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The game, particularly the "Umbrella's End" scenario, contains several elements from the first Resident Evil (2002) film, such as the Red Queen computer, an attack on a high-speed train car inside the Umbrella complex, and the heroes being trapped in a room filled with lasers.

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Unlike previous Resident Evil games, most of the files you collect are profiles of every character and enemy that has appeared in the Resident Evil series up to the end of Umbrella.

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The game was said to mark the first on-screen appearance of Ozwell E. Spencer, one of the founders of the Umbrella Corporation and therefore one of the catalysts for most of the events in the series. At the end of the "Death's Door" scenario, as Ada Wong boards the helicopter, it is revealed that an unnamed male Umbrella official is aboard and is evacuated by Sergei Vladimir. Although he is only seen from behind, his appearance is quite close to Spencer's look in Resident Evil 5 (2009). Whether this man is really Spencer remains doubtful: the man questions Vladimir's decision to steal the Umbrella computer core, an order Vladimir received from Spencer himself; and in Resident Evil 5, Spencer's notebook mentions that he was not nearby when Raccoon City was destroyed.

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In the "Fourth Survivor" scenario, Agent HUNK's face appears for the second time in the entire series. Briefly and with some difficulty, it can be seen reflected in the vial containing the G-virus. In the "4th Survivor" mission of Resident Evil 2 (1998) he could finally be seen unmasked, but his face was only shown from the side. HUNK's full face could be seen in the epilogues of Resident Evil 3: Nemesis (1999), but only after finishing the game on Hard mode.

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This is the first Resident Evil game released for the Nintendo Wii console.

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In the final scenario (Umbrella's End), all the non-boss enemies that appeared in previous Resident Evil games are used in the final battle against Umbrella: Zombies, Crimson Heads, Lickers, Hunters, Spiders, Eliminators, Leeches, Wasps, Bats, Neptune, Ivy Plants, and so on.

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Comic-book-style animation was used for the intro and outro of each scenario.

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Although Leon does not actually appear, he is referenced several times and is depicted in one of the animations.

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The Raccoon City scenario does not present a direct remake of Resident Evil 3: Nemesis (1999), because the city layout resembles that of Resident Evil Outbreak (2003).

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Considering that this game remakes several Resident Evil games, in the original Resident Evil 3 Nemesis you fight the underground grave-digging worm, but in this game you fight it in the street. The same applies to Nemesis; you fight him on the roof of the police department, whereas in the original you fight him many times across several mutated stages, all the way to the abandoned Umbrella factory.

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The "History of RESIDENT EVIL" library file in Resident Evil 5 (2009) mentions Chris and Jill's mission to destroy the Umbrella Caucasus Research Facility in Russia, where they succeeded in destroying a new B.O.W. known as T-A.L.O.S. This mission is only shown in Umbrella Chronicles, in the "Umbrella's End" scenario (the rest of the game consists mostly of simplified reimaginings of existing games), which makes it part of the game's official canon.

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This is the first Resident Evil in which Albert Wesker is a playable character in the main story, not counting the mini-game in CODE: Veronica and the Mercenaries mode of Resident Evil 4.

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Considering that this game includes a remake of Resident Evil 3, the original Resident Evil 3 Nemesis included both Beta and Gamma Hunter types, but this remake game only has the standard Hunters that appeared in Resident Evil 1.

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This is the only Resident Evil game in which a boss uses laser weapons to attack.

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This is the first Resident Evil game in which you are able to destroy objects: lamps, shelves, doors, paintings, lights, statues, anything perishable in the rooms.

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This is the first Resident Evil in which you have no control over the character's directional movement, and you must go wherever the game wants you to go.

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This game marks the first time a sequel and a prequel have been remade. In history, no film or video game had ever remade a sequel or a prequel, only the first installments.

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