and monkey, and may be derived from any organism. Mouse FcγRs include FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16) and FcγRIII-2 (CD16-2 or FcγRIV), as well as any undiscovered mouse FcγRs or FcγR isoforms or allotypes However, it is not limited to these. Suitable examples of such Fcγ receptors include human FcγRI (CD64), FcγRIIa (CD32), FcγRIIb (CD32), FcγRIIIa (CD16) and / or FcγRIIIb (CD16).
Chugai I/II teaches all of the instant claimed residue positions for altering the heterogeneity of the Fc regions:
More specifically, when introducing alterations into the amino acid sequence of a human IgG1 constant region, amino acid residues at one or more positions selected from among 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, and 340 (EU numbering) may be altered.
(2A) In the CH2 region of the Fc region, EU numbering 226th Cys and 229th Cys.
(3A) [5] In the CH2 region of the Fc region, EU numbering 265th Asp.
(4A) [5] In the CH2 region of the Fc region, EU numbering 329th Pro.
(5A) [5] In the CH2 region of the Fc region, EU numbering 239th Ser and 326th Lys.
5(A) separate amino acid substitutions on the respective CH2 region of the first polypeptide and the second polypeptide, and specifically disclose in EU numbering S239, S298, E333, L242, and K334, etc. (see [0020]-[0030], [0121], and [0142]; and [0019]-[0029], [0118], and [0126]).
(6A) a substitution in the CH3 domain to lessen or decrease (attenuate) inter-CH3 domain interaction via charge repulsion is taught by Chugai at
In the technique of suppressing unintentional association of H chains by introducing charge repulsion to the CH2 or CH3 interface, amino acid residues that contact at the interface of other constant regions of the H chain include, for example, EU in the CH3 region Numbering 356th residue, EU numbering 439th residue, EU numbering 357th residue, EU numbering 370th residue, EU numbering 399th residue, region corresponding to EU numbering 409th residue Can be mentioned.
Chugai I/II does not disclose an amino acid substitution of: C226A and C229A; D265A; P329Y; S239D and K326T; and S239D, S298A, E333A, L242C, and K334C.
Genentech and Chugai III teach that in order to manufacture a heterodimer when obtaining a bispecific antibody, adding any amino acid substitution to the hinge domain to prevent a disulfide bond from forming, and performing a substitution of C226 and/or C229 with any amino acid, preferably, C226S and/or C229S, in Table 1 and 2.
Niwa teaches heterodimeric Fc variants comprising one or more asymmetric amino acid mutations in the CH2 domain and having modulate selectivity of binding to FcγRIIb as compared to a parental Fc region, polypeptides comprising the heterodimeric Fc variants and polynucleotides encoding the heterodimeric Fc variants.
Niwa teaches substitutions effecting enhanced CD16a binding as follows:
Niwa teaches: C226A/C229A at
[0489] The production of an antibody half-molecule was attempted by utilizing this property and an amino acid alteration (C226A/C229A: AA) for cleaving an inter-H chain disulfide bond in a hinge domain. A domain-exchanged antibody (hereinafter referred to as IgG1114_AA type) in which for the H chain constant region of a half-molecule, human IgG1 was used as a basic skeleton, and only the CH3 domain was exchanged to a human IgG4 sequence, and further, an amino acid alteration (AA) was added to the hinge domain was used.
Niwa teaches: D265A/P329Y
[0490] In addition, in order to enhance an ADCC activity, a known amino acid alteration for enhancing an ADCC activity was made in the CH2 domain, and further, α1,6-fucose of the N-linked sugar chain that is bound to Asn297 was removed, and finally, a CD16a-binding asymmetric amino acid alteration was introduced. In FIG. 11, a schematic diagram of an IgG1114_AA_AAA_D265A (/P329Y)-type IgG half-molecule is shown. As two types of model antigens, CD4 and CD70 were used.
Niwa teaches: S239D/K326(A)/(W)/(Y)(G)
[0253] Specific examples of the amino acid residue substitution for enhancing the ADCC activity include P247I, A339D, F243L, R292P, Y300L, P396L, T393A, H433P, S239D, S298A, A330L, 1332E, E333A, K334A, and the like. On the other hand, specific examples of the amino acid residue substitution for decreasing an ADCC activity include L235E, P238A, N297A, K322A, P331S, and the like.
[0254] As a specific amino acid residue substitution for increasing the CDC activity, at least one amino acid residue substitution selected from K326A, S267E, H268F, S324T, K274Q, N276K, Y296F, Y300F, K326W, K326Y, E333A, E333S, A339T, D356E, L358M, N384S, K392N, T394F, T394Y, V397M, and V422I is exemplified.
[0110] 46. The second IgG half-molecule according to the above 45, wherein the alteration in the second CD16a-binding domain is at least one amino acid residue substitution selected from K326W, K326G, L328V, L328R, P329Y, P329K, P329W, and A330P numbered according to the EU index.
Niwa teaches: S298A, E333A, and K334
[0081] 31. The antibody composition according to the above 30, wherein the first IgG half-molecule and the second IgG half-molecule include at least one amino acid residue substitution selected from S298A, E333A, and K334A numbered according to the EU index in the CH2 domain.
Lakatos teaches heterodimeric Fc variants comprising one or more asymmetric amino acid mutations in the CH2 domain and having increased selectivity of binding to FcγRIIb as compared to a parental Fc region, polypeptides comprising the heterodimeric Fc variants and polynucleotides encoding the heterodimeric Fc variants.
Lakatos teaches substitutions effecting enhanced CD16a binding as follows:
Lakatos: K326T
[00254] In certain embodiments, the heterodimeric Fc variant is a Strategy 2 variant as described in any one of the embodiments above in which the first Fc polypeptide further comprises a mutation at one or more of positions 235, 237, 239, 264, 266, 267, 269, 270, 271, 272, 273, 323, 326 and/or 332. In some embodiments, the mutation at position 235 selected from L235A, L235D, L235E, L235F, L235H, L235I, L235P, L235Q, L235S, L235T, L235V, L235W and L235Y; the mutation at position 237 selected from G237A, G237F, G237L, G237N, G237T, G237W and G237Y; the mutation at position 239 selected from S239A, S239D, S239E, S239G, S239I, S239L, S239N, S239Q, S239R and S239V; the mutation at position 264 selected from V264A, V264F, V264I, V264L and V264T; the mutation at position 266 is V266I; the mutation at position 267 selected from S267A, S267G, S267H, S267I, S267N, S267P, S267T and S267V; the mutation at position 269 selected from E269A, E269D, E269F, E269G, E269H, E269I, E269K, E269L, E269N, E269P, E269Q, E269R, E269S, E269T, E269V, E269W and E269Y; the mutation at position 270 selected from D270A, D270E, D270F, D270H, D270I, D270N, D270Q, D270S, D270T, D270W and D270Y; the mutation at position 271 selected from P271D, P271E, P271G, P271H, P271I, P271K, P271L, P271N, P271Q, P271R, P271V and P271W; the mutation at position 272 selected from E272A, E272D, E272F, E272G, E272H, E272I, E272L, E272N, E272S, E272T, E272V, E272W and E272Y; the mutation at position 273 is V273A; the mutation at position 323 selected from V323A, V323I and V323L; the mutation at position 326 selected from K326A, K326D, K326H, K326N, K326Q, K326R, K326S and K326T, and the mutation at position 332 selected from I332A, I332L, I332T and I332V.
See also [00266]
Lakatos: L242C
[00688] Additionally, six combinations of two or three stability-enhancing mutations (A287F/M428F, A287F/T250V, M428F/T250V, A287F/M428F/T250V, T250V/L309Q and L242C I336C/V308I) were tested to assess if increased stabilization could be obtained by additive or synergistic effects.
The combined disclosures substantiate introducing effector modulating amino acid substitutions to an antibody Fc CD16A-interacting domains to change the functionality of antibodies through the constant region activity and that render the claims obvious.
(b) As regards claim 14, claim 14 is drawn to a kit comprising the 1st and 2nd half molecules described in claims 1, 9 and 10. Chugai III (WO 2016/159213; US 11142587 (10/6/2016 ((IDS 9/30/2022)) and Niwa et al (US 20210380684 (PTO 892)) teach the kits comprising the Fc variants resulting in CD16a improved binding for the corresponding antibody: US 11142587 (The present invention also provides a kit for use in the treatment method or the prevention method of the present invention, comprising at least the heteromultimer of the present invention, a heteromultimer produced by the production method of the present invention, or the pharmaceutical composition of the present invention. In the kit, for example, a pharmaceutically acceptable carrier, a vehicle, or an instruction stating the usage can also be additionally packaged); and US 20210380684 ([0001] The present invention relates to an antibody composition and a method for producing the same, an IgG half-molecule, and a kit including the IgG half-molecule).
10. Claim(s) 1(5A; L242C/K334C), 9(6B; L242C/K334C), 10(6C; L242C/K334C) and 14 (6D; L242C/K334C) is/are rejected under 35 U.S.C. 103 as being unpatentable over Chugai I/II (WO2013/002362; US 9890218 (IDS 9/30/2022) and WO2014/104165; US 10766960 (IDS 9/30/2022)) and in view of Genentech (JP 2008511337 (4/17/2008 (IDS 9/30/2022)), Chugai III (WO 2016/159213; US 11142587 (10/6/2016 ((IDS 9/30/2022)), Niwa et al (US 20210380684 (PTO 892)) and Lakatos et al (WO 2021/232162) as applied to claims 1, 9 and 10 above, and further in view of Frendeus et al (WIPO; 2019-11-01 (PTO 892) and Jacobsen FW et al., JBC 2017, 292, 1865-1875 (PTO 892).
Claims 1(5A), 9(6B), 10(6C) and 14(6D) are drawn to residues L242C and K334C in the Fc variants for the corresponding generic claims.
Frendeus citing Jacobsen teaches antibody molecules may comprise a modified Fc region having additional substitutions that include L242C, V259C, A287C, R292C, V302C, L306C, V323C, I332C, and/or K334C.
Jacobsen teaches structure-based Fc engineering in an attempt to develop an IgG scaffold with the following properties: (i) no or significantly reduced binding to Fc receptors; (ii) stability similar to that of IgG1 without the heterogeneity of the disulfide isoforms that are present in IgG2; (iii) low or no binding to cynomolgus monkey FcRs, in particular FcRIIa; (iv) desirable developability attributes such as storage stability and PK similar to IgG molecules (no change in binding to FcRn); and (v) can be isolated using established antibody manufacturing processes. See Table 1:
PNG
media_image1.png
324
578
media_image1.png
Greyscale
.
11. Claim(s) 2-5 and 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chugai I/II (WO2013/002362; US 9890218 (IDS 9/30/2022) and WO2014/104165; US 10766960 (IDS 9/30/2022)) and in view of Genentech (JP 2008511337 (4/17/2008 (IDS 9/30/2022)), Chugai III (WO 2016/159213; US 11142587 (10/6/2016 ((IDS 9/30/2022)), Niwa et al (US 20210380684 (PTO 892)) and Lakatos et al (WO 2021/232162) as applied to claim 1 above, and further in view of Frendeus et al (WIPO; 2019-11-01 (PTO 892) and Jacobsen FW et al., JBC 2017, 292, 1865-1875 (PTO 892).
As regards claim 2, Niwa teaches and claims “2. The antibody composition according to claim 1, wherein the antibody composition exhibits an effector function only for a target cell coexpressing the first antigen and the second antigen and damages the target cell”; and 9890218 teaches the half body antibodies wherein the alteration of Fc region function is enhancement of binding activity to an Fcγ receptor, and the Fcγ receptor is at least one or more receptors selected from the group consisting of FcγRIa, FcγRIIa R, FcγRIIa H, FcγRIIb, and FcγRIIIa [CD16a];
As regards claim 3, at least one of the residues is taught by 11142587 for "K409R"; 10766960 for “L368A”; Lakatos teaches [00299] In certain embodiments, the heterodimeric Fc variant comprises a modified CH3 domain comprising mutations based on the “knobs into holes” approach. In some embodiments, the heterodimeric Fc variant comprises a modified CH3 domain in which one Fc polypeptide comprises the amino acid mutations Y349C, T366S, L368A and Y407V, and the other Fc polypeptide comprises the amino acid mutations S354C and T366W.
[00302] In certain embodiments, the heterodimeric Fc variant comprises a modified CH3 domain in which one Fc polypeptide comprises amino acid mutations at positions F405 and Y407, and the other Fc polypeptide comprises amino acid mutations at positions T366 and T394. In some embodiments, the amino acid mutation at position F405 is F405A, F405S, F405T or F405V. In some embodiments, the amino acid mutation at position Y407 is Y407I or Y407V. In some embodiments, the amino acid mutation at position T366 is T366I, T366L or T366M. In some embodiments, the amino acid mutation at position T366 is T366I or T366L. In some embodiments, the amino acid mutation at position T394 is T394W.
AS regards claim 4, 11142587 teaches “the bispecific antibody obtained by mixing two types of antibodies is theoretically 50% of the total amount of antibodies present in the system. Hence, a method for improving the rate of bispecific antibody formation has been studied. The reaction efficiency can be reportedly improved by introducing asymmetric amino acid modification to two types of antibodies, i.e., K409R modification to the H chains of one antibody and F405L modification to the H chains of the other antibody.
As regards claim 5, see the analysis under sections 9 and 10, supra, for element (5A) of claim 1.
As regards claim 7, 20210380684 teaches ratios of fucose and sugars at [0079] 29. The antibody composition according to any one of the above 1 to 28, wherein a ratio of sugar chains in which fucose is not bound to N-acetylglucosamine at a reducing end of the sugar chain among the total N-glycoside-linked type sugar chains bound to an Fc region in the first IgG half-molecule and the second IgG half-molecule is 20% or more.
As regards claim 8, 9890218 teaches IgG1 “Preferred examples of the polypeptides of the present invention include antibodies. More preferred examples include naturally-occurring IgGs, particularly naturally-occurring human IgGs. “Naturally-occurring IgGs” refers to polypeptides belonging to a class of antibodies practically encoded by immunoglobulin gamma genes and comprising an amino acid sequence identical to those of IgGs found in nature. For example, a naturally-occurring human IgG means a naturally-occurring human IgG1, naturally-occurring human IgG2, naturally-occurring human IgG3, naturally-occurring human IgG4, or such. Naturally-occurring IgGs also include mutants spontaneously produced from them; and 11142587 teaches (IgG1) at [16] The production method according to any one of [1] to [15], wherein the heavy chain constant region of the first and/or the second polypeptide is IgG1, IgG2, IgG3, or IgG4 type.
12. Claim(s) 11-12 and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chugai I/II (WO2013/002362; US 9890218 (IDS 9/30/2022) and WO2014/104165; US 10766960 (IDS 9/30/2022)) and in view of Genentech (JP 2008511337 (4/17/2008 (IDS 9/30/2022)), Chugai III (WO 2016/159213; US 11142587 (10/6/2016 ((IDS 9/30/2022)), Niwa et al (US 20210380684 (PTO 892)) and Lakatos et al (WO 2021/232162) as applied to claims 1 above, and further in view of Frendeus et al (WIPO; 2019-11-01 (PTO 892) and Jacobsen FW et al., JBC 2017, 292, 1865-1875 (PTO 892).
As regards claims 11-12 and 18-19, 20210380684 teaches DNA and vectors at
[0112] a) a DNA encoding an amino acid sequence of the first IgG half-molecule according to any one of the above 32 to 39; or [0113] b) a DNA encoding an amino acid sequence of the second IgG half-molecule according to any one of the above 40 to 46.
[0114] 48. A recombinant vector, comprising at least one of the DNAs a) and b) according to the above 47; and 9890218 teaches “Methods for expressing the above-described DNAs include the methods described below. For example, a heavy chain expression vector is constructed by inserting a DNA encoding a heavy chain variable region into an expression vector along with a DNA encoding a heavy chain constant region. Likewise, a light chain expression vector is constructed by inserting a DNA encoding a light chain variable region into an expression vector along with a DNA encoding a light chain constant region. Alternatively, these heavy and light chain genes may be inserted into a single vector.
13. Claim(s) 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chugai I/II (WO2013/002362; US 9890218 (IDS 9/30/2022) and WO2014/104165; US 10766960 (IDS 9/30/2022)) and in view of Genentech (JP 2008511337 (4/17/2008 (IDS 9/30/2022)), Chugai III (WO 2016/159213; US 11142587 (10/6/2016 ((IDS 9/30/2022)), Niwa et al (US 20210380684 (PTO 892)) and Lakatos et al (WO 2021/232162) as applied to claims 1 above, and further in view of Frendeus et al (WIPO; 2019-11-01 (PTO 892) and Jacobsen FW et al., JBC 2017, 292, 1865-1875 (PTO 892).
As regards claims 16-17, 20210380684 teaches pharmaceutical compositions for the Fc variant antibodies at [0407, 0410, 0414] and treatment of the cancer, autoimmune disease or allergic disease at [0394] “The antigen to which the antibody composition of the present invention binds may be any antigen, and preferably, an antigen molecule associated with cancer, an immune disease, an allergic disease” where autoimmunity is taught as [0014, 0016].
As regards Claims 1-12, 14 and 16-19, the combination of cited reference art teaching the engineering of Fc residues for enhanced and/or attenuated effector function with respect to CD16A binding and activity, and the specific residues alone and in combination, that have established this field of art as routine in the design of bispecific antibodies comprising heterodimeric half-mer structures with modulated activity. Accordingly, the requirement of the claims is that of art-known substituted Fc residues that together are predictable in their functional effect on CD16A binding activity, and therefore a reasonable expectation of success ensues from the combination of what is already known to work for the same intended outcome.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,”Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Id. (2) “In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation.” Id. at 416-17, 82 USPQ2d at 1395. (3) “[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious. The Supreme Court further stated that:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill. Id. at 417, 82 USPQ2d at 1396.
Claims 1-12, 14 and 16-19 are obvious in view of the cited reference art.
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.
14. Claims 1-12, 14 and 16-19 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-12, 14 and 16-19 are indefinite for the meaning of the terms “satisfy” or “satisfied” with respect to the elements under generic claims 1, 9-10 and 14. The specification provides no definition whether the terms correspond to one (or more) of the following elements or that all of the elements are required to present in the antibody composition. The POSA cannot reasonably ascertain the full breadth and scope of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Claims 1-5, 7-12, 14 and 16-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 13-21, 23 and 25-26 of copending Application No. 17/280,403 (reference application US 20210380684).
The reference application is not afforded safe harbor protection under 35 USA 121 because the ref claims share no continuity nor a restriction/ speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are overlapping with respect the bispecific antibody comprising half-mer structures comprising a 1st and 2nd polypeptide that comprises engineered Fc regions that provide alternative substitutions for amino acid residues having effects on interaction of the antibody with CD16A binding.
Claim interpretation
Claims 1-5, 7-12, 14 and 16-19 are ambiguous for the meaning of the term “satisfy” or “satisfied” with respect to the elements under generic claims 1, 9-10 and 14 as discussed herein above.
Generic Ref claims specifically recite “one of the following” that the POSA could reasonably assume is singular.
Accordingly, the analysis for non-statutory double patenting is based on at least one of the elements of the reference claims that teach(es) an element under the generic instant claims.
Ref claims 1-2, 13-21, 23 and 25-26
1. (currently amended) An antibody composition, which is an antibody composition against a first antigen and a second antigen that are different from each other, comprising a first IgG half-molecule and a second IgG half-molecule, wherein each of the first IgG half-molecule and the second IgG half-molecule is composed of one immunoglobulin light chain (hereinafter abbreviated as L chain) and one immunoglobulin heavy chain (hereinafter abbreviated as H chain), the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a Fcy receptor IIIA (hereinafter CD16a)-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alteration of the second IgG half-molecule is in a second CD16a-binding domain, and wherein the first and second CD 16a-binding domains are different from each other in the CH2 domain, the first IgG half-molecule includes an antigen-binding domain that binds to the first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration, the second IgG half-molecule includes an antigen-binding domain that binds to the second antigen, and a CD16a-binding activity in the second CD16a-binding domain is attenuated by the alteration, and an inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule wherein the combination of the alteration in the first CD 16a-binding domain and the alteration in the second CD16a-binding domain are one of the following (xl) to (x10):
(x1) the alteration in the first CD16a-binding domain comprises at least L235R, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P;
(x2) the alteration in the first CD16a-binding domain comprises at least S239R, and the alteration in the second CD16a-binding domain comprises at least K326G, L328R, P329Y, P329K, P329W or A330P;
(x3) the alteration in the first CD16a-binding domain comprises at least P238A and S267L, and the alteration in the second CD16a-binding domain comprises at least P329Y;
(x4) the alteration in the first CD16a-binding domain comprises at least D265A, D265E or D265N, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
See Claim 1 (2A) and (3A).
(x5) the alteration in the first CD16a-binding domain comprises at least S267K, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x6) the alteration in the first CD16a-binding domain comprises at least E269P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329W or A330P;
(x7) the alteration in the first CD16a-binding domain comprises at least Y296P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329W or A330P;
(x8) the alteration in the first CD16a-binding domain comprises at least S298E, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329K, P329W or A330P;
(x9) the alteration in the first CD16a-binding domain comprises at least T299A, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x10) the alteration in the first CD16a-binding domain comprises at least A327I, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P.
2. (original) The antibody composition according to claim 1 wherein the antibody composition exhibits an effector function only for a target cell coexpressing the first antigen and the second antigen and damages the target cell.
See claim 2.
13. (previously presented) The antibody composition according to claim 1, wherein the first IgG half-molecule and the second IgG half-molecule include a hinge domain in which at least one amino acid residue of amino acid residues at position 226 and position 229 numbered according to the EU index is substituted.
See claim 1 (2A).
14. (previously presented) The antibody composition according to claim 1, wherein immunoglobulin subclasses of the CH2 domain of the H chain in the first IgG half-molecule and the second IgG half-molecule are IgG1.
See claim 8.
15. (original) The antibody composition according to claim 14, wherein the CH3 domain of the H chain in the first IgG half-molecule and the second IgG half-molecule has a weaker inter-CH3 domain interaction than a CH3 domain of the IgG1 subclass.
See claim 4.
16. (original) The antibody composition according to claim 15, wherein immunoglobulin subclass of the CH3 domain of the H chain in the first IgG half- molecule and the second IgG half-molecule is IgG4.
17. (previously presented) The antibody composition according to claim 1 wherein the antibody composition binds to CD16a through the second CD16a-binding domain in the first IgG half-molecule and the first CD16a-binding domain in the second IgG half-molecule.
18. (previously presented) The antibody composition according to claim 1, wherein a ratio of sugar chains in which fucose is not bound to N-acetylglucosamine at a reducing end of the sugar chain among the total N-glycoside-linked type sugar chains bound to an Fc region in the first IgG half-molecule and the second IgG half-molecule is 20% or more.
See claim 7.
19. (previously presented) The antibody composition according to claim 1, wherein the first IgG half-molecule and the second IgG half-molecule include at least one amino acid residue substitution for further enhancing the CD16a-binding activity in the CH2 domain.
20. (original) The antibody composition according to claim 1, wherein the first IgG half-molecule and the second IgG half-molecule include at least one amino acid residue substitution selected from S298A, E333A, and K334A numbered according to the EU index in the CH2 domain.
21. (currently amended) A first IgG half-molecule, which is a first IgG half-molecule to be used in combination with a second IgG half-molecule, wherein each of the first IgG half- molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a CD 16a-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alteration of the second IgG half- molecule is in a second CD16a-binding domain, and wherein the first and second CD16a-binding domain are different from each other in the CH2 domain,the first IgG half-molecule includes an antigen-binding domain that binds to a first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration,the second IgG half-molecule includes an antigen-binding domain that binds to a second antigen different from the first antigen, and a CD16a-binding activity in the second CD16a- binding domain is attenuated by the alteration, andan inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule;or which is a first IgG half-molecule to be used for producing an antibody composition against a first antigen and a second antigen that are different from each other, the antibody composition composed of the first IgG half-molecule and a second IgG half-molecule, whereineach of the first IgG half-molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a CD16a-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alteration of the second IgG half-molecule is in second CD16a-binding domain, and wherein the first and second CD 16a-binding domains are different from each other in the CH2 domain, the first IgG half-molecule includes an antigen-binding domain that binds to the first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration, the second IgG half-molecule includes an antigen-binding domain that binds to the second antigen, and a CD16a-binding activity in the second CD16a-binding domain is attenuated by the alteration, and an inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule, wherein the combination of the alteration in the first CD 16a-binding domain and the alteration in the second CD16a-binding domain are one of the following (xl) to (x10):
(xl) the alteration in the first CD16a-binding domain comprises at least L235R, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P;
(x2) the alteration in the first CD16a-binding domain comprises at least S239R, and the alteration in the second CD16a-binding domain comprises at least K326G, L328R,P329Y, P329K, P329W or A330P;
(x3) the alteration in the first CD16a-binding domain comprises at least P238A and S267L, and the alteration in the second CD16a-binding domain comprises at least P329Y;
(x4) the alteration in the first CD16a-binding domain comprises at least D265A, D265E or D265N, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
See Claim 9 (2B) and (3B).
(x5) the alteration in the first CD16a-binding domain comprises at least S267K, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x6) the alteration in the first CD16a-binding domain comprises at least E269P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329W or A330P;
(x7) the alteration in the first CD16a-binding domain comprises at least Y296P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329W or A330P;
(x8) the alteration in the first CD16a-binding domain comprises at least S298E, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329K, P329W or A330P;
(x9) the alteration in the first CD16a-binding domain comprises at least T299A, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x10) the alteration in the first CD16a-binding domain comprises at least A327I, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P.
23. (currently amended) A second IgG half-molecule, which is a second IgG half-molecule to be used in combination with a first IgG half-molecule, wherein each of the first IgG half- molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a CD 16a-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alteration of the second IgG half- molecule is in a second CD16a-binding domain, and wherein the first and second CD16a-binding domain are different from each other in the CH2 domain,the first IgG half-molecule includes an antigen-binding domain that binds to a first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration,the second IgG half-molecule includes an antigen-binding domain that binds to a second antigen different from the first antigen, and a CD16a-binding activity in the second CD16a- binding domain is attenuated by the alteration, andan inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule; or which is a second IgG half-molecule to be used for producing an antibody composition against a first antigen and a second antigen that are different from each other, the antibody composition composed of a first IgG half-molecule and the second IgG half-molecule, wherein each of the first IgG half-molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a CD16a-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alteration of the second IgG half-molecule is in a second CD16a-binding domain, and wherein the first and second CD 16a-binding domains are different from each other in the CH2 domain, the first IgG half-molecule includes an antigen-binding domain that binds to the first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration, the second IgG half-molecule includes an antigen-binding domain that binds to the second antigen, and a CD16a-binding activity in the second CD16a-binding domain is attenuated by the alteration, and an inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule, wherein the combination of the alteration in the first CD 16a-binding domain and the alteration in the second CD16a-binding domain are one of the following (xl) to (x10):
(xl) the alteration in the first CD16a-binding domain comprises at least L235R, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P;
(x2) the alteration in the first CD16a-binding domain comprises at least S239R, and the alteration in the second CD16a-binding domain comprises at least K326G, L328R, P329Y, P329K, P329W or A330P;
(x3) the alteration in the first CD16a-binding domain comprises at least P238A and S267L, and the alteration in the second CD16a-binding domain comprises at least P329Y;
(x4) the alteration in the first CD16a-binding domain comprises at least D265A, D265E or D265N, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
See Claim 9 (2C) and (3C).
(x5) the alteration in the first CD16a-binding domain comprises at least S267K, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x6) the alteration in the first CD16a-binding domain comprises at least E269P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329W or A330P;
(x7) the alteration in the first CD16a-binding domain comprises at least Y296P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329W or A330P;
(x8) the alteration in the first CD16a-binding domain comprises at least S298E, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329K, P329W or A330P;
(x9) the alteration in the first CD16a-binding domain comprises at least T299A, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
(x10) the alteration in the first CD16a-binding domain comprises at least A327I, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P.
25. A DNA, which is the following DNA a) or b):a) a DNA encoding an amino acid sequence of the first IgG half-molecule according to claim 21; or b) a DNA encoding an amino acid sequence of a second IgG half-molecule,wherein the second IgG half-molecule is a second IgG half-molecule to be used in combination with a first IgG half-molecule, in which each of the first IgG half-molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alterationin either of a first CD 16a-binding domain and a second CD 16a-binding domain that are different from each other in the CH2 domain,the first IgG half-molecule includes an antigen-binding domain that binds to a first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration,the second IgG half-molecule includes an antigen-binding domain that binds to a second antigen different from the first antigen, and a CD16a-binding activity in the second CD16a- binding domain is attenuated by the alteration, andan inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule.
See claim 11.
26. A recombinant vector, comprising at least one of the DNAs a) and b) according to claim 25.
See claim 12.
29. (currently amended) A kit comprising a first IgG half-molecule and a second IgG half- molecule, wherein each of the first IgG half-molecule and the second IgG half-molecule is composed of one L chain and one H chain, the H chain includes an H chain variable region, a hinge domain altered so as not to form a disulfide bond by substitution or deletion of a part or the whole or modification, and CH1 to CH3 domains, and has alteration in a CD16a-binding domain, wherein the alteration of the first IgG half-molecule is in a first CD16a-binding domain and the alterationof the second IgG half-molecule is in a second CD16a-binding domain, and wherein the first and second CD 16a-binding domains are different from each other in the CH2 domain,the first IgG half-molecule includes an antigen-binding domain that binds to a first antigen, and a CD16a-binding activity in the first CD16a-binding domain is attenuated by the alteration,the second IgG half-molecule includes an antigen-binding domain that binds to a second antigen, and a CD16a-binding activity in the second CD16a-binding domain is attenuated by the alteration, andan inter-H chain disulfide bond is not formed between the first IgG half-molecule and the second IgG half-molecule,wherein the combination of the alteration in the first CD 16a-binding domain and the alteration in the second CD16a-binding domain are one of the following (xl) to (x10):(xl) the alteration in the first CD16a-binding domain comprises at least L235R, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P;(x2) the alteration in the first CD16a-binding domain comprises at least S239R, and the alteration in the second CD16a-binding domain comprises at least K326G, L328R,P329Y, P329K, P329W or A330P;(x3) the alteration in the first CD16a-binding domain comprises at least P238A and S267L, and the alteration in the second CD16a-binding domain comprises at least P329Y;
(x4) the alteration in the first CD16a-binding domain comprises at least D265A, D265E or D265N, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;
See Claim 14 (2D) and (3D).
(x5) the alteration in the first CD16a-binding domain comprises at least S267K, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P;(x6) the alteration in the first CD16a-binding domain comprises at least E269P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329W or A330P;(x7) the alteration in the first CD16a-binding domain comprises at least Y296P, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329W or A330P;(x8) the alteration in the first CD16a-binding domain comprises at least S298E, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329K, P329W or A330P;(x9) the alteration in the first CD16a-binding domain comprises at least T299A, and the alteration in the second CD16a-binding domain comprises at least L328R, P329Y, P329K, P329W or A330P; (x10) the alteration in the first CD16a-binding domain comprises at least A327I, and the alteration in the second CD16a-binding domain comprises at least P329Y, P329W or A330P.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
15. No claims are allowed.
16. The sequences of claim 6 are free from the art: Human IgG1 CH mutant (C226A/C229A/S239D/K326T/D265A/K409R), SEQ ID 248; and Human IgG1 CH mutant (C226A/C229A/S239D/K326T/P329Y/K409R), SEQ ID 252.
17. The following references are found to be pertinent to the claimed invention:
Shields (PTO 892) performed alanine screening of on the Fc region of IgG1 and found combined substitution of Ser (S) 298, Glu (E) 333 and Lys (K) 334 to alanine (S289A/ E333A/K334A) increased binding affinity to CD16A that resulted in augmented ADCC.
Lazar (PTO 892) using the standardized S298A/A333A/K334A as a comparison identified S239D as another candidate residue substitution for in the Fc region for enhanced CD16A binding.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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, Wu Julie can be reached at 571-272-5205. 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.
LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643