In his youth, Norman befriended Otto Octavius during his years in grad school. Together, the two eventually started a business company known as "Oscorp". However, as Norman became more and more obsessed with genetics, particularly a substance called Devil's Breath, the two had a falling out and Otto left Oscorp.
At some unknown point in time, Norman Osborn was elected mayor of New York. Despite this, Osborn was also known for his generally dishonest and condescending nature, as Peter Parker notes of him in his character bio.
Norman appeared in-person when he has his team shut down Otto Octavius' and Peter Parker's lab and cut his funding, due to the site being declared a safety hazard due to a recent accident. Otto insists his previous safety violations were excused, by Norman reminds him that he was the one who excused it and that Otto's equipment should have been confiscated long ago. Norman insists both Otto and Peter work at Oscorp from then on, but Otto rejects his offer.
Later, Norman is seen awarding Officer Jefferson Davis for his bravery and years on the police force until he receives a call from Mister Negative, warning Norman of an incoming attack. Norman escapes immediately before the Demons attack the ceremony, killing many civilians, including Jefferson Davis.
In the aftermath of the attack, Miles Morales, the son of Jefferson Davis, joins F.E.A.S.T. as a volunteer, meets Peter, and quickly befriends him. At the same time, Osborn hires mercenary Silver Sable and her team to take down the Inner Demons. Sable does not trust Peter and constantly makes things difficult for him. Peter continues to pursue Mister Negative and the Inner Demons, discovering that Li has a grudge against Osborn and seeks to steal the Devil's Breath, a bioweapon Osborn inadvertently created while searching for a universal cure for disease. Li manages to steal the Devil's Breath and attempts to deploy it in Grand Central Station, but is foiled by the efforts of both Peter and Mary Jane. Li is subsequently arrested and sent to the Raft, a high-security prison.
Norman denies all wrongdoing and goes as far as to hire Silver Sable and her mercenaries for protection. After Martin Li is apprehended by Spider-Man, he claims credit and encourages the citizens of New York to vote for him in the incoming relection, and this enrages a now unhinged Otto Octavius, who blames him for his financial burdens and stealing his research.
He dons the mantle of Doctor Octopus and frees the convicts from prison, forming the Sinister Six and enlisting their help in dismantling Norman and his empire. Octopus eventually captures Norman himself, intent on forcing him to confess to his crimes. When he refuses, he is thrown from the top of Oscorp Tower, but is rescued by Spider-Man.
Sometime later, Norman resigns from office and is seen in his secret lab, looking at his son Harry. Rather than being in Europe as everyone believes, Harry has been put into a coma until his father can find a "cure" for his illness.
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