Defense lawyer Luciano Ghirga said the paperwork was submitted last Thursday to the Rome-based Court of Cassation.
Knox's lawyers had pledged to turn to Italy's top criminal court after a Florence appeals court in January reinstated a lower court's murder convictions of Knox and her Italian former boyfriend in the slaying of Meredith Kercher in Perugia, Italy, where all three were studying.
The defense filed its case after studying the appeals court's written rationale, issued in April, for the convictions.