Creative and reinventive, here are some wild guesses on what that could be:
- 3D battles in which you actually take control of the Pokémon, making it more of a fighting game (Mortal Combat with Pokémon). (Unlikely)
- Travelling through all known mainserie regions in one game. (Even more unlikely)
- A dark, serious story which is not just a repetition of the four generations before it, with some good plot twists and rivals that are involved in the storyline. (The most unlikely of all :p)
Maybe they'll make another big change to the game mechanics. I think a change in the amount of Pokémon you can carry around would have a rather big impact, and I read somewhere, I think Bulbapedia, that they once were planning to do this for RSE, so it might not be that unlikely.
I'm also guessing that there will be more 3D effects in general. Maybe even a completely 3D game, though I'm not sure if a game as big as Pokémon could be turned into a 3D game for the DS.