Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-22 are pending and being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on May 5, 2026 and February 27, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on January 23, 2024 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim objection
Claim 1 is objected to because of the following informalities:
“the VH or VL domain” at line 5 should have been “a VH or a VL domain” when the phrase “VH or VL domain” first appears in the claim.
“composed of” at line 13 and “is composed of” at line 14 should have been “comprises”.
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 4, 5, 16 and 17 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 “the targeting moiety” in claim 4 renders the claim indefinite because it is not clear which “targeting moiety” is being referring to as there are more than one targeting moiety. One of ordinary skill in the art cannot appraise the metes and bounds of the claimed invention.
Claim 5 recites the limitation "the third targeting moiety" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 16, the phrase "preferably" render the claim indefinite because it is not clear if the narrower recitations following these terms are part of the invention or are merely exemplary. See MPEP § 2173.05(c).
The recitation of “the peptide linker” in claim 16 renders the claim indefinite because it is not clear “the peptide linker” is the first peptide linker or the second peptide linker, or the third peptide linker or the fourth peptide linker. One of ordinary skill in the art cannot appraise the metes and bounds of the claimed invention.
Claim 17 recites the limitation "sixth peptide linker" in base claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-3, 5, 11 and 12 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 fails to limit the parent claim from which they depend as the parent claim 1 is drawn to a set of antigen binding molecules consisting of
a) a first antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a first targeting moiety comprising a first binding site specific for any and all first antigen,
ii. a first peptide linker and
iii. either the VH or VL domain of a second binding site specific for a second antigen, wherein the first targeting moiety is fused to the N-terminus of either the VH or VL domain of the second binding site via the first peptide linker and
b) a second antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a second targeting moiety comprising a third binding site specific for any and all third antigen,
ii. a second peptide linker,
iii. a first Fc region composed of a first and second Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
iv. a third peptide linker and v. the complementary VH or VL domain of the second binding site,
wherein the second targeting moiety is fused to the N-terminus of the first Fc region subunit via the second peptide linker,
wherein the N-terminus of the complementary VH or VL domain of the second binding site is fused to the C-terminus of the first Fe region subunit via the third peptide linker, and
wherein the N-terminus of the second Fc region subunit is fused to a fourth peptide linker, whereas claim 2 requires the first antigen binding molecule further consists of
a fifth peptide linker and
ii. a second Fc region composed of a third and fourth Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
wherein the C-terminus of either the VH or VL domain of the second binding site is fused to the N-terminus of the third Fc region subunit via the fifth peptide linker, and wherein the N-terminus of the fourth Fc region subunit is fused to a sixth peptide linker and claim 3 requires the second antigen binding molecule further consists of (a) a third targeting moiety comprising a fourth binding site specific for the third antigen, wherein the third targeting moiety is fused to the N-terminus of the second Fc region subunit via the fourth peptide linker.
Claim 3 fails to limit the parent claim from which they depend as the parent claim 1 because the second binding molecule further consists of a third targeting moiety comprising a fourth binding site specific for the third antigen.
Claim 11 fails to limit the parent claim from which they depend as the parent claims 5 and 1 because the second antigen binding molecule consists of a fourth, fifth and sixth polypeptide wherein a) the fourth polypeptide comprises from its N-terminus to its C-terminus i. the fourth peptide linker, ii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain, b) the fifth polypeptide comprises from its N-terminus to its C-terminus i. the heavy chain of the second Fab, ii. the second peptide linker, iii. the first Fc region subunit composed from its N-terminus to its G-terminus of an CH2 and CH3 domain, iv. the third peptide linker, v. the complementary VH or VL domain of the second binding site specific for the second antigen, and c) the sixth polypeptide comprises the light chain of the second Fab. As such, the structure of claim 11 is different from the base claim 1.
Claim 12 fails to limit the parent claim from which they depend as the parent claims 5 and 1 because the second antigen binding molecule consists of a fourth, fifth, sixth and seventh polypeptide wherein the second antigen binding molecule consists of a fourth, fifth, sixth and seventh polypeptide, wherein a) the fourth polypeptide comprises from its N-terminus to its C-terminus of i. the heavy chain of the third Fab, ii. the fourth peptide linker, iii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain, b) the fifth polypeptide comprises from its N-terminus to its C-terminus of i. the heavy chain of the second Fab, ii. the second peptide linker, iii. the first Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain, iv. the third peptide linker, v. the complementary VH or VL domain of the second binding site, c) the sixth polypeptide comprises the light chain of the second Fab, and d) the seventh polypeptide comprises the light chain of the third Fab. As such, the structure of claim 12 is different from the base claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-22 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.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art. This problem may arise where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780,1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus."). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number" of species.
In Amgen Inc, v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc, v. Eli Lily & Co.. 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358).
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products - "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
Claim 1 encompasses a set of antigen binding molecules consisting of
a) a first antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a first targeting moiety comprising a first binding site specific for any and all first antigen,
ii. a first peptide linker and
iii. either the VH or VL domain of a second binding site specific for a second antigen, wherein the first targeting moiety is fused to the N-terminus of either the VH or VL domain of the second binding site via the first peptide linker and
b) a second antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a second targeting moiety comprising a third binding site specific for any and all third antigen,
ii. a second peptide linker,
iii. a first Fc region composed of a first and second Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
iv. a third peptide linker and v. the complementary VH or VL domain of the second binding site,
wherein the second targeting moiety is fused to the N-terminus of the first Fc region subunit via the second peptide linker,
wherein the N-terminus of the complementary VH or VL domain of the second binding site is fused to the C-terminus of the first Fe region subunit via the third peptide linker, and
wherein the N-terminus of the second Fc region subunit is fused to a fourth peptide linker.
Claim 2 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen binding molecule further consists of
a fifth peptide linker and
ii. a second Fc region composed of a third and fourth Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
wherein the C-terminus of either the VH or VL domain of the second binding site is fused to the N-terminus of the third Fc region subunit via the fifth peptide linker, and wherein the N-terminus of the fourth Fc region subunit is fused to a sixth peptide linker.
Claim 3 encompasses the set of antigen binding molecules according to claim 1, wherein the second antigen binding molecule further consists of
a third targeting moiety comprising a fourth binding site specific for the third antigen,
wherein the third targeting moiety is fused to the N-terminus of the second Fc region subunit via the fourth peptide linker.
Claim 4 encompasses the set of antigen binding molecules according to claim 1,wherein the targeting moiety is any antibody or any antibody fragment.
Claim 5 encompasses the set of antigen binding molecules according to claim 1, wherein the first targeting moiety is a first Fab, the second targeting moiety is a second Fab and the third targeting moiety is a third Fab.
Claim 6 encompasses the set of antigen binding molecules according to claim 5, wherein the C-terminus of the first Fab heavy chain is fused to the N-terminus of either the VH or VL domain of the second binding site via the first peptide linker.
Claim 7 encompasses the set of antigen binding molecules according to claim 5, wherein the C-terminus of the second Fab heavy chain is fused to the N-terminus of the first Fc region subunit via the second peptide linker.
Claim 8 encompasses the set of antigen binding molecules according to claim 7, wherein the C-terminus of the third Fab heavy chain is fused to the N-terminus of the second Fc region subunit via the fourth peptide linker.
Claim 9 encompasses the set of antigen binding molecules according to claim 5, wherein the first antigen binding molecule consists of a first and second polypeptide, wherein
a) the first polypeptide comprises the light chain of the first Fab and
b) the second polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the first Fab,
ii. the first peptide linker and iii. either the VH or VL domain of the second binding site specific for the second antigen.
Claim 10 encompasses the set of antigen binding molecules according to claim 5, wherein the first antigen binding molecule consists of a first, second and third polypeptide, wherein
a) the first polypeptide comprises the light chain of the first Fab,
b) the second polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the first Fab,
ii. the first peptide linker,
either the VH or VL domain of the second binding site specific for the second antigen,
the fifth peptide linker, and
v. the third Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
c) the third polypeptide comprises from its N-terminus to its C-terminus
i. the sixth peptide linker and
ii. the fourth Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain.
Claim 11 encompasses the set of antigen binding molecules according to claim 5, wherein the second. antigen binding molecule consists of a fourth, fifth and sixth polypeptide, wherein
a) the fourth polypeptide comprises from its N-terminus to its C-terminus
i. the fourth peptide linker,
ii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
b) the fifth polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the second Fab,
ii. the second peptide linker,
iii. the first Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
iv. the third peptide linker,
v. the complementary VH or VL domain of the second binding site specific for the second antigen, and
c) the sixth polypeptide comprises the light chain of the second Fab.
Claim 12 encompasses the set of antigen binding molecules according to claim 5, wherein the second antigen binding molecule consists of a fourth, fifth, sixth and seventh polypeptide, wherein
a) the fourth polypeptide comprises from its N-terminus to its C-terminus of
i. the heavy chain of the third Fab,
ii. the fourth peptide linker, iii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
b) the fifth polypeptide comprises from its N-terminus to its C-terminus of
i. the heavy chain of the second Fab,
ii. the second peptide linker,
iii. the first Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
iv. the third peptide linker,
v. the complementary VH or VL domain of the second binding site,
c) the sixth polypeptide comprises the light chain of the second Fab, and
d) the seventh polypeptide comprises the light chain of the third Fab.
Claim 13 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen binding molecule and the second antigen binding molecule are not linked by a covalent bond.
Claim 14 encompasses the set of antigen binding molecules according to claim 1, wherein neither the first antigen binding molecule alone nor the second antigen binding molecule alone is able to bind to the second antigen.
Claim 15 encompasses the set of antigen binding molecules according to claim 1, wherein either the VH or VL domain of the second binding site of first antigen binding molecule and the complementary VH or VL domain of the second binding site of the second antigen binding molecule are capable of non-covalently associating, thereby forming the second binding site.
Claim 16 encompasses the set of antigen binding molecules according to claim 1, wherein the peptide linker has a length of 5 to 49 amino acids residues, preferably 5 to 29 amino acids residues.
Claim 17 encompasses the set of antigen binding molecules according to claim 1, wherein the first peptide linker has a length of 5 to 45 amino acids residues, the third peptide linker has a length of 5 to 20 amino acid residues, the fifth peptide linker has a length of 9 to 49 amino acid residues, the second, fourth and sixth peptide linker each has a length of 5 to 20 amino acid residues.
Claim 18 encompasses the set of antigen binding molecules according to claim 1, wherein the second binding site is an antibody Fv region.
Claim 19 encompasses the set of antigen binding molecules according to claim 18, wherein the antibody Fv region is specific for any CD3.
Claim 20 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen and the third antigen are present on the same cell and wherein the second antigen is present on a different cell.
Claim 21 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen and the third antigen are different.
Claim 22 encompasses the set of antigen binding molecules according to claim 1, wherein each CH3 domain of the first and second Fc domain subunit and each CH3 domain of the third and fourth Fc domain subunit comprises an amino acid modification promoting the association of the first and second Fc region subunit and of the third and fourth Fc region subunit, respectively.
Regarding antigen, the specification discloses:
[0225] The terms “antigen” or “target antigen” as used herein refers to any molecule of interest that can be bound by one of the binding sites present in an antigen binding molecule according to the present disclosure. Typically, an antigen is a peptide, a protein or any other proteinaceous molecule. Alternatively, an antigen may be any other organic or inorganic molecule, such as carbohydrate, fatty acid, lipid, dye or fluorophore.
[1115] Non-limiting examples of (tumor-associated) antigens include antigens such as AR, AGR2, A1G1, AKAP1, AKAP2, ANGPT1, ANGPT2, ANPEP, ANGPTL3, APOC1, ANGPTL4, AITGAV, AZGP1, BMP6, BRCA1, BAD, BAG1, BCL2, BL6R, BA2, BPAG1, CDK2, CD52, CD20, CD19, CD4, CD8, CD164, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CDKN3, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CLDN3, CLN3, CYB5, CYC1, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, CHGB, CDH20, CDH7, CDH8, CDH9, CD44, CDH1, CDH10, CDH19, CDH20, CDH7, CDH9, CDH13, CDH18, CDH19, CANT1, CAV1, CDH12, CD164, COL6A1, CCL2, CDH5, COL18A1, CHGA, CHGB, CLU, COL1A1, COL6A1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, COL6A1, CTNNB1, CTSB, CLDN7, CLU, CD44APC, COL4A3, DSfHA, DAB2JP, DES, DNCL1, DD2, DL2, EL24, EGF, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, EL2, ESTHA, ELAC2, ENO2, ENO3, ERBB2, ESR1, ESR2, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, ESR1, ESR2, EGF, ERK8, EL12A, EL1A, EL24, ENHA, ELK, ECGF1, EREG, EDG1, ENG, E-cadherin, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FASN, FLJ12584, FLJ25530, F1GF, FLT1, FGFR3, F3, FOSL1, FLRT1, IL12A, IL1A, IL1B, IL2, INHA, IGF1, IGF2, IL12A, IL1A, IL1B, IL2, INHA, IGF1R, IL2, IGFBP6, IL1A, IL1B, IGFBP3, IGFBP6, INSL4, IL6ST, ITGA6, IGF1, IGF2, INSL3, INSL4, IFNA1, IFNB1, IFNG, IL1B, IL6, IGFBP2, IL2RA, IL6, IGF1, IGF2, IGFBP3, IGFBP6, ITGA1, IGF1, ITGA6, ITGB4, INSL3, INSL4, IL29, IL8, ITGB3, GRP, GNRH1, GAGEB1, GAGEC1, GGT1, GSTP1, GATA3, GABRP, GNAS1, GSN, H1P1, HUMCYT2A, HGF, JAG1, JUN, LAMA5, S100A2, SCGB1D2, SCGB2A1, SCGB2A2, SPRR1B, SHBG, SERPINA3, SHBG, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, SERP1NF1, SERPINB5, SERPINE1, STAB1, TGFA, TGFB1, TGFB2, TGFB3, TNF, TNFSF10, TGFB111, TP53, TPM1, TPM2, TRPC6, TGFA, THBS, TEE, TNFRSF6, TNFSF6, TOP2A, TP53, THBS1, THBS2, THBS4, TNFAIP2, TP53, TEK, TGFA, TGFB1, TGFB2, TGFBR1, TGFA, TEV1P3, TGFB3, TNFA1P2, 1TGB3, THBS1, THBS2, VEGF, VEGFC, ODZ1, PAWR, PLG, PAP, PCNA, PRKCQ, PRKD1, PRL, PECAM1, PF4, PROK2, PRL, PAP, PLAU, PRL, PSAP, PART1, PATE, PCA3, P1AS2, PGF, PGR, PLAU, PGR, PLXDCI, PTEN, PTGS2, PDGF, MYC, MMP2, MMP9, MSMB, MACMARCKS, MT3, MUC1, MAP2K7, MKi67, MTSS1, M1B1, MDK, NOX5, NR6A1, NR1H3, NR113, NR2F6, NR4A3, NR1H2, NR1H4, NR112, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, NR6A1, NROB1, NROB2, NR1D2, NR1D1, NTN4, NRP1, NRP2, NGFB, NGFR, NME1, KLK6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, K6HF, KA2, KRT2A, KLK6, KLK3, KRT1, KDR, KLK5, KRT19, KLF5, KRT19, KRTHB6, RARB, RAC2, and ROBO2.
Regarding antigen binding molecule, the specification defines as follow:
[0227] The term “antigen binding molecule” as used herein, refers in its broadest sense to a proteinaceous molecule that specifically binds to at least one antigen. An antigen binding molecule may be composed of one or more polypeptides. Examples of antigen binding molecules are immunoglobulins and derivatives and/or fragments thereof. Antigen binding molecules according to the present disclosure may be based on a regular immunoglobulin (e.g. IgG), in particular of half IgG molecules. The antigen binding molecule as disclosed herein are composed of at least a targeting moiety (such as an antibody Fab fragment) and either an additional VH or VL domain of an antibody Fv domain, wherein neither the VH or VL domain is able to bind to its antigen alone. Accordingly, an antigen binding molecule according to the preset disclosure incorporates a half Fv domain (½ Fv domain) or a half binding site and one or two Fv domains or full binding site and thus can be also denoted as a 1+½ or 1½ antigen or 2+½ or 2½ antigen binding molecule.
Regarding “binding site”, the specification defines as follow:
[0229] As used herein, the terms “binding site” or “antigen binding site” refer to a structure formed by a protein that is capable of binding or specifically binding to an antigen. The binding site need not be a series of contiguous amino acids, or even amino acids in a single polypeptide chain. For example, in a Fv produced from two different polypeptide chains the binding site is made up of a series of amino acids of a VL and a VH that interact with the antigen and that are generally, however not always in the one or more of the CDRs in each variable region. In certain embodiments, a binding site is or comprises or is formed by a complementary antibody variable heavy (VH) and light chain (VL) pair. The VH and the VL which form the binding site can be in a single polypeptide chain or in different polypeptide chains. In preferred embodiments, the binding site is or comprises or is formed by a VH present on a first antigen binding molecule according to the present disclosure and the complementary VL is present on the second antigen binding molecule according to the present disclosure, or vice versa. In some embodiments, the binding site has one VH and one VL. In certain embodiments, the binding site comprises one or more CDRs of an antibody. In other embodiments, a binding site is derived from an antibody mimetic, such as for instance from an affibody molecule, alpha body, anticalin, avimer, DARPin, fynomer, kunitz domain peptide, helix-turn-helix peptide, or monobody.
Regarding “antibody fragment”, the specification defines as follow:
[0231] The term “antibody fragment” as used herein, refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen. Examples of antibody fragments include, but are not limited to, a Fab, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, wherein the Fab heavy chain (HC) is formed by the VH and CH1 domains (VH-CH1) and the Fab light chain is formed by the complementary VL and CL domains (VL-CL). Accordingly, the Fab heavy chain and the Fab light chain are complementary to each other; a F(ab).sub.2, a bivalent fragment comprising two Fabs linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment or Fv region or Fv domain consisting of a dimer of one VL and one VH domain. Accordingly, the VH and VL domain of a Fv fragment or Fv region are complementary to each other; a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two variable domains of the Fv fragment or Fv region are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (referred herein as “single chain Fv” or “scFv”; see e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antibody fragment”. Antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding sites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Pat. No. 5,641,870).
The specification discloses amino acid sequences of antigen binding molecules according to the present disclosure in the B027 format as shown in Figure 1A with monovalent binding to HER2 or EGFR and comprising either the VH or VL domain of the low affinity anti-CD3 antibody according Table 2.
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513
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Table 11: Amino acid sequences of antigen binding molecules according to the present disclosure in the B036 format as shown in FIGURE 1B with varying linker combinations, monovalent binding to HER2 or EGFR and comprising either the VH or VL domain of the high affinity anti-CD3 antibody according Table 3. Constructs 21, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 further compasses a polypeptide encoding the Fab light chain of trastuzumab having SEQ ID NO: 18 whereas Constructs 22, 23, 25, 27, 29, 31 , 33, 35, 37, 39, and 41 further encompass a polypeptide encoding the Fab light chain of cetuximab having SEQ ID NO: 21. All constructs further encompass a third polypeptide encoding the second Fc region subunit (carrying the hole-mutations) having SEQ ID NO: 14.
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673
652
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Note that all these constructs bind to just HER2, CD3 and EGFR.
Regarding linker, the specification discloses amino acid linker sequences are shown in Table 6.
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Table 15: Dual targeting of HER2 and EGFR with different combinations of 1 ½ antigen binding molecules in the B027 and B036 format forming symmetric trispecific antibodies on the cell surface of SKOV-3 cell.
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However, the specification does not describe the structure-identifying information, e.g., amino acid sequences of the heavy and light chain variable region for the first, second, third and fourth binding sites of first, second and third targeting moiety encompassed by the set of antigen molecules, nor describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed set of antigen binding molecules themselves.
Even assuming the first antigen or third antigen is HER2 or EGFR, the disclosure of one species of trastuzumab antibody that binds to HER2 or cetuximab that binds to EGFR is not representative of the genus of antibodies that bind to all HER2 and EGFR. The specification does not describe the amino acid sequences of heavy and light chain variable domains share by members of the genus of antibodies that bind to HER2 or EGFR. There is no limitation on the structure or function of the antibody, or the epitope to which it binds.
Regarding the species of antibodies that bind to HER2, the specification discloses just trastuzumab. The trastuzumab antibody that binds to HER2 comprises a heavy chain variable comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10.
Regarding the species of antibodies that bind to EGFR, the specification discloses just cetuximab wherein the antibody comprises a heavy chain variable comprising SEQ ID NO: 11 and a light chain variable region comprising SEQ ID NO: 12.
However, one species of antibody that binds to HER2 is not representative of the genus of antibodies that bind to any and all HER2. Likewise, one species of antibody that binds to EGFR is not representative of the genus of antibodies that bind to any and all EGFR.
Even assuming the second binding site is Fv that binds to CD3 (claim 19), the specification discloses antibodies that bind to CD3 comprises a heavy chain variable comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2 or a heavy chain variable comprising SEQ ID NO: 59 and a light chain variable region comprising SEQ ID NO: 60. These two antibodies share the same CDRs.
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Thus, the specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed first, second, third and fourth binding sites specific for any and all potential antigens.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Thus a representative number of species of first antigen binding molecule specific for a first antigen, a second binding site specific for a second antigen and a third binding site for s third antigen falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus are not adequately described.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 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).
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.)
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. 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 (see p. 4, 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, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding any antibody fragment (claim 4), the term fragment can be as little as two amino acids or Fc domain. However, two amino acids or Fc domain do not bind to any antigen.
Regarding each CH3 domain of Fc domain subunit comprises any amino acid modification promoting the association of the first and the second Fc region subunit and third and fourth Fc region subunit (claim 22), the term “modification” encompasses deletion, addition, substitution and a combination thereof.
The specification teaches the CH3 domain of first and/or third Fc region subunit, the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C) and in the CH3 domain of the second and/or fourth Fc region subunit the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A) and the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) with numbering according EU index.
However, the specification does not teach any and all modification other than those T366S, Y407V, L368A, Y349C substitution above in the CH3 interface of IgG1 promotes heterodimer.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only trispecific trivalent antibody construct that binds to HER2, CD3 and EGFR comprising a particular combination of a first, a second and a third polypeptides as set in Tables 10, 11, and 15, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a trispecific trivalent antibody construct that binds to HER2, CD3 and EGFR comprising a particular combination of a first, a second and a third polypeptides as set in Tables 10, 11, and 15, does not reasonably provide enablement for a method of removing any and all thrombogenic agents from an immunoglobulin containing solution. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses a set of antigen binding molecules consisting of
a) a first antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a first targeting moiety comprising a first binding site specific for any and all first antigen,
ii. a first peptide linker and
iii. either the VH or VL domain of a second binding site specific for a second antigen, wherein the first targeting moiety is fused to the N-terminus of either the VH or VL domain of the second binding site via the first peptide linker and
b) a second antigen binding molecule consisting from its N-terminus to its C-terminus of
i. a second targeting moiety comprising a third binding site specific for any and all third antigen,
ii. a second peptide linker,
iii. a first Fc region composed of a first and second Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
iv. a third peptide linker and v. the complementary VH or VL domain of the second binding site,
wherein the second targeting moiety is fused to the N-terminus of the first Fc region subunit via the second peptide linker,
wherein the N-terminus of the complementary VH or VL domain of the second binding site is fused to the C-terminus of the first Fe region subunit via the third peptide linker, and
wherein the N-terminus of the second Fc region subunit is fused to a fourth peptide linker.
Claim 2 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen binding molecule further consists of
a fifth peptide linker and
ii. a second Fc region composed of a third and fourth Fc region subunit, wherein each Fc region subunit is composed of an CH2 and CH3 domain,
wherein the C-terminus of either the VH or VL domain of the second binding site is fused to the N-terminus of the third Fc region subunit via the fifth peptide linker, and wherein the N-terminus of the fourth Fc region subunit is fused to a sixth peptide linker.
Claim 3 encompasses the set of antigen binding molecules according to claim 1, wherein the second antigen binding molecule further consists of
a third targeting moiety comprising a fourth binding site specific for the third antigen,
wherein the third targeting moiety is fused to the N-terminus of the second Fc region subunit via the fourth peptide linker.
Claim 4 encompasses the set of antigen binding molecules according to claim 1,wherein the targeting moiety is any antibody or any antibody fragment.
Claim 5 encompasses the set of antigen binding molecules according to claim 1, wherein the first targeting moiety is a first Fab, the second targeting moiety is a second Fab and the third targeting moiety is a third Fab.
Claim 6 encompasses the set of antigen binding molecules according to claim 5, wherein the C-terminus of the first Fab heavy chain is fused to the N-terminus of either the VH or VL domain of the second binding site via the first peptide linker.
Claim 7 encompasses the set of antigen binding molecules according to claim 5, wherein the C-terminus of the second Fab heavy chain is fused to the N-terminus of the first Fc region subunit via the second peptide linker.
Claim 8 encompasses the set of antigen binding molecules according to claim 7, wherein the C-terminus of the third Fab heavy chain is fused to the N-terminus of the second Fc region subunit via the fourth peptide linker.
Claim 9 encompasses the set of antigen binding molecules according to claim 5, wherein the first antigen binding molecule consists of a first and second polypeptide, wherein
a) the first polypeptide comprises the light chain of the first Fab and
b) the second polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the first Fab,
ii. the first peptide linker and iii. either the VH or VL domain of the second binding site specific for the second antigen.
Claim 10 encompasses the set of antigen binding molecules according to claim 5, wherein the first antigen binding molecule consists of a first, second and third polypeptide, wherein
a) the first polypeptide comprises the light chain of the first Fab,
b) the second polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the first Fab,
ii. the first peptide linker,
either the VH or VL domain of the second binding site specific for the second antigen,
the fifth peptide linker, and
v. the third Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
c) the third polypeptide comprises from its N-terminus to its C-terminus
i. the sixth peptide linker and
ii. the fourth Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain.
Claim 11 encompasses the set of antigen binding molecules according to claim 5, wherein the second. antigen binding molecule consists of a fourth, fifth and sixth polypeptide, wherein
a) the fourth polypeptide comprises from its N-terminus to its C-terminus
i. the fourth peptide linker,
ii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
b) the fifth polypeptide comprises from its N-terminus to its C-terminus
i. the heavy chain of the second Fab,
ii. the second peptide linker,
iii. the first Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
iv. the third peptide linker,
v. the complementary VH or VL domain of the second binding site specific for the second antigen, and
c) the sixth polypeptide comprises the light chain of the second Fab.
Claim 12 encompasses the set of antigen binding molecules according to claim 5, wherein the second antigen binding molecule consists of a fourth, fifth, sixth and seventh polypeptide, wherein
a) the fourth polypeptide comprises from its N-terminus to its C-terminus of
i. the heavy chain of the third Fab,
ii. the fourth peptide linker, iii. the second Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
b) the fifth polypeptide comprises from its N-terminus to its C-terminus of
i. the heavy chain of the second Fab,
ii. the second peptide linker,
iii. the first Fc region subunit composed from its N-terminus to its C-terminus of an CH2 and CH3 domain,
iv. the third peptide linker,
v. the complementary VH or VL domain of the second binding site,
c) the sixth polypeptide comprises the light chain of the second Fab, and
d) the seventh polypeptide comprises the light chain of the third Fab.
Claim 13 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen binding molecule and the second antigen binding molecule are not linked by a covalent bond.
Claim 14 encompasses the set of antigen binding molecules according to claim 1, wherein neither the first antigen binding molecule alone nor the second antigen binding molecule alone is able to bind to the second antigen.
Claim 15 encompasses the set of antigen binding molecules according to claim 1, wherein either the VH or VL domain of the second binding site of first antigen binding molecule and the complementary VH or VL domain of the second binding site of the second antigen binding molecule are capable of non-covalently associating, thereby forming the second binding site.
Claim 16 encompasses the set of antigen binding molecules according to claim 1, wherein the peptide linker has a length of 5 to 49 amino acids residues, preferably 5 to 29 amino acids residues.
Claim 17 encompasses the set of antigen binding molecules according to claim 1, wherein the first peptide linker has a length of 5 to 45 amino acids residues, the third peptide linker has a length of 5 to 20 amino acid residues, the fifth peptide linker has a length of 9 to 49 amino acid residues, the second, fourth and sixth peptide linker each has a length of 5 to 20 amino acid residues.
Claim 18 encompasses the set of antigen binding molecules according to claim 1, wherein the second binding site is an antibody Fv region.
Claim 19 encompasses the set of antigen binding molecules according to claim 18, wherein the antibody Fv region is specific for any CD3.
Claim 20 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen and the third antigen are present on the same cell and wherein the second antigen is present on a different cell.
Claim 21 encompasses the set of antigen binding molecules according to claim 1, wherein the first antigen and the third antigen are different.
Claim 22 encompasses the set of antigen binding molecules according to claim 1, wherein each CH3 domain of the first and second Fc domain subunit and each CH3 domain of the third and fourth Fc domain subunit comprises an amino acid modification promoting the association of the first and second Fc region subunit and of the third and fourth Fc region subunit, respectively.
The claims encompass a set of any antigen binding molecules comprising virtually any combination of first, second and third targeting moieties specific for any and all possible first antigen, second antigen, and third antigens.
Enablement is not commensurate in scope with claims as how to make and use the set of antigen binding molecules for treating any cancer.
Regarding antigen, the specification discloses:
[0225] The terms “antigen” or “target antigen” as used herein refers to any molecule of interest that can be bound by one of the binding sites present in an antigen binding molecule according to the present disclosure. Typically, an antigen is a peptide, a protein or any other proteinaceous molecule. Alternatively, an antigen may be any other organic or inorganic molecule, such as carbohydrate, fatty acid, lipid, dye or fluorophore.
[1115] Non-limiting examples of (tumor-associated) antigens include antigens such as AR, AGR2, A1G1, AKAP1, AKAP2, ANGPT1, ANGPT2, ANPEP, ANGPTL3, APOC1, ANGPTL4, AITGAV, AZGP1, BMP6, BRCA1, BAD, BAG1, BCL2, BL6R, BA2, BPAG1, CDK2, CD52, CD20, CD19, CD4, CD8, CD164, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CDKN3, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CLDN3, CLN3, CYB5, CYC1, CCL2, CXCL1, CXCL10, CXCL3, CXCL5, CXCL6, CXCL9, CHGB, CDH20, CDH7, CDH8, CDH9, CD44, CDH1, CDH10, CDH19, CDH20, CDH7, CDH9, CDH13, CDH18, CDH19, CANT1, CAV1, CDH12, CD164, COL6A1, CCL2, CDH5, COL18A1, CHGA, CHGB, CLU, COL1A1, COL6A1, CCNA1, CCNA2, CCND1, CCNE1, CCNE2, COL6A1, CTNNB1, CTSB, CLDN7, CLU, CD44APC, COL4A3, DSfHA, DAB2JP, DES, DNCL1, DD2, DL2, EL24, EGF, E2F1, EGFR, ENO1, ERBB2, ESR1, ESR2, EL2, ESTHA, ELAC2, ENO2, ENO3, ERBB2, ESR1, ESR2, EDG1, EFNA1, EFNA3, EFNB2, EPHB4, ESR1, ESR2, EGF, ERK8, EL12A, EL1A, EL24, ENHA, ELK, ECGF1, EREG, EDG1, ENG, E-cadherin, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FASN, FLJ12584, FLJ25530, F1GF, FLT1, FGFR3, F3, FOSL1, FLRT1, IL12A, IL1A, IL1B, IL2, INHA, IGF1, IGF2, IL12A, IL1A, IL1B, IL2, INHA, IGF1R, IL2, IGFBP6, IL1A, IL1B, IGFBP3, IGFBP6, INSL4, IL6ST, ITGA6, IGF1, IGF2, INSL3, INSL4, IFNA1, IFNB1, IFNG, IL1B, IL6, IGFBP2, IL2RA, IL6, IGF1, IGF2, IGFBP3, IGFBP6, ITGA1, IGF1, ITGA6, ITGB4, INSL3, INSL4, IL29, IL8, ITGB3, GRP, GNRH1, GAGEB1, GAGEC1, GGT1, GSTP1, GATA3, GABRP, GNAS1, GSN, H1P1, HUMCYT2A, HGF, JAG1, JUN, LAMA5, S100A2, SCGB1D2, SCGB2A1, SCGB2A2, SPRR1B, SHBG, SERPINA3, SHBG, SLC2A2, SLC33A1, SLC43A1, STEAP, STEAP2, SERP1NF1, SERPINB5, SERPINE1, STAB1, TGFA, TGFB1, TGFB2, TGFB3, TNF, TNFSF10, TGFB111, TP53, TPM1, TPM2, TRPC6, TGFA, THBS, TEE, TNFRSF6, TNFSF6, TOP2A, TP53, THBS1, THBS2, THBS4, TNFAIP2, TP53, TEK, TGFA, TGFB1, TGFB2, TGFBR1, TGFA, TEV1P3, TGFB3, TNFA1P2, 1TGB3, THBS1, THBS2, VEGF, VEGFC, ODZ1, PAWR, PLG, PAP, PCNA, PRKCQ, PRKD1, PRL, PECAM1, PF4, PROK2, PRL, PAP, PLAU, PRL, PSAP, PART1, PATE, PCA3, P1AS2, PGF, PGR, PLAU, PGR, PLXDCI, PTEN, PTGS2, PDGF, MYC, MMP2, MMP9, MSMB, MACMARCKS, MT3, MUC1, MAP2K7, MKi67, MTSS1, M1B1, MDK, NOX5, NR6A1, NR1H3, NR113, NR2F6, NR4A3, NR1H2, NR1H4, NR112, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR3C1, NR3C2, NR4A1, NR4A2, NR5A1, NR5A2, NR6A1, NROB1, NROB2, NR1D2, NR1D1, NTN4, NRP1, NRP2, NGFB, NGFR, NME1, KLK6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, K6HF, KA2, KRT2A, KLK6, KLK3, KRT1, KDR, KLK5, KRT19, KLF5, KRT19, KRTHB6, RARB, RAC2, and ROBO2.
Regarding antigen binding molecule, the specification defines as follow:
[0227] The term “antigen binding molecule” as used herein, refers in its broadest sense to a proteinaceous molecule that specifically binds to at least one antigen. An antigen binding molecule may be composed of one or more polypeptides. Examples of antigen binding molecules are immunoglobulins and derivatives and/or fragments thereof. Antigen binding molecules according to the present disclosure may be based on a regular immunoglobulin (e.g. IgG), in particular of half IgG molecules. The antigen binding molecule as disclosed herein are composed of at least a targeting moiety (such as an antibody Fab fragment) and either an additional VH or VL domain of an antibody Fv domain, wherein neither the VH or VL domain is able to bind to its antigen alone. Accordingly, an antigen binding molecule according to the preset disclosure incorporates a half Fv domain (½ Fv domain) or a half binding site and one or two Fv domains or full binding site and thus can be also denoted as a 1+½ or 1½ antigen or 2+½ or 2½ antigen binding molecule.
Regarding “binding site”, the specification defines as follow:
[0229] As used herein, the terms “binding site” or “antigen binding site” refer to a structure formed by a protein that is capable of binding or specifically binding to an antigen. The binding site need not be a series of contiguous amino acids, or even amino acids in a single polypeptide chain. For example, in a Fv produced from two different polypeptide chains the binding site is made up of a series of amino acids of a VL and a VH that interact with the antigen and that are generally, however not always in the one or more of the CDRs in each variable region. In certain embodiments, a binding site is or comprises or is formed by a complementary antibody variable heavy (VH) and light chain (VL) pair. The VH and the VL which form the binding site can be in a single polypeptide chain or in different polypeptide chains. In preferred embodiments, the binding site is or comprises or is formed by a VH present on a first antigen binding molecule according to the present disclosure and the complementary VL is present on the second antigen binding molecule according to the present disclosure, or vice versa. In some embodiments, the binding site has one VH and one VL. In certain embodiments, the binding site comprises one or more CDRs of an antibody. In other embodiments, a binding site is derived from an antibody mimetic, such as for instance from an affibody molecule, alpha body, anticalin, avimer, DARPin, fynomer, kunitz domain peptide, helix-turn-helix peptide, or monobody.
Regarding “antibody fragment”, the specification defines as follow:
[0231] The term “antibody fragment” as used herein, refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing spatial distribution) an antigen. Examples of antibody fragments include, but are not limited to, a Fab, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, wherein the Fab heavy chain (HC) is formed by the VH and CH1 domains (VH-CH1) and the Fab light chain is formed by the complementary VL and CL domains (VL-CL). Accordingly, the Fab heavy chain and the Fab light chain are complementary to each other; a F(ab).sub.2, a bivalent fragment comprising two Fabs linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment or Fv region or Fv domain consisting of a dimer of one VL and one VH domain. Accordingly, the VH and VL domain of a Fv fragment or Fv region are complementary to each other; a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two variable domains of the Fv fragment or Fv region are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (referred herein as “single chain Fv” or “scFv”; see e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antibody fragment”. Antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding sites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Pat. No. 5,641,870).
The specification discloses amino acid sequences of antigen binding molecules according to the present disclosure in the B027 format as shown in Figure 1A with monovalent binding to HER2 or EGFR and comprising either the VH or VL domain of the low affinity anti-CD3 antibody according Table 2.
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Table 11: Amino acid sequences of antigen binding molecules according to the present disclosure in the B036 format as shown in FIGURE 1B with varying linker combinations, monovalent binding to HER2 or EGFR and comprising either the VH or VL domain of the high affinity anti-CD3 antibody according Table 3. Constructs 21, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 further compasses a polypeptide encoding the Fab light chain of trastuzumab having SEQ ID NO: 18 whereas Constructs 22, 23, 25, 27, 29, 31 , 33, 35, 37, 39, and 41 further encompass a polypeptide encoding the Fab light chain of cetuximab having SEQ ID NO: 21. All constructs further encompass a third polypeptide encoding the second Fc region subunit (carrying the hole-mutations) having SEQ ID NO: 14.
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Note that all these constructs bind to just HER2, CD3 and EGFR. Regarding the species of antibodies that bind to HER2, the specification discloses just trastuzumab. The trastuzumab antibody that binds to HER2 comprises a heavy chain variable comprising SEQ ID NO: 9 and a light chain variable region comprising SEQ ID NO: 10. Regarding the species of antibodies that bind to EGFR, the specification discloses just cetuximab wherein the antibody comprises a heavy chain variable comprising SEQ ID NO: 11 and a light chain variable region comprising SEQ ID NO: 12.
Regarding linker, the specification discloses amino acid linker sequences are shown in Table 6.
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Table 15: Dual targeting of HER2 and EGFR with different combinations of 1 ½ antigen binding molecules in the B027 and B036 format forming symmetric trispecific antibodies on the cell surface of SKOV-3 cell.
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However, the specification does not teach the structure, e.g., amino acid sequences of the heavy and light chain variable region for the first, second, third and fourth binding sites of first, second and third targeting moiety encompassed by the set of antigen molecules that bind to any first, second and third potential antigens so the one of skill in the art can make and use antigen binding molecules themselves without undue experimentation.
Even assuming the first antigen or third antigen is HER2 or EGFR, the disclosure of one species of trastuzumab antibody that binds to HER2 and one species of cetuximab that binds to EGFR are not representative of the genus of antibodies that bind to HER2 and EGFR from other species. The specification does not teach the amino acid sequences of heavy and light chain variable domains share by members of the genus of antibodies that bind to HER2 or EGFR. There is no limitation on the structure or function of the antibody, or the epitope to which it binds.
Even assuming the second binding site is Fv that binds to CD3 (claim 19), the specification discloses antibodies that bind to CD3 comprises a heavy chain variable comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2 or a heavy chain variable comprising SEQ ID NO: 59 and a light chain variable region comprising SEQ ID NO: 60. Note, these two antibodies share the same CDRs, see Table below.
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The specification does not teach a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can make and use without undue experimentation.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 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).
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.)
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. 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 (see p. 4, 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, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding any antibody fragment (claim 4), the term fragment can be as little as two amino acids or Fc domain. However, two amino acids or Fc domain do not bind to any antigen.
Regarding each CH3 domain of Fc domain subunit comprises any amino acid modification promoting the association of the first and the second Fc region subunit and third and fourth Fc region subunit (claim 22), the term “modification” encompasses deletion, addition, substitution and a combination thereof.
The specification teaches the CH3 domain of first and/or third Fc region subunit, the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C) and in the CH3 domain of the second and/or fourth Fc region subunit the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A) and the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) with numbering according EU index.
However, the specification does not teach any and all modification other than those T366S, Y407V, L368A, Y349C substitution above in the CH3 interface of IgG1 that promotes heterodimerization.
There are insufficient in vivo working examples. It is unpredictable which set of antigen binding molecules is effective for treating any and all possible cancer.
As such, undue experimentation would be required to make and use the claimed set of antigen binding molecules with a reasonable expectation of success, commensurate in scope with the claimed invention.
Closest prior art
US Patent No. 10,633,457 teaches multispecific antibody comprising a VL-CL, a VH-CH1-linker-VL or VH and CH3 wherein the CH3 domain comprises a hole or a knob mutation having the following structure:
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However, the reference multispecific antibody does not comprises a CH2 domain, much less a VH-CH1-linked to VH or VL.
Conclusion
Linker peptide of SEQ ID NO: 31, 33, 51, 52, 53, 54, 55, 56, 101, 103, 104 are free of prior art.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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