Interference No. 104,544 Paper149
McDonald v. Miyazaki Page 23
this region may act to stabilize and increase the half-life of circulating
TPO. There is no suggestion in the de Sauvage publication that the
C-terminal region or any portion of that region possesses any TPO
activity.
[651 The nature of the C-terminal is further confirmed later in the disclosure [1048 at 7:51
54):
An N-terminal fragment or domain thereof encompasses amino acid
residues 1-153, and the C-terminal fragment or domain encompasses
residues 154-332.
[66] McDonald's 666 patent disclosed the unexpected importance of the C-terminal of the
disclosed TPO polypeptide [1048 at 4:51-62):
With respect to the fragments of the TPO molecule, it has now been
surprisingly discovered that both the N-terminal and C-terminal fragments
of TPO are active in stimulating platelet cell increases.
It has now been further surprisingly and unexpectedly discovered that the
C-terminal fragment is that portion of the TPO molecule which is the more
active moiety for advantageously increasing platelet cell counts. This is
surprising and unexpected in view of the above discussed publications,
which conclude that the N-terminal fragment is the active TPO moiety,
and that the role of the C-terminal fragment has not yet been elucidated.
[67] McDonald's 666 patent elaborated further on the relative importance of the C-terminal
fragment, confirmed the identity of the C-terminal as the 17910 amino acid fragment
running from residue 154 to the C-terminal, and linked the C-terminal to the TSF
disclosed in McDonald's 449 patent [1048 at 8:3-31 ]:
With regards to the C-terminal domain, there are six potential sites for
N-linked glycosylation. It is likely then that this domain is glycosylated.
This C-terminal domain of 179 amino acids in length corresponds
particularly well in size with a molecular weight of 15 kD, as described in
U.S. Pat. No. 5,128,499 (McDonald) for the monomer of TPO. This 15 kD
10 332 - 153 = 179.
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