After taking control of the NFC East in New York, the Eagles came back home to face a 6-7 49ers team who were coming off of a 15-point win against the Cardinals. Upon receiving the opening kickoff, the Eagles' first possession began from the 50-yard line after a great return of 48 yards by Quintin Demps. With excellent field position to start, the Eagles would march through 49ers territory and score the game's first touchdown to cap off a 5 play, 50 yard drive on a 19-yard touchdown pass from Donovan McNabb to DeSean Jackson. The 49ers responded within 3 minutes with a 51-yard field goal by Joe Nedney to cut the Eagles' lead down to 7-3. Before the end of the 1st quarter, both teams turned the ball over once: 49ers QB Alex Smith was picked off at the Philadelphia 32-yard line by Quintin Mikell and, during a later possession, the Eagles were stopped on 4th down at their own 29 yard line after RB Leonard Weaver failed to convert on 4th and 1. On the very first play of the second quarter, with the 49ers threatening to score, tight end Delanie Walker's fumble was recovered by Eagles' cornerback Asante Samuel at the Philadelphia 6-yard line. The Eagles turned it into 13 more points, coming off of an 8-yard touchdown run by McNabb and two short David Akers field goals. The Eagles took a commanding 20-3 lead into halftime. In the third quarter, San Francisco held the Eagles scoreless while managing 10 points of their own to trim the deficit to 7. Joe Nedney nailed another field goal, this time from 25 yards, and Alex Smith connected with Josh Morgan on a 12-yard touchdown pass as the Eagles took a 20-13 lead into the 4th. From there, the 49ers would not score again and the Eagles would put the game away with a 2-yard rushing touchdown by LeSean McCoy. The Eagles won the game 27-13. With the win, the Eagles improved to 10-4 and remained atop the division, holding a 1-game lead over the Dallas Cowboys. The Eagles also clinched a playoff berth, the 8th of the Andy Reid/ Donovan Mcnabb era.

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