excipients that catalyze lactam formation in GABAPENTIN, and that must be avoided to obtain good long- term stability, are among the common excipients that are frequently used. There is no suggestion in the prior art that it is necessary to both (1) reduce the mineral acid level below a critical level; and (2) use only excipients that do not catalyze lactam formation.
( Id. at 00319) (emphasis added). Table 1 of the Trondlin declaration sets forth stability data obtained by testing various adjuvants with gabapentin stored under conditions that roughly corresponded to atmospheric conditions set forth in claim 7(ii). Nearly all adjuvants tested promoted lactam formation to some degree, but only some adjuvants promoted lactam formation resulting in unstable formulations, i.e., more than 0.2% by weight gabapentin lactam formed. ( Id. at 000321-22).
A Notice of Allowance issued on January 4, 2000, approximately one month after submission of the Trondlin declaration. The Examiner stated that "as pointed out by applicants, it is considered that the prior art did not recognize the causes of lactam formation in gabapentin formulations. It is considered that applicants' particular combination of limitations is not suggested by the prior art of record." ( Id. at 00342).
C. Teva's Gabapentin Formulations
Teva has submitted two Abbreviated New Drug Applications ("ANDAs") to the United States Food and Drug Administration ("FDA") seeking approval to market generic gabapentin tablets and capsules. Teva's capsule product contains gabapentin as its active pharmaceutical ingredient ("API"), as well as modified maize starch and titanium dioxide as adjuvants, or inactive ingredients.
Teva's capsule formulations are dose proportionate and have the following composition: 74.07% gabapentin API in the granulation; 20% talc USP extra fine in the granulation, which serves as both a glidant and a lubricant; and 5.93% Starch 1500 LM, or pregelatinized starch, in the granulation, which serves as a disintegrant and capsule filler. Starch 1500 LM is a modified maize starch in which the polymer bonds within the starch are physically ruptured. The process of splitting the bonds results in a modified maize starch with better flow and compressibility than unmodified maize starch.
Teva's capsule shell contains titanium dioxide, gelatin, iron oxides, and FD & C dyes. The capsule shell is imprinted with ink 1012. The titanium dioxide that is in Teva's gabapentin capsules is a coloring component of the gelatin capsule shell. In fact, Teva purchases pre-manufactured capsule shells from Warner-Lambert's subsidiary, Capsugel. Capsugel's capsule shells are made up of gelatin and comprise two parts: a body and a cap. Teva uses a grey capsule body and a grey cap for 100-mg capsules, an orange body and an orange cap for 300-mg capsules, and a brown body and a brown cap for 400-mg capsules. The percentage of titanium dioxide in the capsule bodies is 2.0000%, 1.7000%, and 1.3333%, respectively. The percentage of titanium dioxide in the capsule caps is the same as in the capsule bodies.
Teva's gabapentin tablet formulations are dose proportionate and have the following composition: 70.9% gabapentin API; 4.4% povidone USP as a binder; 15.9% microcrystalline cellulose NF as a filler; 1.4% crospovidone NF as a disintegrant; 2% talc USP extra fine as a glidant; 2.9% hydrogenated vegetable oil NF type 1 as a lubricant; 2.5% Opadry(R) Y-1 7000H white as a coating solution; alcohol as a granulation solvent, and purified water as a coating solvent. The Opadry(R) coating solution consists of 1.56% HPMC 2910 5cP USP; 0.78% titanium dioxide; and 0.16% polyethylene glycol 400 NF.