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Progress in establishing marine protected areas (MPAs) in areas beyond national jurisdiction (ABNJ), commonly referred to as the “High Seas”, remains delayed by three high level challenges: (1) gaps in scientific data and knowledge, (2) lack of international and regional capacity, and (3) institutional barriers. In the present study, we created a new comparative framework based on 11 previous lessons learned that we grouped across these three challenges. We used the framework to compare the policy routes that the regional seas OSPAR Commission took pre- and post-2012 to establish MPAs in ABNJ in order to document uptake of previous lessons and identify any transformative improvements in the policy process. We evidence strong uptake of all 11 lessons and many transformations taking place to overcome challenges in scientific data and knowledge and capacity. Examples of uptake included: using multidisciplinary scientific approaches that overturned the concept of ABNJ being data-poor; multiple concurrent policy drivers that created significant momentum and political will; and OSPAR’s Collective Arrangement with the North East Atlantic Fisheries Commission. Many lessons were interdependent, particularly the need for a clear and transparent science to policy process. Transforming future routes to establishing MPAs in ABNJ needs to recognise these interdependencies and recurrent challenges such as climate change and capacity, and build on transformations including the use of big data and artificial intelligence and the role of regional seas commissions as enablers of cooperation.