I think regarding Fallout, there's not many fresh ideas to get from the formula of FO3 any more. It's been like 4 games of that kind already. You can shuffle the setting all the way around the US, but at its heart it'll still be an the same Oblivion-derived RPG where you scavenge shit in the ruins or go kill some raiders because some dude in a shack made of garbage told you so.
That's one of the reasons why 4 is mediocre and 76 is shit, besides Bethesda being spectacularly incompetent.
There's probably two ways out of this, I think:
- Keep the setting, but move away from the RPG genre - there's enough space for other kinds of games set in the Fallout universe. Strategy games would work, perhaps - an RTS with all the factions like the NCR, Supermutants, Brotherhood of Steel, the Enclave, the Legion, or a grand strategy game set in the former USA would work well. There was a good Fallout-themed mod for Hearts of Iron 2 and Darkest Hour called Fallout Doomsday, as I remember.
- Move away from the post-apocalypse - it's been more than 200 years since the war, why the hell is everyone still living like the nukes fell only decades ago? Sooner or later, people would go from scavenging to producing things on their own, from workshops to small scale factories, reconstructing infrastructure, and so one. Only New Vegas has some clues of that - NCR has working railroad transport and enough industrial development to supply its army with M16s, for example. One can make something like Red Dead Redemption - it's the late 2300s, civilization is sweeping across the land and the age of scavenging and raiding is finally coming to an end...