Appeal No. 2003-1469 Page 4
Application No. 08/479,886
and/or 2.” Page 3. “[T]he residues falling within the site 1 domains remain
unmodified (in the case of antagonists, in which only site 2 is disabled by
mutation) or, if modified, the changes to site 1 are selected so as to not disrupt
binding. The reason is that it is not desirable in most embodiments to disable
site 1. Instead the objective is to increase site 1 affinity by about 10% to greater
than 2 fold.” Id.
The specification states that the reason site 1 binding should not be
disrupted is that “the receptors have been found to bind to these two sites in
sequential order, first one site (site 1) and then the other (site 2). The reverse
order has not been found to occur. This understanding is especially important for
the preparation of antagonist ligands. It is important to preserve, if not enhance,
the affinity of the ligand for the first site. Otherwise, the ligand analogue never
binds receptor at all. On the other hand effective destruction or inhibition of the
second site binding is predicate for antagonist activity.” Page 8. Contrariwise, to
function as an agonist, a ligand analogue should have “mutations at sites 1
and/or 2 which increase the ligand affinity for one or both sites.” Page 4.
The specification provides a table showing candidate substitutions for
naturally occurring amino acids, including specified amino acids that are
preferred for the formation of agonists or antagonists. See page 11. The
specification also provides working examples of growth hormone mutants
showing the effect on receptor dimerization of substituting alanine for the
naturally occurring amino acid at various positions. See Table 3.
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