I may be joining this late. I play on the app, randomly generated games, but usually avoid like the plague any random game with Spite as villain. I agree with the commentators who say that he's simply frustrating, rather than fun/challenging. So, whenever I get P.O.ed and really want to whip him, I put together this team, custom-designed to beat Spite: Dark Visionary, Legacy, Wraith, Tempest. If I'm feeling really malignant, I add AA, Nightmist, Tachyon, or DW Fixer.
Spite's two big weaknesses are (1) that he doesn't have any minons/devices/other targets to help him cause damage, so if he can't cause damage or play cards, he's in trouble; and (2) one of his drugs kills the environment cards that would otherwise be damaging the heroes. So, the purpose of this team is to (a) manipulate/play Spite's deck like a bass fiddle, all the while (b) preventing him from doing damage, while leisurely setting up damage combos.
First, it sounds awful, but don't worry about the victims. They are there to distract you, and to make you spend HP and cards that you should be saving. Besides, with the method below, you'll be able to manipulate Spite's deck enough that he won't be able to pull the Forced Entries/On the Prowls necessary to kill them, and if you're feeling really squeamish, use Suggestion to pull them out of the trash and save them.
(a) Deck Manipulation. Look at all of the ways you have to manipulate poor Spite: Dark Visionary's base power, her Precognition and Suggestion cards, Wraith's Infrared Eyepiece(s), Legacy's Take Downs, and Tempest's Into the Stratosphere. From the very first play, these characters have infinite ways to stop Spite from drawing, push bad cards to the bottom of Spite's deck, and bring back destroyed victims. Spite's double-draws don't make it a 100% sure proposition, but you can generally avoid the worst cards and put them all on the bottom of his deck, or if that fails, at least know that they're coming and prepare for them. Once you have out Wraith's Infrared Eyepiece, you can peek at Spite's deck twice every round and send Omicron/Upsilon/Lab Raid/whatever cards to the bottom.
(b) Damage Reduction. Getting a Twist the Ether on Spite itself just about seals his fate -- reduce *every* damage he deals by 1. Combine that with Smoke Bombs, Stealth, Throat Jab, Fortitude, Unearthly Resilience, Decoy Projection, (even Telekinetic Cocoon, if you're really desperate), Heroic Interruption, Stun Bolts....Spite isn't hurting any of your team members. Put a Next Evolution/Lead from the Front on Legacy, and he will eat most of Spite's damage and laugh at it. Add a Twist the Ether, and now Spite cannot deal a single point of damage to any of your players--he has NO cards that do damage by themselves (they all say "...Spite deals X damage..."). If things turn really dire, send all of the damage you can to Tempest -- his incap power makes all heroes immune to one type of damage. Use that on whatever form of damage is making it through your Stun Bolts/Smoke Bombs, and the like. Since he'll be killing most of the environment cards if you let him play the Mind-Phyre drug, the environment won't be hurting the heroes much either. (In that vein, though, between Grappling Hook, Flash Flood, Dark Visionary's innate power/Prophetic Vision to manipulate the environment deck, her Mass Levitation to stop its damage, and Tempest's Reclaim from the Deep to bring back/spam your anti-environment cards, the environment won't be much of a problem in any event.)
Once you've accomplished (a) and (b), which should be reasonably painless with these heroes and their decks, Spite will not be able to (a) pull out his nasty drug cards, or (b) heal (since he can't deal damage), and you can start wiping the floor with him. Keep having Legacy and DV use their powers every turn to tank Spite's damage and control his deck (and occasionally throw in a bit of damage or buffs themselves), while Wraith and Tempest hit him with buffed Razor Ordinance, Gene-Bound Shackles, Lightning Strikes, Chain Lightnings, Ball Lightnings, Localized Hurricanes. Getting a Legacy Ring and/or Inspiring Presence only makes things faster. At this point, you can even let him bring out drugs; since he can't hurt you, he can't heal, and you should have out enough cards to be able to withstand his "return equips/ongoings to your hand" drug. Just keep beating on him, and you should be able to kill him before he flips.
If you're feeling particularly malignant, add in:
Argent Adept -- being able to play 2-3 (or more) extra cards every round lets you find and play your deck manipulation and damage reduction cards that much quicker. If Spite should happen to get out the "everybody discard 5 cards when they use a power" drug, AA has four Vernal Sonatas in his deck, as well as 4 Arcane Cadences to allow you to get teh him to access them.
Nightmist -- Enlightenment gives your heroes extra draws to get to their combo cards, Mistbound completely shuts down Spite's deck, the Amulet of the Elder Gods can redirect his damage right back to him, and Nightmist's versatile healing powers give her a variety of ways to heal herself every round and serve as a tank. Or, put her in MistForm and make her the ultimate tank.
Tachyon -- adds additional damage elimination/redirection with Hypersonic Assault/Synaptic Interruption, and her ability to auto-churn her own deck means that she'll almost assuredly get to those cards quickly, while she waits to for the chance to use some 15-20-point Lightspeed Barrages.
DW Fixer -- particularly helpful when Spite has managed to get the DR drug (Omicron whatever) into play despite your best-laid plans. Unlike regular Fixer, he can play Riveting Crane/Alternating Tiger Crane as 3-pt one-shots that should break through Spite's defenses and/or leave him vulnerable to your heroes. Grease Gun gives all of your heroes a round (more, if Tempest brings it back with Reclaim from the Deep, or Fix himself brings it back with Salvage Yard) of near-total immunity from and the environment. Driving Mantis makes him a damage soak, particularly in conjunction with Pipe Wrench, Smoke Bombs, and/or Stun Bolts. If you get a good enough draw, and can get him set up with Grease Monkey Fist/Harmony/Pipe Wrench or Dual Crowbars, he becomes a damage fiend. The "discard 5 cards when you use a power" drugis just fodder for Salvage Yard -- build up a trash of 10-15 cards, then use Salvage Yard and bring *every* equipment in the trash not just to your deck, but into your hand. The "return ongoings/equipment to your hand" doesn't matter much to him, since he can do three damage whenever he wants just by burning the card with a Bitter Strike, so build him up with ongoings and make him an early target for that drug while your other heroes play their cards. (Also, it's just mean; I have to confess to taking great joy at the idea of Mr. Fixer bludgeoning Spite to death with a crowbar. "Transhuman killer, huh"?" (WHACK!) "Drug-wracked monstrosity, eh?" (CRUNCH!))