Full opinion text
MEMORANDUM INCORPORATING FINDINGS of FACT and ORDER on ISSUES of VALIDITY and INFRINGEMENT 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. PRELIMINARY MATTERS 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 CH2 thus: It may be noted that CH2 is the additive factor in the progression from the methyl group CH3, to the ethyl group C2H5, to the propyl group C3H7. Indeed, the series goes on in the literature here involved to Ci8H37. In the present case, the concern is with a “Markush Group” of three 2,2-di-sub-stituted 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 CH3, C2 H5, C3 Hr, 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 Rx and R2 to symbolize alkyl or aryl groups to be introduced in disubstitution at carbon 2 by using Xx and X2 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 CH2 of carbon 1 and carbon 3 portions as included in the Xi and X2 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-disubsti-tuted, 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-l,3-pro-panediol 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, COCl2. 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-propa-nediol 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. BACKGROUND — “CNS DEPRESSANTS” 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-eonvulsants, 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-psychotie 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 m 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. SCOPE AND CONTENT OF THE PRIOR ART 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. THE EARLIER PERIOD 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 Bi-net (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-l, 3-propane-diol and, while this is uncertain, seems also to have synthesized the diaeetate of that diol and that of 2,2, methylphenyl1,3-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 CH3-CH2C-OCNH2, 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 (C2H5) groups and one methyl (CH3) 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, antieonvulsive action, the prior art references and the other background materials do not go beyond the sedative-hypnotic-anesthetic group even when antieonvulsive 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 byproduce antieonvulsive, 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. THE SECOND PERIOD, FROM THE EARLIER WORK WITH MEPHENESIN UNTIL DR. BERGER’S TRANSFER TO CARTER-WALLACE. 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-l,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 crystalization 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 suggestion of the art or the evident first choice of the investigator interested in improved and prolonged mephenesin-like properties. THE PERIOD OF THE DISCOVERY [Detailed description omitted.] The course of experimentation that finally did lead to the discovery resulted from a meeting between Dr. Berger and Dr. Ludwig on or about January 13 of 1950 reflected in the notebook page marked Exhibit 16k. The discussion resulted in an apparent program which reverted emphatically to DEP, the di-ethyl propanediol which Dr. Berger had recommended for further work and possible commercial exploitation to Squibb. The program visualized preparation of mono and diglycine derivatives of DEP, of mono and dicarbamate esters of DEP, and of mono and di acid succinate esters of DEP. On this same page Dr. Ludwig also outlined the procedures for carrying out the program. [Description of detailed testing and formulation of the original application omitted.] THE EXECUTION OF THE APPLICATION Defendant questions the propriety of the execution of the oath appended to the application for patent, since it might appear that Dr. Ludwig had “signed the application and the assignment in the spaces indicated” without having his signature notarized and that, in consequence, the completed application and oath as filed were never in fact sworn to by Dr. Ludwig before the notary public, and, moreover, could only have been sworn to by him without the page containing the last part of Example 4 and all of Examples 5 and 6 and without Claim 10. (See Exhibits 55 and 2.) Dr. Ludwig’s recollection was, in substance, that after he had prepared the sheet containing the completed and revised Example 5 and new Example 6, he clipped that page to the sheaf of pages including the oath and the assignment form, appended his signature and then turned the whole sheaf over to Dr. Berger, but that later he and Dr. Berger together went to the notary public and he again executed an oath and assignment that formed part, as he recalled it, of a freshly supplied oath form. The form and dating of the oath (Exhibit 2) support Dr. Ludwig’s impression that he completely executed a new oath, and it is consistent with the correspondence referred to above that when the patent application was returned to counsel in the letter (Exhibit 57) of July 26th, the application was complete in text except for a text for Claim 10 and except that the page containing Examples 5 and 6, as prepared by Dr. Ludwig, was not on the same sort of paper as the rest of the application, and comprised a self-complete page rather than a page containing also the ending part of Example 4 as in the final application. Finally, the application did not then contain Claim 10, and it is clear from patent counsel’s letter, Exhibit 58, that patent counsel retyped the page containing the end of Example 4 and all of Examples 5 and 6 and either retyped the page containing Claim 10 or added Claim 10 to the old page. It is clear, too, from the letter that it was then sent off to Washington in its “revised” form without being re-submitted to the patent applicants for a further re-execution. 35 U.S.C. § 115 requires that “The applicant shall make oath that be believes himself to be the original and first inventor of the . . . composition of matter . . . for which he solicits a patent,” and it requires that he make oath before a person authorized by law to administer oaths. Rule 56 of the Rules of Practice of the patent office provides that the patent office may strike from its files any application signed or sworn to in blank or without actual inspection by the applicant, and any application altered or partly filled in after being signed, and — of course — any application fraudulently filed or in connection with which any fraud is practiced or attempted. Under Rule 57, the signature to the oath is accepted as the signature to the application “provided the oath is attached to and refers to the petition, specification and claim to which it applies.” The requirements of Section 115 and of the implementing rules are concerned with substance and not with form. Everything that at the time the patentees supposed that they had invented and intended to claim was before them when the oath was made, including the idea of a species claim for DEP dicarbamate as a composition of matter and not limited by use. The application as filed faithfully presented to the patent office, although partly in retypewritten form, all that the applicants had sworn to and only what they had taken oath was comprised in their invention. Dr. Ludwig, to be sure, did not compose and forward the utterly plain and exactly definitive language of Claim 10-“the compound 2,2-diethyl-l,3-propanediol dicarbamate.” But his memorandum, Exhibit 55, mandated exactly that claim if patent counsel decided to adopt Dr. Ludwig’s recommendation as forwarded to him through Dr. Berger and Mr. Brewer. No defect in the execution of the original application for patent is found to exist. NATURE OF THE APPLICATION In form the original application as filed was simplicity itself. The invention was described as propanediol dicarbamates, that is, 1,3-propanediol dicarbamates with disubstitution of alkyl or aryl radicals having one to six carbon atoms at the middle carbon of the propane chain. The disubstituted radicals can be the same or different ones. So far as properties and implied uses were concerned, the application said simply “we have discovered that the 2,2-disub-stituted-1,3-propanediol dicarbamates of the invention possessed marked anticonvulsant properties.” The DEP dicarbamate is described as “especially effective as an anticonvulsant, possessing an action of considerable duration and intensity.” Much of the application is devoted to the method of preparation; it is described for DEP dicarbamate in Examples 1, 2 and 3 and Example 1 gives some of the physical properties (appearance, water solubility melting point and chemical composition); Example 4 describes the preparation of 2-ethyl-2-n-butyl-l,3-propanediol dicarbamate and Example 5 describes the preparation of 2-ethyl-2-phenyl-1,3-propanediol dicarbamate. Example 6, the one introduced on July 20, is the 2-methyl-2-n-propyl-l,3-propane-diol dicarbamate or meprobamate. Ten claims were presented. Claim 1 was for the class of 2,2 disubstituted propanediol dicarbamates with the substituent groups to be alkyl or aryl groups having not more than six carbon atoms. Claim 2 is the same except that it is limited by the expression “For anticonvulsant purposes.” Claim 3 is “For anticonvulsant purposes, the compound” DEP dicarbamate. Claim 10 was exactly the same as Claim 3 except that it omitted the limiting phrase, “For anticonvulsant purposes.” Claims 4 through 9 were method claims directed to producing the compositions of the patent. PROSECUTION OF 1950 APPLICATION In early February 1951 the examiner rejected all of the claims. Claims 1 and 2 and 3 and 10 were rejected as duplicate, evidently because the addition of the words “For anticonvulsant purposes” did nothing to differentiate the claims. Claims 4 through 9 were rejected on the substantive ground that the methods described were not patentable over Baird, Exhibit J. The claims on the new compositions of matter, that is, the claim for the class and for the DEP dicarbamate were then rejected as not patentable over Baird in view of Berger’s own 1949 article, Exhibit 11, in which he described the anticonvulsant properties of the parent propanediols. The Examiner said that Baird suggested that the particular glycols of Berger can be converted to their dicarbamates and such esters would not be patentable particularly since Berger showed that parent diols were anticonvulsants. The Examiner said, “Their esters would be expected to have similar properties. To convert Berger’s glycols to their esters corresponding to other glycol esters of the same acids as taught by Baird is not deemed to involve [patentable] invention.” The applicants in response (July 23, 1951) cancelled all claims except Claims 1 and 10, the claim for the group of new compositions of matter, and the species claim for DEP dicarbamate. The argument for allowing the claims was that they defined new compounds having properties “not like the most immediately related compounds .... The dicarbamates are more potent and considerably .longer acting than the diols or their ordinary esters. This is believed to be due to the incorporation into the molecule of the nitrogenous moiety which enhances the physiological properties of the diol. In contrast, the combination of acetate or benzoate radicals with the diol markedly reduces its physiological effect.” It was argued that patentability flowed from the “unexpected discovery” that the type of activity was considerably beyond that predictable from the known properties of the parent diols and their “ordinary” esters, that the claimed products possessed “unexpected properties” not ascertainable from knowledge of Berger and Baird, and that it was (therefore) immaterial that Baird suggested that Berger’s diols were convertible to their carbamate esters. Under date of July 11, 1952, the rejection was reiterated as to both claims on the ground that they were not patentable over Baird in view of Berger or conversely. The argument of “unexpected discovery of the type of activity of the claimed compounds,” the Examiner noted, was not substantiated by any verified showing. The Examiner said that the compositions of the invention “have the same type of anticonvulsant properties as the corresponding unesterified glycol of record.” Under date of July 7, 1952, patent counsel answered requesting reconsideration of the rejection of the claims on the ground that an accompanying affidavit of Dr. Berger’s contained the required proof of unexpected properties. THE AFFIDAVIT OF JULY 3, 1952 The affidavit, sworn to July 3, 1952, (as to which see 443 F.2d at 882-883) first briefly described the electroshock test method used and then presented data showing the mean protective dose, expressed in millimoles per kilogram of animal weight, for 5 of the 2,2-disubsti-tuted propanediol dicarbamates, and that the mean protective dose was smaller for the dicarbamate in each instance than for the parent diol except in the case of ethyl-phenyl propanediol dicarbamate. The other disubstituents were (1) methyl ethyl, (2) methyl n-propyl, (3) methyl iso-propyl, and (4) ethyl ethyl. The affidavit asserted that the tabular data showed that many of the dicarbamates possessed considerably greater protective action than their parent compounds and that the finding was unusual because “many other esters of these compounds which have been examined do not show such an increase in anticonvulsant strength.” Two varieties of tests had been used in the discovery and follow up period. Preceding the filing of the July 3, 1952 affidavit, these were electroshock tests and metrazol tests. DEP diacetate electroshock data existed as shown in Exhibits 16t, 16u, and 16v, all pages from the notebooks, and these data have been correlated and tabulated in Exhibit 110-A. That Exhibit translates the milligram dosages used in the notebook pages to the molar basis used in Exhibit 153 (the Berger and Ludwig 1950 paper on DEP homologues and esters) and in the July 1952 affidavit, and some data for the translation show in Exhibit 153. The data would not support a conclusion that DEP diacetate was either longer lasting or more intense in initial effectiveness than DEP. The data are meager and not wholly consistent, as shown by the implicit disagreement in the figures for the 620 milligram dose in the June 8, 1950 experiment (Exhibit 16t) and the August 27, 1951 experiment (Exhibit 16v), and the difference in reported effectiveness to be inferred from the data on the 1950 800 milligram dose and the 1951 940 milligram dose. One DEP datum is omitted from Exhibit 110-A, that is, the test at 60 minutes and 420 milligrams on October 13, 1950, given in Exhibit 16u, which showed 3 of 10 mice protected under electroshock test. Prolonged effectiveness for the diacetate is shown only at the 90 minute intervals and only at the level of 4.35 and 5.53 millimoles per kilogram of animal weight. If only the electroshock data are considered, there was no failure of frankness in contrasting the unimpressive properties of other esters of the parent diols with the enhancement of parent diol properties displayed by their dicarbamates. But there were also in existence when the affidavit was written the data underlying Exhibit 153, the Berger and Ludwig article entitled “The Anticonvulsant Action of 2,2-diethyl-l,3-propanedioI (DEP) and Some of its Homologues and Esters” published in September 1950 and apparently based on work done between January 13, and April 28, 1950. The data and discussion in the article reiterated that under metrazol testing DEP produced “a very marked elevation of [convulsive] threshold,” and the authors showed that the diacetate of DEP also “produced a marked increase of threshold” which decreased more gradually than that of DEP (Exhibit 153). The data are charted in. Exhibit 153, which includes also data on DEP disuccinate. The paper notes that the disuccinate and dibenzoate esters of DEP produced only insignificant elevations of threshold and were practically inactive by metrazol testing. The monoacetate of DEP is said to have behaved like DEP. The control and disuccinate data given at Exhibits 16o, 16z and 16aa and in Table 2 of Exhibit 153 show that DEP disuccinate had little if any anticonvulsant activity, especially as contrasted with the strong anti-convulsant effect of DEP. The summary of the article (Exhibit 153) emphasized that DEP possessed very strong antagnostic properties to the convulsant and lethal effects of metrazol, strychnine and picrotin in doses which did not possess either hypnotic or anesthetic action. Again, it was noted that, “The duration of action of the drug is short.” After remarking that several other 2-substituted-l,3-propanediols possessed anticonvulsant activity of an order similar to DEP’s but were not appreciably longer acting, the summary continued, “The diacetate of DEP has a less intense but more prolonged action than the parent compound. Other esters of DEP show no advantages over the parent compound.” The July 1952 affidavit could fairly present Table I and assert that the dicarbamates had “greater protective action” than the parent diols, and that other esters of the diols do not show such “increase in anticonvulsant strength” notwithstanding the points made in the September 1950 article (Exhibit 153) and the earlier 1949 Berger and Riley paper (Exhibit 14) on “The Preparation and Pharmological Properties of the Acid Succinate of . (Myanesin) [Mephenesin].” The point of the paragraph including the table and the followup remark is made against the background of the earlier belief (Exhibit. 14, 153) that the esterifying moiety would serve the limited role of protecting the pharmacological activity of the parent moiety without modifying its pharmacological effect; the paragraph embodies the new perception — expressed in patent counsel’s remark at page 2 of the July 23, 1951 response (Exhibit 2, page 14), that the enhancement in physiological properties of the parent diol was believed to be due to incorporating into the molecule a “nitrogenous moiety.” The paragraph starting at page one and running over page two of the July 1952 affidavit and giving the Table I data is addressed to that idea of enhancement of pharmacological properties in terms of additive or combination pharmacological effect. The idea is more briefly stated in the next paragraph of the affidavit with the simple and flat statement that many of the carbamates are distinctly better than their parent compounds and that other esters are inferior in action to their parent compounds or completely lack any action. The last paragraph of the affidavit turns to the second idea, that of longer duration. It flatly states that “many of the carbamates” also differ from the parent compound in possessing action of longer duration, and this is supported by a reference to electroshock procedures. The only illustration given is DEP carbamate, which is said to have a similar order of efficacy at the 30 and 90 minute intervals under electroshock testing, while DEP itself does not possess any protective action 90 minutes after administration. Could Dr. Berger fairly put in both the paragraph about improved pharmacological properties and the paragraph about prolongation of effect without mentioning the diacetate experience and referring back to the mephenesin acid succinate with its “less intense but more persistent effect” (Exhibit 14) when contrasted with the parent diol mephenesin ? Exhibit 14, the Berger and Riley paper, which discussed among other things the mephenesin acid succinate, was prior art (and was referred to in Judge Friendly’s opinion as “Berger II,” 443 F.2d at 877). The 1950 paper (Exhibit 153) was not prior art but the matter that it reported could fairly be said to be a part of the program, in its broadest sense, that Dr. Berger continued to pursue at Wallace Laboratories in the search for an improved compound having mephenesin-like properties that would be marked by a longer duration of effect. It is not enough to say that the diacetate data of Exhibit 153 are metrazol data and not electroshock data. Electroshock data may have come into wider use and may have their own specificity of testing superiority, but the 1954 paper (Exhibit 179) on the “Pharmacological Properties” of meprobamate adverts to and tabulates metrazol antagonism data at its table 4, page 420 and includes in the summary at page 422 remarks on the ability of meprobamate to antagonize the convulsant and lethal effects of metrazol and of strychnine and adds that, “It also prevents the occurrence of the tonic extensor phase of maximal electroshock seizures and prolongs barbiturates anesthesia.” In the sharply telescoped final passage to the diearbamate point, the 1949 and 1950 papers, (Exhibits 14 and 153), belong to the next earlier generation of esterification thinking. They related to an idea of body metabolism that would explain prolongation of action as caused by slowing the oxidation of the parent moiety, slowing the pace of the release of the propanyl moiety to activity. The 1949 paper, Exhibit 14 at pages 269, 274, indicated the view that the effect of the acid succination of the mephenesin was to retard the breakdown of the mephenesin succinate into the active agent, mephenesin, and the inactive protective agent, the succinate acid. A diluted and, therefore, necessarily weaker mephenesin effect would be produced, but the slow breakdown would assure continuance of the diluted effect over a longer period. Esterification was viewed as furnishing a brake on the release into action of the pharmacologically unchanged parent diol. The 1950 paper, Exhibit 153, goes no farther than the 1949 paper to which it refers. Omission of all reference to the diacetate prolongation data is consistent with the progress of thinking. Dr. Berger's letter of April 2, 1951 to patént counsel, Exhibit EZ, furnished the ideas incorporated in the response of July 23, 1951; he there points out that dicarbamation enhanced physiological properties and that in contrast acetate and benzoate esterification sacrificed pharmacological properties. Dr. Berger covered the central ideas in part 5 of hjs letter, saying that, “The dicarbamates, however, are more potent and considerably longer acting than the diols or their ordinary esters. This is believed to be due to the incorporation into the molecule of a nitrogenous moiety which enhances the physiological properties of the diol. In contrast, the combination of acetate or benzoate radicals with the diol markedly reduces its physiological effect. We have accumulated considerably (sic) data showing the relative anticonvulsant potencies and duration of action which supports this contention. This data (sic) can be submitted at this time if it is felt that a presentation would help convince the examiner that the type of activity possessed by these dicarbamates is considerably beyond that which could be predicted on the basis of existing knowledge of the activities of the substituted propanediols themselves and ordinary ester derivates of these substituted propanediols.” Nothing appears in the record, and nothing developed in the course of the testimony of Dr. Berger (or of Dr. Ludwig), to indicate that the failure to draw the examiner’s attention to the 1950 diacetate data of Exhibit 153 represented a conscious suppression, or that the idea of affirmatively withholding them occurred either to the Dr. Berger or to counsel (the latter of whom did not appear to have known about the existence of the data). The conclusion is that the omission to mention the diacetate data was not a conscious withholding or suppression of material thought to be relevant and damaging but resulted from the nature of the argument urged and the implicit discarding of the earlier theory that protective esterification prolonged activity by acting as a governor on the rate of oxidation of the parent diol without interfering with the nature of the pharmacological activity or its mechanics of operation. REJECTION OF ORIGINAL APPLICATION Under date of March 12, 1953 the examiner again rejected the two claims remaining in the case, Claims 1 and 10, as lacking invention over Baird in view of Berger I or conversely. The examiner reiterated that Baird suggested the dicarbamation of Berger’s glycols and that the esters were therefore not patentable, particularly since Berger had shown that the 2,2-dialkyl substituted-1,3-propanediols were anticonvulsants, and the esters could be expected to have similar properties. The examiner concluded that for Berger, to convert his' glycols to esters that corresponded to other glycol esters of the same acid as taught by Baird did not involve patentable invention. To the argument of an unexpected discovery of the type of activity as compared with prior art compounds the examiner answered that the affidavit of July 9, 1952, did not substantiate it, since ethyl phenyl diearbamate was within the group of Claim 1 and yet Table 1 in the affidavit showed that the 2,2-ethylphenyl-1,3-propanediol had properties superior to its dicarbamate (in terms of intensity of effect) and that the DEP dicarbamate of Claim 10 was not significantly different in mean protective dose from the parent diol, particularly when the standard error was taken into account. (By using the extremes of the standard error the mean protective dose of the diethylpropanediol could be stated as low as 2.72 and the mean protective dose of the dicarbamate could be stated as high as 2.46.) Finally, the examiner noted that no showing had been made with respect to the homologues and isomers disclosed by Baird and he added, “Homologues and isomers are unpatentable in the absence of a verified showing of unexpected properties.” The last comment reflects allegiance to the principle of In re Henze, 1950, 181 F.2d 196, 200, 37 CCPA 1009 (see infra pp. 1326 to 1327). Contrast In re Fouche, Cust. & Pat.App.1971, 439 F.2d 1237. The examiner concluded by saying that since a definite issue has been reached, the action was made final. It will be noticed that in Table I of the affidavit of July 3, 1952 (Exhibit 2) the methyl-n-propyl propanediol is shown to be somewhat more effective against electroshock than DEP; that result differs from their comparative anticonvulsant activity tested by their antagonism to metrazol as reported in Exhibit 11 (“Berger I”) (the Berger paper of 1949 on the Anticonvulsant Action of 2-sub-stituted-1,3-propanediols). There the mean protective dose of the DEP was markedly lower than that of methyl-npropyl propanediol. Yet the two compounds appear to be isomers (compare Exhibit 2, page 2, line 2 with page 3, line 32), so that translation of the milligram data of Exhibit 11 to the millimoles of Table 1 of the 1952 affidavit would not change the contrast between the metrazol test, showing DEP to be more effective, and the electroshock test showing the methyl-n-propyl to be more effective.' Similarly, the ratio of enhancement of properties through dicarbamation is radically better in the case of the methyl-npropyl than in the case of DEP. There were no further actions in the 1950 application (serial No. 176,764). A new application was filed on August 3, 1953 (Exhibit 3). TEE CONTINUATION IN PART APPLICATION The new application was filed as a continuation-in-part of the earlier application, which it treated as co-pending (Exhibit 3, p. 7, lines 13-14). The original application was finally treated as abandoned only through an Examiner’s amendment made in the very last line of the specification under date of August 23, 1955. The new application disclosed and claimed as a group 3 propanediol dicarbamates, 2-methyI-2-isopropyI-l,3-prop-panediol dicarbamate, 2-ethyl-2-phenyl-l, 3-propanediol dicarbamate and 2-methyl-2-n-propyl-l,3 propanediol dicarbamate (meprobamate). DEP dicarbamate, which had been the only specifically claimed dicarbamate in the earlier application, was altogether omitted. The 2-ethyI-2-n-butyl propanediol dicarbamate of Example 4 in the earlier application was omitted. From the original application were retained only the 2-ethyl-2-phenyl-l,' 3 propanediol dicarbamate and the meprobamate ; added was 2-methyl-2-iso-propyl-1,3 propanediol dicarbamate, which had not been specified in the earlier application but was within the broad group of Claim 1 of the original application. The new application is more elaborate than the earlier application. The specification adds to the disclosure of anticonvulsant properties a disclosure of “marked paralyzing action on voluntary muscles,” which emphasizes that the paralysis is produced without loss of consciousness or impairment of vital functions, such as respiration and heart action. The discussion indicates that the structure most sensitive to the effects of the drugs in the central nervous system are the interneurons. The application states that meprobamate is similar to mephenesin in numerous respects but is of much longer duration of action, and is more effective in oral administration; without explicitly saying that meprobamate shares all of such uses, it is. then said that mephenesin is widely used “in tile treatment of muscle spasm, anxiety and many disorders of the nervous system.” The application introduces the new compounds as possessing “marked anticonvulsant and other properties” and states that they not only have anticonvulsant properties of much greater intensity “than other related compounds” but that they produce an action of much longer duration. Specifically it is said that animal experiment showed that the new compounds have a protective action of longer duration than the diols from which they are derived in preventing the occurrence of electroshock seizures. The tabular data given are those of Table 1 of the 1952 affidavit measured 30 minutes after administration of the compound, supplemented by the data on the dicarbamates for 150 minutes after administration. The filing of the continuation-in-part application (Serial No. 372,144) followed closely the suggestions communicated to patent counsel by Dr. Berger and Dr. Ludwig. Dr. Berger’s immediate reaction to the rejection of March 12, 1953, had been to suggest (Exhibit FC) limiting the case to methyl-ethyl, methyl-npropyl, and methyl-isopropyl propanediol dicarbamate, and to frame the generic claim as one covering 1,3-propanediol carbamates in which one substituent (at the 2 carbon) is CH3 and the second substituent would be an alkyl radical having 2 or 3 carbon atoms; that course selected the dicarbamates from Table 1 of the July 3, 1952, affidavit which were markedly more efficacious than their parent diols, but it omitted the parent composition seemingly most intensely active (on a molar basis) against electroshock seizure, the ethyl-phenyl compound. Dr. Berger also recommended “1 species claim for the methyl-n-propyl derivative which is the compound we are most anxious to protect.” At this point, in addition to the electroshock data disclosed in Table 1 of the July 3, 1952, affidavit (Exhibit 2) meprobamate had been tested for its skeletal muscle relaxant properties by determining its ability to cause test mice to lose their capacity to right themselves when placed on their backs, and for the duration of the loss of that “righting reflex” (See Exhibit 16p of October 11, 1951). The paralyzant or loss of righting capacity was also tested comparatively with mephenesin (Exhibit 16q of April 1, 1952); meprobamate was found both more effective and far longer acting. Meprobamate was tested on oral administration to monkeys (Java and Rhesus) on a limited basis later in 1952; it appeared to the experimenters that it showed striking results (Exhibit 16r). The monkey experiments suggested that meprobamate possessed what is now distinguished as a specific and distinct “tranquilizing” effect on the very aggressive and hard-to-handle Java monkeys particularly. [Description of certain materials published or developed in the 1950-1953 period omitted.] In June of 1953 counsel suggested (Exhibit AB) that, since the original application emphasized the diethyl which was being dropped and did not contain the examples covering the “methyl methyl” (methyl ethyl?) and the methyl isopropyl, it would be preferable to file a continuation-in-part application directed to the three compounds with examples of their preparation and showing the test data exhibiting their meritorious character. Dr. Berger answered patent counsel evidently after further discussion on June 24, 1953 (Exhibit AA) confirming that the continuation-in-part application would be limited to methyl-n-propyl, methyl isopropyl and ethyl-phenyl propanediol dicarbamate as compounds “exhibiting pronounced effectiveness.” Examples were then given for each of the three compounds covering preparation and physical properties. Dr. Berger suggested that because a generic claim could not be drafted without admitting possibly ineffective members, that the group claim simply list the three compounds for a generic claim. (Hence the “Markush type claim” ultimately used; see Ellis, Patent Claims, 1949, 318, § 246.) Dr. Berger suggested emphasizing that the anticonvulsant action was much longer in duration “than that of numerous related compounds” and that the anticonvulsant action “is also greater in intensity than other related compounds.” For the meprobamate, Dr. Berger noted that it, additionally, had marked paralyzing action, related to that of mephenesin, manifested in producing in animals a complete inability to move any voluntary muscles while retaining consciousness and unimpeded vital functions (such as respiration and heart action) and recovering from the paralysis without ill effects. Dr. Berger said, “After administration of smaller doses of this compound the interneurons of the central nervous system are selectively affected. This selective depression of interneurons is of therapeutic value in that it tends to eliminate abnormal impulses in the central nervous system without affecting the normal functioning of the central nervous system. As stated previously, the action of our compound is very similar to that of mephenesin in numerous respects, but differs from it in possessing a very much longer duration of action, and in being more effective on oral administration.” Dr. Berger said that the action of meprobamate lasted 5 to 10 times as long as mephenesin’s. Dr. Berger wrote that the action of the other two compounds was like meprobamate’s but not so intense and unlikely to be of such significance. The new application, Exhibit 3, thus followed Dr. Berger’s letter (Exhibit AA) of June 24, 1953, very closely. The three compounds are presented as possessing “effective central depressant properties.” The “invention” is said to be based on the “discovery” that three of the 2,2-disubstituted-l,3-propanediol dicarbamates possess “marked anticonvulsant and other properties.” The anticonvulsant properties are of “much greater intensity than other related compounds” and the compounds also “produce an action of much longer duration.” That, then, is the first species of central depressant property. Pointedly, the application does not take up where the old application left off, when confronted with the rejection of Claims 1 and 10 essentially on the ground that both the class and the species claimed failed to show that all class members and DEP possessed marked improvement in anticonvulsant properties over the parent diols. The new application does not name the “related” compounds that have less intensity, and longer duration of action is asserted only as compared with the parent diols. That is what Table 1 demonstrates. There is no assertion or explanation of utility based on any general superiority to the traditional anticonvulsants in nature, intensity or duration of anticonvulsant action and there is no description or explanation of suitability for particular occasions or modes of anticonvulsant use. Separately the paralyzant action of meprobamate is presented, as a second species of central depressant property. The meprobamate is described as producing paralyzant action while consciousness and the vital functions of respiration and heart action continue unimpaired, and recovery is without ill effect. The action is described as due to a depressant effect on the CNS leaving the nerves and nerve endings unaffected while the interneurons in the CNS are the structures most sensitive to the drug. The action is described as similar to mephenesin’s in many respects but longer lasting and more effective on oral administration. It is explained that mephenesin is widely used to treat “muscle spasm, anxiety and many disorders of the nervous system,” but that, “The very short duration of action of mephenesin is its greatest drawback.” Table 2 in Exhibit 3 gives data intended to show that the meprobamate is over five times as long-acting as mephenesin at the same weight of dosage. The application describes the method of preparation and supplies examples of preparation and physical properties on each of the claimed compounds. A single claim was presented, that is a group claim for the three dicarbamates characterized as “The 2,2-disubstituted 1,3-propanediol dicarbamates of the group consisting of” the three named dicarbamates chosen. PROSECUTION OF CONTINUATION IN PART APPLICATION [Detailed description of patent office examination omitted.] It cannot be inferred that the prosecution of the patent brought consciously to the attention of the Patent Office the earlier references to esterification and, in particular, the references to the protractive effect of the diacetate except in the manner and to the extent that the subject was directly discussed in Dr. Berger’s affidavit of July 3, 1952 in Exhibit 2. However, none of the data on esterification were secret or internal matters peculiarly within the private knowledge of the inventors. The data were public, were accessible readily to the Patent Office through normal patent office resources, and the file history of the patent contains references that could and may have led directly to examination of the critical esterification materials. When the Examiner rejected (Exhibit 3) the single claim of the new application on the ground that it lacked invention over Berger’s 1949 recital of the 2-disubstituted-l,3-propanediols (Exhibit 11) in view of Baird’s recital of “the propanediol diurethanes” (Exhibit J, 1948), stating that although a showing of superiority in the new compounds had been presented, the dose that must be given before a compound is characterized as ineffective had not been given, he also noted that “no showing of superiority over the propanediol diurethanes of Baird has been presented.” * * * The response to the rejection added three claims, each claim consi