Appeal No. 2005-2207 Page 2
Application No. 09/548,933
of insulin, excitability of nerve cells, transduction of sensory stimuli, and regulation of
renal electrolyte transport.” Specification, pages 1-2. Typically composed of four
heteromeric or homomeric subunits, “[t]hese channels allow the flow of various cations
in and/or out of the cell under certain conditions” and “are regulated, e.g., by calcium
sensitivity, voltage-gating, cyclic nucleotides or other secondary messengers,
extracellular ligands, and ATP-sensitivity.” Id., page 2.
Specialized cells in the heart and brain create rhythmic activity due in large part
to a particular subset of cation channels: hyperpolarization-activated channels that
generate a mixed sodium/potassium pacemaker current known as Ih. Id. The
specification cites a number of references that reflect the level of understanding of the
nature and identity of pacemaker channels at the time of the invention. Id., pages 2 and
3. For example, Ludwig2 reports the molecular cloning and functional expression of
HAC1, a murine cation channel “dually gated by hyperpolarization of the membrane and
by direct binding of cyclic nucleotides” (Ludwig, pages 587 and 590). According to
Ludwig, “[t]he functional properties of the HAC1 current, that is, the voltage-dependence
of activation, ion selectivity, pharmacological profile and modulation by cyclic
nucleotides, concur with the general criteria that characterize Ih in several neuronal and
non-neuronal cells” (id., page 590). Further, “[t]he expression pattern of HAC1 indicates
that it may mediate the current that is involved in control of pacemaker activity in both
central nervous system and cardiac cells” (id.). In addition, Ludwig identified full-length
sequences of two related brain-specific channels, HAC2 and HAC3, “indicating the
2 Ludwig et al., “A Family of Hyperpolarization-Activated Mammalian Cation Channels,” Nature, Vol. 393,
pp. 587-591 (June 1998).
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