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February 18, 1972


Dooling, District Judge.

The opinion of the court was delivered by: DOOLING


DOOLING, District Judge.

 Unfortunately, the present memorandum must be long. However, if the trial program sensibly visualized by Graham v. John Deere Co., 1965, 383 U.S. 1, 17-18, 86 S. Ct. 684, 15 L. Ed. 2d 545 is to be pursued -- and this case peculiarly invites that -- length is inevitable. The prior art brought into the case is very extensive and it requires a fairly discursive description to present it fairly. In addition, there are the background and factual investigations of the sequences of events preceding the invention of meprobamate and relating to the prosecution of the original and continuation applications for the patent in suit.


 The chemical name, or, rather, one chemical name of meprobamate is 2,2-methyl-n-propyl-1,3-propanediol dicarbamate. The diagramatic representations of certain of the compounds involved in the evolution of meprobamate, copied from Chief Judge Friendly's opinion [reversing the preliminary injunction], 443 F.2d at 876, are helpful. The starting molecule is that of propane, a molecule comprising three carbon and eight hydrogen atoms;


 If for the H atom appearing at each end of the propane molecule an OH, representing a hydroxyl radical, is substituted, the result is 1,3-propanediol, which may be represented thus:


 The diol is referred to as a 1,3 diol because a hydroxyl group, OH, is substituted for an H atom at carbon 1 and carbon 3 -- for each carbon atom is given a number usually numbering from left to right, although the literature is not consistent, and, in addition, some of it identifies the carbon atoms by the Greek letters alpha, beta and gamma. It is usual in writing out the diagramatic representations of the diol derivative here involved to show the carbon 1 and carbon 3 parts as CH [2] thus:


 It may be noted that CH [2] is the additive factor in the progression from the methyl group CH [3], to the ethyl group C[2]H[5], to the propyl group C[3]H[7]. Indeed, the series goes on in the literature here involved to C[18]H[37].

 In the present case, the concern is with a "Markush Group" of three 2,2-di-substituted 1,3-propanediol dicarbamates and the disubstitution is by means of substituting for the H atoms attached to the middle C of the propanediol an alkyl radical (that is one of the CH[3], C[2] H[5], C[3] H[7], etc. series) or an aryl radical (characterized by the presence of the benzene ring, represented by a hexagon). The compound of Claim 4 of the patent, meprobamate, is a dicarbamate ester; for the hydroxyl radical at each end of the diol diagram (at carbon 1 and carbon 3) is substituted a carbamate group. The general formula of the carbamate radical is as follows:


 A generalized diagram to illustrate the set of diols and esters to which the products of the patent and their "parent" diols belong is formed by using R[1] and R[2] to symbolize alkyl or aryl groups to be introduced in disubstitution at carbon 2 by using X[1] and X[2] to represent either the hydroxyl group of the starting diol or the organic acid radical substituted for one or both of the hydroxyl groups (OH) in the process of "esterification"; one such organic acid radical substitutable for a hydroxyl group in esterification is the carbamate radical. The generalized formula is as follows:


 In the patent another generalized form is used by treating the CH[2] of carbon 1 and carbon 3 portions as included in the X[1] and X[2] symbols thus:


 The patent in question, No. 2,724,720, issued November 22, 1955, upon application of Frank M. Berger and Bernard J. Ludwig filed August 3, 1953, as a continuation-in-part of an earlier application, filed July 29, 1950, claimed as new products three different, 2,2-disubstituted, 1,3-propanediol dicarbamates, and claimed the three together as a "Markush Group." Directly in issue is only Claim 4 on 2-methyl-2-n-propyl-1,3-propanediol dicarbamate, represented thus:


 It is not essentially denied (although at this point the defendant notes a special exception) that meprobamate was a new composition of matter, a new chemical compound. The "examples" of columns 3 and 4 of the patent describe procedures for obtaining each of the three new compounds. The method described is not new, and, as will appear, there is a history of making carbamates through the use of phosgene, COCL[2]. It has been conceded, for purposes of the present case, that the so-called "Yale I" (Ex. 162) and "Yale II" (Ex. 163) articles are prior art (although it is denied that either inventor knew of the Yale I and Yale II papers at the time of the invention). The Yale II paper at p. 3718 described the making of 2,2-diethyl-propanediol monocarbamate by a phosgene method similar to that described in the patent, but critically differing from it in the molar ratios used. The process, as described in the Yale II paper, produced a very low yield of monocarbamate (2.7% of what would have resulted if all molar quanta had combined in monocarbamate form). Later work by Dr. Berger and his associates indicated that the Yale II procedure would probably yield as a by-product diethyl-propanediol dicarbamate. Yale II did not mention and presumably did not detect any dicarbamate that was produced; the dicarbamate is all but insoluble in the toluene solvent of the Yale II process and in water, which was also involved in the Yale II reaction procedures. The consequence would apparently have been that any dicarbamates would have been in a lost layer of discardable residues between the toluene and water (with their respective solutes) and would have been wasted.

 Apart from that possible, unintended, apparently quite unknown and certainly wholly undisclosed production and existence of one dicarbamate embraced in the original patent application -- and its existence is a chemical probability and not a demonstrated fact -- the dicarbamates of the patent and its applications were both unknown in nature and unsynthesized -- certainly unisolated -- in any known earlier chemical procedure. In that sense each of the three is a wholly new composition of matter and not anticipated in the sense of Section 102 of Title 35. The case is a Section 103 case on unobviousness.

 The issue of infringement is not at this stage of the case a genuine issue either. Davis-Edwards does not deny that it has purchased, used and sold meprobamate without paying tribute to the patent. Davis-Edwards has, however, expressly reserved the point that Carter-Wallace could not enforce the patent against Davis-Edwards because of its alleged patent abuse and anti-trust violations.


 The prior art has been developed in a very full and descriptive way, not in terms of trying to show that there were specific products which themselves indexed the route to the article of the patent but rather by attempting to show that work going back to the last century converged on and, toward the end, immediately implicated the compounds of the patent. To a very considerable extent, the approach has as its premises a special view of the central nervous system depressant drugs as a group and their mode of operation as well as a special view of the nature and mode of operation of meprobamate and the other products of the patent in their asserted roles as anti-convulsants, relaxants of the skeletal muscles and specific tranquilizers for states of anxiety and tension.

 Depressant drugs for use in relation to the central nervous system embrace an immense number of drugs variously identified as anesthetics, analgesics, hypnotics, "narcotics," sedatives and, only more recently and debatably, tranquilizers for specific relief of states of anxiety and tension. An authoritative textbook in the field, copyright in 1941, but in its sixteenth printing in October, 1948 (Ex. AX), defined central nervous system depressant drugs with the note that there were considerable overlappings in the classifications. The classification given was, 1. General anesthetics (e.g. ether, cyclopropane and ethylene); 2. Sedative-hypnotic-soporific drugs, (e.g., barbiturates, chloralhydrate, bromides); 3. Narcotics (e.g., morphine and related alkaloids); and 4. Analgesics and antipyretics (e.g., the salicylates, acetanilid, aminopyrine). In this classification, "anesthesia" meant loss of all modalities of sensation and also loss of consciousness. Surgical anesthesia was differentiated from a lesser "basal anesthesia" obtained by giving sufficient preanesthetic medication inducing unconsciousness but not sufficient depression to permit surgical procedures. Narcosis, variously defined, meant in the classification a condition of analgesia accompanied by deep sleep or stupor, and differing from anesthetic medication in that pain is relieved before sleep or unconsciousness supervenes. Hypnosis in the pharmacological sense meant a condition of sleep produced by a somnifacient drug. Sedation meant a milder degree of hypnosis in which the patient is "awake but calmed." Analgesia meant obtundation of pain, differing from narcosis in relieving pain without stupefaction or unconsciousness. Dr. Berger, one of the co-inventors, differentiated eight classes of central nervous system depressants (Ex. 113). First, sedative-hypnotic-anesthetic; Second, anti-convulsants; Third, analgesics; Fourth, muscle-relaxants -- paralysis; Fifth, anti-anxiety tranquilizers; Sixth, anti-psychotic agents; Seventh, anti-depressants; and Eighth, anti-emetics, and anti-nauseants.

 It is fairly clear from all of the evidence that many of the compounds produced effects that could be accurately described as the specific effect of another class of drugs than that in which the drug in question was primarily classified. An analgesic might have muscle relaxant or anti-convulsant properties or, in the other classification, have both anesthetic and hypnotic or narcotic or analgesic effects. Much might depend on dosage. In general, however, it appears that most, if not all, of the compounds in question when administered in the clinically recommended doses could properly be classified to one or another of the recognized classes.

 In each class of drugs there were in 1950 a great many medically recognized compounds and, in general, they showed a wide range of chemical structures.

 At all the times in question, from the earliest of the references down to date, a very great deal has been known about drug therapy and pharmacology in consequence of clinical experience of demonstrated and measurable effects, and in large areas the predictability of therapeutic effect, the knowledge of dosage and adequate awareness of contra-indications coexisted with an absence of any genuine data that satisfied pharmacologists and therapists of the mechanism by which the drugs produced their effects. In the case of the central nervous system ("CNS") depressants, that was and remains true of a great many of the compounds referred to. Much effort is directed to determining the site of operation of the CNS depressants and the mode of their operation. That work includes not only study of the observable responses of the creature treated with the compound under various tests designed to elicit information about the effect of the drug on different areas of the brain, different paths of neuro-response, the migration of depressant effect and the duration of effect but also analysis of the products of metabolism in an effort to determine what chemical transformations the compounds undergo as they run their course in the body. The evidence notes that while nerve cells, neurons, the nerve tissue making up the brain, are not made up of a wide variety of cells, the differentiation of function in the different parts of the entire nervous system is immense. This observation was intended to bear on the indications that a drug demonstrably operating in one area or against one process will affect other areas and processes as well in certain circumstances, or time phases, or dosages. Hence, repeatedly in the evidence there are references to the primary operation of a compound on the cortex of the brain, on the thalamus, or on the lower spinal region without excluding the idea that the same compound during the same administration operates also on other areas and functions.


 Pursuit of the prior art forming the background of the patented compositions of matter may properly be divided into two major stages, the first stage that preceding the earliest work which Dr. Berger did in the field in England in the mid 1940s, and the second, the period beginning with Dr. Berger's interest in the field during his association with British Drug Houses, Ltd. while he was in England.


 Exploration of the earlier period gave principal but not exclusive emphasis to work done with the carbamates, including N-substituted carbamates, in which other radicals were substituted for one or both of the hydrogen atoms bonded to the nitrogen atom in the carbamate moiety.

 [Detailed description of the prior art omitted.]

 The period preceding Dr. Berger's first work in the field, to the extent exhibited in the prior art and literature presented during the trial, revolves around urethane and its derivatives, in the main. The material demonstrates that a good deal had been done in studying the CNS depressant properties of carbamates, and dicarbamates had been brought into the field of view, as well as the N-substituted carbamates. From the beginning of the cited art, with Binet (Exhibit 169), there was consciousness that the "other" moiety (and, later, the N-substituted group) could also evince independently a CNS depressant effect, and, perhaps in union with the carbamate might in some way contribute to a whole CNS depressant effect or modulate it.

 As for the "other" moiety of meprobamate, Franke (Exhibit BA) had disclosed 2-methyl-2-n-propyl-1,3-propanediol and, while this is uncertain, seems also to have synthesized the diacetate of that diol and that of 2,2, methylphenyl-1,3-propanediol. Methyl propyl carbinol carbamate, or Hedonal, was known and used for its CNS depressant properties. Methyl isopropyl carbinol carbamate had also been disclosed by Bonhoeffer (Exhibit 166) and he claimed soporific properties for it although they have not been shown. Emylcamate of allegedly "much superior hypnotic action" had been disclosed by Thron et al. (Exhibits, AF, AG). Identified by the patentees as diethylmethylcarbinol carbamate and an ester of tertiary alcohol in evident derivation, it can properly be named and diagrammed (Exhibit AF) as a propane derivative, reading from the left CH[3]-CH[2]-C-OCNH[2], with the ethyl and the second meythyl groups diagrammed as disubstituents outriding the carbon one atom adjacent to the carbamate group, and the second oxygen of the carbamate group shown as usual, as double bonded to and located above the carbon of the carbamate group. To emphasize its tertiary alcohol origin as diethyl methyl carbinol carbamate, it could be shown as two ethyl (C[2]H[5]) groups and one methyl (CH [3]) group, each bonded separately to the carbinol carbon. Paquin (Exhibit BR) had disclosed a 1,3 butanediol dicarbamate, and Exhibits BT, BU disclosed a 2-ethyl-1,3 hexanediol dicarbamate.

 While there was, thus, considerable lore about the carbamates, the N-substituted carbamates, the alkyl-carbamate association, diol dicarbamation, and the CNS depressant properties of many of the compositions, the physiological action of the substances, although factually described in terms of the observation of animal tests was not, from later points of view, discriminatingly described.

 Two aspects of the older material and its background should be emphasized.

 First, the carbamates dealt with in the older literature and those implied as readily producible by synthesis were vast in number, and, as what has been said already will indicate, were by no means confined in their activity and utility to the field of sedation, hypnosis and anesthesia. Uses of the compositions in the textile, plastics and lacquer fields were specifically mentioned in some of the material referred to, and there are significant references to the fact that the various carbamates synthesized were intermediates in the development of further organic products. Not only was the carbamate moiety amenable to annexation to an immense variety of moieties similar to the primary, secondary and tertiary alcohols, the diols and diols with substitutions at various carbon points along the carbon chain (which could be very long indeed), but the carbamate moiety itself was, as Kraft and Herbst illustrated, open to a wide range of N-substitutions. In addition to monocarbamation there was the prospect not only of dicarbamation but of "closing" carbamates on each other, as Fischer and Mering (Exhibit CB) illustrated at page b2 in their discussion of diethyl malonyl urea; the authors regarded the class of compositions with which they dealt, derivatives of urea, as an important new class of hypnotics, and they treated their work as producing interesting insights into the relation between structure and sleep inducing properties.

 Second, while there were no doubt already in existence, and there had been for some time in existence certain CNS depressants which had selective action such as, for example, anticonvulsive action, the prior art references and the other background materials do not go beyond the sedative-hypnotic-anesthetic group even when anticonvulsive action is under study, and it appears that muscle relaxant properties, while observed and recorded in the case of animal experiments, were not recognized as a specific kind of useful physiological effect that could be produced without narcosis or hypnosis. The consequence is that even the muscle relaxant effect appears to be, like the anticonvulsant effect where observed, a hypnotic or anesthetic consequence of dosage rather than a primary and selective effect of the drug administered.

 The art cited, while it does not exclude its existence or the existence of literature descriptive of it, does not elucidate a distinction between drugs which act selectively on different parts of the CNS to produce selected effects and drugs which produce a familiar train of general CNS depressant effects that depend on dosage and time lapse to produce mild sedation, sedation, hypnotic effect and surgical anesthesia, and which will in that way also produce anticonvulsive, muscle relaxant and paralytic effects. Muscle relaxation and aversion of convulsion were observed to ensue upon administration of certain of the compositions, but selective effect is not sorted out from the drug-induced total loss of consciousness and total loss of muscular control through the aggregate depressant effect on all senses of nervous action and response.

 It appears long to have been well understood that (from an evolutionary point of view) the oldest parts of the brain, those in the lower and mid-brain, are most closely connected with emotional responses such as joy, hate, rage, love, anxiety, hostility, tension and the like, and, as in the thalamus, those parts of the brain function as connecting centers translating and qualifying stimuli and bringing them into consciousness. The "newer" parts of the brain, particularly the cortex, are associated with individual consciousness, conscious thought, and the formation of judgments. The cortex is spoken of as the "seat of consciousness." It, again, appears to have been well understood that a true hypnotic or sleep inducing drug acts primarily on the cortex, the seat of consciousness, and progresses from the cortex to the thalamus and the limbic regions in the mid-brain as dosage rises toward the anesthetic level. An ideal anti-convulsant must ward off or control convulsions without loss or marked blunting of consciousness and, hence -- ideally -- must avoid depressing the cortex functions so far as possible. Similarly, for some skeletal muscle relaxant purposes, a loss of consciousness or dulling of the sensibilities would be undesirable. A selective muscle relaxant that did not operate also as a sedative or hypnotic or anesthetic would have therapeutic value. The earlier art and background material offered in evidence left these areas largely untracked.


 Dr. Frank M. Berger describes the steps which ultimately led to his and Dr. Ludwig's discovery of meprobamate as starting with work Dr. Berger did in England in the mid-1940's while he was at the research department of British Drug Houses, Ltd.

 [Detailed description omitted.]

 Dr. Berger left the University of Rochester in June of 1949 and joined Carter-Wallace as, in effect, Director of Pharmacological Research and Development.

 In the three preceding years, more or less, at British Drug Houses, Ltd., and at the University and in the work with the Squibb-supplied materials, it must have become increasingly evident, and the various papers reflect the belief, that "mephenesin [see Annex B]-like properties" [anti-convulsant, muscle relaxant, "tranquilizing"] were not of too rare occurrence and were certainly not confined to propanediols or to compounds in the phenoxetol, antodyne (3-phenoxy-propane-1,2-diol) or mephenesin-class. Wholly distinct classes of compounds had some or all of the mephenesin properties, and, nevertheless, new compounds were synthesized and tested even while others were seriously considered for commercial exploitation (such as DEP [see Annex B]), and the shortcomings of the many compounds were as closely studied as their activities. It is possible to see, although this may be the accident of selection imposed by the demands of a particular litigation, that in the CNS depressant field there was an increasing interest and competency in dealing with selectivity of action. References to site of action, speculation about the mechanics of the action, and positive assertion about sites of action and metabolic transformation appear to become more frequent, and differentiation in the nature of the effects shown appears to become more common.

 The period reflects apparent crystallization of views about the role in producing the pharmacological effects of particular radicals, and the relation of that kind of observed effect to structure. But that analysis seemed to turn to an extent on the group or class of compounds with which the particular investigation was concerned. In the period reviewed Dr. Berger seemed to have come to the settled conclusion that the efficacy (in terms of mephenesin-like properties) of the propanediols depended on keeping the hydroxyl radicals available and active in the recipient body. That did not mean that, with the work already done at the University of Rochester on the Squibb samples, inquiry even on propanediol substitutions, was at an end, nor, speaking in terms of mephenesin, only, did the range of alkyl and other substitutions at the various positions offered by the benzene ring and the glycerol moiety already explored exhaust that avenue of approach.

 Work continued to be done to synthesize, test, and choose among compounds, seeking to locate those which invited further inquiry and further production of analogous compounds. There was no absence of suggestions of directions in which it might be fruitful to move. Carbamate esterification of substituted propanediols was among the suggestions with which the prior art was enriched. But it is not possible to say that the state of the art was such as to make carbamate esterification of the propanediols of Berger I (Exhibit 11) the preeminent ...

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