Appeal No. 2003-1668 Page 4
Application No. 08/479,883
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. 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 amino acid
substitutions 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 in
place of the naturally occurring amino acid at various positions. See Table 3.
Discussion
Claims 46 and 54 are representative. Claim 46 is directed to a variant of a
mammalian growth hormone, having at least two mutations in the receptor-
interacting “site 2” region. Claim 54 is also directed to a mammalian growth
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