Merck & Co. v. Olin Mathieson Chemical Corporation

• Citation: 253 F.2d 156
• Decision Date: 03 March 1958
• Docket Number: No. 7473.,7473.
• Parties: MERCK & CO., Inc., Appellant, v. OLIN MATHIESON CHEMICAL CORPORATION, Appellee.
• Court: United States Courts of Appeals. United States Court of Appeals (4th Circuit)

253 F.2d 156 (1958)

MERCK & CO., Inc., Appellant, v. OLIN MATHIESON CHEMICAL CORPORATION, Appellee.

No. 7473.

United States Court of Appeals Fourth Circuit.

Argued October 18, 1957.

Decided March 3, 1958.

Stephen H. Philbin, New York City (Woods, Rogers, Muse & Walker, Roanoke, Va., Frank W. Rogers, Roanoke, Va., E. Cummings Sanborn, Frank M. Nolan, New York City, on brief), for appellant.

John T. Kelton, New York City (William A. Stuart, Abingdon, Va., Leonard A. Watson, Elmer R. Helferich, New York City, Robert Alpher, New York City, on the brief), for appellee.

Before PARKER, Chief Judge, and SOBELOFF and HAYNSWORTH, Circuit Judges.

HAYNSWORTH, Circuit Judge.

This is a suit upon the product claims of patent No. 2,703,302, entitled "Vitamin B12-Active Composition and Process of Preparing Same," issued to Rickes and Wood, assignors of the plaintiff, Merck, on March 1, 1955, upon an application dated December 8, 1952¹. The District Court held the product claims invalid, upon the grounds that they covered a "product of nature" and that there was lack of invention. Merck & Company, Inc., v. Olin Mathieson Chemical Corp., D.C.W.D.Va., 152 F.Supp. 690.

We are not here concerned with the process claims of the patent, for they were voluntarily withdrawn from the case when it appeared that, while the defendant through its E. R. Squibb & Sons division markets the accused products under the trade name "Rubramin," it purchased the B12 active materials from another manufacturer of pharmaceuticals. We are concerned with the three product claims, which are identical except that the minimal active strength is specified in the three claims, respectively, as 440, 1500 and 65,000 LLD units per milligram.

Claim 1 is in the following language:

"1. A vitamin B12-active composition comprising recovered elaboration products of the fermentation of a vitamin B12-activity producing strain of Fungi selected from the class consisting of Schizomycetes, Torula, and Eremothecium, the L.L. D. activity of said composition being at least 440 L.L.D. units per milligram and less than 11 million L.L.D. units per milligram."

In 1926 it was found that pernicious anemia patients were benefited by the addition to their diets of substantial amounts of the liver of cattle. In the succeeding twenty years intensive efforts were made to isolate and identify the substance or substances in liver responsible for the anti-pernicious anemia effect. The search was hampered by the fact that new extracts and concentrates of liver could be tested only by administration to a pernicious anemia patient in relapse. Nonetheless, by 1947 a number of liver extracts and concentrates were available and their relative anti-pernicious anemia potencies had been determined and measured by clinical tests. While those liver preparations were not ineffectual in the treatment of pernicious anemia in most of the cases, they were expensive and some patients were unable to tolerate them.

Though liver fractions of some practical utility had been developed, the medical and scientific worlds remained quite ignorant of the nature of the anti-pernicious anemia principle. There were those who thought it to be a hormone. This seemed logical since it was found in the liver of cattle, and, by definition, a hormone is, while a vitamin is not, produced in the body of the animal. Thus, many believed that pernicious anemia resulted when the individual failed to synthesize the substance within his own body. Others speculated that it might be a vitamin produced by autolysis in the body of the animal after its death. Tests, however, indicated no relation between the liver fractions and vitamins then known. That it could not be a B vitamin was suggested by a test in which the known B vitamins in liver were concentrated, after which the anti-pernicious anemia principle was found to have been left in the filtrate. A group of investigators, observing that continued purification sometimes produced a reduction in potency which could be restored by the addition of inactive materials, concluded that the principle was a combination of several factors or, at least, one primary hematopoietic factor, the activity of which was augmented by the presence of at least three accessory factors. Still others were led by their investigations to conclude that there were two primary factors, one of which, alone, was responsible for the observable reticulocytosis in the patient, while the other, in combination with the first, led to erythropoiesis and the cure of the patient². Most of these divergent theories and opinions were based upon known postulates, and there was support in scientific data for most, or all, of them. Still, no one knew what the substance was. In 1945, Dr. SubbaRow and his associates, after reviewing all of the current learning, could conclude only, "It is, unfortunately, apparently not possible at the present time to reconcile the various claims and facts regarding the material or materials which are present or capable of extraction from liver, and which are therapeutically active in pernicious anemia."

In a quite different field, during the first half of the last decade, a scarcity of alfalfa leaf meal for use as a supplement in poultry feeds prompted a search for substitutes. Experiments revealed that, in sardine fish meal, in dried cow manure and in the dried contents of the rumen of cows, there was an unknown and unidentified nutrient which greatly stimulated the growth of chicks and the efficiency of their feed utilization. It also reduced their mortality. It was established that this "animal protein factor" was not one of the previously known chick growth factors.

It does not appear that the discoverers of the "animal protein factor" experimented with liver or liver products, but Rickes and Wood recited in their patent that liver meal, among other materials, had been used as an additive in poultry feeds. By 1947, it was also known that chicks on a diet which was deficient in an unknown substance could become anemic. It does not appear, however, that anyone related the anti-pernicious anemia principle to the growth stimulating "animal protein factor," nor had anyone experimenting with the "animal protein factor" isolated, identified or determined the nature of the unknown substance that produced the observed effect.

Dr. Mary S. Shorb, a bacteriologist employed by the Department of Agriculture, undertook the development of an assay, or test, for "Factor X," an unidentified substance in liver which stimulated the growth of rats. She selected for investigation a microorganism, Lactobacillus lactis, Dorner, which has high nutritional requirements. She found that the growth of this organism in an amino acid basal medium to which clarified tomato juice had been added was stimulated by the further addition of liver extracts, yeast, orange juice and other substances. Since she did not know the identity of the active principle in either the clarified tomato juice or in the growth stimulants, she referred to them, respectively, as the TJ, or tomato juice, factor and the LLD factor, after the name of the organism she was studying³. Experimenting with liver products having determined value in the treatment of pernicious anemia, she observed that the rate of growth of the Lactobacillus lactis, Dorner ("LLD activity") varied in an almost linear relation to the established anti-pernicious anemia potencies of the liver products she tested. This led her to speculate that her assay might be useful in determining the presence and strength of the anti-pernicious anemia principle in liver products, but of this she was uncertain since her organism was responsive to materials, other than liver, which did not contain, in fact or so far as she knew, any anti-pernicious anemia activity.

In the summer of 1946, Dr. Shorb took a position with the University of Maryland where she continued her efforts to perfect her assay. These efforts were directed primarily to the TJ factor. Some tomato juice, even after clarification, was contaminated with LLD activity, so that this factor was at times unstable and produced erratic results. The stabilization of the TJ factor, whatever the identity of the other factor might be, was essential to the validity of her assay.

In February 1947, officials in Merck's research department having learned of the work of Dr. Shorb, a contract was negotiated between Merck and the University of Maryland pursuant to which Dr. Shorb was to continue her efforts to develop and perfect an assay for the anti-pernicious anemia factor. Meanwhile, it was agreed that she would test with her assay procedure, in its then stage of development, such materials as might be submitted to her by Merck. It was also agreed that such patents and patent rights as might result from her work under the contract would be assigned to Merck.

Beginning in 1938, employees in Merck's research laboratories had worked upon the isolation of the anti-pernicious anemia factor in liver. After some years these unsuccessful efforts were abandoned, but were resumed in 1946 under the direction of Dr. Wood, one of the patentees. In May 1947, Dr. Wood assigned Rickes, a chemist working under his supervision, to an investigation of fermentation materials as a possible source of the anti-pernicious anemia factor. A number of fermentation products derived from the growth of several species of microorganisms were investigated. The results were not promising, until on September 16, 1947, there was produced a composition within the terms of claim 1 of the patent. These compositions were obtained in the eluates of the residue in "spent" Norit after elution of the grisein materials which previously had been adsorbed from the acidified broth of the microorganism, Streptomyces griseus⁴. While grisein, itself, contains none of the desired activity, there followed an intensive search of grisein materials and experimental extraction,...