Document Fragment View

Matching Fragments

e) The Applicant submits that the amended claims are novel and inventive over the cited prior art documents and do not fall under Section 3(e). In this regard, the Applicant submits the following: Beneficially, as stated in the application was filed, the DPP IV inhibitors as included in the present claim set "are distinguished from structurally comparable DPP IV inhibitors, as they combine exceptional potency and a long-lasting effect with favourable pharmacological properties, receptor selectivity and a favourable side-effect profile or bring about unexpected therapeutic advantages or improvements when combined with other pharmaceutical active substances" (page 11 of the description). Linagliptin (BI 1356), a particularly preferred DPP-4 inhibitor of the present application (page 7 of the description, last paragraph, first species) inhibits DPP-4 more effective and longer lasting than the other major DPP-4 inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin, and is thus potent at low therapeutic doses and long-acting. The low dose amount is a particular feature for the provision of combinations of the present DPP IV inhibitor species according to the present claim set, constituting a contribution of the invention over the art. The low oral dose such as recited in the claims reflects said exceptional potency and long lasting effect, and is for at least this reason remarkable and valuably enriching the art. Further, Linagliptin is characterized by unique pharmacokinetics, such as with nonlinear profile (less than dose-proportional exposures). Other gliptins have dose-proportional (fairly linear) oral pharmacokinetie properties. Accordingly, optimization for therapeutic dose of linagliptin is not necessarily trivial. Further beneficially, the combination of linagliptin and metformin was shown to be well tolerated and improved glycemic control more than either monotherapy. For example: Combination of linagliptin and metformin improves glycemic control in type 2 diabetes: A randomized trial with an open-label arm in patients with poor glycemic control: Progression to combination of oral glucose-lowering drugs in patients with type 2 diabetes mellitus (T2DM) is recommended when monotherapy fails to reach treatment targets. This 24-week, double-blind, placebo controlled study randomized 791 T2DM patients. The 6 treatment groups included 2 arms receiving free combinations of linagliptin 2.5 mg bid+ either low- or high-dose (500 or 1000 mg) metformin (MET) bid.

Four monotherapy arms received linagliptin 5 mg q,d, MET 500 or 1000 mg bid, or placebo. Patients with a baseline HbAIc ≥11% received open-label combination therapy with linagliptin 2.5 mg bid+ MET 1000 mg bid (n=66). Mean baseline HbA1c was between 8.5% and 8.7%, and 11.8% in the open-label arm. Placebo- corrected, adjusted mean HbAIc changes after 24 weeks are shown in the figure [figure 1]. For the combination of linagliptin 2.5 +MET 500 or 1000, the placebo corrected reduction in HbAIc was -1.3% and -1.7%, respectively. Both combination regimens were superior to the monotherapy arms. In patients with poor glycemic control, mean change in HbA1c from baseline was - 3.7%. Adverse event rates were similar across treatment arms. The total number of hypoglycemic events during combination treatment was low (in total, 5 [1.8%] randomized patients receiving linagliptin 2.5 + MET 500 or 1000). The difference in body weight after treatment with linagliptin 2.5 +MET 1000 compared with MET 1000 was -0.23 kg. The combination of linagliptin and MET was well tolerated and improved glycemic control more than either monotherapy. Combination of linagliptin with MET significantly improves glycemic control towards treatment targets without weight gain and with a very low risk of hypoglycaemia Figure 1, Therefore, e.g., a particularly suitable and beneficial/positive therapeutic combining effect and usability (e.g. significant efficacy and/or favourable safety) can be achieved by the combinations according to the present invention, thus valuably enriching the art. The above Figure 1 clearly shows the effects of linagliptin (5 qd) alone, metformin (500 bid, 1000 bid) alone, as well as the effects of various linagliptin+metforrnin combinations, particularly the considerable effect in the most right bar in Figure 1 as to the combination linagliptin+metformin in patients with poor glycemic control. The combination of linagliptin and metformin provides significant improvements in glycemic control compared to placebo, to metformin alone, and to linagliptin alone. Thus, the combination therapy of linagliptin with metformin relates to a particular embodiment of the present invention. Furthermore beneficially, in type II diabetes patients who are not adequately controlled on another oral anti- hyperglycemic drug, the combination of a DPP-IV inhibitor of this invention with such other anti- hyperglycemic drug provides a therapeutic benefit to such patients. Especially, in type II diabetes patients who are not adequately controlled on metformin, the add-on combination of linagliptin (which is a DPP-IV inhibitor of this invention) to existing metformin therapy results in a significant and clinically meaningful improvement in glycemic control, without weight gain or increased risk of hypoglycemia; thus such combination provides indeed a "synergistic" (cooperative, complementary or improving) effect. One skilled in the art would not have plainly and inevitably predicted that the specific dosage amount of the DPP-IV inhibitor species in a combination with metformin would provide the (clinically and therapeutically) significant improvements in glycemic control (AI C and FPG) as outlined above.