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Mr. Tinkles contracts a Russian Blue mercenary named Dimitri Kennelkoff, who tricks Lou and places a bomb on Brody's lab door. Kennelkoff battles Lou and Butch, damaging the Brodys’ house until Butch disables the bomb and captures Kennelkoff. During interrogation, the dogs recover a note by Mr. Tinkles from Kennelkoff's stomach.
After a breakthrough involving Lou playing with Scotty, Charles' machine finally finds the formula to a cure for human allergies to dogs. Having bugged the house, Mr. Tinkles and Calico spring a trap for the Brodys. First, Mr. Tinkles travels to a Christmas tree flocking plant under the guise of the plant's comatose owner, Mr. Mason, and sends the employees home, then lures the Brodys with faux tickets to an exhibition game between Uruguay and Chad, capturing the family.
The dogs receive a video from Mr. Tinkles demanding Charles’ research as a ransom for the Brodys, and dogs around the world assemble at a meeting led by the Mastiff. When the assembly decides not to surrender the formula, Lou confronts Butch. Revealing that he was abandoned by his owner, the unsympathetic Butch leaves Lou behind. Desperate, Lou brings Mr. Tinkles the research and is double-crossed. Butch, realizing what has happened, stages a raid of Mr. Tinkles' factory where mice are being prepared to spread the mass-produced allergy.
While Butch, Ivy, Peek, and Sam fight Tinkles' cat forces, Lou frees the Brodys and Calico, who was betrayed by Tinkles, revealing to the family that he can speak. Lou defeats Tinkles but is struck by an excavator as an explosion destroys the factory. Butch rescues the seemingly dead Lou, tearfully admitting that Lou was right to love his adoptive family, and Lou awakens. He decides to return to a normal pet's life with the Brodys until he can serve as a full-grown agent.
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