Case Name: In Re William L. Hartop, Jr. and Edward P. Brandes
Court: United States Court of Customs and Patent Appeals
Jurisdiction: United States
Decision Date: 1962-12-12
Citations: 50 C.C.P.A. 780
Docket Number: No. 6741
Parties: In Re William L. Hartop, Jr. and Edward P. Brandes
Judges: Before Worley, Chief Judge, and High, Martin, and Smith, Associate Judges, and Associate Judge Joseph R. Jackson, Retired
Reporter: Court of Customs and Patent Appeals Reports
Volume: 50
Pages: 780–803

Head Matter:
311 F. 2d 249; 135 USPQ 419
In Re William L. Hartop, Jr. and Edward P. Brandes
(No. 6741)
United States Court of Customs and Patent Appeals,
December 12, 1962
Robert L. FHblack (Edmund, A. Godula, Watson Leavenworth Kelton <£ Taggart, and Garroll F. Palmer, of counsel) for appellants.
Clarence W. Moore (Joseph Schimmel, of counsel) for tlie Commissioner of Patents.
[Oral argument December 6, 1961, by Mr. Niblack and Mr. Schimmel]
Before Worley, Chief Judge, and High, Martin, and Smith, Associate Judges, and Associate Judge Joseph R. Jackson, Retired

Opinion:
Martin, Judge,
delivered the opinion of the court:
This is an appeal from a decision of the Patent Office Board of Appeals affirming the examiner's rejection of appealed claims-30-34, 38 and 39 of the appellants' application, Serial No. 418,468, for a patent on a "Therapeutic Composition." Certain claims were withdrawn from consideration by the examiner "as not being readable on the elected species" and are not before us. No claim has been allowed.
Each of the claims recites a "stable" solution of a "thiobarbituric acid compound." Claims 30 and 31 are representative:
30. A stable solution of a thiobarbituric acid compound having anesthetic or hypnotic properties comprising a water-free solution of a thiobarbituric acid compound selected from the group consisting of a therapeutically useful thio-barbituric acid and the water soluble salts thereof, dissolved in a [sic] an anhydrous alcoholic solvent consisting of a mixture of a parenterally acceptable water-miscible lower aliphatic monohydroxy alcohol and a parenterally acceptable water-miscible lower aliphatic polyhydroxy alcohol, said solvent having dissolved therein a soluble alcohólate of a parenterally acceptable lower aliphatic alcohol and an alkili metal in an amount providing an alkali metal concentration substantially in excess of that required to maintain the said thiobarbituric acid compound dissolved in said solvent as an alkali metal salt.
31. Á stable concentrated solution of a thiobarbituric acid compound having anesthetic or hypnotic, properties comprising a substantially water-free'solution of a thiobarbituric acid compound selected from the group'consisting of a therapeutically useful-thiobarbituric acid and the water soluble salts thereof, dissolved in an anhydrous alcoholic solvent consisting of a mixture of a parenterally acceptable water-miscible lower aliphatic monohydroxy alcohol and a parenterally acceptable water soluble lower aliphatic polyhydroxy alcohol, said solvent having dissolved therein a soluble alcohólate of a parenterally aceeptabe lower aliphatic alchohol and an alkali metal in an amount providing an excess of between about 5% and 30% by weight alkali metal above the weight of the alkali metal in an alkali metal salt of the said thiobarbituric acid compound dissolved in said solvent.
According to appellants' specification, thiobarbituric acid compounds and salts thereof are important as anesthetic and hypnotic agents, especially for inducing surgical anesthesia of relatively short duration. For the latter purpose, dilute aqueous solutions of water-soluble thiobarbiturate salts are injected parenterally. These aqueous solutions are unstable and must be prepared shortly before use by dissolving the dry salts in water. Appellants, consider it uneconomical to use small, individual-dose ampoules of the dry salts and inconvenient to weight and otherwise handle solid materials when preparing these solutions.
Appellants have discovered that certain concentrated, alkaline, non-aqueous solutions of thiobarbiturate salts are relatively stable, have a suitable shelf life, and, just before parenteral administration, can be easily and conveniently diluted with water to produce a clear solution with a therapeutically effective concentration of the thio-barbiturate but yet with a concentration of organic solvents and alkaline material sufficiently low for safe injection.
Appellants prefer to use as a solvent, a mixture of an aliphatic monohydroxy alcohol such as ethyl alcohol and an aliphatic polyhy-droxy alcohol such as propylene glycol, both alcohols necessarily being parenterally acceptable and water-miscible. With regard to the alkaline-material, the specification states:
Since it is necessary that the therapeutic aqueous dilutions of the- thio-barbiturates have a pH of about 10 and preferably about 10.5 to avoid a precipitate forming on diluting with water, it is highly desirable tó include in the thiobarbiturate concentrated organic solvent solution a parenterally acceptable alkaline reagent in an amount sufficient to provide the aqueous dilution thereof with a pH of about 10 and preferably 10.5. For example, sufficient alkali metal alkoxide is incorporated in the concentrated non-aqueous thiobarbiturate solution to provide an amount of an alkali metal between about 5 and 30% by weight in excess of the weight of the alkali metal contained in the alkali metal salt of the thiobarbiturate composition in solution to effectively prevent precipitation on dilution with water.
It is the concentrated, alkaline, water-free, organic solvent solution of the thiobarbituric acid compound which appellants claim as their invention.
Although the examiner's answer discusses three grounds for rejection of the appealed claims, the board reversed the examiner on two grounds and the claims now stand rejected solely on a ground relating to the utility of the claimed, solutions. This rejection involves several intermingled issues each of which we discuss in detail infra. It may be helpful in understanding our disposition of this case to set forth at this point what appear to be the three main points of the Patent Office position in -this case. These are: (1) that the specification at bar discloses that the claimed solutions, after appropriate dilution, are to be administered to humans, (2) that there is doubt of the "safety" of the claimed solutions when so used, and (3) that "safety" must be demonstrated by injecting the diluted solutions into humans. The proposition of law here involved is that if appellants' solutions are not "safe" for the alleged use, they lack the utility required by 35 TJ.S.C. 101.
Before we discuss the several issues, we will set forth and comment on certain other portions of the record.
During the prosecution of the appealed application, appellants submitted an affidavit by Henry C. Spruth, from which we quote the following significant excerpts:
That under Ms supervision, solutions of thiobarbiturates prepared and held as specified in the several herein designated specific examples of the above-mentioned patent application were subjected to anesthetic efficiency tests, acute toxicity tests, and were studied .to determine the effect of the said thiobarbituric solution of the above-identified application on the hemoglobin of the administered subjects;
That the said anesthetic-effect tests were conducted in accordance with the standard procedure established for the biologic testing of Abbott's "Pentothal" thiobarbiturate compound and comprised injecting rabbits of 1.2-2.0 kg. body weight intravenously (25 mg./kg.) in the marginal ear vein with standard therapeutic aqueous dilutions of the test solution which contained 25 mg. Pento-thal per cc. Induction, depth, and duration of anesthesia were observed.

That the acute toxicity tests were conducted in accordance with the standard procedure used for the biologic testing of Abbott's "Pentothal" thiobarbiturate compound and comprised injecting mice of 18-25 grams body weight intravenously in a tail vein with aqueous dilutions of the test solutions diluted to contain 2.5 mg. Pentothal per ce. Injection time for each mouse was 4 to 5 seconds. The LD6o was determined by conventional methods, i.e.: groups óf mice were given graduated doses until the dose was found which would be lethal to 50% of the mice at that dose. This does is the LDso;
That the results of the above tests on compositions prepared and held under the conditions set forth in the following designated specific examples of said U.S. Serial No. 418,468 are as follows:
*
That from nine of the subject rabbits which had been anesthetised with the composition of Example II of the said patent application Serial No. 418,468, the results of which are reported herein, 5 ml. of blood were withdrawn'through a heart puncture after awakening from the last injection and the individual blood samples subjected to analysis. . . .
That the hemoglobin readings on analysis of the serum from the 5 mL blood sample of each of the nine rabbits mentioned above were less than' y2 gram per 100 ml. and that all samples tested were diluted to 0.2 cc. of blood serum in 5 ce. of N/10 HOI;
That the above subject rabbits from which blood had been drawn by heart puncture were then placed in metabolism cages, overnight urine- samples collected, and the urine samples subjected to urinalysis and hemoglobin determination, the results of which are reported herein in Tables A and B:

That it is affiant's conclusion, based on the above comparative data, that there are no significant differences detween the safety and therapeutic effectiveness of regular "Pentothal" powder, reconstituted, and any of the compositions of the specific examples of the said U.S. patent application Serial No. 418,468 and that the said compositions are safe, effective, and reliable for producing the therapeutic effects set forth in the specification. [Emphasis ours.]
At this point, we will comment briefly on the nature of the "thio-barbituric acid compound" involved in this case. The specification states:
The principal thiobarbiturie acid compound used to illustrate the present invention has been the readily available thiobarbiturate compound, sodium ethyl- (1-methylbutyl) -thiobarbiturate, more generally known as "Pentothal" sodium. It should be understood, however, that the herein disclosed invention is Applicable to other barbituric acid compounds containing an atom or functional group which causes the barbituric acid compound to form a precipitate when admixed with water in the absence of a strongly alkaline reagent, such as most of the thiobarbiturie acid compounds.
Except for two of the anesthesia experiments, all of the data set forth in the Spruth affidavit relate to the use of dilute aqueous solutions of sodium ethyl-(1-methylbutyl)-thiobarbiturate, each prepared either by aqueous dilution of one of appellants' "stable solutions" or by dissolving' "Regular 'Pentothal' powder" in water. The latter "powder" is apparently a commercial material known to be useful as an anesthetic and used by Spruth as a comparison or control substance in testing appellants' "stable solutions."
Subsequent to submitting the Spruth affidavit, appellants also submitted an affidavit of Ralph C. Cox which demonstrates that a 2.5% aqueous solution of "commercial Pentothal containing sodium carbonate" has a pH of 10.65, and that two other solutions, each prepared by aqueous dilution of one of appellants' solutions, each containing after dilution 2.5% Pentothal sodium, one containing 10% and the other 30% excess sodium, have pH values of 11.3 and 11.7 respectively.
Coming then to the various issues, first we address ourselves to the controversy concerning the scope of the utility allegations in appellants' specification. Although appellants urged during the Patent Office prosecution of this case and continue to urge before us that their specification, "has never alleged human use of their composition" and that there is "no specific representation of usefulness in humans" in their specification, it is our opinion that one skilled in the art to which appellants' invention pertains would conclude on reading the specification that appellants intend the claimed solutions, after appropriate dilution, will be useful for injection into humans.
We find support for our position in the following paragraph which appears near the end of appellants' specification :
It is evident that in addition to providing an improved highly stable solution of barbituric acid compounds, such as the thiobarbiturates, the present invention also makes it possible for those desiring to use only small amounts of a thiobar-biturate at any one time to purchase thiobarbiturate solutions in large vials from which the individual therapeutic dilutions can be readily prepared and thereby avoid purchasing small individual dose ampoules of the dry acid salt as was heretofore necessary. Thus, the small purchaser such as the individual doctor can now obtain the same economic advantages as was heretofore possible only for the large institutional users. [Emphasis ours.]
We think the references in this paragraph to "the individual doctor" and to "large institutional users" can be construed logically only to involve use of appellants' invention in human therapy.
We find further support for our position in two standard reference works, "The Merck Index of Chemicals and Drugs," 7th Ed., pages 1039-1040 (1960) and "The Dispensatory of the United States of America," 25th Ed., pages 1419-1423 (1955). Both of these discuss the use and value of dilute aqueous solutions of thiopental sodium.in human therapy. In this connection, it should be observed that thio-pental sodium is the "principal thiobarbituric acid compound used to illustrate the present invention." It would be expected that appellants' claimed solutions would be used in place of solid thiobarbituric acid compounds such as thiopental sodium to prepare dilute'-aqueous solutions for human therapy. Therefore, we hold that the disclosed utility of appellants' claimed invention relates to the treatment of humans.
We turn next to the doubt which the examiner expressed as to the safety of appellants' invention when used for human therapy. Several aspects of this question merit discussion. As shown by the Cox affidavit, supra, two of appellants' solutions diluted for injection into human or lower animal veins have higher pH values than that of a comparable solution prepared from "commercial Pentothal containing sodium carbonate." Although his position is not completely clear to us, it appears the examiner was of the opinion that these pH differences are sufficient that "clinical evidence of freedom from vascular damage at the site of injection is a proper requirement." We note, however, that the examiner has given no reason nor has he cited any authority for this position which seems to be involved somehow with his statements that the 2.5 percent aqueous solution of thiopental sodium previously used clinically has "a pH of about 10" and that such a pH "is high enough to cause local thrombosis of the venous lining if the injection were made so rapidly that dilution with the flow of blood in the vessel and the buffering value of the blood itself did not immediately serve to reduce the pH before the endothelium was damaged by a too irritating contact." Apparently the examiner has assumed that injection of a solution with a pH 11.3 or 11.7 is also likely or, perhaps more likely, to cause this type of vein damage and has not considered that one skilled in the art of parenteral injections would presumably use at least the previous degree of caution when making an injection so as to avoid vascular damage.
So we have merely an opinion by the examiner that vascular dam-' age.at the injection site in human beings is possible when appellants' solutions are diluted and injected.
Next we consider the Spruth affidavit which was submitted by appellants early in the prosecution of this case. In his answer, after noting that the tests described in this affidavit are limited to laborar tory animals, the examiner stated:
Applicants stress the fact that the Examiner did not attack the sufficiency of the showing in the Spruth affidavit itself. This point lacks merit since more extensive tests in laboratory animals still would not have served to settle the question of possible damage by reason of its great alkalinity to the blood vessel at the injection site in human beings.
We observe that tbis statement of the examiner does not criticize the Spruth affidavit as a demonstration that appellants' solution is safe and effective when used to induce anesthesia in rabbits. Moreover, nowhere in the record before us has the examiner or the board questioned this aspect of the Spruth affidavit and, with the concurrence of the solicitor expressed at oral argument, we will assume that safety and effectiveness of appellants' invention in rabbits have been established.
The Patent Office has, however, asked for more than proof of safety and effectiveness in rabbits. This is apparent from the statement of the examiner we have quoted supra. Further, in a letter subsequent to his answer, the examiner stated:
Applicants have not affirmatively demonstrated tbe safety in humans of the claimed highly alkaline solutions employed. Tests in animals will not reveal phlebitis or venous thrombosis produced by excessively alkaline materials excepting by autopsy; in humans, pain directs attention to associated symptoms such as inflammation or coolness of the extremity.
In its , consideration of this case, the board interpreted the examiner's position as being based "on the ground that no clear and convincing proof has been adduced that the claimed composition is safe, effective and reliable for the therapeutic effects set forth in the application." The board affirmed the examiner's rejection on that ground. We think that the following statement from the second board opinion in this case represents adequately and correctly the board's basic reason for its affirmance:
The question here presented is whether the composition claimed will, in fact, attain the purpose for which it is disclosed as useful. We consider Judge Holtzoff's decision in Isenstead v. Watson, 157 F. Supp. 7, 115 USPQ 408, to be applicable here. This decision states "that the Patent Office should be very careful, and perhaps even reluctant to grant a patent on a new medical formula until it has been thoroughly tested and successfully tried by more than one physician."
At this point we wish to point out that although the board, in affirming the examiner, referred to the necessity for proof that the "claimed composition is safe, effective and reliable," neither the examiner nor the board has given any reasons for doubting the effectiveness and reliability of appellants'' solutions in inducing anesthesia in any animal, including humans, and we will assume that upon a showing of safety in human therapy, the examiner and the board would have been satisfied as to all three qualities and would have conceded the compositions to be useful under section 101.
Now we must consider two important questions. The examiner and the board have insisted upon "clear and convincing proof" that the claimed solutions, after appropriate dilution, are "safe" for injection into human veins. As we have already discussed supra, we agree with the examiner and the board that one skilled in this art would learn on reading appellants' specification that the claimed solutions are so to be used. What then is "safe" and what degree of "proof" is necessary in a case like this ?
With regard to the first question, the nature of "safety" in the field of drugs and medicaments, we take judicial notice that many valued therapeutic substances or materials with desirable physiological properties, when administered to lower animals or humans, entail certain risks or may have undesirable side effects. True it is that such substances would be more useful if they were not dangerous or did not have undesirable side effects, but the fact remains that they are useful, useful to doctors, veterinarians and research workers, useful to patients, both human and lower animal, and so are useful within the meaning of 35 U.S.C. 101. The use of drugs in medicine is frequently a matter of balancing risks to save a life. "Safety" ¿3 a relative matter. An example relevant here is the obviously useful, commercially and medically acceptable material, solid thiopental sodium, used by Spruth as a control substance. It appears that this material, although apparently widely used in human therapy, is not completely "safe" for that use. For example, as mentioned earlier in this opinion, the examiner himself has discussed the dangers inherent in the injection of 2.5 and 5 percent aqueous solutions of this material into human veins. Further, in the same regard, the "Merck Index," supra, warns:
Concentrated i.v. solns. (5% or more) may cause local thrombophlebitis, arterial injection causes severe burning pain in periphery of extremity. Urticaria and skin rashes have been reported.
Also, the "Dispensatory of the United States," supra, states at page 1420:
A 2.5 per cent, or less concentrated, solution of thiopental sodium is used for intravenous injection. A 5 per cent solution has been used but it is more dangerous and it may cause thrombosis of the vein because of its alkalinity ;
Further, both of these references devote much space to a discussion of "Human Toxicity," "Toxicology" and "Contraindications."
In view of these known dangers in using thiopental sodium in human therapy, it might be expected that a solution such as that claimed by appellants which contains thiopental sodium would be at least as dangerous to use for the same purpose. Therefore it would be completely unrealistic to insist that appellants' solutions be "safe" for use in human therapy. We do not know what criterion the Patent Office would have used had clinical studies relating to the use of appellants' solutions in human therapy been submitted, but we think the proper criterion is whether appellants' solutions are as safe as the previously and widely used and commercially acceptable solid form of pentothal sodium. It is this criterion which we have in mind in considering the second of our two questions, i.e., what degree of "proof" is necessary to demonstrate this degree of "safety."
The Patent Office has insisted on clinical tests, i.e., tests with human patients, to "prove" that appellants solutions are "safe" for human therapy. We do not know what sort of clinical tests would have satisfied the Patent Office, i.e., how many subjects of what age, sex, physical conditions, etc., and what degree of vascular damage, if any, would have been permissible in a "proof" of "safety," but it- is unnecessary to concern ourselves • with that matter because no clinical evidence whatever has been submitted. But that fact does not mean that there Is no evidence of "safety" in the case at bar. On the basis of tests with rabbits, Spruth has stated in his affidavit:
there are no significant differences between the safety of regular "Pentothal" powder, reconstituted, and any of the compositions of the specific examples of [the application at bar] .
There are three important points involved in that statement. The 'qualifications of Spruth to express such an opinion have not been questioned (see footnote 2) ; the rabbit tests involve a side-by-side comparison of what appellants are claiming with a widely used, commercially and medically acceptable material; in our opinion, rabbits are "standard experimental animals" for testing the safety of thiobar-bituric anesthetics.
Bearing in mind that absolute proof of such a proposition as "safety"- of a drug or medicament is impossible and that "proof" of "safety" is relative with the degree of "proof" dependent on the quantity and quality of the available evidence, bearing in mind what evidence of "safety" has been submitted in the case at bar, and bearing in mind that inherent in the'concept of'the "standard-experimental animal" is the ability of one skilled in the art to make the appropriate correlations between the results actually observed with the animal experiments and the probable results in human therapy, we hold that appellants' claimed solutions have been shown to be useful within the meaning of 35 U.S.C. 101. In holding as we do, we realize that ho clinical evidence has been submitted as to the "safety" of these solutions. Therefore there is lacking that degree of "proof" which such evidence would provide. However, we do not believe that such a degree of "proof" is necessary in view of the factual situation in the case at bar. We think that a sufficient probability of safety in human-Nherapy vhas-beemdemonstrated': in. the-, case >at-- bar • to- -satisfy the requirement of 35 U.S.C. 101 that appellants' invention be useful.
Although the case at bar appears to be unlike any previously before this court, we find support for our position in many of the so-called reduction-to-practice cases decided by this court. Some of these are as follows: Harrison et al. v. Cadwell, 17 CCPA 1024, 39 F. 2d 704, 5 USPQ 91; St. John et al. v. Schulze, 18 CCPA 1050, 47 F. 2d 798, 8 USPQ 507; Payne v. Hurley, 21 CCPA 1144, 71 F. 2d 208, 21 USPQ 624; Goodale v. Lund, 25 CCPA 1148, 96 F. 2d 840, 37 USPQ 696; Chittick v. Lyons, 26 CCPA 1382, 104 F. 2d 818, 42 USPQ 132; Taylor v. Swingle, 30 CCPA 1219, 136 F. 2d 914, 58 USPQ 468; Lustig v. Legat, 33 CCPA 991, 154 F. 2d 680, 69 USPQ 345; Morway et al. v. Bondi, 40 CCPA 917, 203 F. 2d 742, 97 USPQ 318; Schnick v. Fenn, 47 CCPA 1174, 277 F. 2d 935, 125 USPQ 567. Although, the subject, matter of those cases varies widely, in each, the requirements for an actual reduction to practice were at issue, and in each, use was' made of certain laboratory experiments, laboratory-scale equipment, "shop tests," or "bench tests" in an attempt to establish reduction to practice. In some of the cases, the court found actual reduction to practice, had been established; in others, no actual reduction to practice was found. However, running through all nine eases cited is the same expressed or implied' criterion, namely, how would one shilled-in-the art interpret the experiments or tests. If the court was convinced that. one shilled in the art would accept a particular test or experiment as a "possibility" or "reasonable certainty" or-"probability" or that'it', was "reasonably predictable" that a tested invention would opérate as' alleged or have the utility alleged, a reduction to practice was. found; otherwise, the court found no reduction to practice.
Of course, the case at bar differs from the above cases in that, the former involves merely an ex parte establishment of utility rather than proof of an actual reduction to practice in a priority dispute.. Qur citation of those cases should not be construed as a suggestion., that the same standard of proof -is applicable in both types of cases..
However, regardless of the issuance of the patent under the-, circumstances of the case at bar,'there is no question but that the-public must be protected absolutely against the advertising and' sale-' and other distribution of harmful drugs, medicines and the like in all. situations, including this one if such be the case. We believe' that Congress has recognized this problem and has clearly expressed its; intent to give statutory authority and responsibility in this area to-Federal agencies different than that given to the Patent Office.-. -This-, is so because the standards established by statute for the advertise-, ment, use, sale or distribution of drugs are quite different than the-requirements under the Patent Act for the issuance of a patent. For-example, the Federal Trade Commission has been given the responsibility of enforcing the Wheeler-Lea amendments to the Federal Trade; 'Commission Act. Also, the Food and Drug Administration has b.een given the responsibility of enforcing the Federal Food, Drug, and Cosmetic Act.
We anticipate tbe argument that the Federal Trade Commission Act and the Federal Food, Drug, and Cosmetic Act do not protect the-public against the advertising and sale or other distribution of harmful drugs in intrastate commerce and that, therefore, Congress must have intended that the Patent Office act in this limited area. We-would not find this argument persuasive. First, we observe that any statutory authority given the Patent Office in this regard would have' to stem from the provision of 35 U.S.C. 101 that a patentable invention: must be "useful." A comparison of this provision with the detailed provisions of the Federal Trade Commission Act and the Federal' Food, Drug, and Cosmetic Act indicates to us that if Congress had intended to use its constitutional authority under the patent clause to do what it might not be able to do under, the commerce clause, it would have enacted drug patent legislation in detail corresponding to* those two acts.
Second, it must be presumed that Congress is aware that almost all of the,States have enacted legislation which gives to the public a-degree of protection against the intrastate advertising and sale or other-distribution of harmful drugs which, in many cases, approximates that protection given by the Federal Food, Drug, and Cosmetic Act.
There is not the slightest indication that Congress intended that the Patent Office, in the course of its examination of patent applications, close up any small hiatus left by the legislatures of those several States who do not protect their citizens against the instrastate advertising and sale or other distribution of harmful new drugs. As we said in In re Krimmel, supra:
. It is not for ns or the Patent Office to legislate and if the Congress desires to give this responsibility to the Patent Office, it should do so by statute.
Therefore, in our judgment, the board has erred in rejecting the appealed claims. We have held that appellants disclose in their specification that their invention is useful in human therapy. The Patent Office has expressed doubt that the invention will be "safe" for that purpose. Although appellants have not supplied clinical data concerning the actual use of their invention in human therapy, they have supplied evidence and expert opinion based on laboratory experiments with rabbits, the "standard experimental animal" for their purpose, that their invention is as safe as a widely used, commercially and medically acceptable material. In our opinion, this evidence indicates a sufficient probability that the invention will be as safe as this latter material in human therapy to satisfy the statutory requirement that the invention be useful.
Although it is true that the advertising and sale or other distribution of appellants' invention for human therapy in interstate and much of the intrastate commerce will not be legally permissible until experiments with humans have been carried out, we do not think it is within the authority or responsibility of the Patent Office to demand such tests in this particular ease in view of the evidence of record. However, no implication is intended here that clinical evidence should not be demanded by the Patent Office under different circumstances. Each case must be decided on its own sets of facts.
For the foregoing reasons, we reverse the decision of the Board of Appeals.
No evidence of decomposition or decrease in potency in these solutions was observed after 13 months at 40° C. or after 24 hours at 100° C.
Mr. Spruth has been Manager of Abbott Laboratories' Bioassay Laboratories since 1935, and his qualifications, particularly with regard to the conclusions expressed in this affidavit, have not been questioned.
The generic name of this substance appears to be thiopental sodium. "Pentothal" sodium is apparently the Abbott Laboratories trademark for the same substance.
The sodium carbonate was sufficient to provide 30% excess sodium.
According to Rose and Rose, "The Condensed Chemical Dictionary," 5th Ed. (1956), pH is defined as:
"A means of expressing, the degree of acidity or basicity of a solution. Thus at normal temperature a neutral solution such as. pure distilled water has a pH of about 7, a tenth-normal solution of hydrochloric acid () has a pH near 1 and a normal solution of a strong alkali such as sodium hydroxide has a pH of nearly 14. ."
The solicitor in Ms brief bas asked tMs'court to take judicial notice of these two reference works. We do this and will refer to them again hereinafter for other reasons.
See footnote 3.
The examiner noted the Cox affidavit value of pH 10.65 for a 2.5 percent solution prepared from "commercial Pentothal" containing 30 percent excess sodium as sodium carbonate, but stated in his answer that "conventional solutions of 'Pentothal Sodium' do not contain excess of the alkali" and that therefore "their pH is even lower" than the 10.65 value reported by Cox. We conclude, however, from a study of the record before us and the "Merck Index" and "Dispensatory" cited elsewhere in this opinion that the "Regular 'Pentothal' powder" used by Spruth as a control substance in his study of the comparative safety of appellants' solutions (see Spruth affidavit,- quoted in part elsewhere in this opinion) also contains a substantial quantity of the alkaline material, sodium carbonate. Indeed, the "commercial Pentothal" used by Cox appears to be the same as the "Regular 'Pentothal' powder" used by Spruth. Hence it would appear that pH 10.65 rather than pH 10 would be a more realistic value for the comparison the examiner has made.
Examiner's answer.
The examiner has pointed out in his answer that the 5 percent solutions-of thiopental sodium "which were sometimes employed in the past" are not now used because '.'the buffering and diluting powers of the blood at the injection site were often insufficient to cope with the twofold effect required in unit time, so a venous thrombosis frequently occurred." However, the examiner also stated in his answer that these 3% solutions "do not have a substantially higher pH than the 2.5 percent solution." Thus, contrary to the suggestion of the solicitor, the fact that a 5 percent solution of thiopental sodium is more likely to cause vascular damage than a 2.5 percent solution is not evidence that-solutions of pH 11.8 or 11.7 are more -likely to cause vascular damage than solutions of pH 10 or 10.65.
See footnote 3 and excerpts from Spruth affidavit.
For example, the "Dispensatory" states under the heading, "Toxicology," in part as follows:
"Respiratory depression is the most difficult problem in the use of this anesthetic agent. Oxygen for inhalation should be available and used (o.s.). The rapidity with which the patient passes through the several levels of anesthesia with thiopental sodium makes it difficult to recognize the presence of an excessive dose,until ,apnea..is .present. .If.it.is injected in .large, single-doses or too rapidly, respiratory arrest often results. While respiration isi being-restored, the brain rapidly becomes desaturated and a painful stimulus in the operative area often rouses the patient; the tendency is to administer another large dose of the drug which again stops respiration. This not only results in unsatisfactory anesthesia but the effect of painful stimuli on the inadequately anesthetized patient may result inj laryngeal spasm or other untoward effects through stimulation of the autonomic nervous system. "
under the heading, "Contraindications," the "Dispensatory" states in part:
"Thiopental sodium should not be used in the home or office as an anesthetic unless facilities for combating respiratory depression are readily available. It is not advocated for children under 10 years of age, although Holly found it useful in children if administered carefully.. It is not advocated for operations on the upper respiratory tract, head or neck where respiratory obstruction may develop as a result of the operation. It is contraindicated in patients with dyspnea or respiratory obstruction. Alone, it is inadequate for operations requiring complete muscular relaxation and it is not advised for procedures requiring more than 30 minutes. It is not used fqr extensive intrathoracic procedures. Thiopental sodium is not advisable in the presence of severe anemia. Caution is required in patients with severe hypotension or hypertension, myocardial disease, congestive heart failure, sepsis, severe obesity and all poor anesthetic risks. "
Appealed claims 30-34 and 38 encompass "thiobarbituric acid" compounds generally, including thiopental sodium. Claim 39 is limited to thiopental sodium recited therein by its systematic name'. See footnote 3.
We use the phrase "standard experimental animals'' as we did in In re Krimmel, 48 CCPA 1116, 292 F. 2d 948, 130 USPQ 215, where we defined it as "whatever animal is usualiy-iused by those shilled in the art to establish the particular pharmaceutical application in question." That case was decided after the briefs in the instant case had been filed but before the oral argument. Although it is not specifically stated in the record that rabbits are "standard experimental animals" for appellants' purpose as defined in Krimmel, the Spruth affidavit indicates they are such and appellants made a statement to the same effect at oral argument. This staiement was not rebutted by the solicitor.
See for example, 52 Stat. 114-117 (1938), as amended, 15 U.S.C. § 52-56 (1958). In particular, see 15 U.S.C. § 52 (a) which states:
•J 52, Dissemination of false advertisements.
(a) Unlawfulness.
It shall be unlawful for any person, partnership, or corporation to disseminate, or cause ¡to be disseminated, any false advertisement—
(1) By united States mails, or in commerce by any means, for the purpose of inducing, or which is likely to induce, directly or indirectly the purchase of foods, drugs, devices, or •cosmetics; or
(2) By any means for the purpose of inducing, or which is likely to induce, directly or Indirectly, the purpose in commerce of food, drugs, devices, or cosmetics.
See also 15 U.S.C. § 54(a), which states in part:
J 54. Same; penalties.
(a) Imposition of penalties.
Any person, partnership, or corporation who violates any provision of section 52(a) of this title shall, if the use of the commodity advertised may be injurious to health because of results from such use under the conditions prescribed in the advertisement thereof, or under such conditions as are customary or usual, be guilty of a misdemeanor, .
52 Stat. 1040 (1938), as amended, 21 U.S.C. § 301-392 (1958). In particular, see 21 U.S.C. § 355, which states in part:
5 355. Veto drugs.
(a) Necessity of effective application.
No person shall introduce dr deliver for introduction into interstate commerce any new drug, unless an application filed pursuant to subsection (b) of this section is effective with respect to such drug.
(b) Filing application; contents.
Any person may file with the Secretary an application with respect to any drug subject to the provisions of subsection (a) of this section. Such person shall submit to the ¡Secretary as part of the application (1) full reports of investigations which have been made to show whether or not such drug is safe for use; (2) a full list of the articles used as components of such drug; (3) a full statement of the composition of such drug; (4) •a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug; (5) such samples of such drug and •of the articles used as components thereof as the Secretary may require; and (6) specimens of the labeling proposed to be used for such drug.
*•*••
(d) Grounds for refusing application to become effective.
If the Secretary finds, after due notice to the applicant and giving him an opportunity for a hearing, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b) of this section, do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions •or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; or (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insuflicient information to determine whether such drug is safe for use under such conditions, he shall, prior to the effective date of the application, issue an order refusing to permit the application to become effective.
We note in passing, however, the following suggestion of Earl W. Kintner in Federal Trade Commission Regulation of Food, Drug and Cosmetic Advertising, 1 Publishing, Entertainment, Advertising and Allied Fields L.Q., 8, 19 (1961):
"Under this section [15 U.S.C. 5 52] the Commission has jurisdiction whenever it appears that false advertisements of these four classes of products are disseminated. (1) by United States mails, (2) in commerce by any means or (3) where there is a local, dissemination of an advertisement which is likely to induce, directly or indirectly, a purchase-in commerce." [Emphasis ours.]
See footnotes 15 and 16.
U.S. Const, art. I, § 8, clause 8.
U.S. Const, art. I, § 8, clauses. . .
Section 16 of the Uniform State Food, Drug and Cosmetic Bill, accepted and endorsed by the Executive Committee of the Association of Food and Drug Officials of the United States, October 1940, reads in part as follows :
"Section 16. (a) No person shall sell, deliver, offer for sale, hold for sale or give away any new drug-unless (1) an, application with .respect-thereto has, become, effeativeiunder-Section 505 of the Federal Act [21 U.S.C. § 355; see footnote 18, supra], or (2) When not subject to the Federal Act unless such drug has been tested and has not been found! to be unsafe for use under the conditions prescribed, recommended, or suggested, in- the labeling thereof, and prior to selling or offering for sale such drug, there has been filed with the_* an application setting forth (a) full reports of investigations which have been made to show whether or not such drug is safe for use; (b) a full list of the articles used as components of such drug; (c) a full statement of the composition of such drug; (d) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug; (3) such samples of such drug and of the articles used as components thereof as the_* may require; and (f) specimens of the labeling proposed to be used for such drug." T'Insert proper designation of State Officer, Board, Department, etc.]
* According to CCH Food Drug Cosmetic L. Rep. (2d ed., 1959), with changes-through May, 1962, this Section 16 or a provision substantially the same has been enacted into law by 25 of the 50 States. Moreover, this reference also indicates that most of the remaining States have enacted legislation providing varying degrees of protection against the advertising, labeling and sale of unsafe drugs.