Merck & Co., Inc. v. Danbury Pharmacal, Inc.

• Decision Date: 31 August 1988
• Docket Number: Civ. A. No. 86-588 MMS.
• Citation: 694 F. Supp. 1
• Court: U.S. District Court — District of Delaware
• Parties: MERCK & CO., INC., Plaintiff, v. DANBURY PHARMACAL, INC., Defendant.

694 F. Supp. 1

MERCK & CO., INC., Plaintiff, v. DANBURY PHARMACAL, INC., Defendant.

Civ. A. No. 86-588 MMS.

United States District Court, D. Delaware.

August 31, 1988.

E. Norman Veasey, and Robert W. Whetzel, of Richards, Layton & Finger, Wilmington, Del., for plaintiff; Joseph M. Fitzpatrick, and Nicholas M. Cannella, of Fitzpatrick, Cella, Harper & Scinto, New York City, of counsel.

Jeffrey M. Weiner, Wilmington, Del., for defendant; Alfred B. Engelberg, Carmel, N.Y., of counsel.

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 Rahway, 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. IV 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),¹ 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.²

The Court held a five day bench trial³ 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").⁴ 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 1.⁵ Danbury 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 Danbury, 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 cyclobenzaprine⁶ under the trade name FLEXERIL in 1977.⁷ 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.⁸

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.⁹

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 compound¹⁰ cyclobenzaprine.¹¹ 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).¹² 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 s 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...