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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Oct 7, 2025 has been entered.
Claims 1, 50-56 and 58-67 are pending.
Claims 58 and 61-66 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1, 50-56, 59-60 and 67, drawn to an isolated multispecific protein that read on (A) as the particular multispecific protein identified in claim 50 (iv); (B) Antibody NKp46-1 as the particular NKp46 (claim 50 part viii); (C) Epitope comprising residues K41, E42, E119, Y121 and/or Y194 identifiable in claim 50 (ix); (D) the protein of claim 53, clause (2); (E) VH and VL CDRs respectively of SEQ ID NO 3 and 4 recited in claim 57 part (a); and (F) CD19 as the particular cancer antigen to which the multispecific protein binds, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/017,886, filed on June 27, 2014, and 62/108,088, filed on January 27, 2015, is acknowledged.
Objection and Rejection Withdrawn
The objection to claims 1, 50-56, 59-60 and 67 is withdrawn in view of the claim amendment.
The rejection of claims 50, 51, 53, 55, 67 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
The written description and enablement rejection with respect to portion of a human Fc domain, any modification or mutation in Fc and antigen binding domain that binds to any antigen of interest of claims 50-51, 53, 55, 56, 59-60 and 67 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph are withdrawn in view of the claims amendment.
The enablement rejection of claims 50-51, 53, 55, 56, 59-60 and 67 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the declaration of Laurent Gauthier under 37 C.F.R. § 1.132.
The provisional rejection of claims 1, 50-56, 59-60 and 67 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 2-5 of copending Application No. 18/432,126 is withdrawn in view of the amendment to copending claims.
The provisional rejection of claims 1, 50-56, 59-60 and 67 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 56-67 and 70 of copending Application No. 18/283,385 is withdrawn in view of the amendment to copending claims.
The provisional rejection of claims 1, 50-56, 59-60 and 67 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 46-59 of copending Application No. 18/568,310 is withdrawn in view of the amendment to copending claims.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1 and 50 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 10 and 11 of U.S. Patent No. 10,519,234. Although the conflicting claims are not identical, they are not patentably distinct from each other because instant claims anticipate the issued claims 10 and 11. The issued claims are generic with respect to cancer antigen whereas instant claims limited the multispecific protein to a first antigen binding domain that binds to human NKp46 and a second antigen binding domain (ABD2) that binds to cancer antigen.
Issued claim 10 recites a multispecific protein comprising any one of the antibody fragment that specifically binds NKp46 comprising: (a) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 3 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 4 (see instant claim 1, elected species); (b) a heavy chain variable region comprising CDRs 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 5 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 6; (c) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 7 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 8; (d) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 9 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 10; (e) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 11 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 12; or (f) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 13 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 14 (species), whereas the multispecific protein of instant claim 1 is generic with respect to the first antigen binding domain that binds to human NKp46 and the second antigen binding domain that binds to any antigen of interest.
Issued claim 11 recites a bispecific protein comprising any one of the antibody fragment that specifically binds NKp46 comprising: (a) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 3 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 4 (see instant claim 1, elected species); (b) a heavy chain variable region comprising CDRs 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 5 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 6; (c) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 7 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 8; (d) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 9 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 10; (e) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 11 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 12; or (f) a heavy chain variable region comprising CDRs 1, 2, and 3 of the heavy chain variable region of SEQ ID NO: 13 and a light chain variable region comprising CDRs 1, 2, and 3 of the light chain variable region of SEQ ID NO: 14 (species).
The issued patent also teaches the bispecific binding protein binds NKp46 monovalently via its anti-NKp46 binding domain, see Example 2, in particular.
Regarding claim 50, the patent also teaches lysis of target cell, see Summary of the Invention.
The patent also teaches the claimed human NKp46 binding domain wherein the ABD comprising a VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO: 4, which are identical to instant SEQ ID NO: 3 and 4, respectively. Thus, the instant claims anticipate the issued claims.
Applicant’s request that that the rejections and provisional rejections are held in abeyance until the present application is otherwise allowable is acknowledged.
Claims 1, 50-56, 59-60 and 67 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,267,897. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope. The issued claims are drawn to multispecific antigen binding protein which promotes the specific lysis of target cells expressing an antigen of interest comprising an antigen binding domain that binds to human NKp46-1 comprising the particular heavy and light chain variable regions, whereas the present claims are generic with respect to the first and second binding domains that bind to human NKp46 and cancer antigen (species).
Issued claim 1 recites a multispecific antigen binding protein which promotes the specific lysis of target cells expressing an antigen of interest, which antigen is specifically bound by a therapeutic antibody or therapeutic antigen-binding antibody fragment,
wherein said multispecific antigen binding protein comprises:
a first antigen binding domain (ABD) which monovalently binds to a human NKp46 polypeptide having the amino acid sequence set forth in SEQ ID NO:1,
a second ABD which comprises a therapeutic antibody or a therapeutic antigen-binding antibody fragment which binds to said antigen of interest expressed by said target cells, and (iii) a CD16A binding polypeptide, wherein:
(1) said NKp46-binding ABD comprises a Fab or comprises a variable heavy (V.sub.H) domain and a variable light (V.sub.L) domain separated by a linker (“scFv”, aka monovalently);
(2) said antigen-binding ABD which comprises said therapeutic antibody or therapeutic antigen-binding antibody fragment is monovalent or bivalent;
(3) said CD16A binding polypeptide comprises a human dimeric Fc domain polypeptide which binds CD16A;
(4) said multispecific antigen binding protein binds to the NKp46 polypeptide monovalently;
(5) said multispecific antigen binding protein when administered to a subject directs NKp46-expressing natural killer (NK) cells and CD16A-expressing NK cells to lyse target cells expressing the antigen of interest by a combination of NKp46-mediated signaling and CD16A-mediated antibody-dependent cell-mediated cytotoxicity (“ADCC”);
(6) said dimeric Fc domain interposes said first ABD and said second ABD; and
(7) said first and second ABD are each connected to said dimeric Fc domain, and one or both of said first and second ABD are connected to the dimeric Fc domain via a flexible polypeptide linker, whereas multispecific protein of instant claims are generic with respect to human Nkp46 and any antigen of interest.
Issued claim 2. The multispecific antigen binding protein of claim 1, wherein the therapeutic antibody specifically binds to an antigen expressed by cancer cells, see instant claim 1.
Issued 3. The multispecific antigen binding protein of claim 1, wherein the therapeutic antigen-binding ABD comprises a Fab or comprises a V.sub.H domain and a V.sub.L domain separated by a linker comprising a linear or cyclic peptide.
Issued 4. The multispecific antigen binding protein of claim 1, wherein the NKp46-binding ABD comprises a Fab.
6. The multispecific antigen binding protein of claim 1, wherein the NKp46-binding ABD is a Fab comprised of a V.sub.H domain and a V.sub.L domain, wherein each of the V.sub.H and V.sub.L domains is fused to a human C.sub.H1 or C.sub.κ constant domain.
7. The multispecific antigen binding protein of claim 1, wherein the NKp46-binding ABD is a Fab comprised of (a) a V.sub.H domain fused to a human C.sub.H1 constant domain and a V.sub.L domain fused to a human C.sub.κ constant domain, or (b) a V.sub.H domain fused to a human C.sub.κ constant domain and a V.sub.L domain fused to a human C.sub.H1 constant domain.
8. The multispecific antigen binding protein of claim 1, wherein the therapeutic antigen-binding ABD is a Fab comprised of a V.sub.H domain and a V.sub.L domain, wherein each of the V.sub.H and V.sub.L domains is fused to a human C.sub.H1 or C.sub.κ constant domain.
9. The multispecific antigen binding protein of claim 1, wherein the therapeutic antigen-binding ABD is a Fab comprised of (a) a V.sub.H domain fused to a human C.sub.H1 constant domain and a V.sub.L domain fused to a human C.sub.κ constant domain, or (b) a V.sub.H domain fused to a human C.sub.κ constant domain and a V.sub.L domain fused to a human C.sub.H1 constant domain.
10. The multispecific antigen binding protein of claim 1, wherein either or both the NKp46-binding ABD or the therapeutic antigen-binding ABD is bound to the Fc domain by a flexible polypeptide linker.
11. The multispecific antigen binding protein of claim 1, wherein the monovalent NKp46 ABD comprises V.sub.H and V.sub.L domain polypeptides selected from the group consisting of: (a) the V.sub.H and V.sub.L domains of SEQ ID NOS: 3 and 4 (NKp46-1); (b) the V.sub.H and V.sub.L domains of SEQ ID NOS: 5 and 6 (NKp46-2); (c) the V.sub.H and V.sub.L domains of SEQ ID NOS: 7 and 8 (NKp46-3); (d) the V.sub.H and V.sub.L domains of SEQ ID NOS: 9 and 10 (NKp46-4); (e) the V.sub.H and V.sub.L domains of SEQ ID NOS: 11 and 12 (NKp46-6); and (f) the V.sub.H and V.sub.L domains of SEQ ID NOS: 13 and 14 (NKp46-9).
12. The multispecific antigen binding protein of claim 1, wherein said flexible polypeptide linker is 2-50 amino acids in length.
13. The multispecific antigen binding protein of claim 1, wherein one of the ABDs is connected to the Fc region via a peptide linker which comprises a hinge domain.
14. The multispecific antigen binding protein of claim 8, wherein the C.sub.K constant domain and the human C.sub.H1 constant domain are each connected to the Fc domain via a hinge domain.
15. The multispecific antigen binding protein of claim 9, wherein the C.sub.K constant domain and the human C.sub.H1 constant domain are each connected to the Fc domain via a hinge domain.
16. The multispecific antigen binding protein of claim 1, wherein said combination of NKp46-mediated signaling and CD16A-mediated ADCC has an additive or synergistic effect on the lysis of target cells expressing the antigen of interest, see instant claim 1.
17. The multispecific antigen binding protein of claim 2, wherein the therapeutic antigen-binding ABD binds to an antigen expressed by hematological cancer cells.
18. The multispecific antigen binding protein of claim 17, wherein the antigen expressed by said hematological cancer cells comprises CD19 or CD20 (species) whereas instant claims are generic with respect cancer antigen.
19. A pharmaceutical composition comprising a pharmaceutically effective amount of the multispecific antigen binding protein of claim 1, see instant claim 60.
The patent also teaches the claimed human NKp46 binding domain wherein the ABD comprising a VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO: 4, which are identical to instant SEQ ID NO: 3 and 4, respectively and Figures 2A-F.
Applicant’s request that that the rejections and provisional rejections are held in abeyance until the present application is otherwise allowable is acknowledged.
Claims 1, 50-56, 59-60 and 67 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-8 and 11 of U.S. Patent No. 11,208,480. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope.
Issued claim 1 recites an isolated hetero-multimeric protein, which does not bind to CD16, and which comprises a first antigen-binding domain (ABD) that monovalently binds to a first antigen of interest and further comprises a second ABD which monovalently binds to a second antigen of interest, comprising:
(a) a first polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region, a second variable domain specific to the second antigen and comprised within the second ABD, and an Fc domain or portion thereof interposed between the first and second variable domains; and
(b) a second polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region selected to be complementary to the CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer in which the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide form a first ABD that binds the first antigen of interest, and
wherein one of the antigens of interest is NKp46 and the other antigen of interest is a cancer antigen; and further wherein the first polypeptide chain comprises a third variable domain fused to the second variable domain, wherein the first and second polypeptide form a CH1-CK heterodimer, the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide chain form an antigen binding domain specific for the first antigen of interest, and the second and third variable domains of the first polypeptide chain form an scFv specific for the second antigen of interest, and still further wherein the hetero-multimeric polypeptide is a dimer with a monomeric Fc domain, having the domain arrangement:
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wherein each V.sub.1, V.sub.2 and V.sub.3 is a heavy or light chain variable region; wherein the Fc domain comprises a CH3 domain with an amino acid mutation to prevent CH3-CH3 dimerization, which Fc domain does not bind to CD16; and further wherein one of the V.sub.1 of the first polypeptide chain and the V.sub.1 of the second polypeptide chain is a light chain variable domain and the other is a heavy chain variable domain, which correspond to instant claims 1, 51(2).
Issued claim 2 recites an isolated hetero-multimeric protein, which does not bind to CD16, and which comprises a first antigen-binding domain (ABD) that monovalently binds to a first antigen of interest and further comprises a second ABD which monovalently binds to a second antigen of interest, comprising:
(a) a first polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region, a second variable domain specific to the second antigen and comprised within the second ABD, and an Fc domain or portion thereof interposed between the first and second variable domains; and
(b) a second polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region selected to be complementary to the CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer in which the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide form a first ABD that binds the first antigen of interest, and
wherein one of the antigens of interest is NKp46 and the other antigen of interest is a cancer antigen; and further wherein the first polypeptide chain comprises a third variable domain fused to the second variable domain, wherein the first and second polypeptide form a CH1-CK heterodimer, the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide chain form an antigen binding domain specific for the first antigen of interest, and the second and third variable domains of the first polypeptide chain form an scFv specific for the second antigen of interest, and still further wherein the hetero-multimeric polypeptide is a dimer with a dimeric Fc domain, which dimeric Fc domain does not bind to CD16, and wherein said hetero-multimeric polypeptide has the domain arrangement:
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wherein each V.sub.1, V.sub.2 and V.sub.3 is a heavy or light chain variable region; wherein the Fc domains comprise a CH2 and a CH3 domain capable of CH3-CH3 dimerization; and further wherein one of the V.sub.1 of the first polypeptide chain and the V.sub.1 of the second polypeptide chain is a light chain variable domain and the other is a heavy chain variable domain, which correspond to instant claims 1, 51(3).
Issued claims 3 recites an isolated hetero-multimeric protein, which does not bind to CD16, and which comprises a first antigen-binding domain (ABD) that monovalently binds to a first antigen of interest and further comprises a second ABD which monovalently binds to a second antigen of interest, comprising: (a) a first polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region, a second variable domain specific to the second antigen and comprised within the second ABD, and an Fc domain or portion thereof interposed between the first and second variable domains which does not bind to CD16; and (b) a second polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region selected to be complementary to the CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer in which the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide form a first ABD that binds the first antigen of interest, and wherein one of the antigens of interest is NKp46 and the other antigen of interest is a cancer antigen; and further wherein the hetero-multimeric polypeptide is a trimeric polypeptide, comprising: (a) a first polypeptide chain comprising a first variable domain (V) fused to a first CH1 or CK constant region, a second variable domain fused to a second CH1 or CK constant region, and an Fc domain or portion thereof interposed between the first and second variable domains; (b) a second polypeptide chain comprising a variable domain fused at its C-terminus to a CH1 or CK constant region selected to be complementary to the first CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer; and (c) a third polypeptide chain comprising a variable domain fused at its C-terminus to a CH1 or CK constant region, wherein the variable domain and the constant region are selected to be complementary to the second variable domain and second CH1 or CK constant region of the first polypeptide chain such that the first polypeptide chain and the third polypeptide chain form a CH1-CK heterodimer bound by disulfide bond(s) formed between the CH1 or CK constant region of the third polypeptide and the second CH1 or CK constant region of the first polypeptide, but not between the CH1 or CK constant region of the third polypeptide and the first CH1 or CK constant region of the first polypeptide such that the first, second and third polypeptides form a CH1-CK heterotrimer, wherein the first variable domain of the first polypeptide chain and the variable domain of the second polypeptide chain form an antigen binding domain specific for the first antigen of interest, and the second variable domain of the first polypeptide chain and the variable domain of the third polypeptide chain form an antigen binding domain specific for the second antigen of interest and further-wherein the trimeric hetero-multimeric polypeptide has the domain arrangement:
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wherein the Fc domain comprises a CH3 domain with an amino acid mutation to prevent CH3-CH3 dimerization; wherein each V-V pairing occurs between a light chain variable domain and a heavy chain variable domain; and further wherein each constant region pairing occurs between a CH1 and a CK, which corresponds to instant claim 53 (1).
Issued claim 4 recites an isolated hetero-multimeric protein, which does not bind to CD16, which comprises a first antigen-binding domain (ABD) that monovalently binds to a first antigen of interest and further comprises a second ABD which monovalently binds to a second antigen of interest, said hetero-multimeric protein comprising: (a) a first polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region, a second variable domain specific to the second antigen and comprised within the second ABD, and an Fc domain or portion thereof interposed between the first and second variable domains which does not bind to CD16; and (b) a second polypeptide chain comprising a first variable domain (V) specific to the first antigen fused to a CH1 or CK constant region selected to be complementary to the CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer in which the first variable domain of the first polypeptide chain and the first variable domain of the second polypeptide form a first ABD that binds the first antigen of interest, wherein one of the antigens of interest is NKp46 and the other antigen of interest is a cancer antigen; and further wherein the hetero-multimeric polypeptide is a trimeric polypeptide, comprising: (a) a first polypeptide chain comprising a first variable domain (V) fused to a first CH1 or CK constant region, a second variable domain fused to a second CH1 or CK constant region, and an Fc domain or portion thereof interposed between the first and second variable domains; (b) a second polypeptide chain comprising a variable domain fused at its C-terminus to a CH1 or CK constant region selected to be complementary to the first CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer; and (c) a third polypeptide chain comprising a variable domain fused at its C-terminus to a CH1 or CK constant region, wherein the variable domain and the constant region are selected to be complementary to the second variable domain and second CH1 or CK constant region of the first polypeptide chain such that the first polypeptide chain and the third polypeptide chain form a CH1-CK heterodimer bound by disulfide bond(s) formed between the CH1 or CK constant region of the third polypeptide and the second CH1 or CK constant region of the first polypeptide, but not between the CH1 or CK constant region of the third polypeptide and the first CH1 or CK constant region of the first polypeptide such that the first, second and third polypeptides form a CH1-CK heterotrimer, and wherein the first variable domain of the first polypeptide chain and the variable domain of the second polypeptide chain form an antigen binding domain specific for the first antigen of interest, and the second variable domain of the first polypeptide chain and the variable domain of the third polypeptide chain form an antigen binding domain specific for the second antigen of interest; and further wherein the trimeric hetero-multimeric polypeptide comprises a dimeric Fc domain which does not bind CD16, which trimeric hetero-multimeric polypeptide has the domain arrangement:
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wherein each V-V pairing occurs between a light chain variable domain and a heavy chain variable domain, and wherein each constant region pairing occurs between a CH1 and a CK, which correspond to instant claim, which correspond to instant claims 1, 51(2).
Issued claim 5 recites a pharmaceutical composition comprising an isolated protein according to claim 1, and a pharmaceutically acceptable carrier, which correspond to instant claim 60.
Issued claim 6 recites a pharmaceutical composition comprising an isolated protein according to claim 2, and a pharmaceutically acceptable carrier.
Issued claim 7 recites a pharmaceutical composition comprising an isolated protein according to claim 3, and a pharmaceutically acceptable carrier.
Issued claim 8 recites a pharmaceutical composition comprising an isolated protein according to claim 4, and a pharmaceutically acceptable carrier.
The patent also teaches the claimed human NKp46 binding domain wherein the ABD comprising a VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO: 4, which are identical to instant SEQ ID NO: 3 and 4, respectively.
Applicant’s request that that the rejections and provisional rejections are held in abeyance until the present application is otherwise allowable is acknowledged.
Claims 1, 50-56, 59-60 and 67 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,692,039. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope. The issued claims are drawn to a species, in particular, multispecific antibody comprising an antigen binding domain that binds to human NKp46-1 and human CD123, whereas the present claims are generic with respect to the cancer antigen of interest.
The patent also teaches the claimed human NKp46 binding domain wherein the ABD comprising a VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO: 4, which are identical to instant SEQ ID NO: 3 and 4, respectively.
Applicant’s request that that the rejections and provisional rejections are held in abeyance until the present application is otherwise allowable is acknowledged.
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 1, 50-56, 59-60 and 67 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.
Regarding claim 1, the recitation of “…multispecific protein…(a) the first and second ABDs comprise heavy chain variable domain (VH) and light chain variable domain (VL) polypeptides, respectively comprising heavy and light chain CDRs specific to the human NKp46 or to the cancer antigen; and (b) the first or second ABD which binds to the human NKp46…” in claim 1 is confusing and indefinite because if the first and second ABDs in (a) and (b) bind to NKp46, the isolated protein is monospecific, NOT multispecific as claimed. Further, the multispecific protein comprises more than two antigen binding sites because “and” at line 9. As such, one of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention. Amending claim 1 part (a) to recite “…the first or second ABDs comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) that binds to the human NKp46 or to the cancer antigen, wherein the cancer antigen is human CD19” would obviate this rejection.
Regarding claim 1, the recitation of VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO 4” in (b) (1) to (6) is indefinite because the skilled in the art would not know the metes and bounds of the recited CDRs peptide in the heavy and light chain variable domain. Deleting all “CDR 1, 2 and 3 peptides of the VH of” and “CDR 1, 2 and 3 peptides of the VL of” would obviate this rejection.
Regarding claim 50, the metes and bounds of claim 50 (vii) render vague and indefinite because the claim recites “has decreased binding to a human Fcγ receptor” but does not recite the particular substitution in the Fc to render decreased binding of which human Fcγ receptor, e.g., CD16a, CD32a, CD32b, CD64. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 1 is rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
In this case, the ABD that binds to human NKp46 in claim 1 (b)(1) to (b)(6) do not share both a substantial structural feature, e.g. six CDRs in the heavy and light chain variable domains, see Table A at p. 61 and a common use that flows from the substantial structural feature. See MPEP 803.02.
Claim 50(v) recites “Fcγ-expressing cells” is indefinite because the cells expressing Fcγ receptor, NOT Fcγ, is required for the multispecific protein to bind to the Fcγ receptor expressing cells. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 50-56, 59-60 and 67 are included in the rejection because they are dependent on rejected claim and do not correct the deficiency of the claim from which they depend.
Claim Rejections - 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.
Claim 50-56 and 67 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.
Claims 50-56 and 67 each fails to further limit the parent claim 1 from which they depend as the parent claim 1 is drawn to an isolated multispecific protein comprising a first antigen binding domain (ABD1) and a second antigen binding domain (ABD2), wherein one of the ABD1 and ABD2 binds to human NKp46 polypeptide and the other binds to a cancer antigen without the Fc domain, whereas
Claims 50 (vii) requires Fc domain which capable of binding to human neonatal Fc receptor (FcRn) and has decreased binding to any human Fcγ receptor, optionally wherein the Fc domain is interposed between the ABD1 and the ABD2;
Claim 50 (ix) requires a human Fc domain, wherein the multispecific protein is capable of binding to human neonatal FcRn and has decreased binding to a human Fcγ receptor compared to a full length wild type human IgG1 antibody;
Claim 50 (x) requires Fc domain which comprises amino acid substitutions L351K, T365S, P395V, F405R, T407A and K409Y (EU numbering as in Kabat);
Claim 50 (xi) requires Fc domain, wherein the Fc domain comprises a CH2 domain and first and second CH3 domains separated by a linker peptide, and wherein the two CH3 domains associate with one another via non-covalent interactions;
Claim 50 (xii) requires an Fc domain interposed between the ABD1 and the ABD2;
Claim 50 (xiii) requires an Fc domain interposed between the ABD1 and the ABD2, wherein the multispecific protein comprises a polypeptide having a domain arrangement:
(ABD1) -- CH2 - CH3 -- (ABD2);
Claim 50 (xiv) requires an Fc domain interposed between the ABD1 and the ABD2, wherein the multispecific protein comprises a polypeptide having a domain arrangement: (ABD1) -- linker - CH2 - CH3 -- linker -- (ABD2);
Claim 50 (xv) requires an Fc domain interposed between the ABD1 and the ABD2, wherein the protein comprises a polypeptide having a domain arrangement: (ABD1) --linker - CH2 - CH3 -- linker - CH3 -- linker -- (ABD2); or
Claim 50 (xvi) a combination thereof.
Claim 51 (1) requires heterodimeric polypeptide comprising:
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Claim 52 requires the multispecific protein according to claim 51, wherein the Va-2 and the Vb-2 together form an antigen binding domain that binds the human NKp46 polypeptide.
Claim 53 requires the multispecific protein according to claim 1, comprising: (1) an isolated heterotrimeric polypeptide comprising
(a) a first polypeptide chain comprising, from N- to C- terminus, a first variable domain (V) fused to a first CH1 or CK constant region, an Fc domain or portion thereof, and a second variable domain (V) fused to a second CH1 or CK constant region;
(b) a second polypeptide chain comprising, from N- to C- terminus, a variable domain fused to a CH1 or CK constant region selected to be complementary to the first (but not the second) CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer, and optionally an Fc domain; and
(c) a third polypeptide chain comprising, from N- to C- terminus, a variable domain fused to a CH1 or CK constant region, wherein the CH1 or CK constant region is selected to be complementary to the second (but not the first) variable domain and second CH1 or CK constant region of the first polypeptide chain; or (2) an isolated heterotrimeric polypeptide comprising: (a) a first polypeptide chain having a domain arrangement: Va-1- (CH1 or CK)a - Fc domain - Va-2 - (CH1 or CK)b, (b) a second polypeptide chain having a domain arrangement: Vb-1 - (CH1 or CK)c, and (c) a third polypeptide chain having a domain arrangement: Vb-2 - (CH1 or CK)d, wherein one of the Va-1 and the Vb-1 is a VL and the other is a VH, one of the Va-2 and the Vb-2 is a VL and the other is a VH; wherein the (CH1 or CK)c dimerizes with the (CH1 or CK)a, and the Va-i and the Vb-1 form an antigen binding domain; and wherein the (CH1 or CK)d dimerizes with the (CH1 or CK)b, and the Va-2 and the Vb-2 form an antigen binding domain.
Claim 54 requires the Fc domain comprises (a) a CH2 domain, and(b) a CH3 domain with an amino acid mutation to prevent CH3-CH3 dimerization comprises amino acid substitutions L351K, T366S, P395V, F405R, T407A and K409Y, or the Fc domain comprises (a) a CH2 domain, and(b) first and second CH3 domains separated by a linker peptide, wherein the two CH3 domains associate with one another via non-covalent interactions.
Claim 55 requires (1) a heterotrimeric polypeptide which comprises
(a) a first polypeptide chain having a domain arrangement:Va-1- (CH1 or CK)a - Fc domain - Va-2 - (CH1 or CK)b,
(b) a second polypeptide chain having a domain arrangement:Vb-1- (CH1 or CK)c - Fc domain, and
(c) a third polypeptide chain having a domain arrangement:Vb-2 - (CH1 or CK) d,
wherein one of the Va-i and the Vb-1 is a VL and the other is a VH, one of Va-2 and Vb-2 is a VL and the other is a VH; (CH1 or CK)c dimerizes with the (CH1 or CK)a, and the Va-1 and the Vb-1 form an antigen binding domain; and the (CH1 or CK)d dimerizes with the (CH1 or CK)b, and the Va-2 and the Vb-2 form an antigen binding domain;
(2) a heterodimer which comprises the following domain arrangement:(Va-1 - Vb-1 - CK) - (hinge or linker) - CH2 - CH3 (Va-2 - Vb-2 -CH1) - (hinge or linker) - CH2 - CH3 wherein the Va-1, the Vb-1, the Va-2 and the Vb-2 are each a VH or a VL, and wherein one of the Va-i and the Vb-1 is a VH and the other is a VL such that the Va-1 and the Vb-1 form the ABD1, wherein one of the Va-2 and the Vb-2 is a VH and the other is a VL such that the Va-2 and the Vb- 2 form the ABD2, wherein one of the ABD1 and the ABD2 binds to the human NKp46 polypeptide and the other binds to the cancer antigen;
(3) a tetrameric antibody comprising two light chain and heavy chain pairs from different parental antibodies and comprising a modified CH3 domain interface so that antibodies preferentially form heterodimer, optionally further wherein the Fc domain is comprising
a human IgG4 Fc domain or a portion thereof, optionally comprising one or more amino acid modifications; e and(4) a multispecific protein comprises the following domain arrangement:Va-1- (CK or CH1) Chain 3 Vb-1-(CKorCH1)-(hinge or linker)-CH2-CH3Chain1Va-2 - (CK or CH1) - (hinge or linker) - CH2 - CH3 Chain 2 Vb-2 - (CK or CH1) Chain 4 wherein the Va-1, the Vb-1, the Va-2 and the Vb-2 are each a VH or a VL, and wherein one of the Va-i and the Vb-1 is a VH and the other is a VL such that the Va-1 and the Vb-1 form the ABD1, wherein one of the Va-2 and the Vb-2 is a VH and the other is a VL such that the Va-2 and the Vb- 2 form the ABD2, wherein the chain 1 and the chain 2 associate by CH3-CH3 dimerization and CH1 and CK are selected such that the chain 3 is capable of associating with the chain 1 and the chain 4 with the chain 2.
Claim 56 requires a human CH2 domain comprising an N297S substitution (EU numbering as in Kabat), and
Claim 67 requires heterotrimeric polypeptide comprising:
(a) a first polypeptide comprising, from N- to C- terminus, a VH fused to a CH1 constant region, an Fc domain, and a second VH fused to a CK constant region;
(b) a second polypeptide comprising, from N- to C- terminus, a VL fused to a CK constant region, and optionally an Fc domain or portion thereof; and
(c) a third polypeptide comprising, from N- to C- terminus, a VL fused to a CH1 constant region, wherein the CK constant region of the second polypeptide form a CH1-CK heterodimer with the CH1 constant domain of the first polypeptide, and wherein the CH1 constant region of the third polypeptide form a CH1-CK heterodimer with the CK constant region of the first polypeptide.
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 the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 50-56, 59-60 and 67 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The 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: the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For claims drawn to a genus, MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus, See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406, M.P.E.P. § 2163, II, A, 3, (a), (ii).
Claim 1 encompasses any isolated multispecific protein comprising a first antigen binding domain (ABD1) and a second antigen binding domain (ABD2), wherein one of the ABD1 and the ABD2 binds to a human NKp46 polypeptide and the other binds to any cancer antigen, wherein the multispecific protein binds to the human NKp46 polypeptide monovalently, and wherein the multispecific protein is capable of directing an NK cell expressing the human NKp46 polypeptide to lyse a target cell expressing the cancer antigen, further wherein:
(a) the first and second ABDs comprise heavy chain variable domain (VH) and light chain variable domain (VL) polypeptides, respectively comprising heavy and light chain CDRs specific to the human NKp46 or to the cancer antigen; and
(b) the first or second ABD which binds to the human NKp46 polypeptide is selected from the group consisting of: (1) an ABD comprising a VH polypeptide comprising CDR 1, 2 and 3 peptides of the VH of SEQ ID NO: 3 and a VL polypeptide comprising CDR 1, 2 and 3 peptides of the VL of SEQ ID NO: 4 (elected species).
The specification discloses a bispecific monomeric Fc-containing polypeptide was constructed based on an scFv specific for the tumor antigen CD19 (anti-CD19 scFv) and an scFv specific for an activating receptor CD3 on a T cell (anti-CD3 scFv). The CH3 domain incorporated the mutations (EU numbering) L351K, T366S, P395V, F405R, T407A and K409Y. Anti-CD19-F1-Anti-CD3 having its CH2-CH3 domains placed between two antigen binding domains, here two scFv, was evaluated to assess whether such bispecific monomeric Fc protein could retain binding to FcRn and thereby have improved in vivo half-lives compared to convention bispecific antibodies.
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However, the specification does not describe the structure, e.g., the six CDRs of heavy and light chain variable domains that bind to any and all cancer antigens encompassed by the claimed multispecific protein. The specification fails to disclose a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the claimed ABD domain comprise heavy chain variable domain (VH) and light chain variable domain (VL), respectively, comprising heavy and light chain CDRs specific to all cancer antigen encompassed by the claimed multispecific protein.
Even assuming the cancer antigen is CD19, the disclosure of just one antibody that binds to just CD19 is not representative of the genus.
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).
There is no limitation on the structure or function of the VH and VL comprising the six CDRs, or the epitope of cancer antigen, e.g., CD19 to which it binds. There is no correlation disclosed in the specification between the function of the antibody to bind to cancer antigen. There is no information in the specification how much variation is permissible for it still bind cancer antigen. Without such as description, one of ordinary skill in the art would be unable to distinguish which antibody would fall within the scope encompassed by the claim and which do not. The specification does not describe a representative number of species falling with 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 VH comprising CDR 1, 2 and 3 and VL comprising CDR1, CDR2 and CDR3 that bind to any cancer antigen, e.g., CD19 encompassed by the claimed isolated multispecific protein themselves.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118, 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).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
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.)
Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873, 2017; PTO-892)
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).
Although one of skill in the art could: make a mAb against a cancer antigen, or screen a human antibody phage display library, test candidates, and produce a corresponding antibody, note that:
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Regarding multispecific protein comprises any Fc domain which has decreased binding to any human Fcγ Receptor, the specification discloses N297S substitution (EU numbering as in Kabat) in the CH2 domain of human IgG Fc.
However, US 6,737,056 to Presta (PTO 892) provides an extensive list of point mutations within an antibody Fc domain and in Tables 6-9 Presta shows the effect of those mutations, alone or in various combinations, on Fc receptor binding. But, that mutational analysis showed each position can have a different effect and that different amino acid substitutions at any given site can have different effects. Thus, a determination of which mutations will result in a particular modified function is not predictable a prior.
Further, it is not sufficient to define the genus solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Similarly, the function of the variant as claimed does not distinguish a particular variant from others having the same activity or function and as such, fails to satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. (Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406).
Given the well-known high level of polymorphism of immunoglobulins/antibodies, one of skill in the art to “visualize or recognize” the members of the genus of ABDs comprise heavy chain variable domain (VH) and light chain variable domain comprising CDRs specific for any and all cancer antigen encompassed by the claimed isolated multispecific protein without (claim 1) or with an Fc domain (claim 50) that has decreased binding to any human Fcγ receptor, other than the human IgG1 Fc comprises a human CH2 domain comprising N297S substitution (EU numbering as in Kabat) (claim 56) and/or a CH3 domain comprises amino acid substitutions L351L, T366S, P395V, F405R, T407A, and K409Y (EU numbering as in Kabat, claim (claim 50 (x)) at the time of filing. Thus, the specification does not disclose a representative number of species of multispecific protein as a pharmaceutical composition for treating any disease such as any cancer, any infectious disease, any inflammatory disease or any autoimmune disease, nor sufficient structure/function relationship correlative to the recited functional properties, e.g., capable of binding to human neonatal Fc receptor (FcRn) and has decreased binding to any human Fcγ receptor to demonstrate possession at the time of filing.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Adequate written description requires more than a mere statement that it is part of the invention. Instead, an “adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed.” See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004).
Therefore, only (1) an isolated multispecific protein comprising a first antigen binding domain (ABD1), a second antigen binding domain (ABD2) and a human IgG1 Fc domain, wherein one of the ABD1 and the ABD2 binds to a human NKp46 polypeptide and the other binds to CD19 cancer antigen, wherein the multispecific protein binds to the human NKp46 polypeptide monovalently, and wherein the multispecific protein is capable of directing an NK cell expressing the human NKp46 polypeptide to lyse a target cell expressing the cancer antigen, further wherein:
(a) the first or second ABDs comprise a heavy chain variable domain (VH) and a light chain variable domain (VL) polypeptides, wherein the VH and VL specific to the human NKp46 or to the CD19 cancer antigen; and
(b) the first or second ABD which binds to the human NKp46 polypeptide is selected from the group consisting of: (1) an ABD comprising a VH polypeptide comprising SEQ ID NO: 3 and a VL polypeptide comprising SEQ ID NO: 4 (elected species), (2) The isolated multispecific protein above wherein the Fc comprises a human CH2 domain and a CH3 domain, wherein the CH2 domain comprises N297S substitution, and binds to human neonatal Fc receptor (FcRn) and has decreased binding to a human Fcγ receptor (Eu numbering as in Kabat), (3) The isolated multispecific protein above wherein the Fc domain comprises amino acid substitutions L351K, T366S, P395V, F405R, T407A and K409Y (Eu numbering as in Kabat) for treating CD19 expressing cancer, (4) The isolated multispecific protein above wherein the Fc domain is interposed between the ABD1 and the ABD2, (5) an isolated heteromeric polypeptide comprising
(1)(a) a first polypeptide chain comprising, from N- to C- terminus, a first heavy chain variable domain (V), a CH1 or CK constant region, a Fc domain, a second heavy chain variable domain and a third light chain variable domain; and
(b) a second polypeptide chain comprising, from N- to C- terminus, a first light chain variable domain (V), a CH1 or CK constant region, and optionally a Fc domain, wherein the CH1 or CK constant region is selected to be complementary to the CH1 or CK constant region of the first polypeptide chain such that the first and second polypeptides form a CH1-CK heterodimer in which:
(i) the first heavy chain variable domain of the first polypeptide chain and the first light chain variable domain of the second polypeptide form an antigen binding domain (ABD1) that binds to CD19 cancer antigen; and wherein the second heavy variable domain and the third light chain variable domain forms an antigen binding domain (ABD2) that binds to a human NKp46 polypeptide; or
(ii) the first heavy chain variable domain of the first polypeptide chain and the first light chain variable domain of the second polypeptide form an antigen binding domain (ABD1) that binds to the human NKp46 polypeptide; and the second heavy chain variable domain and the third light chain variable domain forms an antigen binding domain (ABD2) that binds to the CD19 cancer antigen, wherein the ABD1 or ABD2 comprises a heavy chain variable domain (VH) comprises SEQ ID NO: 3 and the light chain variable domain (VL) comprises SEQ ID NO: 4 that binds to human NKp46; or
(2)(a) a first polypeptide having a domain arrangement selected from:
Va-1- (CH1 or CK)a - Fc domain - Va-2 - Vb-2, and Va-2 - Vb-2 - Fc domain - Va-1- (CH1 or CK)b, and
(b) a second polypeptide chain having a domain arrangement:Vb-1- (CH1 or CK)b, and wherein one of Va-1 and Vb-1 is a VL and the other is a VH, one of Va-2 and Vb-2 is a VL and the other is a VH; wherein the (CH1 or CK)b dimerizes with the (CH1 or CK)a, and the Vb-1 forms an antigen binding domain (ABD1) together with the Va-1, and wherein the Va-2 and the Vb-2 together form an antigen binding domain (ABD2); or
(3)(a) a first polypeptide having a domain arrangement:
Va-1- (CH1 or CK)a- Fc domain - Va-2-Vb-2 and
(b) a second polypeptide chain having a domain arrangement:
Vb-1- (CH1 or CK)b- Fc domain
wherein one of the Va-1 and the Vb-1 is a VL and the other is a VH, one of the Va-2 and the Vb-2 is a VL and the other is a VH; said (CH1 or CK)b dimerizes with the (CH1 or CK)a, and the Vb-1 forms an antigen binding domain (ABD1) together with the Va-1; and the Va-2 and the Vb-2 together form an antigen binding domain (ABD2), and
wherein the ABD1 or ABD2 comprises a heavy chain variable domain (VH) comprises SEQ ID NO: 3 and the light chain variable domain (VL) comprises SEQ ID NO: 4 that binds to human NKp46, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Conclusion
No claim is allowed.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641