Appeal No. 2002-1296 Page 3
Application No. 08/957,038
The present invention involves Transforming Growth Factor-$. As explained by
the specification:
Transforming Growth Factor B (TGF-$) is a potent growth regulatory
protein and a key molecule implicated in various fibrotic (scarring)
disorders. Most of the cells secrete TGF-$1 in a predominantly inactive
high molecular weight form, latent TGF-$ (L-TGF-$). Latent TGF-$ is
composed of an amino-terminal latency-associated peptide (LAP)
noncovalently associated with the carboxyl-terminal mature TGF-$. The
latency-associated peptide, is disulfide-bonded to a second, structurally
unrelated protein, latent TGF-$ binding protein (LTBP), which plays a role
in the processing and secretion of TGF-$ (1).
A major mechanism of regulating TGF-$ activity occurs through factors
which control the processing of the latent to biologically active form of the
molecule. Physiochemical activation can occur by extremes of pH, heat,
chaotropic agents (sodium dodecyl sulfate, urea) and deglycosylation (2,
3, 4, 5). Activation in vivo is more complex and not well understood.
Id., page 1, first and second paragraphs. Since active TGF-$1 is involved in scarring
and fibrotic disorders, agents which sustain the latency of TGF-$1 would be expected to
be useful as anti-fibrotic and anti-scarring agents. Id., pages 2-3.
The assay set forth in claim 15 on appeal is designed to identify compounds that
modulate latent TGF-$1 activation. An important aspect of the assay is the use of
immortalized, non-cancerous macrophages in step (a). Appellants contrast the present
assay with a prior art assay described as a co-culture system stating:
The method of the present invention is simple and is based on homotypic
cell culture. In contrast, in the co-culture model, two cell types must be
present and a number of requirements have to be fulfilled. The cell types
must be either in contact or in very close proximity in order to produce
active TGF-$1 since the co-culturing of endothelial cells on a surface 1-2
mm above a monolayer of smooth muscle cells fails to produce active
TGF-$1. A strong species specificity appears to exist as bovine arterial
endothelial cells do not activate latent TGF-$1 in the presence of either
human or pig smooth muscle cells. The sensitivity of this method of the
present invention could be manipulated since the source of latent TGF-$1
which is activated by macrophages is not limited to fibroblast conditioned
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