Comic Book Resources has posted an interview with "Spider-Man" franchise director Sam Raimi in which he reiterates that what happens in the fourth installment will be up to the writer they are hiring, including the villain(s). Here's a bit from the piece:
Sam: If I was writing it I would have a very strong opinion about that, but we're hiring a writer to come up with his own take. Sony was willing to go either way, we'll just have to wait and see what the writer comes up with. I think anything's possible, though.
I mean, there's been so many different versions, it doesn't have to follow the movies that we've made. I'd very much like to see Tobey Maguire as Spider-Man, so I have a personal interest in that, but certainly anything's possible. Spider-Man's such a big character in the comic books that he could endure a lot of different interpretations. You could start over or you could start with a different aspect of the story than I've focused on in the pictures I've made, we'll just have to wait and see what the writer comes up with.