Kanto/Johto feels like home for Pokemon. I say they make a sequel that involves the Rockets and Mewtwo, and really go all-out with it. Takes place 20 years after RB. Red's grown up and is the last member of the Elite Four (replacing Lance), Silver is the new leader of Team Rocket, Oak is retired and Blue is the professor.
The player is a new trainer from Viridian City who gets swept up in the conflict.
16 Gyms with old, new, and legacy leaders. Game takes place the year the PWT is set to go down in Johto. Lots of new Megas for Kanto/Johto Pokemon.
Mew is part of the story and is obtainable through an unlockable event.
Everything is wrapped up. We never visit those regions again.