A method for determining one or a set of optimal reagent oligonucleotide sequences used in a biochemical method for evaluating a target nucleic acid sequence having a target feature by defining a set of exclusion values or ranking values specific to the biochemical method, generating candidate reagent oligonucleotide sequences, evaluating the candidate reagent oligonucleotide sequences against the exclusion or ranking parameters, selecting at least one optimal reagent oligonucleotide sequence for the selected biochemical method as applied to the target nucleic acid sequence.