Appeal No. 2001-1580 Page 7
Application No. 08/955,090
circularly permuting ligands generally. Pastan states that in some ligands, such
as interleukin-4, the amino and carboxy termini of the protein are situated
relatively close to the active site when the protein is folded into its native
conformation. As a result, when fusion proteins are formed by joining a second
protein to either the amino or carboxy terminus of such ligands, the resulting
fusion may have reduced binding affinity or specificity relative to the native
ligand. See column 6, lines 8-18; column 2, lines 5-26. It was this problem that
Pastan sought to address by joining the native N- and C-termini and creating new
termini by circular permutation. See column 6, lines 19-26.
The prior art relied on by the examiner does not suggest fusing the flt3
ligand to another protein at the N- or C-terminus. Rather, the examiner’s
rationale for combining the references was that “such circularly permuted
proteins are expected to retain or have improved binding properties to the
receptor to which they bind, as compared to the non-permuted forms.”
Examiner’s Answer, page 6. The basis for this position is Pastan’s statement
(column 5, lines 61-64) that “[t]he present invention provides for circularly
permuted ligands which possess specificity and binding affinity comparable to or
greater than the specificity and binding affinity of the native (unpermuted) ligand.”
We do not find that this statement, considered in view of the prior art as a
whole, would have provided the requisite motivation or expectation of success.
Pastan provides a single example of a successful circularly permuted ligand.
See Examples 1 and 2, columns 19-23 (showing that circularly permuted
interleukin-4 retained activity, both alone and as a fusion protein with
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