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September 1, 1945

CLARK & CLARK et al.

The opinion of the court was delivered by: FORMAN

This is an action brought by Smith, Kline & French Laboratories, a Pennsylvania corporation, assignee of Gordon A. Alles, of Monterey Park, California, to whom United States Letters Patent No. 1,879,003 was issued on September 27, 1932. The plaintiff charges the defendants Clark & Clark, a New Jersey corporation, Charles L. Morris, Robert Brinton Morris trading as Professional Laboratories, David M. Olmstead, Benjamin Zirin and Standard Medical Laboratories, a New Jersey corporation, with infringement of the said patent and unfair competition, and seeks profits and damages arising therefrom.

An answer was filed by Clark & Clark, Charles L. Morris, and Robert Brinton Morris trading as Professional Laboratories, who by way of counterclaim seek injunctive relief and damages against the plaintiff. The suit is not pressed against David M. Olmstead, Benjamin Zirin and Standard Medical Laboratories.

The answering defendants take the position that they did not infringe the plaintiff's patent for the reason that it lacked validity in that: (1) Alles was not the original inventor; (2) the composition claimed was not new or novel in that one skilled in the art could ordinarily produce the same; (3) that the descriptions contained in the letters patent are ambiguous and indefinite and do not disclose the invention in clear and concise terms so as to enable one skilled in the art to produce the same; (4) that the claims of the patent are excessive, vague, ambiguous, and indefinite and (5) that the composition is an unpatentable combination of old and well-known elements produced in an obviously customary manner.

 Other contentions raised at the trial were that the disclaimer filed by Alles on August 29, 1934, is invalid; the patent and the claims of the disclaimer are invalid for the reason that no invention is involved to find that an old product works for a known use, particularly in a field where it was known that products of the type involved were useful. The defendants further contended at the trial that if it is assumed that the discovery is patentable as an old product for a known use, then the claims of the disclaimer were invalid because they failed to 'particularly point out and distinctly claim' the invention as required by law.

 In addition to a denial of infringement upon their part, the defendants likewise denied that they have been guilty of unfair competition as alleged by the plaintiff. Affirmatively, the defendants insist that they are entitled to recover against the plaintiff their provable damages for unfair competitive practices upon the part of the plaintiff, which forms the substance of their counterclaim.

 The invention relates to a composition of matter purporting to be useful for therapeutic purposes. The specifications describe the invention and state that the composition is physiologically active and produces effects in animals and man similar to the effect of the salts of ephedrine.

 In his patent Alles originally claimed:

 '1. As a new composition of matter, a salt of 1 phenyl-2-aminopropane.

 '2. As a new composition of matter, the hydrochloride of 1-phenyl-2-aminopropane.'

 His disclaimer follows:

 'He disclaims so much of claim 1 of said patent as is in excess of the following:

 "As a physiologically active therapeutic agent capable of producing effects in animals and man similar to the effect of salts of ephedrine, a salt of 1-phenyl-2-aminopropane.'

 'He disclaims so much of claim 2 of said patent as is in excess of the following:

 "As a physiologically active therapeutic agent capable of producing effects in animals and man similar to the effect of salts of ephedrine, the hydrochloride of 1-phenyl-2-aminopropane."

 The composition 1-phenyl-2-aminopropane is also chemically known as phenylisopropylamine and benzylmethyl carbinamine.

 The salts of the composition 1-phenyl-2-aminopropane, which is the subject of the Alles patent and of this action, was in 1938 given the generic name 'amphetamine sulfate' by the American Medical Association, by which name it will be generally referred to hereinafter. It is the identical compound which is prepared and sold by the plaintiff under the brand or trade name of 'Benzedrine' or 'Benzedrine Sulfate.'

 In Part I of this opinion we will discuss the patent phase of this case and in Part II we will take up the phases of unfair competition.

 Part I

 The Patent

 Amphetamine sulfate may be said to be more closely allied with the field of sympathomimetic amines than with any other field in medicine, pharmacology or chemistry. It is the knowledge of the art in this field that is advanced as the prior art upon which was based the discovery of amphetamine sulfate for therapeutic purposes.

 The autonomic nervous system, by which every single structure of the body is brought under a dual control, consists of two branches, the central nervous system and the sympathetic nervous system. There is also a division of the sympathetic nervous system known as the parasympathetic nervous system.

 The central nervous system consists of the brain and spinal cord, and some structures of the brain are independent of the sympathetic nervous system. In the central nervous system is generated, among others, mood, feeling of energy, feeling of sleeplessness, capacity to have appetite for food or sex. Examples of diseases of the brain are epilepsy and Parkinson's disease.

 The sympathetic nervous system stems from the central nervous system and starts from points of the spinal cord and a structure at the lower part of the brain and winds its way through every organ of the body. It extends peripherally to the eye, to the skin, to every blood vessel, to the heart, to the lungs, to the gastro-intestinal tract and through every portion of the organism.

 The parasympathetic nervous system innervates the active organs of the body, such as the stomach, the intestines, the uterus, the prostate or principally those organs which have smooth muscle tissue.

 A sympathomimetic amine is a substance which stimulates the peripheral parts of the sympathetic nervous system. Examples of this action are constriction of the blood vessels, increased rate and force of the heart beat, a rise in blood pressure, dilation of the pupils of the eye, relaxation of the bronchial muscles, a rise in blood sugar, increased metabolic rate, decreased activity of the gastro-intestinal tract of the stomach and intestines.

 Prior Art

 The following literature constitutes the prior art, some of which was offered by the defendants as anticipatory of the Alles' claims:

 1. 'On a Few Derivatives of the Phenylmeth-Acrylic Acid and of the Phenyl-Iso-Butyric Acid,' by L. Edeleano, published in the Berichte der Deutschen-Chemischen Gesellschaft (Ber. Dtsch. Chem. Gesell. 20:616, 1887).

 2. 'Handbuch der Organischen Chemie,' by Dr. F. Beilstein, Dritte, Umgearbeitete Auflage, Verlag von Leopold Voss (Hamburg und Leipzig), 1896 and Vierte Auflage, Die Literatur Bis 1, January 1910 Umfassend, Verlag von Julius Springer (Berlin), 1929.

 3. 'Chemical Structure and Sympathomimetic Action of Amines,' by G. Barger and H. H. Dale, published in The Journal of Physiology (Cambridge University Press, London), Vol. XLI, 1910-1911, p. 19 et seq.

 4. 'Adrenaline and Other Derivatives of Ethylamine,' by Percy May, published in The Chemistry of Synthetic Drugs (Third Edition, Revised), 1921 (Longmans, Green and Co., London), p. 129 et seq.

 5. References to the publications of Doctors K. K. Chen and Carl F. Schmidt may be found in the bibliography of their article entitled 'Ephedrine and Related Substances,' published in Medicine, Vol. IX, No. 1, February, 1930.

 6. 'The Beckmann Rearrangement Involving Optically Active Radicals,' by Lauder W. Jones and Everett S. Wallis, published January 8, 1926, in The Journal of the American Chemical Society, Vol. XLVIII, January-June 1926, p. 169 et seq.

 7. 'dl-B-Phenylisopropylamine and Related Compounds,' by Donald Holroyde Hey, published in 1930 in the Journal of Hey, published in 1930 in the Journal of Soc., p. 18 et seq.).

 1. Edeleano-1887

 'The salts of the base are mostly very easily soluble in water, while the platinum double salt represents a compound difficultly soluble in water and crystallizing in matted small needles.'

 The synthesis of this product by Edeleano was purely a chemical attempt and involved no physiological testing. Edeleano's statement relating to the solubility of the salts of the phenylisopropylamine base did not carry with it the procedure for the preparation of any salts of the base he described, nor did it describe any salt of phenylisopropylamine.

 Alles makes no claim that he was the first discoverer or inventor of the base of this composition. Edeleano stated that he prepared the composition, provided a method for such preparation and described the completed product in certain respects. There is no question that Edeleano did prepare the base of this substance. He made no reference whatsoever to its use for any purpose. There appears no reason, nor the suggestion of one, that he worked with this base other than purely from a chemical standpoint. He entitled his article 'On a Few Derivatives of the Phenylmeth-Acrylic Acid and of the Phenyl-Iso-Butyric Acid' and under the heading 'Method of Preparation of Phenylmethacrylic Acid' set forth an account of what he did in his laboratory. He said nothing that gave rise to an inference that the substance had any effect or that it was useful for any purpose. Edeleano stated that the salts of the base were easily soluble in water, while the platinum double salts were soluble with difficulty.

 From this the defendants ask us t infer that Edeleano actually prepared the identical salt of this base which Alles claims as a patent. It is obvious that Edeleano prepared certain salts of the base, but it is quite impossible to determine which salts he prepared. He did not describe the method of preparation of the 'easily soluble' salt of the base with any characteristics by which it could be identified as a particular salt.

 It appears that certain salts of this base are easily soluble in water, some are not so soluble and others are not soluble at all. Hence, there is no disclosure by Edeleano of any particular salt of the base. We cannot say that Edeleano experimented with the salts, much less that he particularly prepared a salt which would be useful for therapeutic purposes.

 At this point, however, it is urged that the addition of sulphuric acid or hydrochloric acid to a base, in order to convert it into a salt, is a method used commonly by chemists, and that with the base described by Edeleano, together with the application of this well-known method of conversion, any skilled chemist could arrive at the composition which is the subject of this patent claim. A skilled chemist, following Edeleano's methods as described in his paper and applying the knowledge of his profession and of the art prior to Alles, might very well be able to produce a salt of 1-phenyl-2-aminopropane, but not a substance having the effects of the Alles' compound for therapeutic purposes. To prepare such a substance requires original experimentation on the part of the chemist as to effect of the substance upon animals and man. Edeleano's disclosure taught only the manner by which the base of the compound could be prepared and referred incidentally to two salts thereof without further identification. It is insufficient as an anticipation of a disclosure of effect and therapeutic usefulness of a certain salt of the base.

 2. Beilstein -- 1896

 As evidence of an ancient disclosure of the patent, the defendants directed attention to 'The Handbook of Organic Chemistry,' compiled by Beilstein, an encyclopedia of organic compounds, 1896 edition, in which was listed the base of phenylisopropylamine as follows:

 '12 -- (a) -- Aminopropylbenzol (Phenisopropylamine) C6H5.CH2.CH(NH2).CH3. B. Beim Behandeln des Amids der Methylbenzylessigsaure mit (1 Mol.) Brom und (5 Mol.) Kalilauge (von 4%), unter Abkuhlen (Edeleano, B.20,618). -- Flussig. Siedep.: 203 degrees.'

 Substantially the same content of the listing appears in the 1929 Edition of Beilstein. No mention is made in this later listing, the last to be published prior to the Alles patent, of the salt of phenylisopropylamine. Of course, these are only references to the paper by Edeleano and add nothing to the prior art.

 In 1895, two English scientists, Mather and Schaffer, published a paper concerning the effects produced by the introduction into animals of an extract of the suprarenal glands. This extract consisted of a salt solution of the tissues of the glands that lie at the upper pole of the kidney. They described as effects a marked rise of blood pressure, which stimulated a great deal of interest at the time. Several physiologists and chemists succeeded within a few years in the isolation in relatively pure form of a solution containing the active principle of this extract. By the year 1901 it became known as adrenaline or epinephrine. A chemical composition for these compounds was soon developed and it became possible to produce them in the laboratory synthetically instead of taking them from the animal body.

 Adrenaline was one of the first of the sympathomimetic amines. It had the disadvantages, for purposes of therapeutic use, of being ineffective orally and of having no prolonged action. The work in this field was therefore directed toward finding a compound of greater intensity of action, i.e., one that acts upon the sympathetic nervous system in smaller doses.

 3. Barger and Dale -- 1910

 In 1910, Barger and Dale published their article in The Journal of Physiology (Cambridge University Press, London, Vol. XLI, 1910-1911, p. 19 et seq.), wherein they described a series of tests of a large number of synthetic derivatives of this type in which they set up certain specifications that have stood the test of time. These compounds are known by the term 'sympathomimetic amines,' which was introduced by Barger and Dale and defined by them as 'a term which indicates the relation of the action to innervation by the sympathetic system, without involving any theoretical preconception as to the meaning of that relation or the precise mechanism of the action.' Their experiments were done upon animals whose spinal cords were cut at the base of the axis vertebra and the neural arch of the vertebra was removed. The brains of the animals were completely destroyed.

 In their article Barger and Dale make the following statement:

 'Taking B-phenylethylamine as our starting point, we investigated first the effect of varying the length of the side-chain. It was shown that lengthening the carbon chain of the purely aliphatic bases up to a certain point was attended with increase of activity. In the case of the fatty-aromatic base, however, we found that the side-chain of two carbon atoms gave the optimum of activity. Aniline, which has no side-chain, and is therefore a purely aromatic base, had none of the specific action; benzylamine had a mere trace; and aphenylethylamine, in which, again, only one carbon atom intervenes between the amino-group and the aromatic ring, was also very feebly active. Increasing the side-chain beyond two carbon atoms also resulted in a decline of activity, phenylpropylamine being much less active than phenylethylamine (Fig. 4). The optimum constitution of a fatty-aromatic amine for the production of the sympathomimetic action is, therefore, that which is found in adrenine itself, viz. a benzene ring with a side-chain of two carbon atoms, of which the second bears the amino group.' At p. 29, supra.

 They arrived at the following conclusions, among others, as a result of their experiments:

 '(1) An action simulating that of the true sympathetic nervous system is not peculiar to adrenine, but is possessed by a large series of amines, the simplest being primarily fatty amines. We describe all such amines and their action as 'sympathomimetic.'

 '(2) Approximation to adrenine in structure is, on the whole, attended with increasing intensity of sympathomimetic activity, and with increasing specificity of the action.

 '(3) All the substances producing this action in characteristic manner are primary and secondary amines. The quarternary amines corresponding to the aromatic members of the series have an action closely similar to that of nicotine.

 '(4) The optimum carbon-skeleton for sympathomimetic activity consists of a benzene ring with a side-chain of two carbon-atoms, the terminal one bearing the amino-group. Another optimum condition is the presence of two phenolic hydroxyls in the 3:4 position relative to the side-chain; when these are present, an alcoholic hydroxyl still further intensifies the activity. A phenolic hydroxyl in the 1 position does not increase the activity.' Pp. 58, 59, supra.

 Alles found optimum activity in phenylisopropylamine (1-phenyl-2-aminopropane) which is a chemical structure in which is included a side-chain of three carbon atoms, but the amino group is attached to the middle carbon atom. This structure is different from that of phenylpropylamine and was not considered by Barger and Dale in their experimentation. They omitted to investigate the potentiality of the compound constructed by Alles. They fell short of disclosing the optimum activity later developed by Alles when he proved that phenylisopropylamine had a greater pressor activity than any other compound theretofore considered. They confined their research to sympathetic effects in the field of sympathomimetic amines.

 It must also be observed that no intimation as to effects on the central nervous system is given by Barger and Dale. Their experiments precluded any such effects because they worked on animals devoid of central nervous systems.

 4. Percy May -- 1921

 In 1921, a volume entitled 'The Chemistry of Synthetic Drugs' was published (Longmans, Green and Co., London). The author, Percy May, in a chapter concerning 'Adrenaline and Other Derivatives of Ethylamine,' summarized the literature on the subject. He added no new data but quoted the conclusions of Barger and Dale in their entirety.

 5. Chen and Schmidt -- 1923

 In the year 1923, Dr. Carl F. Schmidt, presently Professor of Pharmacology at the University of Pennsylvania, went to Peking, China, to take temporary charge of the Department of Pharmacology in the Peking Medical College. His work involved research in Chinese drugs. Several Chinese drugs were studied with no noteworthy results.

 At the end of that year a young Chinese scientist, K. K. Chen, a graduate in chemistry of the University of Wisconsin, went to Peking to work with Dr. Schmidt. Although the Chinese thought that their drugs were potent, Dr. Schmidt had been unable to confirm this conception. At one of his family conclaves in China Dr. Chen's uncle, a druggist, upon hearing this view, became rather indignant and stated that he knew from personal experience that there was at least one Chinese drug that was potent -- ma huang.

 Dr. Chen brought some of this drug with him to Peking and an extract of it was injected into an animal, producing a sharp rise in blood pressure. This action was surprising, for the experiments conducted by Dr. Schmidt involving the injection of many plant extracts into animals always produced a drop in blood pressure.

 Dr. Chen succeeded in isolating crystals from the plant, ma huang, which crystals he identified as an alkaloid. Several experiments were made with the crystals and it was found that the active principle was a sympathomimetic substance. Experiments with the drug upon patients proved that it was effective and had a relatively low toxicity.

 A search for a name for the drug resulted in the discovery that it had already been isolated in 1887 by a Chinese chemist named Nagai, who had called it ephedrine. The drug was brought to the United States in 1924 and results of various clinical studies were published by Chen and Schmidt from time to time thereafter. (References to these publications may be found in the bibliography of a lengthy article published by them in Medicine, Volume IX, No. 1, February 1930.) Since 1924 the drug has been in use quite extensively.

 Although ephedrine was isolated and its chemical structure known for many years, it was regarded as a very toxic substance until it was introduced in this country by Chen and Schmidt. It had several advantages over the other drugs in the field, like adrenaline or epinephrine, in that it produced the same effects when taken orally and its duration of action was a matter of hours rather than minutes. Physiologically, ephedrine stimulates the peripheral parts of the sympathetic nervous system, resulting in constriction of blood vessels, acceleration of the heart, dilation of the pupils, decreased movement of the gastro-intestinal tract and relaxation of that tract and the bronchi. It has certain stimulant effects upon the central nervous system previously not described in compounds of this series. These effects upon the brain cells are comparable with that of caffeine. They manifest themselves in restlessness, nervousness, tremors, anxiety, insomnia in some individuals, and in an appreciable number of cases, particularly in women inclined to be nervous, may lead to nausea and vomiting. A depressant action upon the heart muscle, similar to myocardial depressants, imposes a limitation upon the therapeutic usefulness of the drug. It is extensively used to shrink mucous membranes when congested. Ephedrine, being orally effective and possessing a duration of action, displaced adrenaline. Prior to its discovery, there existed no better compound having the action which adrenaline had upon the peripheral sympathetic nervous system. Compounds of the same general type which had been made and tested were found to be weaker than adrenaline.

 This work in ephedrine produced for the first time in the field of sympathomimetic amines not only effects upon the sympathetic nervous system but concomitant effects upon the central nervous system. However, it did not result in encouraging the exploitation of the latter effects, but rather regarded ...

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