Application of May
| Decision Date | 20 April 1978 |
| Docket Number | Appeal No. 77-600. |
| Citation | 574 F.2d 1082 |
| Parties | Application of Everette L. MAY and Nathan B. Eddy. |
| Court | U.S. Court of Customs and Patent Appeals (CCPA) |
Jerome M. Teplitz, Washington, D. C., attorney of record, for appellants; Marvin R. Stern, John C. Holman, Washington, D. C., Thomas G. Ferris, Norman J. Latker, Bethesda, Md., of counsel.
Joseph F. Nakamura, Washington, D. C., for the Commissioner of Patents; Gerald H. Bjorge, Washington, D. C., of counsel.
Before MARKEY, Chief Judge, and RICH, BALDWIN, LANE and MILLER, Judges.
This is an appeal from the decision of the Patent and Trademark Office (PTO) Board of Appeals (board) sustaining the examiner's rejection under 35 U.S.C. § 103 of claims 1-13 of application serial No. 45,553,1 filed June 11, 1970, for "Alpha-Levo Benzomorphan Analgesics Having Non-Addictive and Morphine Antagonistic Properties." We affirm the rejection of claims 1 and 6, and reverse the rejection of claims 2-5 and 7-13.
Broadly stated, the subject matter of this appeal involves a certain class of analgesic compounds, i. e., pain-relieving drugs, and the method of using them to effect analgesia. More specifically, appellants characterize their invention as residing in the discovery that the acid addition salts of certain levo and alpha-levo isomers of N-methyl benzomorphan exhibit a unique combination of neuropharmacological properties, to wit, analgesic potency comparable to that of morphine coupled with nonaddictiveness and the absence of other undesirable side effects.
The appealed claims read:
An understanding of the subject matter involved in this appeal, as should be apparent from the claims reproduced above, requires, at the very least, a familiarity with certain aspects of stereochemistry and pharmacology.
Appellants' compounds exhibit the condition known as stereoisomerism, namely, for a given R and R1, isomers will exist that differ from each other only in the way the atoms are oriented in space (but are like one another with respect to which atoms are joined to which other atoms). Two stereoisomers will be either enantiomers or diastereoisomers, depending on whether or not the two isomers are mirror images of each other. In appellants' compounds, when R1 is substituted, i. e., when hydrogen is replaced, the resulting structure exists as two pairs of diastereoisomers, referred to by either the prefix alpha (a) or beta (ß), each pair differing from each other in the spacial orientation of the C-9 substituent. Each diastereoisomeric form, itself, has two separate enantiomers, referred to by either the prefix levo (-) or dextro (+), whose structures differ only in being mirror images of each other. Enantiomers are sometimes referred to as optical isomers since the levo and dextro forms are capable of rotating the plane of polarized light to the left and right, respectively. A mixture of equal parts of the levo and dextro forms of a compound is known as a racemate and is referred to by the prefix (±). A racemic mixture is optically inactive.
Applying the above nomenclature to the appealed claims, when R1 is substituted, the claims are limited to the levo enantiomer of the alpha diastereoisomer (the broken line from C-9 to R1 signifies the alpha isomer; a solid line from C-9 to R1 would signify the beta isomer). When R1 is not substituted, the claims are limited to the levo enantiomer (there is no diastereoisomerism unless R1 is substituted).
Switching to pharmacology, in order to determine the neuropharmacological properties of a compound, certain laboratory test properties are ascertained. Those relevant here will briefly be discussed.
Analgesic Activity (E.D.50) is the dose in mg/kg which produces the desired effect in 50% of a given mouse population. A low value is indicative of a potent analgesic.
Physical Dependence Capacity (PDC) is a measure of whether the test drug will suppress withdrawal symptoms in morphine-addicted monkeys which have had their regular morphine injections withheld. PDC is rated as high, intermediate, low, or no capacity. PDC is used as a measure of addiction potential.
Morphine Antagonism is a measure of whether the test drug is capable of producing withdrawal symptoms in a non-withdrawn, morphine-addicted monkey. The antagonist activity is measured against nalorphine, which is the standard morphine antagonist. The precipitation of withdrawal symptoms in addicted monkeys has been taken as evidence that a drug may be assumed to be nonaddicting in man.
Toxicity (L.D.50) is the dose of the test drug in mg/kg which is lethal to 50% of a mouse population. A high value is indicative of low toxicity.
Therapeutic Index (L.D.50/E.D.50) is a mathematical expression of the safety margin of a compound. A high value is indicative of an effective analgesic which is relatively nontoxic.
May,2 which we view as the most pertinent reference, discloses a broad genus of benzomorphans represented by the formula wherein R is a member selected from the group consisting of hydrogen and the hydroxy, alkoxy and acyloxy radicals; R1 is a member selected from the group consisting of hydrogen, methyl, straight chain alkyl, and aralkyl radicals; R2 is a member selected from the group consisting of hydrogen alkyl, methylene and substituted methylene radicals; and R3 is a member selected from the group consisting of hydrogen and the alkyl radicals — and especially compounds of such formula wherein the alkyl portions of the said members contain from 1 to 4 carbon atoms, with the limitation that when R2 is hydrogen R is other than hydrogen.
As to the above compounds May states:
Certain products of this invention have been discovered to show superior analgesic and tranquilizing powers of a potentially medically useful type and there is evidence that they may have less addiction potential and toxicity than presently-used pain-relieving drugs, as well as other advantages including possible oral effectiveness.
It is disclosed that these compounds can be provided as racemates, as separated optical isomers, and as separated diastereoisomers. It is further disclosed that virtually all of the neuropharmacologic activity is due to the levo, as opposed to the dextro, isomer.
May states that of the benzomorphans forming the subject of his invention, those which have been evaluated by animal tests include:
wherein R is a member selected from the group consisting of hydrogen, hydroxy and methoxy and R1 is a member selected from the group consisting of methyl and phenethyl, R1 being methyl when R is other than hydroxyl.
The benzomorphans corresponding to the above general formula were preferably administered in the form of their salts, "the hydrobromide and hydrochloride salts being especially suitable."
Of particular significance is the express disclosure of a-(-)-2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan, which is a species within appellants' claim 1; May is silent on whether or not this specific compound was found to be addictive, but he does state that its therapeutic index is superior to that of morphine sulfate. With respect to a -(±)-2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan, the racemate of the above alpha-levo compound, May indicates that it showed physical dependence liability in monkeys comparable to morphine, and that the beta racemate is the analgesically more potent diastereoisomer. Finally, with respect to the a -(-) and ß -(±) forms of 2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan, May comments that they are "promising candidates for clinical use."
Chignell et al.3 expressly disclose, inter alia, a -(±)-2,9-dimethyl-2'-hydroxy-5-propyl-6,7-benzomorphan, which is the racemate of the compound in appealed claims 5 and 10; the beta diastereoisomer is also disclosed, and is indicated to be analgesically more potent than the alpha isomer. They further indicate that the alpha racemate has an E.D.50 comparable to morphine, while having, like other members of the alpha series, little or no capacity to suppress withdrawal symptoms in monkeys, i. e., little or no PDC. It is stated that a nearly complete separation of these two parameters is seen with the alpha isomer.
Beckett et al.4 indicate that the analgesic activity of the benzomorphans resides chiefly in the levo isomers.
Fullerton et...
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