The United States patent examiner was already well enough informed. On November 10 the Collip and Best application was rejected on the ground of there being two prior American patents. By far the most important of these was U.S. patent number 1,027,790, awarded on May 28, 1912, to the researcher who had forestalled them all, Georg Zuelzer! There is no record of Toronto’s reaction to this news. It may have been astonished surprise, for none of Toronto’s publications before this date contains any reference to Zuelzer. If Macleod and company knew of Zuelzer’s work they had forgotten it or not bothered with it. Their next paper about insulin began with a reference to Zuelzer.68
It was possible to pursue the patent application to a higher level. Late in November, Riches represented Toronto at a hearing before the chief American patent examiner, who was impressed, friendly, and helpful. The Torontonians were advised to present all the evidence they could muster regarding the clinical results of their process. Macleod went to Washington to testify. Telegrams and affidavits were solicited from Joslin, Allen, and Woodyatt. Banting asked Charles Evans Hughes to do what he could to have the patent commissioner expedite matters: Hughes obliged with a useful letter to the patent commissioner describing what insulin had done for Elizabeth. Toronto’s amended patent application stressed the major differences between its method and Zuelzer’s, and argued forcefully that neither Zuelzer, who had admitted as much in his patent application, nor any other researcher had been able to produce a non-toxic anti-diabetic extract. Toronto had.* Murlin may have gone to Washington himself intending to contest Toronto’s claim. If so, his effectiveness was more than nullified by the fact that his fellow Rochesterian, Dr. John R. Williams, considered him to be the next thing to a quack and confidentially supplied Macleod and Lilly with inside information undermining Murlin’s claims about his clinical tests.69 As they had promised, Lilly amended their duplicate patent application to remove all conflict with Toronto’s priority.
On January 23, 1923, an American patent on both insulin and Toronto’s method of making it was awarded to the discoverers.70 Before that, however, there had been an important formality. Some months earlier, Lilly’s patent attorney had pointed out that one Dr. F.G. Banting seemed to have played a major role in the invention that Collip and Best were trying to patent. There was a distinct danger of a Collip-Best patent being voided on the ground of their not being the sole inventors, and even of charges of perjury being brought against Collip and Best. Whatever he felt about his Hippocratic oath, Banting’s name simply had to be on the patents. At the formal request of the Insulin Committee, and with assurances that the university would defend him against any criticism, Banting agreed to have his name added to the application.71 The British and Canadian patents, which were non-controversial, were also finally in the names of Banting, Collip, and Best. For a consideration of one dollar each, the three men recognized by patent offices as the discoverers of insulin promptly assigned their patent rights to the Board of Governors of the University of Toronto. The Board assigned the British patent to the Medical Research Council.
There had been no continuing friction between Toronto and Indianapolis in the handling of the basic patent application. At first it seemed as though the “Iletin” question was also going to be resolved. At the end of September, Lilly agreed that the word “Insulin” would be used as the generic name of the pancreatic extract in all the clinical publications, with “Iletin” being used only to refer to the specific Lilly product.72 Then, at the same December meeting with Allen, Joslin, and Toronto’s Insulin Committee which had decided to recommend a reduced unit, Clowes apparently also committed Lilly to abandoning the use of “Iletin.” The Insulin Committee’s minutes record as one of the conclusions of that meeting:
The Eli Lilly Co. will immediately take the steps necessary to discontinue using the name Iletin for their preparation. They will in future use the name Insulin (Lilly). The Toronto committee have given this question much consideration, and they are very anxious that the name Insulin be adopted for whatever product is manufactured with their approval and endorsation.73
Macleod sent a copy of these minutes to Clowes in Indianapolis. Later in January, when Lilly started selling insulin, the product was still named Iletin. The words “Insulin, Lilly” had been added in small print underneath “Iletin” on the label.
Clowes was apparently over-ruled or repudiated on the trade name by the Lilly family themselves. They considered retention of “Iletin” vital to the company’s future handling of insulin.
The Lilly problem as a commercial organization with a major investment to protect was to develop a strategy for maintaining its lead in the marketing of insulin after its head-start period had ended. What would happen when Toronto started licensing other American manufacturers, who might have very small start-up costs compared with Lilly’s very heavy research and development expenditures? Brand or trade names are used in retailing to encourage consumers to distinguish among products, and in the hope of stimulating consumer loyalty to brands they like. The drug industry has been no exception in trying to build markets for products through establishing trusted brand names; and, whether one agrees with them or not, its representatives are sincere in arguing that a brand name is a valuable guarantee of product quality.
The Lilly executives believed that Toronto had accepted this brand-name strategy from the beginning – indeed had supplied the suggestion to call it “Iletin.” They thought Toronto understood the importance of a brand name to the company, and claimed that without such an understanding they never would have accepted a situation in which, after the experimental period, they would be just another licensee.74
The company tried to interest Toronto in alternative approaches. Admitting that it might seem “to a degree selfish,” J.K. Lilly suggested to Clowes that Toronto would get the very best results by licensing only one company in each country to make insulin. That way there would be great efficiencies of scale in manufacture, no competition for raw materials, economy in testing, minimal advertising costs. And no squabble over brand names.75
The idea of giving a private company an American monopoly on insulin was of course unthinkable. J.K. Lilly probably threw it out as a gambit in his struggle over “Iletin,” and, just as important, in the company’s manoeuvring to persuade Toronto to extend its exclusive licence, which would expire on May 30, 1923. As winter changed to spring, Clowes bombarded Toronto with endless letters offering all possible reasons for renewing the licence for another year.
Most were variations on the theme that Toronto was largely responsible for the unforeseen delays in getting insulin on the market. First there had been the hold-ups in the experimental program the previous summer while supplies had to be rushed to clinicians. Now there was the deliberate restraint from distribution, which Toronto had requested, to await publication of the clinicians’ papers and other literature. Lilly had not had time to enjoy or exploit its monopoly, and its whole position would be undercut if Toronto arranged for other American manufacturers to come on the market on June 1. Clowes described the situation very frankly to Defries of Connaught:
…I had always understood that the Toronto Committee realized our predicament and that a tacit understanding existed to the effect that we should be granted an extension of time so far as the experimental period was concerned, sufficient to permit us to expand our output to the point of supplying the entire requirements of the United States for a period of at least a few months, which would enable us to recover our initial expenditures, and, what is far more important, pull the price down to a point at which competition would be unattractive.
… If our competitors were to start level with us without any of our initial costs…we should be severely handicapped. Our only chance to make a good recovery is to have a six months monopoly during which period we supply the entire United States.76
Whatever tacit understanding might have existed, there was nothing in writing to justify an extension. Toronto thought about the situati
on and decided not to extend Lilly’s privileges. “Insistent requests from the manufacturers, the granting of licenses to several manufacturers in England, our published statements, the satisfactory evolution of manufacturing methods are among the reasons,” Macleod wired Clowes.77
The company graciously accepted Toronto’s decision. Probably because it was already playing its trump card: Lilly was applying for a patent on Walden’s method of isoelectric precipitation. This was perfectly allowable within the terms of the agreement. But C.H. Riches believed that the claims in the Walden application were so broadly drawn that if it were accepted Lilly would control totally American insulin production. “In my opinion,” Riches wrote Macleod, “these product claims have been drawn for the deliberate purpose of securing to the Eli Lilly Company a monopoly in the United States of the production and sale of Insulin by any method whatsoever, and conflicts with the policy of the University in doing the greatest good for the greatest number.”78
Toronto had its own trump card to play. In the autumn of 1922 a team at Washington University in St. Louis, led by Dr. Phillip Shaffer, had discovered the isoelectric precipitation method of purifying insulin independently of Lilly. Shaffer’s method might be patentable in its own right; certainly it could be used to interfere with Lilly’s patent application. At a meeting of the Insulin Committee on April 2, it was decided to send Riches and Defries to St. Louis to consult with Shaffer about patenting his method (“it would leave in the hands of the University something to offer to other manufacturers which would put them in a position to compete with the Eli Lilly Co.,” the minutes record rather forlornly, “and at any rate it would show these manufacturers that the University had done all in its power… “). At the same time Toronto decided to inform the American Medical Association’s Council on Pharmacy, which was considering Lilly’s submission of Iletin for approval, that the discoverers themselves did not approve of the company’s use of its trade name. The furthest Toronto would go would be to allow “Iletin” to be used in brackets and in small print after “Insulin.”79
The Canadians found Shaffer convinced that he and his associates, Doisy and Somogyi, were the discoverers of the isoelectric precipitation method. They would oppose the Lilly application if Toronto wanted them to.80 Armed with this consent, Riches and Defries went on to Indianapolis for a showdown with the American manufacturers.
The surrender came in a characteristic four-hundred-word telegram from Clowes to the Insulin Committee:
While we consider ourselves legally and morally entitled under our agreement with committee to take out strongest possible patents on our discoveries and whilst we are not in the least concerned about Shaffers claims as our process is superior to and differs essentially from his and we are satisfied of our priority, nevertheless we would not consider doing anything that might embarrass Toronto University….81
Lilly agreed, in effect, to enter into a patent pool, allowing Toronto to make Walden’s and any of their other improvements available to other licensed American manufacturers. In turn, though, they had exacted a key concession from Toronto. The Insulin Committee agreed to drop its objections to “Iletin” – which were blocking approval by the AMA-so long as the identification “Insulin, Lilly” was given equal prominence on the company’s label.82 In the bargaining in Indianapolis, the Americans had possibly reminded Toronto that flexibility was in both their interests. A breakdown in relations and a patent fight between Lilly, Shaffer, and Toronto could well remove Toronto from the American scene entirely and considerably diminish its glory for the discovery. As it worked out, everyone was satisfied except Shaffer and his colleagues, who soon came to feel that Toronto and Lilly were hogging the glory for the momentous improvements in insulin production.83 At the end of June, a new, non-exclusive licensing agreement was concluded. During this spring of friction and negotiation, the fears of the Lilly people must have been considerably eased when they realized that it would take many more months before Toronto would be ready to license competitors. Lilly’s effective monopoly actually lasted through the second year, for the first of the new American licensees, Steams, did not start selling its insulin until June 1924.
VI
There was a distinct possibility in the spring of 1923 that all of these struggles about patents, licences, and so on, might be sheer wasted time. Toronto and Lilly were making insulin from cattle and pork pancreas. The basic patent had been amended to cover insulin made from fish à la Macleod’s recent work and enthusiasm – though firms located in Indiana and Ontario would be in serious trouble if the best raw material was found in the sea. And the patents did not cover anti-diabetic substances made from other ingredients. Would it be possible to find such substances? Banting and Best had thought that the best proof of the potency of their pancreatic extracts came when they kept the depancreatized dog, Marjorie, alive for ten weeks. In the spring of 1923, in a lab several thousand miles from Toronto, another depancreatized dog was being kept alive for week after week. It was being given injections of an anti-diabetic extract made from onion greens. This extract, named “glucokinin,” actually seemed to work better than insulin. Its discoverer was J.B. Collip.
The trail Collip followed to glucokinin began in Toronto in January 1922, as he reflected on the team’s discovery that its pancreatic extract caused glycogen formation in diabetic animals. “It was predicted by me,” he wrote fifteen months later, “that wherever glycogen occurs in nature a substance somewhat analogous to that produced by the pancreas of higher animals would be found.”84 Among the lower animals a great deal of glycogen could be found in clams (Collip had shown this in earlier work) and at a plant level it was present in yeast and other fungi. Did clams and yeast also contain insulin? Or something like it?
The idea was taken up in Toronto that winter. W.P. Warner, W.B. Dixon, and C.S. Dixon found in yeast a substance that, in several experiments, lowered the blood sugar and reduced the urinary sugar of diabetic dogs. For some reason they chose not to publish their results, and the work was dropped.85 As soon as he got back to Alberta that spring Collip picked it up again. He had clams shipped in from the Pacific coast, made an extract of their tissue using his insulin method, and injected it into rabbits. The extract worked: his rabbits’ blood sugar gradually fell until they suffered hypoglycemic convulsions and died.86
Perhaps because of the expense of getting a clam supply, Collip then turned back to yeast. He tried extract after extract in late 1922, failing every time. Collip was a very frustrated young scientist that winter – deeply embittered by the lack of credit coming his way for the discovery of insulin, harassed by the need to make insulin for diabetic patients in Edmonton’s University Hospital, desperate to get on with his difficult research.87
On January 26, 1923, Collip got his first clearly positive results with yeast extracts,* and quickly began multiplying his findings, using a variety of extracts of both baker’s and brewer’s yeast. At the same time he was rethinking his hypothesis and beginning to wonder whether something analogous to insulin might be present in nature wherever sugar was burned.88 After consulting botanists at the University of Alberta, Collip began experimenting on other plants, starting with the green onion, in quest of the universal hypoglycemic agent.
Collip was not the only researcher working along these lines. In November 1922 the idea of an insulin-analogue in plants occurred to Best and D.A. Scott after a conversation about insulin with Woodyatt. They, too, consulted botanists, and on New Year’s Day, 1923, began work with dahlia tubers and potatoes. Their results were inconclusive. In England, however, another pair of young scientists, L.B. Winter and W. Smith, had been pursuing the yeast question; in mid-February Winter and Smith publicly announced that an insulin-like substance existed in baker’s yeast.
The announcement caused great consternation at the Medical Research Council. Would manufacturers stop work on animal pancreas to await leavening of the yeast situation? Reassuring letters were issued to the manufacturers. Patent appli
cations were quickly amended. There was also consternation on the part of Winter and Smith’s supervisor at Cambridge, the distinguished biochemist F.G. Hopkins. He was not worried about the possibility of unsound science and a premature announcement; instead he was upset that his own students had beaten him to the punch. Hopkins, too, had been getting good results from yeast, but had not been quite ready for publication. “The enterprise of the partners is terrific!” he wrote ruefully. Winter and Smith were already testing their yeast extract on a human diabetic, and seemed to be getting good results.89
Collip had started testing his yeast and onion extracts on depancreatized dogs. In Toronto the news of Winter and Smith’s findings stimulated Best and Scott to try again with their vegetable substances. They made extracts of potatoes, rice, wheat, beetroot, and celery – every one of which lowered the blood sugar of normal rabbits.90
The most extensive of all the “beyond insulin” research had gone on at Lilly in the summer of 1922, where, according to Clowes, they had investigated yeast, fungi, clams, and other marine forms, “in fact every possible source of insulin.” Nothing had worked very well, but now – determined to maintain an advantage, for they were facing a possibility of having to write off their total investment in animal insulin – the Americans were ready to start up again. Clowes wanted to know much more about yeast.91 Macleod was still working on extracting insulin from fish, as were chemists at the Mayo Clinic in Minnesota. There would be immense rewards for the discovery of something better than the insulin now being used. An American newspaper reported in February 1923, that “the race to discover the source of quantity production of insulin…is going on in every medical centre in the U.S. and Canada.”92
The Discovery of Insulin Page 25
