In July 2005, the producers openly discussed the possibility of following Extinction with a sequel titled Resident Evil: Afterlife, with the announcement of plans to shoot and set the film in Tokyo, Japan. During the film's production, actor Chris Durand stated that talks were held to set the film in Alaska during the winter time.
In September 2006, it was announced that casting had been underway for Resident Evil 4, and that Jensen Ackles was in talks for portraying Leon Kennedy. However, bringing Leon as a character in an upcoming film would contradict promotional information from Resident Evil: Apocalypse. Screen Gems created a faux newspaper, The Raccoon City Times, that detailed the background of Jill Valentine, and included that she was dismissed from the S.T.A.R.S. (Special Tactics and Rescue Squad) after the death of her partner, Leon Kennedy. During an interview with Bloody Disgusting, while promoting Extinction, Ali Larter confirmed she would reprise her role "100% if asked". Oded Fehr jokingly mentioned if his character was to return for a new film, he would have to be cloned like Milla's character in Extinction. Despite Resident Evil: Extinction being billed on the official website and elsewhere as the final installment of the Resident Evil film series, Rory Bruer, Sony's head of distribution explained, "It absolutely would not surprise me considering the success of the franchise that they find a way to come up with another. It's a real possibility". In an October 18, 2007 interview with IGN regarding the continuation of the franchise, however, producer Jeremy Bolt said, "It's not our intention [to make a follow-up to Extinction]. But we've been very pleased that the third part of the franchise has done so well. Paul Anderson has reported that there is a possibility of a fourth film and is talking to Sony about it."
On January 29 2009, Arrow in the Head News reported that Paul W.S. Anderson is nearly finished with the script for Resident Evil 4 and is currently on draft two. The article claims that Anderson is writing but will not direct. The story is more in tune with RE2 in terms of style but with better dialogue and a darker tone. There's enough hand to hand combat in the script for the producers to bring in a martial arts choreographer. The story reportedly takes place in Tokyo and Alaska (with Toronto standing in for Alaska). Patrick Tatopoulos will return to be in charge of the creature effects while Michael Lantieri will be the new Special FX supervisor (in terms of the practical effects). Casting will start before any more changes are made to the script and they plan on securing a director once Milla Jovovich officially signs on.
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