Before SWAN, CHASE, and FRANK, Circuit Judges.
The issues on this appeal are whether claim 2 of the plaintiff's United States Patent No. 2,161,198, granted to it on June 6, 1939, as the assignee of Laszlo Reiner, the applicant, for an "Insulin Preparation" is valid and, if valid, whether it has been infringed by the defendant.
Insulin was discovered by Banting and his fellow workers in 1922. In about a year standard insulin, as later adopted by the United States Pharmacopoeia, which will herein be called insulin, became adequately available for use in the control of diabetes with a resulting marked improvement in the condition of sufferers from that disease. Such insulin need not be described for present purposes further than to say that it is an acid protein sold in a clear solution which cannot be administered orally and is usually injected subcutaneously. It supplements the natural secretions which enable the normal person to digest carbohydrates without having an excessive amount of sugar accumulate in the blood stream, and during the period of its activity proper dosage brings about a sufficiently close approximation to normal conditions to obviate danger and much discomfort from the disease.
Insulin, however, has serious disadvantages, except in emergency use, since its onset is comparatively quick and its effect of comparatively short duration, usually reaching its peak in from three to four hours and becoming practically inactive after four to six hours. The injections have to be repeated at what are often inconveniently close intervals and frequent punctures of the skin are thus made necessary.
Much time and thought have been devoted to the search for a compound with insulin as a base whose effect would be somewhat, though not unduly, delayed after the injection was made and whose effect would be prolonged. In 1935 a Dane named Hagedorn found that insulin could be combined with protamine, a basic protein, to form a solution which would have a reasonably delayed onset and have its activity prolonged throughout a period of about twenty-four hours. In January 1936 he published an article setting forth this discovery. The delayed onset and prolonged action properties of this solution could be adjusted by varying the proportion of insulin to basic protein to suit more nearly the needs of individual patients, and the prolongation could also be effected by choosing a basic protein that would form less soluble precipitates. Hagedorn said in his article, "In order to realize this idea different groups of substances have been tried; kyrin, histones, globines and protamines, but only the last mentioned group have given such solubility results that a clinical experiment has been found justified."
The action of the insulin varies, up to the point of its exhaustion, according to the rate of its dissemination after injection into the body. This rate depends, as Hagedorn made clear, upon the relative insolubility of the insulin compound compared to that of insulin alone, at the pH*fn1 value of the body tissues.He pointed out that preparations of insulin could be given varying rates of onset and duration of activity by combining insulin with other proteins which had a more basic (less acid) isoelectric zone*fn2 than insulin itself. When this was done the acidity of the insulin was modified by the bascity of the other protein in the precipitate; and the compound, being less soluble than insulin at the pH of the body tissues, would be absorbed more slowly and the effect of the insulin in it would be correspondingly lasting.
Hagedorn filed his application for a United States Patent for a "Therapeutic Product and Process" on February 14, 1936, and Patent No. 2,076,082 was granted to him on April 6, 1937, covering his preparation of insulin and protamine.
In March 1936 Bischoff applied for a patent for an "Insulin Preparation" and disclosed in his specifications that prolonged activity and a consequent reduction in the number of necessary injections could be obtained by the addition of a histone to insulin as the precipitant. He published articles on his work in March 1936, and in an article appearing in September 1936 he said that "the histones, being well known as protein precipitants, presented themselves as more or less obvious possibilities." He mentioned thymus histone in his specifications and described the results of tests made with that preparation and also said that "Similar results were obtained with the histone from chicken blood cells." It is not clear, however, whether the last mentioned histone was from the hemoglobin of the blood. This application was granted and the patent issued as No. 2,121,900 on June 28, 1938. Though that was after the date of the application for the patent in suit, the disclosure, if made before the plaintiff's date of invention, is competent evidence so far as it is relevant on the question of priority of invention regardless of what he claimed. Messler v. United States Rubber Company, 2 Cir., 148 F.2d 734; Alexander Milburn Co. v. Davis-Bournonville Co., 270 U.S. 390, 46 S. Ct. 324, 70 L. Ed. 651. The plaintiff has made no attempt to carry his date of invention back of the date of his application and the Bischoff disclosure was before that.
Scott and Fisher combined protamine insulin with zinc, obtained an improved product and in 1936 published a description of what they had done. This preparation was given a wide clinical test in this country during that year and early in the next. They were granted American patents which were assigned to Toronto University, and the defendant became a non-exclusive licensee for the United States under them. It put this preparation on sale in commercial quantities in this country on February 1, 1937.
On the same day Reiner applied for the patent in suit on an "Insulin Preparation" made to overcome the disadvantages inherent in the use of insulin alone by combining insulin with globin or with globin and zinc. He said in his specifications:
"In accordance with the present invention, I have found that quick acting and prolonged lowering of the blood sugar content can be obtained by combining the insulin with globin, the animal protein occurring in hemoglobin, to form labile compounds or compositions from which the insulin is slowly released.
"Human globin is preferred, although globin from other sources, such as ox globin or rabbit globin may be used. The insulin and globin are mixed in proportions adapted to produce the most beneficial results and are used in the form of a precipitate in a suitable electrolyte. The rate of activity of the insulin can be controlled by varying the ratio of globin and insulin and the pH value of the electrolyte, the higher proportion of insulin being adapted to produce a quicker action and vice versa. The pH value is made such that the dissociation or decomposition of the composition and the release of the insulin takes place at the desired rate.
"In some instances zinc may be combined with the insulin-globin composition to increase the activity of the insulin and to assist in producing the desired ...