The problem of non-selective cleavage of all terminators, whether they have been incorporated or not seems to be the most significant one. Is engineering a selective polymerase really the best solution here? If you don't top-up the reaction with un-cleaved terminators, won't the reaction become slower and slower as you go? The ideal solution is somehow have terminators that will only get cleaved after incorporation (maybe due to conformational changes); but I can see how that's probably even harder to engineer than a selective polymerase.

I can see that the complex microfluidics and reagent cycling can be a big added complexity/cost. The continuous process is definitely more elegant, but also seems really difficult to get right for longer read lengths and I wonder if it is really worth it.

What would be the potential benefits of the continuous process? I guess cheaper reagents since it is a one-pot process and faster sequencing speed since you don't need to cycle reagents?