Interference No. 104,544 Paper149
McDonald v. Miyazaki Page 24
fragment readily self-associates under appropriate conditions to the active
30 kD TPO dimer. By way of previous results, it was shown that this 30 kD
dimer possesses no EPO or EPO-like activity.
While the N-terminal fragment of TPO possesses some activity with
regards to increasing numbers of platelets, it has now been unexpectedly
and surprisingly discovered that the C-terminal fragment is the more
active moiety or ligand of the TPO molecule. This moiety or ligand binds
the c-Mpl receptor, which is the receptor for TPO. It is the C-terminal
fragment then that unexpectedly stimulates the observed increase in
platelet cell counts in the MAIDS animal model described hereinafter.
The biological activity of the C-terminal fragment of the TPO of the
present invention of substantially increasing platelet cell counts is
demonstrated by its ability to stimulate platelet cell production in vivo in
thrombocytopenic mice infected with murine leukemia virus (LP-BM5).
This mouse model (MAIDS) is correlated with the thrombocytopenia
observed in HIV/AIDS patients, and is therefore believed to be predictive
of efficacious treatments for increasing platelet counts in such patients, as
well as other conditions inducing thrombocytopenia.
[68] We find clear and convincing evidence that McDonald's 666 patent disclosure identifies
C-terminal TPO as a specific 179 amino acid C-terminal fragment of the de Sauvage
TPO sequence.
[69] We further find clear and convincing evidence that McDonald's 666 patent disclosure
links the C-terminal fragment with the TSF disclosed in McDonald's prior art 449 patent.
[70] We further find clear and convincing evidence that McDonald's 666 patent disclosure
purports that the C-terminal TPO fragment associated with TSF is the factor mainly
responsible for the therapeutic benefits of the claimed method.
[71] In the face of a rejection over apparent prior art (in particular, Lok and de Sauvage),
McDonald submitted an declaration to antedate the references pursuant to 37 C.F.R.
§ 1.131 [1054].
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