Internal input overvoltage protection
ESD diodes can be a drag

You are correct that U2 can be powered this way -- I've seen this before when trying to hook programming cables up to otherwise unpowered circuit boards, aggravated by the typical order of connections where GND is connected first and disconnected last.  While it won't necessarily trigger latchup as C2 will be mostly charged when the Vcc is turned back on, it can be quite aggravating as U2 may run when it shouldn't.

There are a couple possible fixes.  If U1 and U2 are on separate boards, mating the GND connection between the boards last works around this problem -- it's what I did to avoid this for things like programming cable hookups.  If U1 and U2 are on the same board, or the connector mating order needs to be GND-first, a suitable isolator (if this is a low speed digital signal, a jellybean 4N35 optocoupler and its associated resistors will do the job) will break the power path up as long as the output side supply/pullup is wired to U2's Vcc supply.  (In the two-board case, this means it goes on the same board as U2.)