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The spotlight shone brightest on LeSean McCoy in the build-up to this clash as he returned to Philadelphia for the first time since his high-profile departure in the summer, but it was a current Eagles running back who had the first say on proceedings when Darren Sproles burrowed over from a yard out.
McCoy was proving effective on the ground against his former club, but the Bills' opening score came from the arm of Tyrod Taylor as he sent a pass deep downfield for Sammy Watkins to complete a 47-yard touchdown.
It was another big play that provided the next touchdown, this time from the Eagles as Sam Bradford found Nelson Agholor with a 53-yard pass straight down the middle to hand the rookie his first NFL score.
Dan Carpenter pulled three points back with a 38-yard field goal later in the second quarter, but Caleb Sturgis responded with a kick of his own in the closing stages of the first half to open up a seven-point lead at the break.
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Sturgis and Carpenter exchanged field goals again at the start of the third quarter before Mike Gillislee found a route through the middle from 19 yards to tie things up.
Bradford's attempt to get his side back in front on the next drive ended at the Bills' five-yard line when he was intercepted by Leodis McKelvin, but winning the ball back so deep inside their own territory almost proved to be the Bills' undoing.
McCoy looked like having an unwanted say on the result when he was tackled in his own endzone for a safety, but the play was overturned for an offensive holding penalty.
The Eagles refused to be denied, however, and a third kick from Sturgis proved to be the difference when Taylor's pass on what would have been the final drive of the game was intercepted by Ed Reynolds.
The result sees the Eagles move on to 6-7 for the season, while the Bills now have the same record in the AFC East.