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How about a game set in a period before the pokeball was invented? Not pokemon centers, so you'll need to use food to heal your pokemon. Money can be used to buy food and items. Teams don't really exist, you just have pokemon companions. Every counter is like the safari zone, where it only has a chance of actually becoming a partner pokemon that you can use in battle. If a pokemon faints in battle, it revives after 1 hour naturally, or with an expensive food. Routes are massive and the region is undeveloped in terms of civilisation.
Difficulty is maximized this way.