in rats did not reveal any adverse effects on male or female fertility with brimonidine tartrate or timolol maleate. Clinical trials Two prospective, randomized, double-blinded, phase III clinical trials were conducted at 53 sites in the United States to compare the IOP-lowering efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol maleate fixed combination twice daily with 0.2% brimonidine tartrate three times daily or 0.5% timolol maleate twice daily in patients aged 18 or older who had ocular hypertension or glaucoma. When assessed over a 3-month period, pooled results from a total of 1159 patients showed significantly greater mean IOP decrease from baseline with the brimonidine/timolol combination (4.9-7.6 mmHg) than with brimonidine monotherapy (3.1-5.5 mmHg) or timolol monotherapy (4.3-6.2 mmHg) across all follow-up visits. Similar efficacy results were reported during 12-month follow-up: mean IOP decrease from baseline was 4.4-7.6 mmHg with brimonidine/timolol combination, compared to 2.7-5.5 mmHg with brimonidine and 3.9-6.2 mmHg with timolol. The incidence of treatment-related adverse events with the brimonidine/timolol combination was lower than that with brimonidine monotherapy but higher than that with timolol monotherapy. A 12-week prospective, randomized, double-blinded study in 371 glaucoma and ocular hypertension patients with inadequate IOP control on monotherapy compared the efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol fixed combination twice daily with the concomitant use of 0.2% brimonidine tartrate twice daily and timolol 0.5% twice daily. The IOP-lowering effect of the fixed combination group was shown to be non-inferior to that of concomitant therapy. Incidence of adverse events was similar between groups. Society and culture Brand names Allergan holds at least six active patents protecting Combigan from generic competition. Several generic companies challenged the validity of the patents and filed Abbreviated New Drug Applications (ANDA) seeking market entry. Allergan responded by filing a lawsuit against the ANDA filers. In Allergan, Inc. v. Sandoz, Inc., the US Court of Appeals for the Federal Circuit ruled that Allergan's composition-related patent claims were invalid based on obviousness, because brimonidine and timolol had already been marketed in the claimed concentrations. However, Allergan's method claim (US Patent No. 7,030,149), which states "reducing the number of daily topical ophthalmic doses of brimonidine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy", was held to be non-obvious. As a result, generic companies are prevented from marketing generic