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Full Opinion
(after stating the facts as above),
•' It certainly falls within claim 1 if it be free from inert and associated gland-tissue. No one supposes that these words mean that the actual cellular structure of the tissue remains, for the process involves its -destruction, though, were-this not so, the words might quite naturalfy have been so understood. That meaning being eliminated, what is the most'natural meaning? -I think it can only mean those organic chemical súbstances, regardless of the structure, out of which the gland-tissue is composed and of the same chemical composition in which they exist and make up the gland-tissues. To these may well be added those substances arising in the normal metabolism of the .tissue of other organs or of the glands themselves, which, being carried in the blood, might remain in the glands at death. Such of these substances as have not the physiological activity of the “principle,” now known, are the “inert and associated gland-tissue” mentioned in the claim. • Nor can this mean.a new chemical disintegration of the “gland-tissue” so described of which there is much in Adrenalin and-over six ;.times as'much in Adrin. This substance, ammonium magnesium phosphate, Is a new and' inorganic substance arising from the regrouping of atoms which have, it is true, been a part of the gland-tissue, but which have been broken from the molecules which constituted their original form. Since the chemical distinction between “substances” depends, not upon the presence of the same atoms, but upon their definite structural association in known proportion into molecules, it is illegitimate to consider as “gland-tissue” those substances which, while they represent in part the same atoms, have by rearrangement and by addition of.new atoms created new molecules. Moreover, the patent itself corroborates this view. The crude product was the patented substance, and it appears (page 2. lines 50-70) that the patentee understood perfectly well that without purification there would be inorganic matter in the crude product. • Moreover, the amendment in the Patent Office of the words “inert constituents” to the words “inert and associated gland-tissue” clearly indicate the patentee’s intention.
The question remains, however, whether Adrin is in fact free from organic tissue, and upon this there is some dispute. Sadtler found that under the -biuret test Adrin showed a rose color. This indicated proteids, and .for organic sulphur he used the nitro prusside sodium test. These tests in Chandler’s opinion are so delicate that they will detect a mere trace, and Sadtler does not dispute that fact. The question may perhaps be best decided by considering first whether Adrin is sub- , stantially as free as Adrenalin from organic matter, and then considering whether Adrenalin itself is “practically free” within the meaning of the claims. One test much relied on by both experts is that of physiological activity. Adrin, having a much higher ash than Adrenalin, ought to show a correspondingly lower activity. In fact, it shows a more than correspondingly lower activity, thus indicating the presence of some other substance not inorganic, i. e., organic. It would seem that Adrin had therefore somewhat more organic contamination
Sadtler upon this question calls attention to the results of his modifications of Von Furth’s process, in which he showed much ingenuity. These so-called Von Furth intermediate products were three: Precipitate 5 — A—3, Precipitate 1 — B, “Crystalline Base.” The first and third were negative in reaction to these biuret and other tests, and the second showed only a slight reaction. This indicated that all were free, .or nearly free, from organic impurities; yet the amount of ash in each was very different. In 5-A-3 it was over 31 per cent., in 1-11 it was about 7 per cent., and in “Crystalline Base” about 26 per cent. Now the physiological activity of .5--A-3 equalled that of crude Adrenalin, though the ash was more than seven times as great, while that of “Crystalline Base” was only one-eighth that of either. Similarly, 1-B had an activity equal to Adrenalin ; the ash being- also substantially the same. Both experts conceded that the sole physiologically active agent is the principle itself, and the result seems to be that the reason for the discrepancy between the activities must he the presence of organic substances not detected by Sadtler’s tests. Against this there is Chandler’s opinion that the conditions of crystallinity preclude (lie presence of organic matter, an opinion shared by Sadtler when dealing with Moore’s Dialysate, and we have in the case of “Crystalline Base” purely negative test reactions. Why 5-A-3 shows an activity so disproportionate to the ash, I cannot say; it shows a similar disproportion to the Adrenalin purified, though less absolutely. I think that, to solve this apparent contradiction of evidence, one must have recourse, first, to the fact that the use of Adrenalin has been now sufficient to show that it is “practically free,” and to the presumption from the patent itself that the disclosure answers the claims. Apparently the only difficulty ever arising from the intravenous use of Adrenalin was due to too strong solutions. These did cause destruction of tissue at .the point of injection; but even they gave no evidence of contamination. I therefore hold that Adrin infringes claim 1.
Claim 2 is the same, with the addition of the words that the product is a “whitish” color. It appears that neither crude Adrin nor Adrenalin is, properly speaking, white. Each is a light j'ellow brownish color. Commercial Adrin is, however, near enough to a white to comply with the claim.
Claim 3 is like claim 1, except that the words “inert constituents” are substituted for “inert and associated gland-tissue.” Now it tin
In claim 4 it is provided that the product shall melt at about 207 degrees centigrade. Now Adrin has not been shown to have melted even at 220 degrees and upwards. The difference proportionately is not great, and the patent is entitled to have a generous construction, yet I cannot think that a product is affirmatively shown to have a malting point of about 207 degrees when there is no proof of when it will melt at that heat, and there is proof that it will not melt at 220 de- „ grees. It is true that Chandler says (Q. 10) that he had subjected the Adrin to all the tests required by the patent, and found that they corresponded; but this general statement cannot stand in the face of the express testimony of Sadtler upon that particular experiment. If the explanation of the experts be correct, that the high melting point is due to the -mineral impurities, this finding is consonant with the finding that Adrin is not free from inert constituents. I therefore hold claim 4 not infringed.
Claim 6 is for . a crystalline substance, and that Adrin certainly is. The only question which can arise is as to whether the base is crystalline, or whether it owes its crystalline character to the mineral admixtures. This claim, I think, should be construed as meaning that the substance is crystalline, however large or small the degree of mineral impurities may be. It is of no consequence if the crystals are composed in part of the earthy matter. So far as the substance is purified, the crystals 'will increasingly become crystals of the active principle.
Claim 7 is. eliminated by my decision in regard to the melting point.
1 The new characteristic of claim 9 is that it shall have an alkali reaction. I do not understand that this is denied, and the same is true of claims 11 and 12.
The defendant’s expert concedes that claim 13 covers the substance and claim 14 is involved in the decision of claim 12.
The .defendant’s Adrin answers all the characteristics of claim 15; the only question being as to the crystalline substance, which matter I have already passed upon.
Obviously the Adrin cannot infringe claim 16. I therefore find that the dry product infringes claims 1, 2, 6, 9, 11, 12, 13, 14, and 15.
The next question is whether the defendant’s solution infringes any of the claims of patent No. 730,176. The solution is of a salt of Adrin
“Salts of the substance possess tlie same physiological properties as the substance itself and constitute new substances not claimed herein, but claimed in another application.”
Again, claim 7 is for a substance “soluble in acids and forming salts therewith.” The second patent was divided out upon the insistence of the examiner, who found that the bases of the salt were substances of separate and distinct chemical composition. Whatever, therefore, may be the proper scope of the claims of the patent, there can be no doubt that the patentee did not intend them to cover any salt, but that he distinguished the salt as a new substance not claimed in his mother patent. It so happens in my judgment that in this respect he was very fortunate, as will later appear.
The question next arises of the validity of all claims infringed by the dry product. This is attacked, first, because they are anticipated in the art; and, second, for a number of technical grounds which I shall take up in turn. The anticipations I will deal with first, because, in the view which I have taken of the two patents, that is the simpler consideration. The patentee originally attempted to claim the active principle itself. This was in his first application where he claimed process and product; but the examiner would not allow these claims, basing his rejection upon his interpretation of American Wood Paper Co. v. Fibre Disintegrating Co., 23 Wall. 566, 23 L. Ed. 31, that no product is patentable, however it be of the process, which is merely separated by the patentee from its surrounding materials and remains unchanged. After some argument upon this score, the patentee voluntarily divided out the product patents expressing such intention on December 22. 1902. When he came to file his product patent, he proceeded upon the same theory, first claiming the active principle of the glands. The examiner required a division, but raised no objection to the form in which these claims were given. In his amendment of March 13, 1903, which was about two months after his first application, he changed all the claims so that they read substantially as they do at present and were not limited to the active principle. I think that this effected a substantial change in meaning, and that the defendant is right in insisting that the claims are now broader than a mere claim for the chemically free base, or active principle, and that they cover any substance
For example, if Abel had isolated the base of his monobenzoylated salt, or Yon Furth the base of his sulphate, Takamine would have been open to attack by either upon the theory that, even conceding that in neither case the base was that of the active principle alone and not in chemical composition, yet as a substance it corresponded to the claims. This he could have avoided had he limited his claims to the isolation of the active principle itself, and it would then have been of no consequence whether Abel’s or Von Furth’s compound had practically answered as well as his own. Nevertheless, as I have already said, .the claims of patent No. 730,176 do not cover a salt and are especially designed to exclude a salt. It so happens, moreover, that all of four alleged anticipating products never existed except in the form of a salt. This Sadtler concedes. When I come to consider patent No. 753,177, I shall take up each of these products separately to see whether they anticipate the claims of that patent which covers the salts; but the only necessary question here is: Since they were not actually themselves bases, whether pure or impure, whether it involved invention to produce the base of Takamine. This question does not deserve any extended consideration. The difficulties of the old products were so great as made any substantial advance from them important. It is enough that Takamine was the first to isolate any base whatever, all other products existing in the form of a salt, because prior investigators were all trying to reduce the principle down as purely as possible. The invention was therefore novel.
Nor do any of the claims call for only an “effect.” That rule I understand to mean nothing more than that the claims must not be too abstract. I do not think that any of the claims in the patent are at all abstract, but each forms a concrete enough criterion to test the product intended. There is no claim which selects a single characteristic or function. The very phrase “physiological characteristics and reactions of the suprarenal glands” refers to some 15 lines of the specification (page 2, lines 102-116), and this phrase is always coupled with at least two other differentia. That is sufficient to identify the product in my judgment in every case.
A final objection goes to the fact that the patent covers solutions as well as dry products, and that this solution is not stable. I agree with the defendant that the solution mentioned in patent No. 730,176 does not include a solution of the salt, and it is also in evidence that a plain aqueous solution is not stable in any sense of the word. On page 3, line 23 et seq., the patentee uses the following words:
*104 “The substance may be kept in the solid form or in solution, and, where in the claims I have used the terms ‘substance,’ I desire it to be understood as referring to either the solid or the solution form of the substance, except when such signification would be plainly inconsistent with the terms of the particular claim.” ..
There is indeed no way to avoid- the conclusion, therefore, that the patentee has wrongfully specified his aqueous solution as stable, unless such an adjective would be plainly inconsistent with the terms of the particular claims. Now the infringed claims in which this word appears are Nos. 1 and 2. In these it is use'd in conjunction with the word “concentrated,” and it appears beyond a doubt that the solution is not a concentrated substance, but, on the contrary, a highly dilute one. Thus, page 2, lines 104-107, the specifications mention solutions of 1 to 1,000' and 1 to 10,000. Moreover, the art knew that the only solutions of the suprarenal gland therapeutically possible were very dilute, though not to the extent indicated in the specification. I think • that, considering this knowledge both from the patent itself and from the existing art, it is apparent that the two claims are “plainly inconsistent” with a solution, though the complainant appears to be content otherwise. And therefore I think that a solution is not comprehended by the adjective “concentrated.” Indeed, without more knowledge than that it was a solution of the base, I should have no trouble in holding that it was not “concentrated.” If so, the objection disappears to the instability of the solution, and the claims are valid, for no one asserts that the crystals are instable.
I therefore hold that dry Adrin infringes claims 1, 2, 6, 9, 11, 12, 13, 14, and 15.
The only serious question which does arise upon the issue of infringement is whether the defendant’s solution is “stable” or “inert” to the action of the air; these words being defined as used only in “a practical or commercial sense.” The complainant attempts to help out this word by insisting that at least in claims 1 and 2 the addition of the preservative such as chloretone or chloroform can be considered as
The question therefore arises: What is commercial stability ? There is no question that the boric acid adds to the stability of the base itself in solution, though even in a stopper bottle the defendant’s Adrin without the preservative elements will not last for a long time. There is no evidence of just how long it takes for the solution without a preservative to become unfit for use. A slight discoloration owing to. oxidation from contact with the air is not sufficient to be injurious,, for it is only when after exposure it becomes a dark color that its therapeutic use ceases. Making allowance for the character of the patent itself which is in my judgment a pioneer, I am not disposed to construe the words “commercially stable” as not extending to the defendant’s solution. That Takamine could not have meant more than the stability which in fact exists is indicated by the fact that it was known when the patent was applied for just what was the actual degree of stability of the solution without a preservative, and it can hardly be supposed that he was deliberately intending to misinform the public upon a matter as to which he could have no possible reason for so doing; at least, I can see nothing- which he could gain by overstating in his patent the stability of the solution. Rather I prefer to interpret the words as controlled by his actual knowledge and as meaning only such stability as he himself then knew to exist. This is especially so since the alternative seems to be to hold the patent void as not containing an adequate disclosure to support the claims. I do.
The question next arises of validity, and upon this the defendant urges two objections: First, the novelty of the patent; and, second, its forfeiture, because it has been publicty used in this country for more than two years prior to the filing of the application.
At the taking of testimony, the defendant introduced a great number of allegedly prior compositions; but in its brief it has omitted consideration of any but four, which are respectively Moore’s Dialysate, Abel’s Monobenzoylate Salt, Von Furth’s Sulphate, and Von Furth’s Iron Compound. The defendant’s failure to deal with the other substances mentioned in the testimony indicates that it does not rely upon those. It will be necessary therefore to consider only the four above mentioned.
It is now supposed that the active principle which Takamine first isolated exists in the gland itself in the form of a salt; that is to say, in combination with an acid. For some time after the discovery in 1894 by Oliver and Schafer of the physiological action of the supra-renal glands, it had become customary to make therapeutic use of the substance by drying and powdering the glands and selling- them in the form of a liquid solution preserved with chloretone. This the complainant itself had done, and the substance in that form attained a large and important use in therapy. Indeed, it was on occasion even used in intravenous injection; but, as the principle itself in this form was in physical admixture with many organic substances so as to form an apt nidus for bacteriological culture, the result was an extremely dangerous substance for injection into the body. The complainant, it is true, speaks of the demonstrated asepsis of the substance in this form; but that, I think, was too strong a statement, .not in fact justified by the facts, and, indeed, as soon as Takamine Adrenalin became known, the use of the dry gland solution with a preservative practically disappeared altogether, so that the disadvantages of the original substance have the clearest proof in subsequent history. The too extravagant claims, even, of the complainant, for the aseptic character of the powdered dried glands, must therefore, in the light of subsequent facts, be disregarded.
Much had been ascertained about the substance itself prior to Takamine without which his invention would certainly have been impossible.; but no one, as I have already said, had succeeded in chemically isolating the principle as now chemists suppose has been done. Indeed, it was not originally known whether the principle existed as a definite chemical compound in the gland itself, or whether it might not be a condition resulting from the coexistence of definite substances in the gland which might altogether disappear upon their dissociation. It is too much to say that the last statement remained uncertain after the disclosures of Abel and Von Furth; but the defendant itself does not assert that they ever succeeded in definitely isolating the principle out of combination.
The first of the four products is Moore’s Dialysate. This discovery is set forth in an article in the Journal of Physiology by B. Moore, April, 1895. The successful experiment was described as follows: The dried glands were first extracted with ether. Then they were placed in absolute alcohol for three weeks. Both these steps were to remove the other substances from the glands. An extract was then made with a small quantity of distilled water, and the filtrate thus arising was allowed to dialyze into distilled water through parchment. The defendant has put in evidence three products of this process, the first of which showed an activity of about one-third that of Adrenalin; the second was the process carried down by evaporation to a crystalline salt; and the third was the precipitation of the active base from this salt by ammonia. The third is obviously the creation of Takamine’s subsequent invention, and is not claimed to be an anticipation. There is considerable dispute as to the importance of the changes in the process wdiich Sadtler adopted, particularly because he protected the extract with water during digestion by a film of paraffine so as to prevent any oxidation from contact with the atmosphere. Sadtler, on the other hand, insists that all the devices which he used were so common for chemists that it must be presupposed as an incident to Moore’s process. However that may be, the resulting activity of the product is only one-third that of Adrenalin, and such a deficiency can hardly be accounted for except by the hypothesis that the substance is not as free as Adrenalin from inert substances. The Dialysate, it is true, shows no reaction to the biuret test which discovers proteid matter, and yet there is no reason to suppose that all inert substances can be of a mineral character, since there is in the process nothing chemically to change the organic substances extracted from the glands. Unless mineral substances existed as such in the gland and were carried out into the extract along with the salt, it is hard to see how the presence of so large a quantity of inert substances as is indicated by the small activity of the resultant Dialysate can be accounted for except upon the theory that they are organic substances from the gland itself. I do not forget that Sadtler says that such substances are colloidal, and so could not enter a Dialysate; but yet it is conceded that the natural salt itself is a crystalline organic product, a conclusion which seems at variance with the universality of the statement that all these or
However this may all be; it is clear that Moore’s experiment will not in any event serve as an anticipation. The description is so vague that at least two distinguished and ingenuous chemists cannot agree upon just what the process was. It was certainly not intended to be a set of directions for producing a commercially useful drug, even by skilled chemists, and it did not result in being so used, though the demand was great. While it did of course form a part of the science in the sense that it added to the store of knowledge about the active principle, the best prdof that experts did not regard it as a satisfactory solution of what all were seeking is that Abel and Von Furth, who were both generous investigators, never treated it as of any consequence. Nor may this be laid down to their ignorance of Moore’s work, because it was published in a well-known technical magazine, and was almost certainly known to such skillful and persistent scientists. It was at most only a laboratory experiment without practical and commercial fruit, for there is not the slightest evidence that any one has ever used it in a single instance. Such disclosures do not enrich the art in the sense required for an anticipation. The test is whether the disclosure would have answered itself for the claims of a patent, and that it obviously would not do. Sadtler has now, it is true, thrown down the active principle by Talcamine’s process; but it is an awkward process, which no one would think of substituting for the directer method first disclosed by the mother patent here in suit. I do not therefore regard Moore’s Dialysate as an anticipation of any of the claims.
The next supposed anticipation is Abel’s Monobenzoylated Salts. This is the salt of a base constituted in part by the atoms which together make- up the active 'principle in question — Adrenalin—and for the remainder by a benzoyl radical; that is, a group of other atoms having their own proper integrity within the molecule. Now, the present science of chemistry presupposes that substances retain their identity so long as the atomic structure of their molecules remains the same, not only in the number-and kind of atoms which go to com-' pose them, but in their relative arrangement to one another, about which, as I understand it, final knowledge is not yet ascertainable. When two molecules come into permanent association, one being an acid and the other a base, a salt results; but chemists do not suppose that such association is of the same kind as that within the molecules themselves. Thus, as has been shown, the association may be broken, and the two substances dissociated, while each resumes its proper characteristics; the molecules retaining throughout their identity. Abel never succeeded in procuring a substance which contained the molecule of the active principle ás such. His monobenzoylated compound had all the atoms of the base, but in atomic association within
Claims 1 and 2 are, however, specifically, limited to “the blood pressure raising principle” of the glands .in chemical combination with another substance. The “principle,” so mentioned, is the organic substance first isolated by Takatnine and does not include any other substance, whatever its properties may be. There is no room for ambiguity, because the word is used to cover only that product which all had been trying to get; that is, the “free base.” Had Abel ever succeeded in isolating his monobenzoylated base, a serious question might have arisen as to whether that was a valid anticipation of the claims of patent No. 730,176, which, as has been seen, do not refer to the “principle”; hut the claims of the present patent are drawn more nicely and speak in obviously chemical terms. The “principle” is the isolated principle which is described in the disclosure, but not the claims, of patent No. 730,176. Nor will it answer to say that the “principle” is chemically combined with the benzoyl radical as mentioned in these claims. In the first place, there is no evidence that the benzoyl elements add to the stability of the compound, and the “nonsuprarenal substance” of the claims must have that effect. But the difficulty goes deeper than that. The principle does not exist at all, as I have said, till it is broken away from the benzoyl radical. It cannot be said to be in combination with the radical, because the very word “principle” presupposes its molecular integrity, not varied by the atomic union of any other group. The purpose of the claims is quite clear, and they speak in technical terms, with a corresponding limitation of scope. It will need no argument to show that it was invention to produce the “principle,” notwithstanding the prior discovery of the monobenzoylated salt.
Similarly of claims 5 and 6, which speak of “the herein-described product of the suprarenal glands.” Whatever the scope of the claims in No. 730,176, the product there described — which is the same as that described in No. 753,177 — is the “crude product,” and that, as I have already shown, is not the same chemical substance as Abel’s base. Indeed, these claims are even more limited than claims 1 and 2, since they are limited practically to salts of the free base, with some inorganic impurities admixed. The patentee could, of course, if he liked, make his claim in narrow language and cover specifically only
However, I cannot interpret claim 3 as so limited. Here the patented product is not defined by the process or the chemical active principle, but by the properties of the product itself. That is in quite a different category and is anticipated by any product, whether chemically identical or not, which possesses the stated qualities. These qualities are those of the “salt,” free from other constituents of the gland. It is anticipated by any substance which will have the physiological activity of the salt, and will be as stable and as pure. I omit reference to the chemical reactions because nothing turns upon these. Does Abel’s salt conform to these requirements ? It is certainly physiologically active, indeed apparently as active as Adrenalin. It is likewise as stable as that product. There remains therefore only the question of its purity; that is, of its freedom from the other organic constituents of the gland. Sadtler testifies that it is so free, and Chandler cannot definitely say to the contrary except as he so infers from its gross appearance (XQ. 159, 160). I must conclude, therefore,'that it does answer the requirements of claim 3.
The only remaining question is whether as a publication it is a valid anticipation. It does not appear to have been ever used in practice; but that is not necessarily conclusive, for it was not merely a tentative experiment without adequate disclosure. On the contrary, it was fully described and, published in well-known medical journals, and the disclosure would have answered the claims of a patent. While it was in a sense a laboratory experiment, it was published as a direction for all who wanted to use it, unlike Moore’s vague disclosures, which were meant: rather for investigators. In view of such publications, Takamine cannot claim to have been the first to 'discover a stable and pure salt having the physiological activity of the suprarenal gland.
’As to the fourth claim, the question depends wholly upon. what meaning- is given to “compound” and what to “constituent.” Chandler, especially when dealing with Von Furth’s zinc sulphate, lays especial stress upon the word “compound” as indicating atomic association in a single molecule, an interpretation which would here result in making Abel’s salts an anticipation.. It is so used in the eleventh edition of the Encyclopedia Britannica, sub tit. Chemistry, and I think it must be so understood in the claim. The word “constituent” would then include those elements of the gland from which it is separated, and from those Abel’s salts have been separated. The benzoyl, radical is not from the gland, but is introduced by the process itself. Such a construction leads to the invalidity of claim 4.
The next alleged anticipating product is Von Furth’s Sulphate. This product was patented to Von Furth in Germany on May 16, 1899, and was offered upon the market in Germany. There is therefore no ground for objecting to it as an anticipation provided that it falls within claims 1, 2, 5, and 6.
The' first question is whether Von Furth succeeded in isolating a salt of the free base, for concededly he did not produce it as a base