Section 103 rejections are the most problematic to overcome. Section 103 prevents granting a patent where the claimed subject matter would have been obvious before the filing date of the claims at issue. In making a 103 rejection, the examiner combines references, taking elements from one reference and adding elements from other references to arrive at the claimed invention at issue.
Due to the fact that the examiner combines references, overcoming a 103 rejection can be difficult simply for the fact that not every element must be present in a single reference. This makes the pool of potential invalidating prior art much broader, and therefore more difficult to avoid.