I'm sure that subject line caught your attention. And I'm thinking it could happen.
Allow me to explain.
The best thing about the first 3 movies is how well they blend all of the BIG moments of Spidey's illustrious history. Think about it:
NORMAN/GREEN GOBLIN: check
DOC OCK: check
SPIDER-MAN NO MORE: check
MJ/PETER RELATIONSHIP: check
MJ LEARNING SECRET IDENTITY: check
ALIEN COSTUME: check
VENOM SAGA: check
These are most of the big moments and they've been handled, combined... whatever very well by Sam Raimi and crew. Of course I can't say that with 100% certainty with regards to 3 because I haven't seen the movie yet. But the plot points are there.
Now, when one considers the history of Spidey, there aren't a lot of major points left. Here's a quick list:
DEATH OF CAPTAIN STACY
DEATH OF GWEN STACY
DEATH OF AUNT MAY
And as far as stories go, I don't see Spider-Man 4 being about Sin Eater (not kid friendly) or Kraven's Last Hunt (Kraven, with no powers, does not leave room for a slam bang fight at the end unless they monkey around with his character) and, I think (and hope) we can forget about Sins Past, Civil War or that mystical mumbo jumbo. I think we can leave spider-slayers out as well. And any stories with guest stars although that would be cool! And I think we can rule out the extra arms, cosmic spidey, iron spidey, Carnage and the Savage Land.
So, for big stories, and I mean BIG stories, all that leaves, in my opinion, is the Clone Saga. Love it or hate it, it WAS the biggest, longest spidey saga of them all. And, given that Sam Raimi likes to focus on the early (6os/70s) aspect of Spidey's history, this could be something they might look at. The original Clone Saga dates from 1975. Right in Sam Raimi's wheelhouse. I know the "experts" running Marvel these days would not be happy about it, but, really, what else is there?
The Spider-Man movies, thankfully, have used villain that tie into Peter Parker's personal life. Well, with the Goblins out of the mix, Venom done, who else is there? Curt Connors/Lizard seems to be a direction they would like to go in.
But, keeping with the idea that the villain has to be someone close to Peter, the Clone Saga could be the next step. Here are some movie plot points that might work.
Gwen, being introduced in 3, could be killed the way here father was in the comics. Or MJ could be since they've flipped the roles in the movies -- MJ coming first, then Gwen. Killing one of them this way would take care of 2 big moments in one. Plus with Peter/MJ married, and that appears to be set up in 3, this opens the door for Baby May coming on the heels of Aunt May's death. And Baby May was part of the later Clone Saga. Personally I don't see them killing MJ because the general consensus is that Tobey and Kirsten have too much chemistry. You wouldn't want to play around with that.
Connors as the Lizard would fit a version of the Clone Saga because you can put that arm regeneration down under gene manipulation.
The Jackal (hopefully they'd use him) in cloning Gwen (or MJ) would keep the story as personally tied to Peter as you can get. And Spider-Man fighting himself at the end, well, can anything be more personal?
So could we see a version of The Clone Saga in Spidey 4. I'd have to say I hope so. The original Jackal arc from the 70s is still my all-time favorite Spidey story. And Pete's reaction to the Gwen clone ripped his guts out. Juicy story fare for the Spidey films. I think a more down to earth, controlled version of the Saga would work. I hope they do it.
The thing is, not every villain has personal ties to Peter/Spidey. They'd either have to create ties (like they do with Sandman) or stick to the canon. And don't forget that with each movie, you get diminishing returns in the villain department. Shocker, Scorpion, Rocket Racer? Can villains like these carry a movie? Maybe. But who will Spidey fight in Spider-Man 11? Gibbon?
Well, whatever direction they go in, I just hope Sam Raimi is at the helm. His love and respect for the source material shines through in the movies. I'd hate to lose that.