Appeal No. 2005-2207 Page 4
Application No. 09/548,933
underlie various neurological diseases as well. Id., page 717. Finally, Santoro teaches
that acetylcholine and norepinephrine exert their actions on heart rhythm through
modulation of pacemaker channel activity, and that direct binding of cyclic AMP
modulates pacemaker channel activation. Id.
Thus, the Ludwig and Santoro references reflect a general consensus in the art
that pacemaker activity in the brain, and probably the heart, is due, at least in part, to
the HAC family of hyperpolarization-activated, cyclic nucleotide-gated channels.
“The present invention provides . . . a nucleic acid encoding a human HAC3
alpha subunit, identified and cloned from human tissue” (Specification, page 8).
“Functionally, hHAC3 is an alpha subunit of a voltage-gated channel that is activated
upon hyperpolarization” (id., page 10). Structurally, hHAC3 “contains six membrane
spanning domains (S1-6), including a voltage sensing domain (S4) and an ion-
conduction pore between S5 and S6, as well as a putative cyclic nucleotide binding
domain region that has a conserved amino acid sequence” (id.). Based on hHAC3’s
structure and function, the specification discloses that hHAC3 “is a member of the HAC
family of potassium channel monomers . . . [which] have significant roles in maintaining
the resting potential and in controlling excitability of a cell” (id., page 8).
When functionally expressed in Xenopus oocytes, hHAC3 monomers formed “a
classic Ih channel that passe[d] both sodium and potassium” and “that open[ed] upon
hyperpolarization” (id., page 63). Analysis of hHAC3 expression patterns revealed
“especially high [expression] in the putamen, thalamus, caudate nucleus, medulla,
occipital lobe, substantia nigra, spinal cord and fetal brain” (id.), and “moderate levels
[of expression] in . . . the amygdala, cerebellum, cerebral cortex, frontal lobe,
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