8, ll.50-53). Claim 11 limits the mineral acid in claim 7(i) to hydrochloric acid. (Col. 8, ll.54-55).
The written description of the '482 patent explains research efforts concerning the role of certain adjuvants in the gabapentin lactam conversion process. Lactam formation in gabapentin formulations was caused in part by "catalytic effects" of the ingredients-the adjuvants-that are combined with gabapentin to make a formulation. (Col. 4, ll.58-62). For example, where Poloxamer NF was the "sole" adjuvant, it did not impair the stability of the active material gabapentin. (Col. 4, ll.64-67). The specification also indicates that an adjuvant can be acceptable under one condition but not acceptable under a different condition. In one test using polyethylene glycol (PEG) as an adjuvant, "cyclization to the lactam took place to a considerable extent"; whereas when used with "very pure active substance," i.e., very pure gabapentin, "PEG was found to be indeed usable as an excipient." (Col. 5, ll.1-14). The specification goes on to explain that
[i]n order to establish which adjuvant materials promote the lactam formation, laborious serial investigation had, therefore, to be carried out....
The following adjuvant materials, for example, reduced the stability of the compounds (I) and should be avoided in the preparation of pharmaceutical compositions: modified maize starch, sodium croscarmelose, glycerol behenic acid ester, methacrylic acid co-polymers (types A and C), anion exchangers, titanium dioxide, and silica gels such as Aerosil 200.
(Col. 4, l. 62-Col. 5, l. 10 (emphasis added)). It also identifies thirteen adjuvants found to have "no noticeable influence" on the stability of gabapentin. (Col. 5, ll.11-17).
The patent then summarizes the conditions that should be maintained to achieve a pure and stable pharmaceutical composition:
[i]n order not to exceed the upper limit of 0.5% by weight of gabapentin lactam (referred to the gabapentin), which is regarded as being permissible, and in order to ensure the storage stability not only of the active material but also of the corresponding pharmaceutical forms of preparation, the following procedures are to be maintained:
1. The active materials of formula (I) must be prepared as highly purified, nonderivatized free amino acids, for example, from the corresponding hydrochloride by ion exchange. The proportion of remaining hydrochloride admixtures should thereby not exceed 20 ppm. The same also applies to other mineral acids.
2. In the case of pharmaceutical preparations or compositions, by the precise choice of adjuvant materials, every catalysis of the lactam formation must be suppressed.
3. By controls, it must be ensured that the above conditions are fulfilled. As a rule, this is the case when the lactam formation, under the storage conditions generally applicable for medicaments, does not increase within a period of time of 1 year after production of the pharmaceutical compositions or of the active material by more than 0.2% by weight and preferably 0.1% by weight, referred to the pure active material.
(Col. 5, ll. 18-41 (emphasis added)).