The accused infringer may also have a variety of substantive defenses. The most common defenses are non-infringement or invalidity of the patent at issue.

Another substantive defense is inequitable conduct. Inequitable conduct is a very powerful defense because it can render the entire patent unenforceable. An allegation of inequitable conduct usually arises when an accused infringer learns that the patentee had knowledge of a material prior art reference prior to the issuance of the patent but failed to cite the reference. However, since the accused infringer must also establish that the failure to cite was intentional, the standard for proving inequitable conduct is quite high. Accordingly, instances of inequitable conduct are rare.

There are also many other more common equitable defenses, such as laches, estoppel, unclean hands and patent misuse.