I'm going to put the cat among the pigeons, I've a feeling that Fed won't make the semis, that he will have a surprise loss to one of the Americans and although a good draw, Nole will not get past Del Po this time. If you remember Nadal, Federer, and Nole all won their 1st GS against someone not expected to make the Final. So.......
Nole is more vulnerable than Federer for sure. Also, he's not playing with the same gut and his game is also not nearly as good as last year. So Del Potro does have a slim chance to take him out, but only him as I see it. It will be still tough to beat Nole because there are a couple of things that will keep him motivated: one, he needs to defend his title; second, and this is more important, he’d like the No. 1 ranking back from Federer. But as I’ve said just last year that winning is very easy defending is not. Anyway, going back to the original point, there’s also Isner but Isner will have to stay fresh and focused to make the semi but it's not too farfetched either.
Federer, I am not sure, who pose a real threat in his qtr. It's not the same Fish as last year either but he can definitely put up a fight, take a set etc., but to beat Federer at the USO will be a huge deal for him, so even if he goes ahead of Federer by any chance, he’ll probably falter because of the mental toughness he lacks in general. Berdych is the only guy who can take Federer out before the semi, but he will have to get there first. I hope he gives his all to make that far but it all remains to be seen.
There is a chance, however, that one of the top guys may have to play a guy in the final who's never made a final before. There are all sorts of possibilities in fact.