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1. The region is much more linear in its layout. You can only really travel forwards or backwards and they're not really inter-connected. There are very few optional areas too.
2. The colours are a lot darker compared to other Pokemon games.
3. The music is a lot blander and feels more like a generic JRPG than a Pokemon game.
4. The story is forced on you a lot heavier than the older games.
5. It featured an all new Pokedex, although a lot of the designs were callbacks to older Pokemon so it felt like they were cheap imitations at first. Although as time has gone on, I've gotten use to the designs so they don't feel as out of place now.
6. The battle sprites had really stiff animations that look weird at first.
7. The dynamic camera and a mix between sprites and 3D models just felt awkward, especially after so many years of a fixed, top-down camera perspective.
8. The intro movie shows off some random king, it's the first time a Pokemon game had a story that revolved around human characters rather than Pokemon themselves.
They do feel quite different.