The FDA will still give you regulatory exclusivity if you get an off patent drug approved in a new indication.

https://www.fda.gov/drugs/development-approval-process-drugs...

Orphan drug exclusivity is 7 years. The FDA will not approve a generic version of that drug for the same indication for 7 years after your approval.

Of course the challenge is that doctors are free to prescribe whatever they want, including compounded versions of your drugs.

There are ways around it (formulation), but it's not like there is no option at all if you don't have a patent.