Manny Pacquiao's best chance is to out hustle Mayweather. He needs to throw 100 punches around from different angles and move constantly like he used to five years ago. Unfortunately for Pacquiao, he hasn't shown that level of sustained activity for quite some time.
Pacquiao struggles against counter punchers the most. Juan Manuel Marquez is an adept counterpuncher, who knocked out Pacquiao and has fought him tough three other times. Mayweather is big and faster than Marquez. Mayweather's defense is also better.
Pacquiao's southpaw stance shouldn't be a big issue for Mayweather. He's done well against lefties recently, but it may take longer for Mayweather to settle into a good rhythm.
Mayweather did seem sick and worn down in an interview on TNT on Thursday Night., If he's sick, it could change the dynamic. Mayweather uses hand speed and timing to succeed.
If Mayweather is well, his counter right should control the fight during the earl portions. Pacquiao should get a couple of hard lefts in and that will mean Mayweather will get a tad bit more touched up than usual. But by the middle rounds, I expect Mayweather to be firmly in control and Pacquiao's punches becoming more and more sparse. By the late rounds, Mayweather will pot shot with lead straight rights from the outside. Mayweather will control the fight, but the scores will be a little closer than they should be because Pacquiao will try to steal rounds late with activity. Mayweather will win with scores in the 8-4, 7-5 range, but it won't be that close in reality.