THE FIRST SYNTHESIZED ORAL CONTRACEPTIVE: ORIGINAL U.S. PATENT OFFICE PRINTING OF PATENT #2,744,122, FOR NORETHISTERONE, USED BY GREGORY PINCUS IN CLINICAL TRIALS AND EVENTUALLY MARKETED AS ONE OF THE FIRST BIRTH-CONTROL PILLS IN THE UNITED STATES
DJERASSI, Carl; MIRAMONTES, Luis and ROSENKRANZ, George. United States Patent Office 2,744,122. Patented May 1, 1956. Delta4-19-NOR-17alpha-ETHINYLANDROSTEN-17beta-OL-3-ONE and Process. [Washington, DC: United States Patent Office, 1956]. Quarto (7-1/2 by 11 inches), single leaf of wove paper printed on recto and verso for two pages; custom card portfolio. $12,500.
Rare original United States Patent Office printing of patent number 2,744,122, the patent for norethisterone, the first synthesized oral contraceptive, developed from Mexican yams by a team of chemists led by Carl Djerassi in 1951, and one of three synthesized oral contraceptives used by Gregory Pincus—with whom Djerassi shares the title of “the father of birth control pill”—in early clinical trials.
Djerassi started working at the small pharmaceutical company Syntex in Mexico City in 1949. There he established how to synthesize cortisone from a natural product derived from the Mexican yam. He then found that the same starting compound could yield norethisterone, a mimic of progesterone, which controls the female menstrual cycle. Norethisterone was the first highly active oral progestogen to be synthesized, followed soon after by noretynodrel (1952) and norethandrolone (1953), which were synthesized by Frank B. Colton at Searle in Skokie, Illinois.
In early 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of the Worcester Foundation for Experimental Biology (WFEB) in Shrewsbury, Massachusetts, first met American birth control movement founder Margaret Sanger at a Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood. Stone helped Pincus obtain a small grant to begin hormonal contraceptive research. Unbeknownst to Pincus, Sanger and Stone, the actual chemistry of the Pill had already been invented, but neither Djerassi nor the obscure Mexico City lab where he worked had tested their orally effective form of synthetic progesterone as a contraceptive. Pincus’ research started on April 25, 1951, with reproductive physiologist Min Chueh Chang continuing the 1937 experiments of Makepeace, et al. which showed that injections of progesterone suppressed ovulation in rabbits.
Progesterone was abandoned as an oral ovulation inhibitor following these clinical studies due to the high and expensive doses required, incomplete inhibition of ovulation, and the frequent incidence of breakthrough bleeding. Looking for an alternative, Pincus asked his contacts at pharmaceutical companies to send him synthetic chemical compounds with progestogenic activity. Chang screened nearly 200 chemical compounds in animals and found the three most promising were Djerassi's norethisterone [the present patent] and Colton's noretynodrel and norethandrolone.
Ultimately Pincus and Rock selected Colton's noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Djerassi's norethisterone very slight androgenicity in animal tests. When combined with mestranol, noretynodrel was given the proprietary name Enovid, which went on to become the first oral contraceptive marketed as such in the United States in 1960. Both Enovid and Norlutin (norethisterone) were approved in the U.S. for gynecological disorders such as endometriosis as early as 1957, and both were used off-label for birth control purposes. While Enovid was the first to be marketed as a birth-control pill, norethisterone—when combined with mestranol—was named Ortho-Novum in the United States in 1963 and prescribed for birth control, making it the second progestin after Enovid to be used in an oral contraceptive.
While both Pincus and Djerassi have alternately been called “the father of the birth control pill,” Djerassi was among the earliest of scientists to pioneer the chemical bases of what would become the Pill, and he would be the first to gain national recognition for his contribution. He was inducted into the National Inventors Hall of Fame in 1978 for patent 2,744,122 (this one). Colton was inducted a decade later in 1988 for patents 2,691,028; 2,725,389. Pincus was inducted nearly three decades later in 2006 for 2,666,015. By chemically synthesizing a steroid mimic of the hormone progesterone, Djerassi paved the way for the oral contraceptive pill, allowing women for the first time to safely and reliably take control of their own reproductive choices. Djerassi's conviction that the Pill made the sexual liberalization of the 1960s possible is widely shared, and chemical control of the fertility cycle was a key ingredient in subsequent advances in reproductive technologies, beginning with in vitro fertilization (IVF) in the late 1960s.
This is an original Patent Office printing, contemporaneous with the issuance of the patent. After copies of the first official printing had been exhausted, later printings would be a photocopy; the present document is printed and thus original.