containing less than 0.5% by weight of a compound of Formula VIII wherein n is as defined above and less than 20 ppm of an anion of a mineral acid in combination with a pharmaceutically acceptable carrier wherein the carrier does not promote the formation of a lactam of formula VIII. ( Id. at 00176). In the same filing, Warner-Lambert distinguished U.S. Patent No. 4,894,476 ("the Butler patent") as not recognizing "the need for a stable lactam-free gabapentin product" and, instead, teaching the use of additives that would result in an "unstable product." ( Id. at 00179-80). In a November 1995 Office Action, the patent examiner rejected claim 21 as anticipated and, alternatively, unpatentably obvious in light of prior art. ( Id. at 00185-87). Warner-Lambert responded that it had "provided support in the specification ... that only certain adjuvants can be used in preparing a stable pharmaceutical preparation" because some "common adjuvants actually promote lactam formation." ( Id. at 00200).
In further response to the November 1995 Office Action and a July 1996 examiner interview, Warner- Lambert submitted declarations of named inventors. The declaration of Uwe Gebhardt stated that "without knowledge of the teaching of the present invention, the list of excipients suggested by Satzinger would result in an unstable product containing at least one excipient promoting instability concerning the lactam content." ( Id. at 00211) (emphasis in original). In November 1996, the examiner issued a "final" rejection of Warner-Lambert's claims 1, 6, 7, and 21-23 under 35 U.S.C. s. 103 as unpatentable over prior art. ( Id. at 000249-55). Warner-Lambert responded by filing an amendment that replaced claim 21 with new claim 24. New claim 24, which ultimately became claim 7 of the '482 patent, described a gabapentin composition "consisting essentially of" the "one or more pharmaceutically acceptable adjuvants that do not promote conversion of more than 0.2% by weight of the gabapentin to its corresponding lactam form" when stored for one year under specified atmospheric conditions. ( Id. at 00258). Still more rejections based on prior art followed.
A January 1998 Office Action again prompted Warner-Lambert to distinguish its gabapentin formulation from prior art on the basis of certain adjuvants. In a December 9, 1999 Second Submission After Final Rejection, Warner-Lambert focused on the specific elements of Claim 24, and noted that it required three things:
The GABAPENTIN in the solid dosage form must have a low level of lactam, i.e., less than 0.5%;
The GABAPENTIN used to prepare the solid dosage form must have a low level of mineral acid as
measured by mineral acid anion, i.e., less than 20 parts per million; and
3. The composition must be formulated with an excipient that does not catalyze the formation of GABAPENTIN lactam, i.e., no more than 0.2% over one year at 25 (deg.)C.
(Pros. Hist. at 00308). Warner-Lambert further emphasized that "all three claim limitations must be considered as a whole." ( Id.). As to prior art, Warner-Lambert noted that "[o]ut of the universe of available adjuvants, one must select particular ones, and avoid others. Applicants submit that there is nothing in the prior art that suggests that better stability will result from selecting those particular adjuvants." ( Id. at 00291). It further pointed out that while it might have been obvious to try an adjuvant from Butler that works, "it would not have been obvious how to obtain a stable pharmaceutical formulation each and every time since Butler provides no guidance as to which excipients to use." (Pros. Hist. at 00313). A December 1999 declaration of Friedrich Trondlin, submitted in support of Warner-Lambert's filing, similarly explained that