He won a decision against the company on April 9, 1903, and a confirmation of the judgment on March 14, 1904. While attorney general, Knox was sent to Paris to examine the title of the New Panama Canal Company, successor of De Lesseps' company, which had offered to sell its property and interests in the Isthmus to the United States for $40 million. Upon his certification of clear title, the offer of the French company was accepted. He drafted legislation which created the Department of Commerce and Labor in 1903, and was partly responsible for drafting that giving the Interstate Commerce Commission effective control of railroad rates.
On June 10, 1904, Governor Pennypacker of Pennsylvania appointed Knox to fill the vacancy caused by the death of U.S. Senator Matthew S. Quay. He took his seat on July 1 and subsequently was elected for a full term of six years. As senator, he was active and influential, especially in railroad-rate legislation; he served on the judiciary committee, took a prominent part in the Panama Canal tolls debate, and, for a time, was chairman of the committee on rules. He resigned the senatorship on March 4, 1909, and became secretary of state under President Taft, with whom he had formed an intimate friendship which continued through the Roosevelt-Taft feud until Knox's death.
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