If quick high-resolution referencing (page x, yth paragraph, zth line) is necessary, I think the way to handle it is to reference a phrase on that line ("the cat ran"...), which the reader can search for. If the search interface is lacking, that's an epub reader failure, not a format failure. Or, if the search option is considered insufficient (it does require typing with a [virtual] keyboard), paragraphs can be numbered—as many ancient works or works in translation already are, because such works have many editions and can't be layout-exact copies of each other.
If paragraph referencing is necessary, visibly styling the paragraphs with numbers helps dramatically. There's no reason it has to be exclusive to high-profile ancient or classical works, like Plato [1].
Classic poetry and plays, where referencing needs to be most exact and fast, already tend to give up any hope of everyone using the same edition, and simply avoid flowed text and then number the lines.