The opinion of the court was delivered by: POLITAN
Since its issuance, Merck has been the owner by assignment of the entire right, title and interest in the following United States Letters Patent: Number: 3,781,430 (hereinafter referred as to " '430"), Issue Date: 12/25/73, Expiration Date: 12/24/90, Applicant: Edward J. Cragoe, Jr., Title: Diuretic Formulations. The validity of this patent is the subject matter of this litigation.
Diuretics are valuable therapeutic agents as they are useful in the treatment of cardiovascular and renal diseases. Their use is indicated in the management of all types and grades of severity of congestive heart failure in which diuretic therapy improvement is required. Due to the resulting loss of water and electrolytes, dramatic improvement is noted in peripheral and pulmonary edema, dyspnea, orthopnea, cough, ascites and pleural effusion. Diuretics also provide effective therapy in various forms of renal edema, e.g., edema associated with nephrosis and certain types of nephritis. Their administration results in prompt excretion of retained fluid and electrolytes with consequent benefit to the patient. The desired electrolyte to be excreted is sodium chloride.
Although diuretics are often life-saving because of the above beneficial therapeutic effects, most of them have the disadvantage of causing the excretion of appreciable amounts of potassium ions. When an excessive loss of potassium ions occurs, a severe muscular weakness and feeling of extreme physical exhaustion results.
Merck's '430 patent describes and claims compositions for oral administration comprising combinations of amiloride hydrochloride and hydrochlorothiazide, and methods for the use of such combinations in the treatment of hypokalemia. For ease of reference, both the free base form of amiloride and its hydrochloride salt form (amiloride hydrochloride) will be referred to simply as amiloride. Amiloride is a so-called potassium-sparing diuretic -- i.e., it causes the excretion of unwanted sodium without also causing the excretion of potassium. Hydrochlorothiazide, on the other hand, is a so-called potassium-eliminating diuretic, causing both the desired effect of sodium excretion but the undesired effect of potassium loss. The combination of amiloride and hydrochlorothiazide results in a reduction in the amount of potassium ions that are eliminated, without a reduction in the amount of sodium ions that are eliminated.
Claims 1 and 4 of the '430 patent cover, respectively, compositions for oral administration comprising amiloride and hydrochlorothiazide and a method of treating hypokalemia by oral administration of such compositions, wherein the ratio of amiloride to hydrochlorothiazide ranges from about 1:1 to 1:10 by weight. The remaining claims 2, 3, 5 and 6 are specific to Merck's commercial product, which comprises a combination of 5 mg amiloride and 50 mg hydrochlorothiazide and its method of use in treating hypokalemia:
"2. A composition according to claim 1 wherein amiloride hydrochloride and hydrochlorothiazide are combined at a ratio of 1 to 10 by weight.
3. A composition for oral administration which comprises 5 mg of amiloride hydrochloride and 50 mg of hydrochlorothiazide.
5. A method according to claim 4 wherein amiloride hydrochloride and hydrochlorothiazide are at a ratio of 1:10 by weight.
6. A method according to claim 5 which contains 5 mg of amiloride hydrochloride and 50 mg of hydrochlorothiazide."
On October 15, 1985, Biocraft submitted an abbreviated new drug application ("ANDA") under § 505(j) of the Food, Drug and Cosmetic Act (21 U.S.C. § 355(j)), seeking approval from the FDA to market a copy of Moduretic under a generic name, but likewise containing 5 mg amiloride and 50 mg hydrochlorothiazide. Pursuant to 35 U.S.C. § 271(e)(2), Biocraft's submission of that ANDA constituted an act of infringement of Merck's '430 patent as a matter of law. Thus, infringement is not an issue in this litigation. The only issues in this case are whether Merck's '430 patent is valid and enforceable.
As part of its ANDA, Biocraft asserted that the '430 patent is invalid. As required by statute, on October 15, 1985 Biocraft provided Merck with a statement of the factual and legal bases upon which Biocraft premised its invalidity assertions. Merck thereafter filed the Complaint commencing this patent infringement suit. Biocraft filed its Answer and Counterclaim on December 16, 1985, asserting that the '430 patent was invalid or unenforceable. Merck filed its Reply to Counterclaim on December 24, 1985.
The FDA approved Biocraft's ANDA for a generic copy of Moduretic on or about July 15, 1987. The effective date of the FDA's approval of Biocraft's ANDA was April 17, 1988, subject to this Court's power to modify such effective date in accordance with 35 U.S.C. § 355(j)(4)(B)(iii). In the course of the trial, this Court issued an interlocutory injunction restraining Biocraft from marketing its generic copy of Moduretic pending final decision in this case.
As hereinbefore indicated, the '430 patent claimed that the combination of amiloride and hydrochlorothiazide produced results supporting the issuance of a patent. Specifically, the '430 patent contains the following statements:
The invention involves the coadministration of a pyrazinoylguanidine compound with one of the abovementioned potassium eliminating diuretics to thereby result in a reduction in the amount of potassium ions that are eliminated, without a reduction in the amount of sodium ions that are eliminated. In fact, more sodium ions are eliminated than would be forecast from a knowledge of the natriuretic effects of the individual drugs. The co-administration of these drugs therefore results medically in a synergistic therapeutic accomplishment.
Medically, synergism is obtained when two drugs react favorably. With respect to separate administration of a potassium sparing diuretic and a sodium excreting diuretic, neither of the diuretics can be successfully administered over a period of time without causing undesirable effects on the patient. More specifically, when a sodium excreting diuretic is administered over a period of time, the patient excretes the necessary quantity of undesired Na (sodium) but in addition thereto excretes the desired K (potassium), thus subjecting the patient to a hypokalemia state. When a potassium sparing diuretic is administered separately over a period of time, the patient achieves the desired K (potassium) balance but the quantity of undesired Na (sodium) excretion is not obtained. Therefore, the favorable reaction existing between these classes of diuretics is that the potassium sparing diuretic potentiates the natriuretic effect of sodium excreting diuretics while simultaneously reversing the K (potassium) excretion to the desired positive level.
Before embarking on the sea of invention, certain basic guideposts applicable to this Court's review of the ...