Appeal No. 2004-1259
Application No. 09/832,355
tyrosine kinase, which causes autophosphorylation of the receptor as well as of other
substrates, eventually leading to increased cell proliferation. During this process the
ligand-receptor complex is internalized into the intracellular compartments where it is
degraded... [H]uman angiogenin ... shows RNAse and ribosomal inactivating activities
besides its angiogenic activity... Human angiogenin is also a potent inhibitor of protein
synthesis in cell free extracts, but extracellular angiogenin is not cytotoxic toward a wide
variety of cultured cells.” Yoon, p. 1436. The EGF-angiogenin fusion protein
“maintained receptor binding activity of EGF and RNase activity of angiogenin in a
single peptide and actively inhibited growth of human EGFR-positive target cells in
culture.” See abstract, page 1435. The examiner notes that the EGF receptor is, like
the VEGF receptor, a tyrosine kinase receptor. Answer, pages 14-15. See also
Rockwell, Col. 1, lines 60-66.
The examiner acknowledges that Yoon does not teach a fusion protein
comprising VEGF and angiogenin. Answer, page 15. To make up for this deficiency,
the examiner relies on Gill and Rockwell. Gill teaches that Kaposi’s sarcoma (KS) cells
express VEGF receptors, and that the cell growth and KS cell survival depend upon
VEGF. Rockwell teaches that flk-1 (VEGFR-2, Answer, page 15) receptor expression is
probably induced during glioblastoma tumor formation, and that high levels of flk-1 are
expressed by endothelial cells that infiltrate gliomas.
The examiner argues (Answer, page 15),
[i]t would have been obvious to one of ordinary skill in the art at the time
the invention was made to substitute VEGF 121 for the EGF in the fusion
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