How often can they apply a fine of that amount?

If they can apply it yearly, they can fine 2.2 billion per year, which is over a third of Qualcomm's 5.3 billion per year profit.

Sure it's a simple napkin calculation, but as long as the napkin calculation comes out to "not worth it" that's fine.

Source for numbers: http://markets.businessinsider.com/stock/QCOM/financials

Well yes, but that's only a fine, I'm sure there are other legal means (i.e. voiding business license) for those who refuse to comply with a law continuously.

How it went down with Microsoft was cumulative fines as time goes.

I wondered what the ultimate reason was for Microsoft to bow down and apply the required changes to windows, but I imagine being labeled as a recurent law breaking business might have a lot of side effects.

At a very small scale, I knew engineers that didn’t want to apply for MS jobs because of that. I wonder if individual states or other regulation agency also would change their stance regarding a company once behavior change requested by the EU are ignored on a regular basis.

How would that work with a company like Qualcomm, that doesn't sell directly to consumers, and whose products are embedded in devices manufactured outside the EU? Technically, wouldn't it only be doing business with Apple?

Revoke the EU certification for the specific devices they manufacture