Application of Carabateas
| Decision Date | 27 May 1965 |
| Docket Number | Patent Appeal No. 7266. |
| Citation | 345 F.2d 1013 |
| Parties | Application of Philip M. CARABATEAS. |
| Court | U.S. Court of Customs and Patent Appeals (CCPA) |
Laurence & Laurence, Washington, D. C. (Dean Laurence, Herbert I. Sherman, Washington, D. C., of counsel), for appellant.
Clarence W. Moore, Washington, D. C. (J. E. Armore, Washington, D. C., of counsel), for the Commissioner of Patents.
Before WORLEY, Chief Judge, and RICH, MARTIN, SMITH, and ALMOND, Judges.
This appeal is from the decision of the Board of Appeals affirming the examiner's rejection of claims 1 and 2 in patent application serial No. 860,368, filed December 18, 1959, for "Compositions and their Preparation." Product claim 7 has been allowed.
Appellant's invention, in its composition aspect, which is all we are concerned with in this appeal, is described in the specification as "residing in the concept of a composition having a molecular structure in which a lower-acyloxy substituent is attached to the remaining 4-position of 4-aryl-1-omega-aromatic-omega-oxo-(lower - alkyl)-piperidines." A stated object of the invention is "to provide useful * * * substituted-piperidines having a novel combination of substituents attached to the 1- and the 4-positions of the piperidine ring." Whereas appellant acknowledges the existence of piperidines having a variety of substituents, including aryl and lower-acyloxy, in the 4-position and piperidines having an omega-aromatic-omega-oxo-(lower-alkyl) group in the 1-position, it in his contention that the invention, for the first time, provides piperidines bearing all three of these substituents, and that these piperidines are not only structurally unobvious but possess unobvious or unexpected beneficial properties.
The subject matter on appeal and its relation to the prior art can best be described by the following structural formula, wherein the ring positions are designated by arabic numbers:
Claim 1 defines the compound wherein R is hydrogen, that is, 1-(3-oxo-3-phenyl-propyl) -4- phenyl -4- propionoxypiperidine. Claim 2 defines the compound wherein R is CH3, that is, 3-methyl-1-(3-oxo-3-phenyl-propyl) - 4- phenyl -4-propionoxypiperidine. Both claims have been treated together, below and in this court. We will continue to treat them together and refer hereinafter to the claimed compounds simply as "appellant's compounds." It will be observed that the "4-aryl," discussed above, is 4-phenyl and the "1-omega-aromatic-omega-oxo-(lower-alkyl)" is 1-(3-oxo-3-phenylpropyl), the "3" in this expression meaning the third or "omega" (end) carbon atom in the "propyl" group counting from the piperidine ring, as opposed to the "3-position" in that ring.
For the most part, all of the above discussed portions of appellant's compounds can be ignored since structurally speaking they differ from the compounds of the primary reference in the nature of the substituent in the "other" 4-position, that being propionoxy in appellant's compounds.
Although not per se part of the instant appeal, the so-called "process aspect" of appellant's invention is described in the specification "as residing in the concept of reacting a 4-aryl-1-omega-aromatic-omega-oxo- (lower-alkyl) -4- piperidinol with a lower-acylating agent," an acyl anhydride or an acyl halide being preferred. This is admitted to be a well known type reaction for preparing "esters," which appellant's compounds are, and should be observed as involving a rather large alcohol, the piperidinol, and a smaller (relatively speaking) acyl compound as reactants. Thus, the compound of claim 1 is prepared by reacting 1-(3-oxo-3-phenylpropyl) -4- phenyl -4- piperidinol hydrochloride with propionic anhydride and the compound of claim 2 is prepared by reacting 3-methyl-1-(3-oxo-3-phenylpropyl)-4-phenyl-4-piperidinol hydrochloride with propionyl chloride, the product in each case being treated with aqueous sodium hydroxide solution in order to convert it to the free base form, as it appears in the claim. The point about process is mentioned only because appellant makes the argument that his compounds are sometimes termed "simple esters" by reason of their having been prepared from a rather complex alcohol and a small acyl compound, citing a footnote in our In re Ward decision, 329 F.2d 1021, 51 CCPA 1132, and that this renders his compounds structurally unobvious over the art compounds since the latter comprise a rather simple alcohol moiety and a large acid or acyl moiety. Furthermore, so the argument goes, "all students of organic chemistry"
O | | know that an ester, R-C-OR', cannot be expected to behave like, or have properties like, the "reverse"1 O | | ester R-O-C-R', unless R and R' are closely similar in structure. We will answer this contention below.
Appellant's compounds "possess the inherent applied use characteristics of exerting a pronounced analgesic effect in animal organisms, as evidenced by pharmacological evaluation in rats according to standard tests procedures." Specifically, the compounds of claims 1 and 2 have been shown to possess, respectively, 9 times and 6 times the analgesic activity of the compound of the primary reference cited by the examiner. The results of this showing have been admitted by the examiner, the board, and the Patent Office Solicitor.
The prior art of record is:
Elpern I 2,846,437 Aug. 5, 1958
Elpern II 2,850,500 Sept. 2, 1958
Pohland II 2,904,550 Sept. 15, 1959
Pohland III 2,951,080 Aug. 30, 1960
Cutler et al. 2,962,501 Nov. 29, 1960
Braenden et al., "Bull. World Health Organ.,"
Vol. 13, pp. 956 and 962 (1955)
Cutler, the primary reference, relates generally to a class of N-substituted piperidine compounds which are "highly potent analgesics." They are prepared through a sequence of steps, the first intermediate products being a group of compounds which includes the ethyl ester of N-substituted-4-phenyl-4-piperidine-carboxylic acid. Structurally, this compound is the "reverse ester" of the compound of claim 1, it is specifically named in the reference (as its hydrochloride salt), and the intermediates of which it is a member are said to "themselves have a high degree of analgesic activity" and "are themselves potent analgesics." No particular test results or data in this regard are given.
In an effort to establish that esters, closely related to2 and of the type represented by the appealed claims, frequently exhibit substantially equivalent analgesic properties with respect to their "reverse esters," the examiner cited two pairs of secondary references, Elpern I and II and Pohland II and III.
Elpern I discloses lower alkyl 4-phenyl-1-(substituted-alkyl) piperidine-4-carboxylates, i. e., compounds of the formula
wherein X is a lower alkylene group, Z can be oxygen, and Ar can be phenyl. The compounds are said to be "many times more potent as analgesics than meperidine * * *." Specifically, ethyl 4-phenyl-1-(3-phenoxypropyl) piperidine-4-carboxylate (as its hydrochloride salt) was found to be approximately twelve times as effective an analgesic as meperidine hydrochloride. The "1-(2-phenoxy-ethyl)" homolog was found to be about six times as effective as the same standard compound and the "1-(4-phenoxy-butyl)" homolog three times as effective as meperidine hydrochloride. In each of these tests, the compound was administered intraperitoneally in aqueous solution.
Elpern II discloses, inter alia, the "reverse esters" of Elpern I, hence of the type on appeal. They are described as being "many times more effective than the commercial analgesic meperidine hydrochloride" and it is further said that they "can be formulated in the manner conventional for potent analgesics * * *." The compound 1-(3-phenoxy-propyl)-4-acetoxy-4-phenylpiperidine, as its hydrochloride salt, was found to be approximately 180 times as potent an analgesic as meperidine hydrochloride when measured subcutaneously, and 24 times as potent as meperidine hydrochloride when measured intraperitoneally. In addition, the Elpern II compounds are said to possess "a relatively low toxicity * * *."
The Pohland references are, we believe, cumulative to the showing of the above discussed secondary references and accordingly will not be considered since it is believed unnecessary...
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