Opinion ID: 216975
Heading Depth: 3
Heading Rank: 2

Heading: CMC as a Solubility-Enhancing Component

Text: The district court found that one of ordinary skill in the art would not have turned to CMC as a solubility enhancer. In response, Apotex presents two arguments. First, it points out that Alphagan® and Refresh Tears®, which contains CMC, were routinely prescribed together. This fact alone does not establish that it would have been obvious to combine the two in a single formulation. Two ingredients might be therapeutically effective when used separately as part of an overall treatment regimen, yet be incompatible or ineffective when combined in a single solution. Second, Apotex argues that the claimed invention would have been obvious in light of journal articles by Thorsteinn Loftsson from 1994 and 1997. The district court found that the Loftsson references do not disclose or suggest the use of CMC in connection with any α-2 adrenergic agonist, let alone brimonidine. We agree. The earlier of the two Loftsson articles is entitled The Effect of Water-Soluble Polymers on DrugCyclodextrin Complexation. Cyclodextrin is a cylindrical molecule with a hydrophobic center and hydrophilic exterior. It acts as a carrier for hydrophobic drugs. Loftsson tested the effect of polymeric solubility enhancers, including CMC, on the water solubility of cyclodextrindrug complexes. Notably, many of the asserted claims of the related patents recite a solution that is substantially free of cyclodextrins. Even in the case of the claims that lack that proviso, we see no error in the district court's treatment of the Loftsson references. Apotex relies heavily on Loftsson's statement that the addition of a very small amount of [CMC] resulted in a significant increase in the aqueous solubility of most of the drugs tested. While acknowledging that neither of the two Loftsson articles discusses the use of CMC in connection with brimonidine or even the generic class of α-2-adrenergic agonists, Apotex argues that the articles certainly would have suggested as much to one of skill given that [they] disclosed CMC enhancing the solubility of the many soluble active ingredients with which it was tested. However, Apotex provided no expert testimony or other evidence to support that proposition, and the generalization made by counsel on appeal does not undermine the district court's contrary determination following the trial. Finally, Apotex argues that the district court imported an unclaimed limitation to distinguish the Loftsson references. Loftsson assessed the water solubility of various mixtures, consisting of cyclodextrin, CMC, and a subject drug, after heating the mixture at 120°C for 20 minutes. The 1997 Loftsson paper makes the need for the heating step explicit: [s]imply adding the polymers to the solutions without heating does not enhance the complexation or the drug availability. The asserted claims that recite CMC neither require nor exclude a heating step. Apotex contends that the district court erroneously used the absence of a heating step to distinguish the claims from the 1997 Loftsson reference. We disagree. Allergan's expert testified that the high temperature needed to observe the increase in solubility can lead to decomposition of a drug such as brimonidine and to alterations in its crystalline structure. The need for the heating step and its apparent incompatibility with brimonidine further establishes that Loftsson does not teach the combination of brimonidine and CMC. Accordingly, we see no error in the district court's findings based on the Loftsson references.