On
May 8, 2017, Celltrion filed two filed two petitions for inter partes review of Genentech’s U.S. Patent No. 6,407,213, which
covers methods for humanizing an antibody by replacing the CDR flanking regions
of a mouse antibody with human flanking regions, and then reverting back to the
mouse sequence at certain positions in the flanking regions to keep the mouse
CDRs in optimal conformation. Mylan
previously filed two IPR petitions (IPR2016-01694 and IPR2016-01693) against the‘213
Patent, but settled with Genentech before the PTAB had a chance to institute an
IPR proceeding.
Herceptin
is a humanized mouse monoclonal antibody. Mouse monoclonal antibodies can
possess a desirable therapeutic effect, but patients receiving mouse antibodies
experience a human anti-mouse antibody (HAMA) immunogenicity response. To
neutralize the HAMA response, the constant region and the variable framework
regions flanking the Complementarity Determining
Regions (CDRs) are replaced with human sequences, leaving only the
CDRs of the mouse. This extensive humanization, however, has the drawback
of changing the conformation of the mouse CDRs, making the antibody less
effective. To maintain the effectiveness of the antibody, Genentech’s
patent claims substituting some of the amino acids from the human flanking
regions back to the mouse sequence.
Genentech’s
‘213 Patent claims a “humanized antibody” with amino acid substitution in the Framework Regions (FR) flanking the CDRs:
1. A humanized antibody variable domain comprising
non-human Complementarity Determining Region (CDR) amino acid residues which
bind an antigen incorporated into a human antibody variable domain, and further
comprising a Framework Region (FR) amino acid substitution at a site selected
from the group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L,
69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H,
utilizing the numbering system set forth in Kabat.
30. An antibody which binds p185HER2 and comprises a humanized antibody variable domain, wherein the
humanized antibody variable domain comprises non-human Complementarity
Determining Region (CDR) amino acid residues which bind p185.sup.HER2
incorporated into a human antibody variable domain, and further comprises a
Framework Region (FR) amino acid substitution at a site selected from the group
consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L,
85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, 75H, 76H, 78H and 92H,
utilizing the numbering system set forth in Kabat
60. The antibody of claim 30
wherein the residue at site 78H has been substituted.
Claims
30 and 60 specify that the antibody is an
antibody that binds to p185HER2, which is the target for
Genentech’s Herceptin. These claims also have a substitution at 78H
(absent in claim 1), which both Mylan and
Celltrion admit is present in Herceptin.
Celltrion’s position is that the prior art teaches the claimed
substitution, including the substitution at residue 78H.
Below are relevant excerpts from Celltrion’s IPR petitions.
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Queen 1990 [WO 1990/07861] thus provided a detailed rationale
for substituting particular amino acids, and how to do it in a detailed and
objective way. Queen 1990 explicitly instructed a POSA to look to the
“Brookhaven Protein Data Bank” (i.e., the PDB database) to identify the
framework residues that: “could interact with the CDR atoms” (Criterion IV; Ex.
1050 at 14:21–25); were conserved (Criterion II; or were adjacent to CDRs
(Criterion III). Ex. 1003 at ¶¶120–26, 259–60. A POSA following this roadmap would
have quickly determined that 19 light (L) chain ((4L, 58L, 62L, 66L, 67L, 73L,
85L and 105L (CDR contact residues) and 23L, 25L, 33L, 35L, 49L, 53L, 57L, 88L,
90L, 97L, 98L) (Kabat and Chothia adjacent residues)) and 23 heavy (H) chain
residues (2H, 24H, 39H, 45H, 69H, 71H, 73H, 76H, 78H, 93H and 103H) (CDR
contact residues) and 25H, 30H, 33H, 36H, 49H, 52H, 56H, 66H, 94H, 95H, 102H and 103H (Kabat and Chothia adjacent
residues)), including claim 1 positions 4L, 58L, 66L, 67L, 69L, 73L, 2H, 36H,
45H and 69H, as well as adjacent residues 98L and 36H, meet these requirements.
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The
substitutability of residues 71H, 73H, 78H and 93H would not have been
surprising or unexpected. The importance of heavy chain residue 71H was
well-known by those in the field, including patentees. See Ex. 1001 at 3:1–8
(recognizing framework residues that “critically affect[] the conformation of
particular CDRs and thus their contribution to antigen binding,” citing to Tramontano.
Dr. Riechmann also cites to antibody 4–4–20 (4Fab), having a cluster of close
contacts (less than 3Å) at 73H, 78H and 93H, which “emphasizes the relative
importance of these contacts made . . . in maintaining antibody conformation.”
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The
PTAB has not yet made a decision on the IPR petitions.
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