Appeal No. 1997-3122
Application No. 08/082,848
BACKGROUND
“Glutamate, the major excitatory neurotransmitter in the brain, acts through several
receptor subtypes.” “[A]cting at [the] N-methyl-D-aspartate (NMDA) subtype of receptors,
[glutamate] is responsible for neurotoxic damage in vascular strokes,” as demonstrated by
the fact that “selective antagonists of NMDA glutamate receptors prevent neuronal cell
death in animal models of hypoxic-ischemic brain injury.” “Glutamate mediated
neurotoxicity has also been implicated in neurodegenerative disorders such as
Alzheimer’s and Huntington’s diseases.” Specification, pages 1 and 2 (citations omitted).
It is also recognized that “[d]uring the normal course of a vascular stroke or
neurodegenerative disease, glutamate released from adjacent nerve terminals activates
+2 +2
the NMDA subclass of glutamate receptors to increase intracellular Ca . . . [t]he Ca
+2
binds to calmodulin, activating NOS [nitric oxide synthase] . . . Ca entry also activates
calcineurin, which dephosphorylates and activates NOS.” “The NO [nitric oxide] generated
by NOS diffuses to adjacent cells,” which die “[i]f sufficient quantities of NO are produced.”
Specification, page 4. Finally, it has been shown that “inhibitors of nitric oxide synthase
prevent neuronal cell death.” Specification, page 2.
Immunophilins, e.g., cyclophilin and FK-506 binding protein (FKBP), are “[h]igh-
affinity receptor proteins in the cytoplasm that combine with such immunosuppressants as
cyclosporin A, FK506, and rapamycin . . . [they] are important in transducing signals from
the cell surface to the nucleus . . . [and] [d]rug-immunophilin complexes are implicated in
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