definiens: means a Change of Control that closes prior to achievement of the Third Milestone in which the Changeof Control Acquiror ( or its Affiliate, if applicable ) agrees in writing to submit the P188 NDA to the FDA for FDA Approval ( or, ifthere are unexpected safety or regulatory issues, to conduct activities to address or resolve such issues ) until the earlier of ( x ) the datethat, beginning at the Effective Time and thereafter, the aggregate expenditure related to the program involving the Target Producton which the P188 NDA is to be based is at least $ 15,000,000 ( the ) and ( y ) the fourth ( 4th ) anniversary ofthe Effective Time ; provided, however, a Triggering Event shall relieve the Change of Control Acquiror ( or its Affiliate, ifapplicable ) of such obligations . The Aggregate Expenditure shall be reasonable and shall consist solely of direct costs related to theprogram involving the Target Product and shall include out - of - pocket expenses incurred by Acquiror and the Change of ControlAcquiror ( or its Affiliate, if applicable ), as well as expenses of employing individuals to the extent their primary functions are tocontribute to the programs involving the Target Product . For clarity, reasonable expenses incurred or realized in connection withaddressing or resolving a safety issue related to the Target Product would be considered expenses related to the program involvingthe Target Product