Man, there are so many cool unused villains. I'm really excited that Beenox is trying to fit some in as it seems.
Mr. Negative (although I agree that he wouldn't really fit into this story)
Tombstone (now THAT would be something!)
Hydro-Man (could make for a really epic boss fight, trying to drown Spidey and flood the place)
Speed Demon (maybe goofy, but could make for a pretty fun boss fight or chase)
Tarantula (OK I admit, I don't know much about him but he seems cool and is one of the newer villains I think)
The Boomerang (also a goofy villain, but could still make for a fun boss that Spidey could make lots of fun about)
(Classic) Hobgoblin? (sure his 2099 version has been used but that doesn't count imo)
The Spot (IMO, he's a cool villain due to his powers, and would also make for an epic boss battle)
The Swarm (another goofy villain but could still be really cool to battle out)
The Enforcers (haven't been used as far as I know and would be pretty cool)
Trapster (just for fun)
But hey, guys, we have all forgot about......THE CHAMELEON!
I remember how many of us during the development of SD and after its release talked alot about Chameleon never making it to any game before and that he would be cool to have in a game and all. There were actually many of us wanting him in a game. Maybe Beenox listened? He's one of Spidey's most famous villains that still has never been used.