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>remove "save anywhere" and "pokemon centers are free" - add in save points and paid healing, save points are placed at the front of gyms, pokemon centers, 'dungeons', e.g. forests, caves, evil team bases, etc.
>penalty for blacking out is going back to a save point
>gyms, dungeons, etc. cannot be left when you enter. the first gym and first set of dungeons, you can, but the game warns you heavily the rest will not be so kind
>battles now default to you having the same amount of pokemon as whomever you're fighting: all trainers will have a minimum of 3 pokemon
>it is now much more difficult to run away from wild encounters. additionally, wild pokemon have boosted stats, and can attack randomly in singles, doubles or triples battles, and will have better AI and even strategies tailored to their level moveset (i.e. the electric area will have pokemon who love to use discharge + lightningrod or volt absorb)
>tms are no longer infinite, but will operate by a weighted system, the better a TM, the fewer copies of it you'll receive on getting it. however you can get any tm in the game an infinite amount of times through certain means (such as trainer gauntlets or mini dungeons)
>evs no longer are obtained on defeating pokemon, but the player is encouraged to get vitamins, which will usually be locked behind hard trainers or sidequests. ivs/natures are removed
>while you can deposit as many mons as you like into the PC, withdrawing or changing Pokemon out from the PC is now very expensive, and scales with the number of badges you have. you can earn coupons to make the process free, but they're not easy to come by
>finally 'standard' things like limiting item usage in battle, a hard exp curve which doesn't allow you to overlevel the next boss by much if at all, shift mode nixed from the game
There are probably other things, but this would be a start