All the interesting villains? Hardly. While the top 4 are done (GG, Doc Ock, Venom and Harry....in that order) there are some great villains left, albeit we can't use some of t hem for obvious reasons, like Hobgoblin for redundancy and Kingpin is over at Fox.
But there is The Lizard, Kraven, Black Cat (if Felicia is introduced one movie prior) albeit she would end up being more of an ally and partner than a vilain, but also Electro if done properly and Scorpion, etc.
No villains aren't the problem. The problem is keeping the Peter Parker stories interesting. Pete's struggles and triumphs are what made the first -two special and what seem to be driving the third. We don't want the next three just to become like Batman as we wait to see what villains are next. I think the logical step is Peter wanting to start a family. Albeit it would age him and is something that comic book Peter is rapidly coming to have to face before Marvel presses the reset button on him next year unfortunately.