DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's election without traverse of Group I (claims 1-9, 14, and 17) filed on March 13, 2026 is acknowledged.
Applicant's further election with traverse of Group A (1) (claim 7) filed on March 13, 2026 is acknowledged. The traversal is on the ground(s) that the multispecific antibodies of Group A (claims 7-9) share a unifying structure, which is recited in the claim from which each of claims 7-9 depend, namely, independent claim 1, thus, the subject matter of Group A (claims 7-9) does not encompass distinct inventions and election of an invention within Group A should not be required. This is not found persuasive for the following reasons: first, contrary to applicant’s argument that the multispecific antibodies of Group A (claims 7-9) share a unifying structure, said multispecific antibodies in claims 7-9 are against completely different antigens, and have distinct VH and VL. Therefore, these multispecific antibodies share neither structure nor function. While the multispecific antibodies seem to share structural similarity in their constant regions, however, due to their unrelated structures in VH and VL and functional properties, a prior art reference anticipating or making obvious of one of the claimed multispecific antibodies would not render the other two multispecific antibodies obvious under 35 U.S.C. 103. Therefore, non-coextensive searches would be required for the three sets of sequences, which would constitute undue burden. Further, if applicant believes that the multispecific antibodies of claims 7-9 are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. Furthermore, this application is not a national stage entry of the prior PCT application, therefore, applicant’s argument based on a unifying property does not apply here even if it were the case.
Applicant's species election without traverse of species 1 (the antibody of claim 2) filed on March 13, 2026 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 1-14, 16 and 17 are pending; and claims 1, 2, 7, 14 and 17 are under consideration. Claims 3-6, 8-13 and 16 are withdrawn from further consideration as being drawn to a non-elected invention/species.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “BIAcore” at page 12, line 29), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant should review the specification for other trademarks and make corrections as required.
b. There are references in this specification that should be placed on an information disclosure statement if application would like them considered.
There are also what appears to be claims under an additional embodiment section; if they are claims they should be placed on a separate page.
Objections to the Claims
5. Claims 14 and 17 are objected to because of the following informalities:
a. Claim 14 recites “comprising a multispecific antibody according to claim 1 ...”; the following is suggested: “comprising the multispecific antibody according to claim 1”, since it is a dependent claim.
b. Claim 17 is incomplete because it is dependent from a non-elected claim, claim 10. Appropriate correction is required.
Double Patenting
6. 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/proces/file/efs/guidance/eTD-info-I.jsp.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of U.S. Patent No. 8,268,314; claim 3 of U.S. Patent No. 8,703,130; and claim 3 of U.S. Patent No. 9,708,396 in view of Schaefer et al. (Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11187-92); Kannan (I) (US 2014/0154254, 6/5/2014); and Kannan (II) (US 2010/0286374, 11/11/2010), as applied to claims 1, 2, 7, 14 and 17 below. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons:
Claim 3 of the ‘314, ‘130, and ‘396 patent is directed to a bispecific antibody against human VEGF and Ang-2, which comprises a first set of VH and VL of SEQ ID NO: 7 and 8, and a second set of VH and VL of SEQ ID NO: 52 and 53, wherein SEQ ID NO: 7, 8, 52 and 53 are 100% identical to the present SEQ ID NO: 30-33, respectively; or methods of treatment with the antibody (alignments are presented below for applicant’s convenience).
‘314 patent
ALIGNMENT(INSTANT SEQ ID NO 30):
Query Match 100.0%; Score 676; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
Qy121 VSS 123
|||
Db121 VSS 123
US-12-572-289-7
Filing date in PALM: 2009-10-02
Sequence 7, US/12572289
Patent No. 8268314
GENERAL INFORMATION
CURRENT APPLICATION NUMBER: US/12/572,289
CURRENT FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 7
LENGTH: 123
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 31):
Query Match 100.0%; Score 562; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
US-12-572-289-8
Filing date in PALM: 2009-10-02
Sequence 8, US/12572289
Patent No. 8268314
GENERAL INFORMATION
CURRENT APPLICATION NUMBER: US/12/572,289
CURRENT FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 8
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 32):
Sequence 52, US/12572289
Patent No. 8268314
GENERAL INFORMATION
CURRENT APPLICATION NUMBER: US/12/572,289
CURRENT FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 52
LENGTH: 129
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 704; Length 129;
Best Local Similarity 100.0%;
Matches 129; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
Qy 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
Qy121 QGTMVTVSS 129
|||||||||
Db121 QGTMVTVSS 129
ALIGNMENT (INSTANT SEQ ID NO 33):
Sequence 53, US/12572289
Patent No. 8268314
GENERAL INFORMATION
CURRENT APPLICATION NUMBER: US/12/572,289
CURRENT FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 53
LENGTH: 110
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: light chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 579; Length 110;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
Qy 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
‘190 patent
ALIGNMENT(INSTANT SEQ ID NO 30):
Query Match 100.0%; Score 676; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
Qy121 VSS 123
|||
Db121 VSS 123
Filing date in PALM: 2012-08-09
Sequence 7, US/13570333
Patent No. 8703130
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/13/570,333
CURRENT FILING DATE: 2012-08-09
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 7
LENGTH: 123
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 31):
Query Match 100.0%; Score 562; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
Filing date in PALM: 2012-08-09
Sequence 8, US/13570333
Patent No. 8703130
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/13/570,333
CURRENT FILING DATE: 2012-08-09
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 8
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 32):
Filing date in PALM: 2012-08-09
Sequence 52, US/13570333
Patent No. 8703130
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/13/570,333
CURRENT FILING DATE: 2012-08-09
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 52
LENGTH: 129
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 704; Length 129;
Best Local Similarity 100.0%;
Matches 129; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
Qy 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
Qy121 QGTMVTVSS 129
|||||||||
Db121 QGTMVTVSS 129
ALIGNMENT (INSTANT SEQ ID NO 33):
Filing date in PALM: 2012-08-09
Sequence 53, US/13570333
Patent No. 8703130
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/13/570,333
CURRENT FILING DATE: 2012-08-09
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 53
LENGTH: 110
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: light chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 579; Length 110;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
Qy 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
‘396 patent
ALIGNMENT(INSTANT SEQ ID NO 30):
Query Match 100.0%; Score 676; Length 123;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 60
Qy 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
Qy121 VSS 123
|||
Db121 VSS 123
Filing date in PALM: 2014-02-27
Sequence 7, US/14192213
Patent No. 9708396
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/14/192,213
CURRENT FILING DATE: 2014-02-27
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 7
LENGTH: 123
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 31):
Query Match 100.0%; Score 562; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK 107
Filing date in PALM: 2014-02-27
Sequence 8, US/14192213
Patent No. 9708396
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/14/192,213
CURRENT FILING DATE: 2014-02-27
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 8
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <VEGF>bevacizumab
ALIGNMENT (INSTANT SEQ ID NO 32):
Filing date in PALM: 2014-02-27
Sequence 52, US/14192213
Patent No. 9708396
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/14/192,213
CURRENT FILING DATE: 2014-02-27
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 52
LENGTH: 129
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: heavy chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 704; Length 129;
Best Local Similarity 100.0%;
Matches 129; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNY 60
Qy 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSPNPYYYDSSGYYYPGAFDIWG 120
Qy121 QGTMVTVSS 129
|||||||||
Db121 QGTMVTVSS 129
ALIGNMENT (INSTANT SEQ ID NO 33):
Filing date in PALM: 2014-02-27
Sequence 53, US/14192213
Patent No. 9708396
GENERAL INFORMATION
TITLE OF INVENTION: Bispecific anti-VEGF/anti-ANG-2 antibodies
FILE REFERENCE: 25401
CURRENT APPLICATION NUMBER: US/14/192,213
CURRENT FILING DATE: 2014-02-27
PRIOR APPLICATION NUMBER: 12572289
PRIOR FILING DATE: 2009-10-02
PRIOR APPLICATION NUMBER: EP 08017607.6
PRIOR FILING DATE: 2008-10-08
PRIOR APPLICATION NUMBER: EP 08021834.0
PRIOR FILING DATE: 2008-12-16
NUMBER OF SEQ ID NOS: 136
SEQ ID NO 53
LENGTH: 110
TYPE: PRT
ORGANISM: Artificial
FEATURE:
OTHER INFORMATION: light chain variable domain, <ANG-2>Ang2i_LC06
Query Match 100.0%; Score 579; Length 110;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QPGLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER 60
Qy 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHYVFGTGTKVTVL 108
The teachings of Schaefer et al. and Kannan teach the advantages and methods of making crossover antibodies and amino acid substitutions in the constant regions for bispecific antibodies:
Schaefer et al. discloses a generic approach for the production of bispecific IgG antibodies ("CrossMab") by immunoglobulin domain crossover, or by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody; that this "crossover" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur, which increases the yield of the desired bispecific antibody and reduces side-product like homodimer (abstract, page 11187, the paragraph bridging the two columns, and page 11188, Figure 1, for example). Additionally, Schaefer et al. teaches three possible "CrossMab" formats, i.e., CrossMabFab, CrossMabVH-VL and CrossMabCH1-CLAIM; and that applying the three possible "CrossMab" formats, bispecific antibodies against angiopoietin-2 (Ang-2) and VEGF-A were generated, and they can be produced by standard techniques, exhibit stabilities comparable to natural antibodies, and bind both targets simultaneously with unaltered affinity (see e.g., abstract, and page 11188, Figure 1C-E). Schaefer et al. also specifically teaches an anti-VEGF/Ang-2 bispecific antibody and identifies bevacizumab and LC06 as the parental antibodies. Schaefer et al. also teaches that additional strategies may be employed to improve yield / reduce side-product further, such as titrating the ratio of heavy and light chain during transient expression (see e.g., paragraph bridging pages 11190 and 11191).
Schaefer et al. does not teach amino acid substitutions in the CH and CL regions.
Kannan (I) (US 2014/0154254) teaches methods of generating heterodimeric antibodies from two different preexisting antibodies (page 1, [0005]), and that heterodimeric IgGs could be produced by engineering the heavy chain and light chain of the two different antibodies in such a way that they can assemble exclusively into a heterodimeric antibody without other contaminating species, which includes electrostatic steering achieved by engineering interface residues between the light chains (LC) and the heavy chains (HC) that prevents mis-pairing of light chains to the non-cognate heavy chains when two different heavy chain and light chain pairs are assembling to form a desired four-chain heterodimeric antibody; and that an exemplary strategy comprises introducing one or more negatively-charged residues (e.g., Asp or Glu) in a first light chain (LC1) and one or more positively-charged residues (e.g., Lys, His or Arg) in the companion heavy chain (HC1) at the LC1/HC1 interface while introducing one or more positively-charged residues (e.g., Lys, His or Arg) in a second light chain (LC2) and one or more negatively-charged residues (e.g., Asp or Glu) in the companion heavy chain (HC2) at the LC2/HC2 interface; and the electrostatic steering effect directs the LC1 to pair with HCl and LC2 to pair with HC2, as the opposite charged residues (polarity) at the interface attract, while the same type of charged residues (polarity) at an interface causes repulsion, resulting in suppression of the unwanted HC/LC pairings (page 4, [0039]). Additionally, Kannan (I) teaches that the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more positive-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more negative-charged amino acids; alternatively, the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more negative-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more positive-charged amino acids (page 1, [0008]), wherein one or more amino acids in the CH1 domain of the heterodimeric antibody at an EU position including, among others, K147 and K213, is/are replaced with a charged amino acid (page 6, [0059]); and one or more amino acids in the CL domain of the heterodimeric antibody at a position (EU and Kabat numbering in a kappa light chain) include, among others, E123 and Q124, are replaced with a charged amino acid (page 8, [0071]). Further, Kannan (I) teaches that "antibody" refers to an intact antibody, or a binding fragment thereof, which includes, among others, F(ab')₂, Fab, Fab', etc. (page 11, [0083] and [0084]). Kannan (I) at para. [0326] states that the method minimizes undesired side-product caused by heavy chain homodimer.
Kannan (II) (US 2010/0286374) teaches a strategy to reduce the ability of the domain to interact with itself, i.e., form homodimers by altering the interaction of antibody domains (page 1, [0005], lines 1-3; and [0006], lines 1-4); and the kappa light chain-heavy chain contacts within the interface are shown in Table 5 (page 11), wherein E123 of the kappa light chain is an interface residue and in contact with V125, F126 and K213 of the heavy chain; and Q124 of the kappa light chain is an interface residue and in contact with F126, L145 and K147 of the heavy chain, thereby providing additional guidance on which light chain and heavy chain substitutions to pair.
Therefore, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify a bispecific antibody such as Schaefer et al.’s Ang-2-VEGF CrossMabFAB with additional amino acid substitutions at positions of K147 and/or K213 of CH1 with Asp (D) or Glu (E), and E123 and Q124 of CL with Lys (K), His (H) or Arg (R), and to make a pharmaceutical composition thereof following the teachings of Schaefer et al. and Kannan. The person of ordinary skill in the art would have been motivated to do so for the potentially additive effect of the two different approaches in reducing side products and improving the yield when making a bispecific antibody; and reasonably would have expected success because the recombinant technology and peptide synthesis had been well established in the art, and making amino acid substitutions of a polypeptide using these technologies is routine in the art. Additionally, Schafer et al. specifically suggests additional techniques may be combined with its technology, e.g., titrating heavy and light chain, to achieve optimized heterodimer formation and minimize side product; therefore there was a reasonable expectation of success that adding the method of Kannan—which has the same purpose as Schafer et al. or titrating heavy and light chain, i.e., reducing side-product formation to optimize yield of the bispecific antibody—would further reduce unwanted side-product formation and therefore better achieve the objectives of Schafer et al. Additionally, it is obvious to combine prior art elements according to known methods to yield predictable results. Here, Schaefer et al. and Kannan (I)/(II) include each element claimed, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. One of ordinary skill in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately (i.e., promote heterodimerization to reduce side products and thereby increase the yield of multispecific antibodies). One of ordinary skill in the art would have recognized that the results of combining the two approaches were predictable because Kannan (I) cites Schaefer et al. as a “promising” technology within the same field of endeavor at para. [0004], and does not suggest that the two techniques, that achieve the same objective, are at all incompatible.
Schafer et al. and Kannan do not explicitly disclose the SEQ ID NOs recited at instant claim 7.
Schaefer et al. specifically teaches an anti-VEGF/Ang-2 bispecific antibody and identifies bevacizumab and LC06 as the parental antibodies; the '314 patent provides the corresponding light and heavy chain variable domain sequences for bevacizumab and LC06. Therefore, it would have been obvious to make a CrossMab of the anti-VEGF and Ang-2 bispecific antibody of '314 patent. Therefore, the conflicting claims are not patentably distinct from each other.
Claim 7 is also provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 4 of copending Application No. 19/558,964; in view of Schaefer et al. (Proc Natl Acad Sci U.S.A. 2011 Jul 5;108(27):11187-92); Kannan (I) (US 2014/0154254, 6/5/2014); and Kannan (II) (US 2010/0286374, 11/11/2010). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons:
Claim 4 of the '964 patent is directed to a bispecific antibody against human VEGF and Ang-2, which comprises a first set of VH and VL of SEQ ID NO: 7 and 8, and a second set of VH and VL of SEQ ID NO: 52 and 53, wherein SEQ ID NO: 7, 8, 52 and 53 are 100% identical to the present SEQ ID NO: 30-33, respectively (alignments presented above correspond to the same SEQ ID NOs).
The teachings of Schaefer et al. and Kannan teach the advantages and methods of making crossover antibodies and amino acid substitutions in the constant regions for bispecific antibodies:
Schaefer et al. discloses a generic approach for the production of bispecific IgG antibodies ("CrossMab") by immunoglobulin domain crossover, or by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody; that this "crossover" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur, which increases the yield of the desired bispecific antibody and reduces side-product like homodimer (abstract, page 11187, the paragraph bridging the two columns, and page 11188, Figure 1, for example). Additionally, Schaefer et al. teaches three possible "CrossMab" formats, i.e., CrossMabFab, CrossMabVH-VL and CrossMabCH1-CLAIM; and that applying the three possible "CrossMab" formats, bispecific antibodies against angiopoietin-2 (Ang-2) and VEGF-A were generated, and they can be produced by standard techniques, exhibit stabilities comparable to natural antibodies, and bind both targets simultaneously with unaltered affinity (see e.g., abstract, and page 11188, Figure 1C-E). Schaefer et al. also specifically teaches an anti-VEGF/Ang-2 bispecific antibody and identifies bevacizumab and LC06 as the parental antibodies. Schaefer et al. also teaches that additional strategies may be employed to improve yield / reduce side-product further, such as titrating the ratio of heavy and light chain during transient expression (see e.g., paragraph bridging pages 11190 and 11191).
Schaefer et al. does not teach amino acid substitutions in the CH and CL regions.
Kannan (I) (US 2014/0154254) teaches methods of generating heterodimeric antibodies from two different preexisting antibodies (page 1, [0005]), and that heterodimeric IgGs could be produced by engineering the heavy chain and light chain of the two different antibodies in such a way that they can assemble exclusively into a heterodimeric antibody without other contaminating species, which includes electrostatic steering achieved by engineering interface residues between the light chains (LC) and the heavy chains (HC) that prevents mis-pairing of light chains to the non-cognate heavy chains when two different heavy chain and light chain pairs are assembling to form a desired four-chain heterodimeric antibody; and that an exemplary strategy comprises introducing one or more negatively-charged residues (e.g., Asp or Glu) in a first light chain (LC1) and one or more positively-charged residues (e.g., Lys, His or Arg) in the companion heavy chain (HC1) at the LC1/HC1 interface while introducing one or more positively-charged residues (e.g., Lys, His or Arg) in a second light chain (LC2) and one or more negatively-charged residues (e.g., Asp or Glu) in the companion heavy chain (HC2) at the LC2/HC2 interface; and the electrostatic steering effect directs the LC1 to pair with HCl and LC2 to pair with HC2, as the opposite charged residues (polarity) at the interface attract, while the same type of charged residues (polarity) at an interface causes repulsion, resulting in suppression of the unwanted HC/LC pairings (page 4, [0039]). Additionally, Kannan (I) teaches that the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more positive-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more negative-charged amino acids; alternatively, the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more negative-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more positive-charged amino acids (page 1, [0008]), wherein one or more amino acids in the CH1 domain of the heterodimeric antibody at an EU position including, among others, K147 and K213, is/are replaced with a charged amino acid (page 6, [0059]); and one or more amino acids in the CL domain of the heterodimeric antibody at a position (EU and Kabat numbering in a kappa light chain) include, among others, E123 and Q124, are replaced with a charged amino acid (page 8, [0071]). Further, Kannan (I) teaches that "antibody" refers to an intact antibody, or a binding fragment thereof, which includes, among others, F(ab')₂, Fab, Fab', etc. (page 11, [0083] and [0084]). Kannan (I) at para. [0326] states that the method minimizes undesired side-product caused by heavy chain homodimer.
Kannan (II) (US 2010/0286374) teaches a strategy to reduce the ability of the domain to interact with itself, i.e., form homodimers by altering the interaction of antibody domains (page 1, [0005], lines 1-3; and [0006], lines 1-4); and the kappa light chain-heavy chain contacts within the interface are shown in Table 5 (page 11), wherein E123 of the kappa light chain is an interface residue and in contact with V125, F126 and K213 of the heavy chain; and Q124 of the kappa light chain is an interface residue and in contact with F126, L145 and K147 of the heavy chain, thereby providing additional guidance on which light chain and heavy chain substitutions to pair.
Therefore, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify a bispecific antibody such as Schaefer et al.’s Ang-2-VEGF CrossMabFAB with additional amino acid substitutions at positions of K147 and/or K213 of CH1 with Asp (D) or Glu (E), and E123 and Q124 of CL with Lys (K), His (H) or Arg (R), and to make a pharmaceutical composition thereof following the teachings of Schaefer et al. and Kannan. The person of ordinary skill in the art would have been motivated to do so for the potentially additive effect of the two different approaches in reducing side products and improving the yield when making a bispecific antibody; and reasonably would have expected success because the recombinant technology and peptide synthesis had been well established in the art, and making amino acid substitutions of a polypeptide using these technologies is routine in the art. Additionally, Schafer et al. specifically suggests additional techniques may be combined with its technology, e.g., titrating heavy and light chain, to achieve optimized heterodimer formation and minimize side product; therefore there was a reasonable expectation of success that adding the method of Kannan—which has the same purpose as Schafer et al. or titrating heavy and light chain, i.e., reducing side-product formation to optimize yield of the bispecific antibody—would further reduce unwanted side-product formation and therefore better achieve the objectives of Schafer et al. Additionally, it is obvious to combine prior art elements according to known methods to yield predictable results. Here, Schaefer et al. and Kannan (I)/(II) include each element claimed, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. One of ordinary skill in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately (i.e., promote heterodimerization to reduce side products and thereby increase the yield of multispecific antibodies). One of ordinary skill in the art would have recognized that the results of combining the two approaches were predictable because Kannan (I) cites Schaefer et al. as a “promising” technology within the same field of endeavor at para. [0004], and does not suggest that the two techniques, that achieve the same objective, are at all incompatible.
Schafer et al. and Kannan do not explicitly disclose the SEQ ID NOs recited at instant claim 7.
Schaefer et al. specifically teaches an anti-VEGF/Ang-2 bispecific antibody and identifies bevacizumab and LC06 as the parental antibodies; the '314 patent provides the corresponding light and heavy chain variable domain sequences for bevacizumab and LC06. Therefore, it would have been obvious to make a CrossMab of the anti-VEGF and Ang-2 bispecific antibody of copending Application No. 19/558,964. Therefore, the conflicting claims are not patentably distinct from each other.
Claim Rejections - 35 USC § 112
7. 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.
a. Claims 1, 2, 7, 14 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite that amino acids having positions “are substituted independently from each other by an amino acid selected from [list.]” The specification does not provide an explicit definition for this phrase; therefore, does independent substitution require the amino acids to be substituted with different amino acids selected from the list, or can they also be substituted with the same amino acids selected from the list? Appropriate clarification and/or correction is requested.
b. Claims 1, 2, 7, 14 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite, e.g., “first heavy chain derived from a first antibody.” The specification does not provide a definition for the term “derived from.” Does “derived from” include domain replacements and amino acid substitutions not recited in the instant claims? Appropriate clarification and/or correction is requested.
c. Claim 17 is 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. The claim recites an “antibody obtained by a method according to claim 10.” The specification does not provide a definition for the term “obtained by.” Does “obtained by” include additional method steps not recited in claim 10? Appropriate clarification and/or correction is requested.
d. Claims 1, 2, 7, 14 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims recite, e.g., amino acid substitutions at positions having “numbering according to Kabat” or “numbering according to EU index of Kabat.” The numbering system of Kabat is not a part of the instant invention; however, the position of the specific amino acid substitutions is a critical part of the claimed invention. It is unclear what positions the substitutions will have by the claim-recited numbering systems since they are in reference to generic domains, e.g. “constant domain CL of the first light chain.” Although parenthesis may be appropriate when defining an abbreviation or acronym, the inclusion of parentheses for anything else, raises uncertainty as to whether the feature in the parentheses is optional or always present. Thus, this introduces ambiguity to the scope of the claims because it is unclear if the limitation in parentheses is required or exemplary. Clarification of the claim is required to ascertain their metes and bounds. The Office suggest deleting the limitation in parentheses to overcome the rejection. Clarification and/or correction is required.
Claim Rejections - 35 USC § 103
8. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
9. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 1, 2, 14 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Schaefer et al. (Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11187-92) in view of Kannan (I) (US 2014/0154254, 6/5/2014), and Kannan (II) (US 2010/0286374, 11/11/2010).
Claim 1 is drawn to a multispecific antibody, comprising a first light chain and a first heavy chain derived from a first antibody which specifically binds to a first antigen; and a second light chain and a second heavy chain derived from a second antibody which specifically binds to a second antigen, wherein: in the second light chains the variable domain VL is replaced by the variable domain VH of the second heavy chain and the constant domain CL is replaced by the constant domain CHi of the second heavy chain; and in the second heavy chains the variable domain VH is replaced by the variable domain VL of the second light chain and the constant domain CHi is replaced by the constant domain CL of the second light chain; and wherein in the constant domain CL of the first light chain the amino acids at position 124 and 123 (numbering according to Kabat) are substituted independently from each other by an amino acid selected from lysine (K), arginine (R) and histidine (H); and wherein in the constant domain CHi of the first heavy chain the amino acids at position 147 and 213 (numbering according to EU index of Kabat) are substituted independently from each other by an amino acid selected from glutamic acid (E) or aspartic acid (D); or wherein in the constant domain CL of the second heavy chain the amino acids at position 124 and 123 (numbering according to Kabat) are substituted independently from each other by an amino acid selected from lysine (K), arginine (R) and histidine (H); and wherein in the constant domain CHi of the second light chain the amino acids at position 147 and 213 (numbering according to EU index of Kabat) are substituted independently from each other by an amino acid selected from glutamic acid (E) or aspartic acid (D).
Claim 2 is drawn to the multispecific antibody according to claim 1, wherein in the constant domain CL of the first light chain the amino acids at position 124 and 123 (numbering according to Kabat) are substituted independently from each other by an amino acid selected from lysine (K), arginine (R) and histidine (H) and wherein in the constant domain CHi of the first heavy chain the amino acids at position 147 and 213 (numbering according to EU index of Kabat) are substituted independently from each other by an amino acid selected from glutamic acid (E} or aspartic acid (D), and wherein in the constant domain CL of the second heavy chain the amino acid at position 124 (numbering according to Kabat) is substituted by an amino acid selected from glutamic acid (E) or aspartic acid (D); or wherein in the constant domain CL of the second heavy chain the amino acids at position 124 and 123 (numbering according to Kabat) are substituted independently from each other by an amino acid selected from lysine (K), arginine (R) and histidine (H) and wherein in the constant domain CHi of the second light chain the amino acids at position 147 and 213 (numbering according to EU index of Kabat) are substituted independently from each other by an amino acid selected from glutamic acid (E) or aspartic acid (D), and wherein in the constant domain CL of the first light chain the amino acid at position 124 (numbering according to Kabat) is substituted by an amino acid selected from glutamic acid (E) or aspartic acid (D).
Claim 14 is drawn to A pharmaceutical composition comprising a multispecific antibody according to claim 1 in combination with at least one pharmaceutically acceptable carrier.
Claim 17 is drawn to a multispecific antibody obtained by a method according to claim 10 (i.e., a method for the preparation of a multispecific antibody according to claim 1, comprising the steps of: a) transforming a host cell with vectors comprising nucleic acids encoding: the first light chain as defined in claim 1 derived from a first antibody which specifically binds to a first antigen; ii) the first heavy chain as defined in claim 1 derived from a first antibody which specifically binds to a first antigen; iii) the second light chain as defined in claim 1 derived from a second antibody which specifically binds to a second antigen; and iv) the second heavy chain as defined in claim 1 derived from a second antibody which specifically binds to a second antigen; b) culturing said host cell under conditions that allow synthesis of said multispecific antibody; and c) recovering said multispecific antibody from said host cell culture.)
Schaefer et al. discloses a generic approach for the production of bispecific IgG antibodies ("CrossMab") by immunoglobulin domain crossover, or by exchange of heavy-chain and light-chain domains within the antigen binding fragment (Fab) of one half of the bispecific antibody; that this "crossover" retains the antigen-binding affinity but makes the two arms so different that light-chain mispairing can no longer occur, which increases the yield of the desired bispecific antibody and reduces side-product like homodimer (abstract, page 11187, the paragraph bridging the two columns, and page 11188, Figure 1, for example). Additionally, Schaefer et al. teaches three possible "CrossMab" formats, i.e., CrossMabFab, CrossMabVH-VL and CrossMabCH1-CLAIM; and that applying the three possible "CrossMab" formats, bispecific antibodies against angiopoietin-2 (Ang-2) and VEGF-A were generated, and they can be produced by standard techniques, exhibit stabilities comparable to natural antibodies, and bind both targets simultaneously with unaltered affinity (see e.g., abstract, and page 11188, Figure 1C-E). Schaefer et al. also teaches that additional strategies may be employed to improve yield / reduce side-product further, such as titrating the ratio of heavy and light chain during transient expression (see e.g., paragraph bridging pages 11190 and 11191).
Schaefer et al. does not teach amino acid substitutions in the CH and CL regions.
Kannan (I) (US 2014/0154254) teaches methods of generating heterodimeric antibodies from two different preexisting antibodies (page 1, [0005]), and that heterodimeric IgGs could be produced by engineering the heavy chain and light chain of the two different antibodies in such a way that they can assemble exclusively into a heterodimeric antibody without other contaminating species, which includes electrostatic steering achieved by engineering interface residues between the light chains (LC) and the heavy chains (HC) that prevents mis-pairing of light chains to the non-cognate heavy chains when two different heavy chain and light chain pairs are assembling to form a desired four-chain heterodimeric antibody; and that an exemplary strategy comprises introducing one or more negatively-charged residues (e.g., Asp or Glu) in a first light chain (LC1) and one or more positively-charged residues (e.g., Lys, His or Arg) in the companion heavy chain (HC1) at the LC1/HC1 interface while introducing one or more positively-charged residues (e.g., Lys, His or Arg) in a second light chain (LC2) and one or more negatively-charged residues (e.g., Asp or Glu) in the companion heavy chain (HC2) at the LC2/HC2 interface; and the electrostatic steering effect directs the LC1 to pair with HCl and LC2 to pair with HC2, as the opposite charged residues (polarity) at the interface attract, while the same type of charged residues (polarity) at an interface causes repulsion, resulting in suppression of the unwanted HC/LC pairings (page 4, [0039]). Additionally, Kannan (I) teaches that the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more positive-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more negative-charged amino acids; alternatively, the CH1-domain or the CL-domain comprises an amino acid sequence differing from wild-type IgG amino acid sequence such that one or more negative-charged amino acids in wild-type IgG amino acid sequence are replaced with one or more positive-charged amino acids (page 1, [0008]), wherein one or more amino acids in the CH1 domain of the heterodimeric antibody at an EU position including, among others, K147 and K213, is/are replaced with a charged amino acid (page 6, [0059]); and one or more amino acids in the CL domain of the heterodimeric antibody at a position (EU and Kabat numbering in a kappa light chain) include, among others, E123 and Q124, are replaced with a charged amino acid (page 8, [0071]). Further, Kannan (I) teaches that "antibody" refers to an intact antibody, or a binding fragment thereof, which includes, among others, F(ab')₂, Fab, Fab', etc. (page 11, [0083] and [0084]). Kannan (I) at para. [0326] states that the method minimizes undesired side-product caused by heavy chain homodimer.
Kannan (II) (US 2010/0286374) teaches a strategy to reduce the ability of the domain to interact with itself, i.e., form homodimers by altering the interaction of antibody domains (page 1, [0005], lines 1-3; and [0006], lines 1-4); and the kappa light chain-heavy chain contacts within the interface are shown in Table 5 (page 11), wherein E123 of the kappa light chain is an interface residue and in contact with V125, F126 and K213 of the heavy chain; and Q124 of the kappa light chain is an interface residue and in contact with F126, L145 and K147 of the heavy chain, thereby providing additional guidance on which light chain and heavy chain substitutions to pair.
Therefore, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify a bispecific antibody such as Schaefer et al.’s Ang-2-VEGF CrossMabFAB with additional amino acid substitutions at positions of K147 and/or K213 of CH1 with Asp (D) or Glu (E), and E123 and Q124 of CL with Lys (K), His (H) or Arg (R), and to make a pharmaceutical composition thereof following the teachings of Schaefer et al. and Kannan. The person of ordinary skill in the art would have been motivated to do so for the potentially additive effect of the two different approaches in reducing side products and improving the yield when making a bispecific antibody; and reasonably would have expected success because the recombinant technology and peptide synthesis had been well established in the art, and making amino acid substitutions of a polypeptide using these technologies is routine in the art. Additionally, Schafer et al. specifically suggests additional techniques may be combined with its technology, e.g., titrating heavy and light chain, to achieve optimized heterodimer formation and minimize side product; therefore there was a reasonable expectation of success that adding the method of Kannan—which has the same purpose as Schafer et al. or titrating heavy and light chain, i.e., reducing side-product formation to optimize yield of the bispecific antibody—would further reduce unwanted side-product formation and therefore better achieve the objectives of Schafer et al. Additionally, it is obvious to combine prior art elements according to known methods to yield predictable results. Here, Schaefer et al., Kannan (I) and Kannan/(II) include each element claimed, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. One of ordinary skill in the art could have combined the elements as claimed by known methods, and in combination, each element merely performs the same function as it does separately (i.e., promote heterodimerization to reduce side products and thereby increase the yield of multispecific antibodies). One of ordinary skill in the art would have recognized that the results of combining the two approaches were predictable because Kannan (I) cites Schaefer et al. as a “promising” technology within the same field of endeavor at para. [0004], and does not suggest that the two techniques, that achieve the same objective, are at all incompatible.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
11. Claims rejected under 35 U.S.C. 103 as being unpatentable over Schaefer et al. (Proc Natl Acad Sci US A. 2011 Jul 5;108(27):11187-92); Kannan (I) (US 2014/0154254, 6/5/2014); and Kannan (II) (US 2010/0286374, 11/11/2010); as applied to claims 1, 2, 14 and 17 above, and further in view of Baehner et al. (US 8,268,314, 9/18/2012).
Claim 7 is drawn to the multispecific antibody according to claim 1, wherein the multispecific antibody specifically binds to human Angiopoietin-2 and human VEGF, wherein: the antibody comprises a variable heavy chain domain (VH) according to SEQ ID NO: 32 and a variable light chain domain (VL) according to SEQ ID NO: 33; and the antibody comprises a variable heavy chain domain (VH) according to SEQ ID NO: 31 and a variable light chain domain (VL) according to SEQ ID NO: 30.
The teachings of Schaefer et al., Kannan I and Kannan II are reviewed above.
Schaefer et al., Kannan I and Kannan II do not teach the limitations “ specific bispecific antibody to the human Ang-2 and VEGF as recited in claim 7”.
Baehner et al. teaches bispecific antibodies against human VEGF and Ang-2, which include a bispecific antibody comprising a first set of VH and VL of SEQ ID NO: 7 and 8, and a second set of VH and VL of SEQ ID NO: 52 and 53, wherein SEQ ID NO: 7, 8, 52 and 53 are 100% identical to the present SEQ ID NO: 30-33, respectively (abstract, and claim 3, for example; see also alignments provided in double patenting section). Additionally, Baehner et al. teaches CrossMab of the bispecific antibodies (column 37, line 61, and column 10, for example). Further, Baehner et al. teaches a pharmaceutical composition comprising said bispecific antibody, which can be used for the treatment of cancer (column 7, lines 43-45, for example).
Therefore, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify Baehner et al.’s bispecific anti Ang-2 and VEGF antibody following the approaches taught by Schaefer et al. and Kannan. The person of ordinary skill in the art would have been motivated to do so in order to improve the yield and to facilitate purification of the bispecific antibody, and for cancer treatment; reasonably would have expected success because the recombinant technology and peptide synthesis had been well established in the art, and making amino acid substitutions of a polypeptide using these technologies is routine in the art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
12. No claim is allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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