So, with a POD from 1800 onward, have at least one Regional Party in the United States with at least 3 Seats in the House and one in the Senate.
The Party cannot be a Protest or Splinter Party, but instead has to be a party rooted in the Region and with a Multicycle presence in Congress, in at least one State Government and on the ballot.
Bonus points for the Party being powerful enough to Require a coalition in one of the legislative Houses. (This could be as simple as the Senate being split 49-48-3.)
And yeah, is this plausible, or would the American 2 Party System essentially prevent it from becoming a long term thing?