Chemical & Engineering
NEWS AUGUST 15, 1966
The Chemical World This Week The pill—generally safe, but! The eagerly awaited Food and Drug Administration report on oral contraceptives issued this week has at least one factor in common with the mating game: Things are fine at the start and the future might look good; but the real test is over the long haul. This is the more-or-less expected conclusion reached by the 13-member Committee on Obstetrics and Gynecology assembled last winter by FDA. The committee ended its eight-month study by affirming the general safety and efficacy of such compounds but falling far short of giving them a clean bill of health. "In the final analysis," concluded the committee (headed by Dr. Louis M. Hellman, chief of obstetrics and gynecology at the Downstate Medical School, Brooklyn, N.Y.), "each physician must evaluate the advantages and the risks of this method of contraception in comparison with other available methods or with no contraception at all. He can do this wisely only when there is presented to him dispassionate scientific knowledge of the available data." The last sentence contains the rub. For while the committee finds "no adequate scientific data" showing direct cause-effect connection between the pills and cancer and blood vessel abnormalities, they raise questions over various metabolic effects on patients and their offspring. In the words of the panel: "The committee has taken full cognizance of certain very infrequent but serious side effects and of possible theoretic risks suggested by animal experimental data and by some of the metabolic changes in human beings." So what the 13 experts call for is a drastically stepped-up research and surveillance program involving FDA, industry, and physicians. The metabolic effects section could indeed be looked on as the most pertinent section of the report. After accepting what has been the controversial theory that the compounds work by inhibiting synthesis or release of the luteinizing hormone by the pituitary gland, the panel agrees that the patient's menstrual cycle returns to normal in four to eight weeks. Then comes the caution:
"There are, however, no prolonged followup studies to ascertain the growth and development of infants born after cessation of therapy." As for long-term effects on the woman herself: "The effects of prolonged suppression of ovulation are unknown and require further investigation." Such statements are not designed to silence the critics of this type of birth control. Diabetes receives full attention on the basis of current carbohydrate metabolism data. While many of the results have been contradictory, the committee shows concern over certain studies that point to definitely diabetogenic effects of the oral contraceptives. In some of those studies, abnormal glucose tolerance tests turned up in 40% of the women taking the pills. Women with family histories of diabetes had even higher levels. Other studies have shown no such consequences. Nevertheless, "Adverse effect of the progestins upon carbohydrate metabolism reported m several recent communications indicates a potentially serious problem, if valid." The panel puts forth an outline for a group-oriented control study taking into account the general unknowns about diabetes metabolism. Perhaps the most serious cautionary note concerns effects of the drugs on masculinization of the female fetus. The committee says clear evidence exists that the agents malform the genital tract of fetuses exposed to the drug during the first 16 to 18 weeks of
gestation. Mothers haven't been harmed, but evidence for masculinization of offspring is called "unequivocal. These anatomic abnormalities are correctable, but the effect upon subsequent reproductive functions and psycho-sexual development is unknown." The committee also discussed studies reporting eye complications, migraine headaches, lactation inhibition, liver abnormalities, and gland functions. Effects in each area are considered minor for the general population of women, but in no case should the research door be closed. Drug makers should be happiest over the committee's comments on thromboembolic disease, cancer, and efficacy. Oral contraceptives first came under fire for allegedly causing blood clots in veins. After a look at every available source of data on the subject the committee concluded that "If oral contraceptives act as a cause [of thromboembolic disease], they do so very infrequently relative to the number of users." One study, in fact, showed lower incidence of such problems among oral contraceptive users than among the general population. But the committee attributed this to underreporting of adverse reactions by physicians. For uterine, cervical, and breast cancers, the committee played down the carcinogenic effect of oral contraceptives on humans. But, significantly, it did note high incidences of carcinogenesis in animals given large doses of the hormones. While ani-
Committee studying oral contraceptives recommends: • A large retrospective study of drug's possible relation to thromboembolism • Additional controlled population-based prospective studies • A review and strengthening of FDA's mechanism for storing, retrieving, and analyzing surveillance data • A conference between FDA and drug makers to improve data reporting • Labeling uniformity • Dropping the time limit on administration AUG. 15, 1966 C&EN
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mal results cannot be transferred directly to human beings, "There is, nevertheless, a warning that an altered endocrine environment in human tissues might result in an abnormal expression or potentiation of growth, as in experimental animals." The committee gave the compounds an A— for efficacy in controlling fertility indefinitely. But it differs with claims for success in treating menstrual abnormalities. "Cyclical bleeding," a term often used by manufacturers to mean menstrual regularity, should not be construed as such, the committee notes. FDA hopes the report will not silence critics of the oral contraceptives. It prefers that the report widen the dialogue. "There's every indication," an FDA spokesman notes, "that the agency is happy with the report and is currently working to put the recommendations into effect." The report criticizes FDA for: too little feedback of data to manufacturers of pills submitted to the agency; not having investigational guidelines for the benefit of manufacturers; and unreliable data retrieval among offices within FDA (the agency's various files, for example, contain different figures for the number of deaths among women taking the pills).
Laser patent valid For the second time Gordon Gould's challenge to the validity of the basic patent on the laser has been rejected. The U.S. Court of Customs and Patent Appeals has upheld an earlier decision of the Board of Patent Interferences awarding the patent to Nobel Laureate Charles H. Townes and his brother-in-law Dr. Arthur L. Schawlow. Dr. Townes and Dr. Schawlow hold U.S. Patent 2,929,922, the basic patent on the laser. This patent, issued on March 22, 1960, on an application filed July 30, 1958, was assigned to Bell Telephone Laboratories. Mr. Gould's application for a patent on the laser was filed on April 6, 1959, and was assigned in 1960 to TRG, Inc., a subsidiary of Control Data. In November 1957, the time Mr. Gould claims he conceived the laser, he was a graduate student in physics at Columbia and also worked as a research associate in the Columbia Radiation Laboratory. At this time, Dr. Townes was a professor of physics at Columbia and served as a consultant to Bell Labs. Dr. Schawlow was a research physicist at Bell Labs. According to the court, both Dr. Townes and Mr. Gould rely on the dates of filing patent applications (July 30, 1958, and April 6, 1959) for 20 C&EN AUG. 15, 1966
Nobel Laureate Townes U.S. 2,929,922 upheld
"constructive reduction to practice" of the invention; neither party claims actual reduction to practice before these dates. Under such circumstances, the court says, well-established interference law requires the junior party (Mr. Gould) to prove, by a preponderance of the evidence, two things: conception of the invention before July 30, 1958, and reasonable diligence in reducing the invention to practice from a time just prior to this date to his filing date of April 6, 1959. The board ruled that Mr. Gould had failed to prove either conception or diligence and the court upheld the board's ruling. To prove his earlier conception of the laser, Mr. Gould relied on data in a bound notebook. The pages in the notebook relative to the subject were witnessed by a notary public on Nov. 13, 1957. To operate successfully, the sidewalls of a laser must be "transparent to the pumping energy and transparent to or absorptive of the other energy radiated thereat/' the court says. Mr. Gould concedes that his notebook does not state this in so many words but he claims that even a relatively untrained layman could see that the apparatus would have to be constructed that way. Mr. Gould also submitted testimony from experts that the description was sufficiently clear that anyone of ordinary skill could build a laser. Dr. Townes also introduced expert testimony that the notebook did not disclose enough information to permit this. In the court's opinion, the information in Mr. Gould's notebook could be interpreted in several plausible ways as to what he actually had in mind when he made the entries. As a re-
sult, the court ruled that Mr. Gould's notebook "is too ambiguous to justify the conclusion that he possessed a definite and permanent idea of the complete and operative invention or that he made his invention sufficiently plain to enable those skilled in the art to understand it." Since the court had decided that Mr. Gould had failed to prove his case for prior conception of the laser, it could have turned down the appeal right there. However, it went on to consider whether Mr. Gould had been reasonably diligent in reducing his conception to practice. Summarizing his activities from November 1957 to December 1958, Mr. Gould estimated that he spent about 1000 hours acquiring the knowledge which enabled him to develop the laser. During this period there were no months or weeks in which he did not work on the laser. "In our view, Gould's testimony taken as a whole does not set forth adequate facts to support a finding of that continuity of activity which constitutes reasonable diligence," the court says. Even without corroboration, the court finds that Mr. Gould's testimony is not enough to establish adequately what he did and when he did it. Little effort has been made to identify particular activity during the critical period—July to December 1958—or to establish how such activity related to reducing the invention to practice. Merely stating that there were no weeks or months that he did not work on the laser is not enough without supporting facts to show specifically what the work consisted of and when it was performed, the court says. "While we do not depreciate the amount of time complex theoretical work of this sort might require," the court says, "the total period of time sought to be blanketed by [Mr. Gould's] notebook is great—on the order of 13 months—and we have no way of satisfying ourselves that unexplained lapses have not occurred." The only avenue of relief left for Mr. Gould is an appeal to the Supreme Court. So far, he has not indicated whether he will pursue the matter further.
FTC order hits joint firms The Federal Trade Commission's first antimerger order concerning joint ventures will dissolve all of the joint ventures between Phillips Petroleum and National Distillers & Chemical within 90 days. The two major ones are Alamo Industries (polypropylene) and A-B Chemical (polyethylene); two others are in Europe. The four
