Good question. I think there wouldn't necessarily be a problem if Milan took QftNW around 1650; after he's exhausted Holy War, PrawnStar could just go for the America's himself. Ideally, without prior map spread he would have 50 years to build up his colonial empire before interference. If anyone took QftNW earlier, he would be forced to move. Best option is something like the operation against Novgorod, cutting them down to size in Europe so he wouldn't have to jump ahead in the Americas. But as you and Taylor say, Milan is probably too big for that.
The second option is to intercept or distract explorers. Catch 'em with the fleet while at war or stir up pirates in hopes that they'll return to clean up. Novgorod's turned around to fight pirates, so that might work for a bit.
The third alternative is to start on America earlier than originally planned. England could settle the coasts to prevent others colonizing. Colonial range is a factor. Milan's ports are mostly in Italy and Scandinavia so it might be they don't reach very far. In any case, colonizing the costs to seal off the New World is expensive but not BB-costly if England gets there first. To protect them during war, there is the fleet; again, expensive but it doesn't cost BB as long as Milan doesn't seize a colony. The biggest problem would be to prevent them from taking lands off the native nations. That's exactly the situation in east Africa where Mutapa needs to be sealed off from Brunei, only the American natives' coastline is much longer so it would require more Colonial CB conquests before their proper time.
The closer to 1650, the better the third option looks. With luck, PrawnStar might even make it there. If I'm not mistaken, Milan is not coded as an early or second-wave explorer. The Russians are, as it's usually useful for settling Siberia.