Appeal No. 1997-3122
Application No. 08/082,848
the mechanism of action of the immunosuppressant drugs, cyclosporin, FK506, and
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rapamycin.” “Besides their role in the immune system, . . . cyclophilin and [FKBP] are
highly concentrated in the brain in discrete neuronal structures where they are co-localized
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with the Ca activated phosphatase, calcineurin,” and it has been demonstrated that “FK-
506 and cyclosporin A, which bind to FKBP and cyclophilin, respectively, inhibit
calcineurin, and . . . both drugs enhance the phosphorylation of a number of proteins in the
brain.” Specification, page 2 (citations omitted).
According to page 4 of the specification,
It is a discovery of the present invention that immunosuppressant-type drugs,
such as FK-506 and cyclosporin A, which bind to immunophilins, block
glutamate neurotoxicity that is mediated by N-methyl-D-aspartate (NMDA)
receptors. Upon binding of FK-506 and cyclosporin A to their respective
immunophilins (binding proteins), the activity of the calcium-activated
phosphatase calcineurin is inhibited. Thus treatment with this class of drugs
increases the phosphorylation of proteins which are substrates of
calcineurin. It is a further discovery of this invention that phosphorylated nitric
oxide synthase (NOS) is a substrate for calcineurin. A model which
accounts for these findings is that immunosuppressant-type drugs block
neurotoxicity by inhibiting calcineurin, thereby increasing the phosphorylation
of NOS, thereby inhibiting production of nitric oxide.
The specification contains various examples demonstrating that NOS is a substrate
for calcineurin and that FK-506 enhances phosphorylation of NOS (Example 1); that FK-
506 and cyclosporin A, but not rapamycin, markedly diminish NMDA neurotoxicity in
primary cerebral cortical neuronal cultures (Example 2); and that enhanced
3 Illustrated Dictionary of Immunology, J.M. Cruse and R.E. Lewis (eds.), CRC
Press, Boca Raton, Florida, 1995, “immunophilins,” page 163 (copy attached).
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