Full opinion text
OPINION MURRAY M. SCHWARTZ, Chief Judge. The plaintiff-patentee Merck & Co., Inc. (“Merck”), is a corporation organized and existing under the laws of New Jersey, with its principal place of business in Rah-way, New Jersey. Pretrial Order, Dkt. 53', at 5 (“Pretrial Order”). The defendant Danbury Pharmacal, Inc. (“Danbury”), is a corporation organized and existing under the laws of Delaware, with its principal place of business in Danbury, Connecticut. Id. On October 31, 1986, Danbury filed an abbreviated new drug application (“ANDA”) with the Food and Drug Administration (“FDA”) seeking permission to sell a generic version of the drug cyclobenzaprine. Cyclobenzaprine in hydrochloride form is marketed under the trade name FLEXERIL by Merck. Merck brought this action December 17, 1986, pursuant to 21 U.S.C. § 355(j)(4)(B)(iii) (Supp. IY 1987), charging Danbury with infringement of Merck’s United States Patent No. 3,882,246 (the “ ’246 patent”). The ’246 patent describes a method of use of cyclobenzaprine to treat certain types of skeletal muscle disorders. FLEXERIL is covered by the claims of the ’246 patent. Under 1984 amendments to the Patent Act, 35 U.S.C. § 271(e)(2) (Supp. IV 1987), Danbury’s ANDA certification that the ’246 patent is invalid and unenforceable and notice to Merck of that certification constitutes infringement of the ’246 patent. Approval of Danbury’s application by the FDA is deferred pursuant to section 355(j) of the Food, Drug and Cosmetic Act while the validity and enforceability of the patent. The Court held a five day bench trial from February 8 through 12, 1988. In view of the admitted infringement and Danbury’s having not begun sales, the sole issues for determination at trial were the validity and enforceability of the patent. After trial, the parties submitted proposed findings of fact and conclusions of law and post-trial argument was held on August 9, 1988. This opinion constitutes the Court’s findings of fact and conclusions of law pursuant to Rule 52(a) of the Federal Rules of Civil Procedure, based upon the testimony, documentary and live, including assessment of the demeanor of witnesses and positions presented at trial and the post-trial submissions. Danbury seeks a declaration that the ’246 patent is invalid for obviousness under 35 U.S.C. § 103 (1982 & Supp. IV 1987) (“section 103”), that the patent is unenforceable due to Merck’s inequitable conduct before the Patent and Trademark Office (“PTO”), and that Merck is not entitled to the filing date claimed because of failure to adequately specify the invention in the initial application in accordance with 35 U.S.C. § 112 (1982) (“section 112”). The basis for Danbury’s claim of obviousness is, briefly, that because “both cyclobenzaprine and amitriptyline were known in the prior art and ... a significant body of information was available with respect to their respective chemical, pharmacological and clinical properties,” this prior art “would have taught a person skilled in the art that both cyclobenzaprine and amitriptyline were muscle relaxants.” Defendant Danbury’s Proposed Findings of Fact and conclusions of Law (“DFF”) at 1. Dan-bury also charges Merck with inequitable conduct, asserting that “no patent would have been granted but for the misrepresentations and omissions with respect to the scope and content of the prior art and the nature and quality of the alleged invention” made during the prosecution of the patent. Id. Danbury’s section 112 claims rests on the lack of an explicit statement in Merck’s initial patent applications describing the invention’s particular effect on muscle strength or coordination. Due to this lack of specificity, according to Dan-bury, the ’246 patent fails under 35 U.S.C. § 102(b) (1982), because the claimed subject matter was published in the interim between the initial applications and the continuation-in-part application that led to the issuance of the patent. Merck counters that the prior art publications cited by Danbury do not make the invention obvious, that Merck’s omissions during the prosecution of the patent were immaterial and that no misrepresentations were made, and that the initial patent application described the invention sufficiently, satisfying section 112’s requirements. The Opinion is divided into two parts: findings of fact and conclusions of law. The areas covered in the first part will be: (a) Chemical Structures and Technical Terms; (b) The Development and Initial Testing of Cyclobenzaprine; (c) Synthesis and Early Work with Amitriptyline; (d) Prior Art; (e) Dr. Share’s Work with Cyclobenzaprine; (f) Expanded Clinical Testing of Cyclobenzaprine; (g) Merck’s Clinical Testing of Amitriptyline as a Muscle Relaxant; (h) Merck’s FDA Submissions; (i) Prosecution of the ’246 Patent; and (j) Cyclobenzaprine’s Commercial Record. The second part of the Opinion will address the parties’ legal theories and make conclusions law with regard to: (a) Burden of Proof; (b) Obviousness: 35 U.S.C. § 103; (c) Inequitable Conduct; (d) Section 112; and (e) Attorney Fees. I. FINDINGS OF FACT The FDA approved Merck’s application to market cyclobenzaprine under the trade name FLEXERIL in 1977. The FDA limited its approval to use of FLEXERIL as “an adjunct to rest and physical therapy for relief of muscle spasm associated with acute painful musculoskeletal conditions.” DX 10 at MF067603. FLEXERIL’s FDA-approved dose is 10 milligrams three times daily, with a maximum dose of 60 milligrams per day. Id. at MF067604. In its ANDA, Danbury seeks approval to market a generic version of FLEXERIL at the same dosage and for the same purposes. Merck filed its initial patent application in Canada on July 7, 1970. See DX 79. The following year, Merck applied for a United States patent. DX 79. After submitting several amendments and two continuation-in-part applications, Merck’s U.S. patent issued on May 6, 1975. PX 200. A. Chemical Structures and Technical Terms Before embarking on the voyage through the record in this case, it is worthwhile to pause and ponder the various technical terms which will be encountered during the trip. The Court is hopeful that a somewhat prolonged detour now will avoid a plethora of definitions and explanations later. Cyclobenzaprine, amitriptyline, and imipramine are all “tricyclic” compounds, that is, they share the same basic structure: comprising a central seven membered ring flanked on opposite sides by six-membered benzene rings. PX 307-310. There are thousands of tricyclic compounds that share this configuration. Engelhardt Tr. 639-643. Amitriptyline differs from cyclobenzaprine in that there is a single carbon-carbon bond in amitriptyline at the 10,11 position, while cyclobenzaprine has a carbon-carbon double bond at the 10,11 position. Tr. at 645-50 (Engelhardt). The outer angles formed by atoms or molecules making up the three rings of the tricyclic compounds discussed here are numbered beginning at the upper point of the right benzene ring, as seen on a planar representation. As seen in planar representation, the 10,11 position corresponds to the horizontal segment at the top of the seven membered ring in the middle of the 6-7-6 tricyclics. Imipramine also has a single carbon-carbon bond at the 10,11 position. Tr. 645 (Engelhardt). The presence of the double bond in cyclobenzaprine creates a rigidity in the molecule not found in amitriptyline; thus the two compounds have differing three-dimensional configurations, and two distinct isomers of cyclobenzaprine may be isolated at room temperature, whereas amitriptyline and imipramine molecules are too flexible to allow identification of separate isomers at room temperature. Tr. at 646-48 (Engelhardt). Imipramine also differs from amitriptyline and cyclobenzaprine in the attachment of the side chain to the seven membered ring. In imipramine, the side chain is attached to the central ring through a carbon-nitrogen bond, which allows the side chain to rotate around the bond. In amitriptyline and cyclobenzaprine, a carbon-carbon double bond links the side chain to the central ring. As with the presence of the double bond at the 10, 11 position, the rigidity of the carbon-carbon double bond stiffens this portion of the molecule. Tr. at 648 (Engelhardt); PX 307-310. Listed in the margin are several technical (chemical, pharmacological, or medical) terms that bear on the resolution of the instant claims. The definitions, except where noted, were agreed upon by the parties. B. The Development and Initial Testing of Cyclobenzaprine In 1956, as part of Merck’s Mental Health Program, an employee of Merck, Dr. Edward L. Engelhardt and a Merck consultant, Dr. Arthur C. Cope, synthesized the tricyclic compound cyclobenzaprine. Drs. Engelhardt and Cope developed a number of compounds for study as possible tranquilizers. Plaintiff’s Trial Exhibit (“PX”) 202; Trial Transcript (“Tr.”) at 603 (Engelhardt). Cyclobenzaprine was among the resulting compounds tested; it demonstrated activity in animal tests used to predict tranquilizing activity in humans. Tr. at 604 (Engelhardt). During 1957 and 1958, cyclobenzaprine was the subject of a battery of tests, including tests for atropine-like activity. Tr. at 604-07 (Engelhardt); DX 21; MFF H 17. Atropine-like or anticholinergic activity refers to the resemblance of a compound’s activity to that of atropine, an antispasmodic agent widely used at the time in treating Parkinson’s disease patients. DX 32 at 285; PX 287, 292. Anticholinergic or atropine-like activity describes the action of a substance in “antagonizing] or blocking] the transmission of impulses from a variety of certain ‘cholinergic’ nerves and the neurons or organs they supply (including muscles or glands) by blocking the effects of the neurotransmitter acetylcholine.” Court Exhibit (“CX”) 1 at 1 (Glossary of Technical Terms). As Dr. Melvin Van Woert, defendant’s expert witness, explained more fully at trial: A. [Anticholinergic action is] action ... to block the communication between two nerve cells that require acetylcholine, a neurotransmitter____ Acetylcholine is necessary for one nerve cell to communicate with another in a particular area of the brain, not all areas, but in that particular area of the brain. It is extremely important in the area of the brain where the pathology of Parkinson’s disease occurs. Q. What is the effect of an anticholinergic action with respect to Parkinson? A. It blocks — let’s call it a Parkinsonian area of the brain____ It blocks the cholinergic transaction. The action of acetylcholine at that particular spot, it’s an anticholinergic, acts against that cholinergic. By acting against it-it reduces the symptoms of Parkinson’s disease. Q. What effect does that have on muscle tone? A. It reduces muscle tone in the Parkinson patient. Tr. at 178-79 (Van Woert). The tests were summarized in a Merck report denoted “MK-130 Preclinical Evaluation” (the “preclinical evaluation”) dated Feb. 10, 1958 (DX 21). Some of the tests were used to measure muscle relaxant activity, but cyclobenzaprine did not display any muscle relaxant activity under the tests employed. Tr. at 606 (Engelhardt); MFF ¶ 18. Cyclobenzaprine did display, however, “considerable ataraxic (tranquilizing) activity in animals.” DFF II2 at 3; DX 21 at MF015534. “In all species that ataraxic effect was manifested by a unique hypnotic or sedative action, which, unlike barbiturates and other depressants, was not accompanied by predepression excitement, appreciable ataxia or other evidence of motor deficit.” Id. Cyclobenzaprine also displayed anticholinergic activity: It is anticipated that the atropine-like activity of MK-130 may prevent the appearance of Parkinsonian-like tremors, which is emerging as a characteristic side effect of the more potent phenothiazine-type tranquilizing drugs in man. This concept is based upon the fact that Parkinsonian tremor in its natural form or produced by tranquilizing agents in man is most effectively treated by agents possessing atropine-like activity____ Such considerations strongly suggest that the atropine-like action of MK-130 may represent a useful ancillary activity to its basic tranquilizing properties. DX 21 at MF015550. The preclinical evaluation led Merck to conduct clinical investigations of cyclobenzaprine’s tranquilizing and antidepressant activities in man. Tr. at 752-53 (Strickland); DX 78 at MF102579; MFF ¶ 19. While cyclobenzaprine showed some tranquilizing activity, its activity was no better than known tranquilizers. Cyclobenzaprine also showed some antidepressant activity, but produced a number of undesirable side effects. DX 78 at MF102579. The results of the clinical probes were included in Merck’s Revised Clinical Operational Plan, dated Oct. 5,1970 (DX 62). “In 1958-59, in open clinical trials involving 12 investigators and 294 patients, MK-130 was shown to have some activity in the treatment of depressive states____ Although the drug was also shown to have antipsychotic activity, these preliminary studies did not show it to offer any advantage over the standard effective ... [tranquilizers].” DX 62 at MF001634. After experimenting with cyclobenzaprine as a veterinary tranquilizer, which yielded some positive results, but not at a level making cyclobenzaprine superior to other available drugs, testing on cyclobenzaprine was halted around 1960. Tr. at 619-20 (Engelhardt); DX 19 at MF093046-47; MFF ¶ 21. C. Synthesis and Early Work with Amitriptyline Dr. Engelhardt also synthesized amitriptyline, as part of the same Merck Mental Health Program. Tr. at 620 (Engelhardt); MFF ¶ 22. According to Merck, “amitriptyline was put through the same battery of tests used to evaluate cyclobenzaprine, and Merck concluded it was inactive as a tranquilizer.” Tr. at 620 (Engelhardt); MFF ¶ 23. When Dr. Engelhardt learned in May 1958 that the chemically related compound imipramine had shown clinically useful antidepressant activity, he advocated that Merck clinically evaluate amitriptyline as an antidepressant. Tr. at 620-22 (Engelhardt); DX 7 (In re Merck, No. 85-2740 (Fed.Cir.) (Joint Appendix)). Amitriptyline was clinically tested, and the tests demonstrated its clinical efficacy as an antidepressant. The FDA approved the drug for this use in 1961. Merck marketed it under the trade name ELAVIL beginning in that year and continuing until the present. Tr. at 621-22 (Engelhardt). D. Prior Art There are two lessons plain in the prior art collected by Danbury: (1) amitriptyline’s (and to a lesser extent cyclobenzaprine’s) possible usefulness as a muscle relaxant was known; and (2) amitriptyline and cyclobenzaprine share, to differing degrees, similar pharmacological properties. Danbury seeks to draw from the two lessons the conclusion that cyclobenzaprine’s muscle relaxant activity was obvious and that therefore Merck is not entitled to its patent. The soundness of that conclusion is examined in the Court’s conclusions of law, section II, part B, of this Opinion. 1. Amitriptyline’s Usefulness as a Muscle Relaxant The first lesson taught by the prior art concerning the pharmacological properties of amitriptyline is that, in addition to its established use as an antidepressant, the compound exhibited significant activity as a muscle relaxant. Merck disputes this, relying mainly on the fact that amitriptyline’s accepted use was in the area of antidepressant activity and that given its years of use in treating depression, one would have expected amitriptyline’s muscle relaxant activity to have surfaced. Danbury’s response is twofold. First, Danbury argues that amitriptyline’s track record as an antidepressant is consistent with its muscle relaxant activity, because depressed patients frequently exhibit increased muscle tone, some of amitriptyline’s effectiveness in treating depression may be attributed to its muscle relaxant activity. Second, Dan-bury asserts that the nonclinical prior art contains explicit references to amitriptyline’s utility as a muscle relaxant. A careful review of the prior art evidence and the testimony at trial convinces the Court that amitriptyline did show activity as a muscle relaxant and that Merck knew of this activity. However, as will be explored later, the conclusion that amitriptyline was a known useful muscle relaxant does not lead automatically to the ultimate conclusion that use of cyclobenzaprine as a selective muscle relaxant was obvious for the purposes of 35 U.S.C. § 103. Three categories of prior art publications form the bedrock of the lesson that amitriptyline displays muscle relaxant activity: (i) the mid-1960s publications by Sinha et al; (ii) the Lance work on tension headache; and (iii) the use of amitriptyline and other anticholinergics in the treatment of Parkinson’s disease. Taken together with an eye toward their impact at the time, these references strongly indicate amitriptyline’s effectiveness as a muscle relaxant. (i) The Sinha publications: Sinha and his colleagues published three articles in 1965 and 1966. Two were published in the Japan Journal of Pharmacology, and the third appeared in Arch. int. Pharmacodyn. DX 39, 40, 41. The articles disclose that imipramine, amitriptyline, and desipramine display muscle relaxant activity in animal tests: Our studies clearly demonstrate the potent central muscle relaxant activity of imipramine, desmethyl-imipramine and amitriptyline. Increased muscle tone is a common accompaniment of reserpine syndrome and is consistently present in patients of depressive psychosis. These agents antagonize the increased motor activity induced by reserpine. Clinically, they are effective antidepressants. In view of the increased muscle tone in depressive states and the effective central muscle relaxant property of these agents, it seems probable that this property of these agents might be playing some role in their antidepressant action. A controlled clinical trial of imipramine and its congeners as central muscle relaxants in certain spastic musclar [sic] disorders seems warranted. DX 39 at 256 (16 Jap.J.Pharm. 250, 256 (1966)). A great deal of time at trial was directed to the validity and reliability of the Sinha publications. Merck identified several supposed flaws in Sinha’s methodology, and argues now that “[a]s a result of these and other deficiencies, the Sinha articles” are immaterial. Post-Trial Brief of Plaintiff Merck & Co., Inc., Dkt. 64, at 35. Smith, the plaintiff’s expert, claimed that those skilled in the art would have disregarded Sinha because of these flaws. Tr. at 842-55 (Smith). Share testified that he did disregard Sinha. Tr. at 446 (Share). On the other hand the defendant’s expert, Van Woert, felt that the tests conducted by Sinha, contrary to the Merck expert testimony, were supportive of the conclusions drawn; i.e., that the three compounds demonstrated muscle relaxant activity. Tr. at 162 (Van Woert). The Court finds it unnecessary to resolve the conflict on Sinha’s methods because there is ample evidence that, regardless of their hindsight critique, Merck personnel were influenced by the Sinha publications at the time. For example, the initial selection of cyclobenzaprine resulted from a decision by Dr. Gleason, the Merck chemist in charge of the muscle relaxant program, to request from Merck’s sample collection compounds “related to amitriptyline.” DX 48. This request came in the form of a memorandum dated January 25, 196[7] : Results of the Veratramine Test on amitriptyline and recent report on central muscle relaxant activity of amitriptyline (Sinha et al, Jap.J.Pharmacol. 16:250, 1965) suggest submission of analogues to our muscle relaxant screen. Could you please let me known what compounds are available in your sample library related to amitriptyline, protriptyline, cyproheptadine, etc____ DX 48 at MF000929. Cyclobenzaprine was one of the first twenty-three compounds selected for the screen as a result of the Gleason memorandum. DX 49, 50; Tr. at 311-12. The memorandum gives no indication that Sinha’s methods struck Gleason as suspect. To the contrary, the memorandum corroborates Danbury’s position that the technical deficiencies Merck now finds in Sinha are at least partially litigation-inspired. Additionally, Engelhardt cites Sinha in a chapter on muscle relaxants in a 1970 book. DX 89. Although he does not recall the substance of the conversation, Engelhardt testified that he discussed the Sinha article with Share before including it in the chapter. Tr. at 692-95 (Engelhardt). A further indication of the reliance placed on Sinha during the muscle relaxant research is the Rooney note. Dr. Rooney took over Gleason’s position as the chemist in charge of the muscle relaxant program in 1968. He wrote an undated note on a copy of the Sinha article: This is literature art which might be quoted against patent applications in the tricyclic series for muscle relaxation. Fortunately, cyclobenzaprine is not mentioned. DX 95. The reference to “patent applications” suggests that the note dates from sometime after Merck seriously contemplated or had applied for what would mature into the ’246 patent. Finally, during an October 1970 meeting regarding the development of eyclobenzaprine and amitriptyline as muscle relaxants the Sinha article was noted. The minutes of the meeting contain the following observation: It was pointed out that a publication in the Japanese Journal of Pharmacology several years ago, which claimed that amitriptyline has muscle relaxant properties will probably preclude obtaining use patent on this compound. DX 57 at MF093716. Arther, Merck’s patent attorney, did not attend the October meeting, but later opined that no patent could be obtained for amitriptyline as a muscle relaxant due to the Sinha articles. DX 88. The Court agrees with Danbury that the foregoing references do not display any detectable criticism of Sinha’s methods or conclusions. Rather, the references strongly suggest that the Sinha articles were taken seriously by the personnel involved in the muscle relaxant program at the time, and that those personnel accepted that amitriptyline might have potential as a muscle relaxant. (ii) the Lance work on tension headache: An article published by Lance in 1964 found amitriptyline’s effect on patients suffering from tension headache “highly significant.” DX 34 at MF089759. Lance opens the article with the statement that “[a] constant factor in the production of tension headache appears to be inability of the patient to relax the muscles of the face, scalp, and neck.” Id. at MF089757. He describes analyzing amitriptyline’s favorable effects on patients for evidence of “any clinical pattern [that] could lead one to predict success of failure for this treatment in any particular patient.” The results were surprising: The majority of patients gave no indication of being depressed, and “depressive symptoms” noted in the [results] were minor. A cross-section of patients was examined by one of our colleagues from the department of psychiatry ... who made an estimate of depression on the Hamilton rating scale____ There was no evidence that amitriptyline influenced selectively those patients who had some degree of depression. Id. at MF089760. Lance’s results answer Merck’s assertions that tension headache results are not relevant because of the incidence of depression in tension headache and that tension headache does not reveal anything useful about muscle relaxant activity. Depression may be related to tension headache; however, Lance’s results indicate that amitriptyline’s activity in tension headache is not limited to its antidepressant action. Moreover, Merck’s own treatment of tension headache in the past belies its current position. Merck sponsored a second tension headache study by Lance, the results of which were reported by March 1972. DX 68 at MF001776. The second study focused on the activity of cyclobenzaprine in treating tension headache and found “[cyclobenzaprine] comparable in its efficacy with ... amitriptyline.” Id. Share cited Lance’s work in a 1975 publication in support of the assertion of cyclobenzaprine’s efficacy in treating hypertonic muscle disorders. DX 99 at MF004764J. Additionally, Smith stated in his 1965 treatise that sustained muscle contractions are symptomatic of tension headaches. DX 36 at 2. The Court finds that Merck knew of amitriptyline’s muscle relaxant activity in the treatment of tension headaches. (in) the use of amitriptyline and other anticholinergics in the treatment of Parkinson’s disease: Danbury also characterizes as material prior art describing amitriptyline’s usefulness in treating the muscle rigidity and tremor associated with Parkinson’s Disease. DX 31, 32, 33; Tr. at 176-202 (Van Woert). The utility of amitriptyline and the other tricyclic antidepressant compounds for this purpose was attributed to their anticholinergic activity. Cyclobenzaprine was known to be a more potent anticholinergic agent than amitriptyline both as a result of Merck’s pre-1960 clinical evaluation of that compound ... and the Metys publication____ The expectation that cyclobenzaprine would be effective against Parkinsonian tremor and rigidity was first expressed by Merck in its 1958 Pre-elinical Evaluation and that expectation is reinforced by the clinical use of amitriptyline and imipramine in the treatment of Parkinson’s disease during the 1960’s. DFF ¶ 21. Merck’s responds that anticholinergic activity is not the equivalent of muscle relaxant activity, and adds that the complexities of Parkinson’s disease defeat Danbury’s attempt to draw the inference that anticholinergics would be expected to indicate muscle relaxant action. On this point, the two sides apparently differ, because Van Woert testified that the use of anticholinergics resulted in a reduction of muscle tone in Parkinson’s patients. Weighing both sides, it appears that drugs displaying some usefulness in treating Parkinson’s would be likely candidates for testing for muscle relaxant activity. Anticholinergics were one class of compounds tested by Share in the veratramine screen he developed as part of his initial research. However, Danbury does not argue that the evidence of amitriptyline’s (and cyclobenzaprine’s) anticholinergic activity portends selective action on hypertonic muscle. For that matter, neither the tension headache evidence nor the Sinha studies suggest any kind of selective action, i.e., action reducing abnormal muscle tone without affecting normal muscle tone. 2. Amitriptyline and Cyclobenzaprine Share Similar Pharmacological Properties The prior art also reveals that amitriptyline and cyclobenzaprine, contrary to Merck’s general position, share similar pharmacological properties. Several pri- or art publications teach that amitriptyline and cyclobenzaprine behave similarly in a variety of tests. Although the two compounds display a differing degree of potency, the evidence supporting similarities is substantial. Initially it is noteworthy that, according to Merck’s own published work, compounds which differed only by the presence or absence of a double bond were routinely measured and ordinarily exhibited comparable pharmacological behavior, DX 14, 15. This casts grave doubt on Merck’s contention that there would be no reason to expect cyclobenzaprine to exhibit similar pharmacological activity to amitriptyline. Furthermore, in tests comparing the two compounds, generally analogous pharmacological activity was observed. In an article by Metys et al, recording a Czechoslovakian study of anti-Parkinson’s drugs with antidepressants, cyclobenzaprine and amitriptyline were found to display similar pharmacological traits. DX 30 at 262. Differences were present as well: “Of the antidepressive substances tested, only proheptatriene [cyclobenzaprine] was antagonistically effective against oxotremorine in doses similar to those of the central cholinolytics.” Id. As Danbury argues, this difference in potency is more one of degree than of quality. It is nonetheless a true difference. Overall, however, the authors reported that “[a]ll of the antidepressants tested reduced the intensity of the tremor induced by oxotremorine to approximately the same extent.” Id. This finding is generally supportive of the finding that amitriptyline and cyclobenzaprine exhibit certain pharmacologically parallel actions. Other publications strengthen the proposition that amitriptyline and cyclobenzaprine are pharmacologically similar. An article published in 1962 by Stewart et al finds the central nervous system effects of the two compounds comparable. DX 26. And a 1963 Metysova publication found cyclobenzaprine “identical to the independently represented amitriptyline” in the type of effect noted on the central nervous system. DX 29 at 40 (translation). Given this evidence, the Court is comfortable in characterizing amitriptyline and cyclobenzaprine as sharing a pharmacological resemblance. Absent prior art demonstrating that amitriptyline had selective muscle relaxant activity, pharmacological resemblance does not lead inevitably to the conclusion that the prior art contains the reasonable expectation that cyclobenzaprine would be a selective skeletal muscle relaxant. However, Danbury objects that even cyclobenzaprine is not truly selective. To examine the persuasiveness of Merck’s case for cyclobenzaprine’s selectivity as well as to test Dan-bury’s obviousness claims, a review of the research leading to Share’s claimed invention is helpful. E. Dr. Share’s Work with Cyclobenzaprine 1. Merck-Frosst’s Skeletal Muscle Relaxant Program Dr. Nathan Norman Share, the inventor of the use of cyclobenzaprine as a selective skeletal muscle relaxant, holds a Ph.D. in pharmacology and has done post-doctoral work in autonomic nervous system function. Tr. at 347-48 (Share). Share headed the pharmacology department of Charles E. Frosst Laboratories (“Frosst”). Tr. at 349 (Share). Shortly after Share began work at Frosst, it was acquired by Merck. Id. Subsequently, Merck personnel met with Share and suggested that Share’s research group undertake two research projects. Out of a list of several projects, Share chose the skeletal muscle' relaxant project and one other project. Tr. at 354,-54A (Share). The muscle relaxants then available functioned effectively but nonselectively: i.e., they produced generalized depression of the patient and reduced normal muscle tone as well as affecting hypertonic muscle. Tr. at 355-56 (Share); 836 (Smith). Share sought a selectively acting muscle relaxant which would only affect the desired relaxation (the hypertonic muscle) and not normal muscle tone, that is, a drug “without behavioral depressant effects which would impair the normal motor activity associated with the ability to carry out the tasks of daily living.” Tr. at, 356 (Share). Share began his research with two goals in mind: first, to develop superior animal test models, because he felt the existing models were not the best possible identifiers; and second, to use the new models to identify a selective skeletal muscle relaxant. Tr. at 357 (Share). He initially reviewed the literature to determine the state of the art. Share’s literature search revealed that extant muscle relaxants shared properties in common with minor tranquilizers and sedatives. He determined therefore that drugs in these categories should be screened using the classical skeletal muscle relaxant tests in order to form a data base for purposes of comparing the compounds tested in the main phase of his research. DX 43 at MF009845; Tr. at 360-61 (Share). In connection with his first goal, Share developed the so-called veratramine test, which he believed offered advantages over the classical screening tests due to its supposed specificity to hypertonic activity, particularly that related to tremors and convulsions. MFF II38. The classical models were inferior in Share’s view “because they could not detect relaxation of hypertonic activity alone, but rather they measured relaxation of normal muscle — precisely what Dr. Share’s research sought to avoid.” MFF ¶ 36 (Tr. at 360 (Share)). The extensive testing conducted to develop the initial database included veratramine, an alkaloid (a substance of an organic nitrogenous base; atropine is one, as is cocaine). When the researchers injected mice with veratramine, the drug produced tremors, convulsions, and death. This effect was already known at the time of Share’s research, see DX 36 at 70 (Smith article), but Share apparently was the first to utilize veratramine as a screen for skeletal muscle relaxant activity. DX 44; Tr. at 363-66 (Share); MFF ¶ 38. The veratramine test was fully in place by late 1966. It consisted of two parts: (1) testing each compound in five mice “to determine whether the test drug was capable of preventing any or all of the triad of responses produced by veratramine [tremors, convulsions, and death] ...”; (2) if three or more of the mice were protected from any of the responses, the second part of the test was run, which consisted of calculating the ED50 (the effective dose at which 50% of the animals were protected from tremors, convulsions, and death). MFF 1141; DX 45 at MF000932; Tr. at 369-70 (Share). Compounds that passed the second part of the test were deemed “leads.” Tr. at 370 (Share). Share tested eighty-eight compounds in the initial phase of the test; twelve were selected for the second phase. PX 211 at MF009811; Tr. at 375-76 (Share). Share’s testimony was that he first became interested in testing tricyclic compounds as a result of Dr. Smith’s article, DX 36, which “referred to the muscle relaxant properties of the tricyclic compound chlorpromazine.” MFF ¶ 46; Tr. at 377, 494-95 (Share). Chlorpromazine is sold as a tranquilizer. MFF 1147. According to Merck, Dr. Gleason ordered samples of tricyclics for Share’s tests at Share’s request. Tr. at 377 (Share); Dep. of Gleason at 11-12, 32-34; MFF ¶ 48. However, the memorandum written by Gleason to the personnel at the sample collection demonstrates that the tricyclics were also ordered as a result of the Sinha article. The pertinent part of the memorandum bears repeating: Results of the Veratramine Test on amitriptyline, and (a) recent report on central muscle relaxant activity of amitriptyline (Sinha et al, Jap.J.Pharmacol. 16: 250, 1965) suggest submission of analogues to our muscle relaxant screen. Following this request, twenty-three compounds were forwarded to Share for submission to the muscle relaxant test. Cyclobenzaprine was one of the two most active compounds reported by Share. “It protected % mice from tremors, % mice from convulsions and lk mice from death. Amitriptyline also was among the 23 tricyclic compounds tested, but it was rated ‘inactive’ since it failed to protect any mice from tremors or death and protected only 2 mice from convulsions.” MFF 1151 (citations omitted); Tr. at 377-82 (Share); DX 50 at MF009928-29. Share’s group continued to identify new lead compounds through February 1968. PX 218 at MF010116; Tr. at 385 (Share). At that time, cyclobenzaprine and other lead compounds were subjected to “more rigorous follow-up tests in larger animals (such as rabbits and cats).” MFF 11 57. The more rigorous tests were designed to further winnow the lead compounds and determine which were candidates for clinical tests. Tr. at 386 (Share). Share felt, for various reasons, that the cat tests were among the more important follow-up tests. Tr. at 386-87 (Share), at 233-34 (Van Woert). Share utilized several cat tests. One was the decerebrate model, “in which the test compound’s effect against artificially produced rigidity was measured.” MFF II 59. The results of cyclobenzaprine in this type of test were as follows: [Cyclobenzaprine] show[s] a good order of activity in abolishing the rigidity. [It] ha[s] a long duration of action (> 2 hrs) and showed no toxic manifestations at the blocking doses. Compared to mephenesin, diazepam and chlorpromazine in this type of study, both M-27-67 [cyclobenzaprine] and M-36-67 are more active than mephenesin, but less active than diazepam and chlorpromazine. PX 218 at MF010116. Another test, a more sophisticated one according to the plaintiff, was the ischemic cord rigidity test. In this test, a surgical procedure was performed to temporarily abolish the blood supply to the spinal cord in order to produce anoxia (a lack of oxygen) and destruction of certain neurons in the spinal cord, resulting in a persistent hind-limb rigidity. Share Tr. 391-392; Van Woert Tr. 130-131. By February 8, 1968, Dr. Share had tested eight known reference compounds from various therapeutic classifications in the ischemic cord rigidity model to establish a data base for this test____ MFF II 60; Tr. at 391-93 (Share). Amitriptyline was among the first eight compounds tested with the ischemic cord rigidity test. Cyelobenzaprine was the most effective. PX 218 at MF010117. Share reported that cyelobenzaprine exhibited “a good order of activity against both decerebrate and ischemic cord rigidity in the cat,” whereas diazepam (VALIUM) was “relatively ineffective” in one of the tests and chlorpromazine caused some undesirable effects. PX 219; Tr. at 393-94 (Share). Amitriptyline’s results in the ischemic cord and decerebrate rigidity tests were “far less active” than cyelobenzaprine’s: Further studies were carried out with [cyelobenzaprine]____ Cyelobenzaprine is still the most active lead compound. In a study involving a total of nine cats, the activity of this compound in abolishing decerebrate rigidity at low doses was consistent and long lasting and had a stabilizing effect on the knee-jerk at the blocking doses. In two cats amitriptyline had a weak and shortlasting effect____ The most active compound in this preparation is still M-27-67 (cyelobenzaprine). PX 220 at MF010579-80. During the veratramine assay, Share developed another screening tool, the MEP-RIA test. Tr. at 395-96 (Share); PX 220; PX 212. Eventually, both the veratramine and the MEPRIA tests were being run concurrently, in part to determine which test better served as a predictor of muscle relaxant activity. Tr. at 395-98 (Share); PX 223 at MF010153. In the MEPRIA test, like the veratramine test, cyclobenzaprine proved the most successful. PX 223 at MF010153; Tr. at 398-99 (Share). The MEPRIA test turned out to be a superior screen, and in November — December 1968, the MEPRIA screen alone was used. PX 224. Follow-up studies on cyelobenzaprine continued, and in January 1969, Share summarized the latest results he’d obtained: Further studies on the muscle relaxant properties of cyelobenzaprine in various rigid cat preparations are in progress. In the decerebrate cat, cyelobenzaprine, diazepam and chlorpromazine are approximately equiactive. However, in the ischemic-cord rigid cat preparation, only cyelobenzaprine appears to be active____ PX 224 at MF010160-61; Tr. at 400-01 (Share). Share compared cyelobenzaprine with diazepam and chlorpromazine “because those compounds were considered to be the best of the clinically available centrally acting skeletal muscle relaxant agents at that time. Neither diazepam nor chlorpromazine, however, was selective in its ability to reduce hyperactive muscle activity.” MFF ¶ 72. A February 1969 report, “Cyclobenzaprine A Pharmacological Report,” describes in detail Share’s views of cyclobenzaprine’s properties: Pharmacological studies have demonstrated that cyelobenzaprine possesses a unique pharmacodynamic action. This was shown by its ability to reduce or abolish the skeletal muscle hyperactivity in all animal models tested, at dose levels which had no observable behavioral depressant effects. The characteristics of the skeletal muscle relaxant activity of cyelobenzaprine apparently differs from that of chlorpromazine and diazepam. In these experiments, cyelobenzaprine was found to be less potent than diazepam in both intact and spinal ... sectioned mice, whereas chlorpromazine was inactive. However, the slope of the dose-response curve for cyclobenzaprine in intact and spinal mice were virtually identical, whereas that for diazepam was considerably flattened in spinal mice. This suggests that in contrast with chlorpromazine and diazepam, cyclobenzaprine may have a more specific action on the hyperactivity of skeletal motor systems at the spinal cord level. Thus, the activity of cyclobenzaprine appears to be highly consistent in several animal models exhibiting tonic skeletal muscle hyperactivity. The spectrum of pharmacologic activity appears to be sufficiently unique to suggest its usefulness in a wide range of clinically occurring spastic conditions. PX 225 at MF020185-87. Amitriptyline’s results as a muscle relaxant were not as spectacular as cyclobenzaprine’s results. However, in the June 1970 pharmacological report summarizing cyelobenzaprine’s muscle relaxant properties, data on amitriptyline were included along with two “benchmark” compounds, chlorpromazine and diazepam. DX 53. Amitriptyline’s muscle relaxant activity surpassed that of the two benchmark muscle relaxants. Additionally, “Dr. Share’s report was uniformly regarded by Merck personnel as demonstrating that amitriptyline, as well as cyclobenzaprine, exhibited sufficiently impressive muscle relaxant activity to justify clinical trials.” DFF If 31; DX 56 (“Amitriptyline appears to be as active orally and have duration comparable to MK-130.”); DX 57 (Cyclobenzaprine’s reduction of skeletal muscle hyperactivity “shared by amitriptyline, although the latter compound is less potent in this respect and seems to be less consistent in its activity.”). In the light of this evidence, as well as the other record evidence collected by Dan-bury at DFF ¶ 31, the Court concludes that amitriptyline did display effectiveness as a skeletal muscle relaxant, but cyclobenzaprine was superior in potency and selectivity- 2. The First Clinical Tests of Cyclobenzaprine as a Muscle Relaxant The first clinical studies of cyclobenzaprine’s effectiveness as a skeletal muscle relaxant were conducted in June 1970 by Dr. Molina-Negro. PX 236. Merck’s Research Management Council had approved the clinical tests in July 1969. PX 231 at MF098742; Tr. at 711-12 (Beyer). Molina-Negro reported his first results on June 16, 1970. PX 236 at MF098448-49; Tr. at 413-15 (Share). Although the results were only of the first two patients studied, the report detailed dramatically favorable effects corroborating Share’s animal studies. For this reason, the report caused excitement. Tr. at 713-14 (Beyer). F. Expanded Clinical Testing of Cyclobenzaprine Molina-Negro’s dramatic study results spurred further clinical trials. Tr. at 715 (Beyer), 757 (Strickland). Merck determined to study cyclobenzaprine in three major clinical areas: A) spasticity; B) rigidity; and C) muscle spasm or splinting. DX 62. Merck claimed at trial that cyclobenzaprine, despite its limited approved use (as a therapeutic agent for relief of local muscle spasm), showed efficacy in treating rigidity and spasticity as well. Danbury contests this characterization. Having assessed the evidence and in particular Merck’s internal documents, the Court concludes that cyclobenzaprine’s effectiveness in treating spasticity and rigidity is highly limited. Several clinical studies were conducted to determine cyclobenzaprine’s utility in treating each of these disorders. DX 19; DX 68; DX 69; Tr. at 759-69 (Strickland). Initial reports were encouraging: Following our discussions re MK-130 it is apparent that we already have data highly suggestive that it is active in the following conditions: 1. Cerebral Palsy 2. Parkinsonism 3. Cerebral Spasticity 4. Selected cases of spinal cord spasticity Other neurological conditions and local muscle spasm will require additional time and effort to develop sufficient information to prove or disprove efficacy. PX 251; Tr. at 759-60 (Strickland). 1. Spasticity Clinical studies of spastic patients are made difficult by the great variety in location of the causal lesion, and by the assortment of symptoms. Merck emphasizes this difficulty as an explanation for its patent’s claims of effectiveness in treating spasticity in light of cyclobenzaprine’s eventually unfavorable results in the spasticity area. See MFF 11118; Tr. at 757-58 (Strickland). The initial results were favorable. Later spasticity study results were reported in March 1972. DX 68. In two double blind studies of children with cerebral palsy: Nine of 12 patients on MK-130 showed slight improvement as did 5 of 11 on placebo. There were some anticholinergic side effects and the early results do not yet allow a conclusion as to whether this compound is or is not effective in Cerebral Palsy. DX 68 at MF001774; Tr. at 762 (Strickland). An international study of cerebral palsy patients revealed mixed results. In one study in Ansink, Netherlands, seven of nine patients showed remarkable progress. The other two studies were “less definitive.” DX 68 at MF001775; Tr. at 763-64 (Strickland). Overall, in cerebral palsy patients, cyclobenzaprine showed some effectiveness, but further study (as reported in October 1972) indicated that cyclobenzaprine’s usefulness in treating this disorder was limited. DX 71 at MF003364; Tr. at 767-68. Additional study results on cyclobenzaprine’s usefulness in treating spasticity were recounted at an October 1972 Merck meeting: A total of 14 domestic clinical studies were started in which 140 patients with spasticity were treated. There were 55 patients in the seven pilot studies and an additional 85 patients in the seven controlled studies. The results of the pilot and controlled studies in this condition reveal that some selected patients do show a favorable response as measured by overall improvement in function and by measurement of spasticity, rigidity, and changes in ability to perform the tasks of daily living. When compared against placebo, however, the improvement is not a significant one. So we conclude that the drug is not of therapeutic use in the treatment of muscle spasticity and rigidity associated with spinal cord or cerebral injury or disease. DX 71 at MF003362; Tr. at 766 (Strickland). Share attended meetings at which the results of the spasticity studies was discussed. Tr. at 441 (Share); DX 66; DX 68. He believed the inconsistency of the results resulted from indiscriminate patient selection. In Share’s opinion, patients with hyperphasic disorders (as opposed to those with hypertonic disorders) would not respond to cyclobenzaprine. Although cyclobenzaprine did help relieve spasticity in “a certain select group of patients suffering from spastic conditions,” its results were insufficient to enable Merck to conclude it was effective in that clinical area. 2. Rigidity Merck conducted clinical tests of Parkinson’s patients’ responses to cyclobenzaprine to obtain information on its utility in treating muscle rigidity. MFF ¶ 129. By February 1971 Merck had received preliminary information on the utility of cyclobenzaprine in treating Parkinsonism. Six patients were studied: five of the six responded well, “with significant increase in function comparable to treatment with L-Dopa.” DX 66 at MF001325. Tr. at 761 (Strickland). Results of another study were reported in March 1972. The patients in this study were those who experienced side effects from L-Dopa, or who did not respond to L-Dopa. Four patients improved. DX 68 at MF001774;- Tr. at 762-63 (Strickland). While Merck’s results in area of rigidity showed some promise, ultimately Merck personnel concluded in November 1972 that cyclobenzaprine “is not of therapeutic use in the treatment of muscle spasticity and rigidity associated with spinal cord or cerebral injury or disease.” DX 72 at MF097309 (MK-130 In-Depth Review Meeting Minutes). Thus, Merck’s present claim that cyclobenzaprine showed usefulness in treating muscle rigidity patients is unpersuasive. The Court concludes that cyclobenzaprine is not and was not viewed by Merck as a viable treatment for muscular rigidity. The clinical evidence on the drug’s utility in treating - muscle spasm however is different. 3. Muscle Spasm Cyclobenzaprine’s clinical results in the treatment of muscle spasm were significantly more favorable than the results obtained in the spasticity and rigidity studies. In the March 1972 review of clinical outcomes, two studies by Aiken and Oates strongly indicated cyclobenzaprine’s efficacy in the treatment of muscle spasm. The Aiken and Oates results spurred Merck to the decision to further investigate the usefulness of cyclobenzaprine in muscle spasm “with carefully chosen studies.” DX 68 at MF001773. “Initiation of new studies” for spasticity and Parkinson’s disease, by contrast, were “deferred.” Id. The Aiken and Oates studies revealed that cyclobenzaprine performed well in patients suffering from muscle spasm. As the March 1972 review minutes noted: The studies by Dr. Aiken and Dr. Oates show the drug is effective in the treatment of spasm. Generally, side effects of dry mouth and drowsiness were observed but were not incapacitating and were reduced by adjustment of dosage. Dr. Aiken had 15 out of 19 patients with good to excellent responses versus 3 out of 18 on placebo. Dr. Oates had 15 out of 32 patients with good to excellent responses versus 5 out of 28 with placebo. DX 71 at MF003366-68. And in November 1972, Merck concluded: The two double-blind controlled studies in patients with post-traumatic voluntary muscle spasm show MK-130 to be significantly more effective than placebo. We conclude that MK-130 is an effective drug in the treatment of this condition. The side effects, drowsiness, dry mouth and bad taste, are significantly more frequent in the MK-130 group ... and will be the ones most commonly seen when the drug is used in outpatients. DX 71 at MF003372; DX 72 at MF097312 (emphasis added). Cyclobenzaprine was then extensively studied for usefulness in treating local muscle spasm, with consistently favorable results. In 1975, Merck applied for FDA approval of the use of cyclobenzaprine for treatment of muscle spasm. In 1977, the FDA sanctioned the use of cyclobenzaprine “as an adjunct to rest and physical therapy of muscle spasm associated with acute painful musculoskeletal conditions.” MFF If 140; Tr. at 758-59; DX 9; DX 10. 4. Drowsiness, Sedation and Cyclobenzaprine’s Selectivity Merck and Danbury have spent a considerable amount of time disputing cyclobenzaprine’s propensity to produce sedation or drowsiness. Merck offered testimony that drowsiness was distinct from sedation, defining drowsiness as “primarily a subjective, personal sensation, involving a feeling of being sleepy, wanting to go to sleep, or the sensation of beginning to go to sleep.” MFF If 141; Tr. at 828, 937 (Smith), 781 (Strickland). Danbury disputes this characterization, asserting that drowsiness is in effect an advanced degree of sedation. Tr. at 78-79 (Van Woert); DFF ¶[ 42 (“[I]t is evident that drowsiness is an outward manifestation of a degree of sedation.”). Turning first to Merck’s position that the distinctions between drowsiness and sedation are significant and that drowsiness cannot be equated with sedation: At least the latter part of this position rings true, but the significance of the two terms does not end there. The more important point is whether drowsiness is related to sedation, or is a form of sedation. And while some Merck trial witnesses contested the relationship of drowsiness and sedation, others conceded that there was no significant difference between drowsiness and sedation. The reason this question so preoccupies the parties is that Merck’s patent to a large degree rests on cyclobenzaprine’s selective action, i.e., its ability to reduce abnormal (hypertonic) muscle tone without reducing normal muscle tone and thus interfering with the patient’s daily activities. Side effects such as drowsiness and to a greater extent sedation suggest nonselectivity. However, the possibility exists that cyelobenzaprine may be selective in certain aspects and nonselective in others. Although Danbury challenges Merck’s differentiation of drowsiness and sedation, the Court is unaware of a charge by Dan-bury that cyclobenzaprine causes muscle weakness or loss of coordination. It is also unclear to the Court whether or not all (or any) forms of sedation result in a reduction of normal muscle tone. In any event, Dan-bury has not carried its burden of proving that cyclobenzaprine fails to act selectively with respect to its effects on normal tone. As for drowsiness, it appears incontestable that drowsiness falls within the range of “sedative” effects, and is a problematic side effect of the drug: to this extent, cyclobenzaprine is less selective than Merck claims. G. Merck’s Clinical Testing of Amitriptyline as a Muscle Relaxant Amitriptyline has been sold as an antidepressant since 1961. The FDA has never approved it for use as a muscle relaxant. In 1966, as part of the veratramine screening test, Merck ascertained that amitriptyline was “more potent with respect to tremors and convulsions than several of the commercially available muscle relaxants.” Tr. at 492-A (Share). The following January Gleason wrote the memorandum to the sample library which references inter alia the Sinha article’s conclusions with regard to amitriptyline’s muscle relaxant activity. DX 48. Then, in May 1967, Share reported the results of the veratramine test of the compounds sent in response to Gleason’s memorandum. This report was the first explicit written indication of cyclobenzaprine’s activity as a muscle relaxant. DX 50; DFF ¶ 29. Merck characterizes amitriptyline’s results in Share’s tests as inconsistent, of shorter duration than cyclobenzaprine’s, and accompanied by ataxia and tremors, contraindicating its use as a muscle relaxant. DX-53 at MF004865-66 (Tables 7 & 8); DX 18 at MF093347-48 (Tables 7 & 8); Tr. at 424-428 (Share); Tr. 718-719 (Beyer). Merck contends that the reasons for pursuing testing of amitriptyline were primarily due to “marketing and competitive impetus.” MFF ti 154. A Merck internal memorandum partially corroborates this contention. PX 243 at MF001553. Tr. at 719, 723 (Beyer). But the memorandum also may be read to support Danbury’s contention that amitriptyline’s muscle relaxant properties were neither unknown nor uninteresting to Merck: Amitriptyline may possess some of the unique attributes of MK-130 as a muscle relaxant. However, any discussion of the market potential of MK-130 vs. amitriptyline appears premature since the limited data obtained in animals suggest differences in the mode of action of the two compounds and since we lack any clinical data confirming the effectiveness of amitriptyline as a muscle relaxant in man. Anyway, we could expect essentially the same competition from HLR on amitriptyline in this new indication as we expect on MK-130. PX 243. at MF001553. Minutes from a Research Management Council meeting on January 6, 1971, similarly support the concern with Roche’s entry into the muscle relaxant market, and the consequent interest in marketing amitriptyline. Amitriptyline was tested in spastic patients, and, like cyclobenzaprine, found ineffective. Tr. at 152 (Van Woert), 437 (Share); DX 64 at MF102799, 102828-29, 102861062, and 102895-96; PX 255 at MF098295-96. However, Merck’s research Program Plan for 1972 discussed possible therapeutic uses for amitriptyline: ELAVIL did not show a significant effect in spasticity of voluntary musculature associated with CNS injury or disease. However, our initial trials with MK-130 in patients respond, and resulted in our narrowing our criteria for selection for treatment. The patients treated should have some residual voluntary muscle power. Flexor spasms without associated spasticity, as in patients with transected cords, do not respond. It is not clear whether more precise patient definition would have affected the results. DX 65 at MF096279. Interestingly, the need for more precise patient population definition is also cited by Merck in support of its arguments that cyclobenzaprine displayed some efficacy in the treatment of spasticity. Merck did not pursue clinical studies of amitriptyline in areas other than spasticity, claiming among other reasons that the compound’s poor results in that clinical area caused a lack of interest in continuing clinical testing. PX 258 at MF001407. Perhaps the most understandable reason proffered is the length of time amitriptyline had been on the market as an antidepressant. Tr. at 401-02, 404-05, 419-20 (Share), 630-31 (Engelhardt). Another notable explanation is that amitriptyline produced ataxia and other adverse side effects. Tr. at 885-86 (Smith). Danbury argues that Merck’s failure to test amitriptyline further is most plausibly explained by the reality that Merck could not have obtained a patent for amitriptyline as a muscle relaxant in light of the Sinha publications. The undated note by Rooney lends some support to this theory. Despite the doubt created by the defendant’s evidence of the muscle relaxant activity exhibited by amitriptyline, the Court finds the differences in potency and the incidence of ataxia in amitriptyline (which is not present in cyclobenzaprine at effective doses) sufficient explanation for the disparate expenditure of clinical resources. Cyclobenzaprine’s initial results in Molina-Negro’s spasticity studies were dramatically favorable. Although these results were not borne out in later studies, they probably provided the impetus for more extensive testing of cyclobenzaprine, especially in light of Share’s results with the compound in animal tests. The most troubling component of Merck’s treatment of the amitriptyline test results occurs in connection with the submission of applications for approval of cyclobenzaprine to the FDA and the prosecution of the Share patent. H. Merck’s FDA Submissions As part of its inequitable conduct theory, Danbury relies on the information Merck submitted to the FDA during the same general time frame of the patent prosecution (1970-1975). There are striking contrasts between the data prepared and sent to the FDA and the data submitted to the patent examiner at the PTO. The full significance of these contrasts will be discussed in the portion of the Opinion addressing the Court’s conclusions of law. Merck submitted its first Investigational New Drug (“IND”) application to the FDA in September 1970. DX 18. The IND contained data from studies of cyclobenzaprine in animals, as well as the initial Molina-Negro spasticity resulté. Id. The IND also contained data on amitriptyline’s activity as a muscle relaxant. Id. The previous June, Share had drafted a report in preparation for the FDA application. DX 53. The June 1970 report also included amitriptyline data. Id. The interpretation of that data and the reasons for including them are disputed by the parties. Share maintains that the data were included solely because Merck’s management felt that the FDA “would request a comparison [of amitriptyline and cyclobenzaprine] because the chemical analogs are so close that they [the FDA] would be hard pressed to believe that there was this unique difference [between the two compounds].” Tr. at 432 (Share). According to Share, his belief in amitriptyline’s lack of potential as a muscle relaxant never wavered, and therefore he did not inform Merck’s patent agent, Arther, of the amitriptyline data or of the amitriptyline prior art. Tr. at 419-20 (Share). Cyclobenzaprine’s selectivity was emphasized in Merck’s IND, submitted to the FDA in September 1970 (DX 18), and in “Merck’s Revised Clinical Operational Plan” dated October 5, 1970 (DX 62). The IND described