Patents key to pharma – provides resources and incentive for discovery

On its face, the change in formulation might seem relatively straightforward, and some might go so far as to characterize it as obvious and unworthy of patent protection. The original formulation, Lumigan 0.03%, contained 0.03% by weight of bimatoprost (the active ingredient) and fifty parts per million (“ppm”) benzalkonium chloride (“BAK”), among other ingredients. BAK is a 210 preservative used to inhibit bacterial growth in ophthalmic solutions. 211 Pharmaceutical chemists knew, however, that BAK is cytotoxic and that it can damage the cells on the ocular surface and cause undesirable side effects. 212 Allergan, the company that developed the original 0.03% formulation of Lumigan, invested in research to identify some means for reducing the drugs adverse side effects while maintaining therapeutic efficacy. After exploring 213 several alternative formulations of the active ingredient, Allergan scientists discovered that the corneal permeability of bimatoprost could be significantly increased by raising the concentration of BAK from fifty ppm to 200 ppm. This 214 change in formulation allowed for the use of a significantly lower concentration of bimatoprost (0.01%) to achieve an efficacy similar to that of the 0.03% solution, while causing less frequent and less severe hyperemia. Allergan 215 patented this new formulation, and obtained FDA approval to market Lumigan 0.01% for the same indications as the original Lumigan 0.03% product. 216 Significantly, without the prospect of effective patent protection for the new formulation, Allergan would have had little incentive to make the substantial investment in time and money to develop and obtain FDA approval for this improved formulation. Generic companies challenged Allergan’s formulation patents on a number of grounds, including the alleged obviousness of the invention, but ultimately the Federal Circuit affirmed a district court’s decision upholding the validity of the patents. The district court found the solution to the problem at which Allergan 217 scientists ultimately arrived was not only unexpected, it was in fact actively discouraged by the teachings of the prior art. For example, the prior art taught 218 that the use of BAK as a preservative should be minimized in ophthalmic formulations to avoid safety problems, and the appellants’ own expert, in summarizing the prior art’s widespread concern regarding the chemical’s toxicity, described BAK as “a natural-born killer” that was “from Satan.” The district 219 court found that, prior to Allergan’s invention, “BAK was known to cause increased IOP, hyperemia, dry eye, and damage to corneal cells, and to exacerbate other eye disorders,” and that “those known side effects would have discouraged a person of ordinary skill from using higher concentrations of BAK in a bimatoprost formulation, especially when fifty ppm BAK was known to be an adequate preservative in Lumigan 0.03%.” 220 The district court also found the prior art taught that BAK would not increase the permeability of bimatoprost, but in fact, might actually decrease it. Working 221 against this conventional wisdom, “Allergan’s inventors surprisingly determined that the opposite was true, namely, that 200 ppm BAK enhanced the permeability of bimatoprost.” According to the Federal Circuit, the record showed “that the 222 prior art ‘criticize[d], discredit[ed], or otherwise discourage[d]’ the use of 200 ppm BAK in a bimatoprost formulation.” The Federal Circuit concluded that 223 “the district court did not clearly err in finding that the claimed formulation exhibited ‘unexpected results,’ which differed in kind, not just in degree, from the prior art.” In effect, by investing in research that explored alternative 224 formulation strategies that ran counter to conventional wisdom, Allergan scientists had come up with a fundamentally different product—one that could not have been predicted based on prior knowledge, and one which provided patients with a safer and more effective course of treatment. This is the very sort of innovation that should be promoted by patents. As noted by the Federal Circuit, the difference between the 0.03% and 0.01% formulations is essentially “the difference between an effective and safe drug and one with significant side effects that caused many patients to discontinue treatment.” Unfortunately, the recommendations of the Guidelines cast a 225 shadow of uncertainty over the availability of effective patent protection for inventions of this type. 226 It is important to remember that Allergan’s patents on the 0.01% formulation would not cover the original formulation and hence, should not create an obstacle to any generic company that decides to bring the original 0.03% formulation to the market. Of course, in view of its improved safety-efficacy profile, doctors 227 and their patients might prefer the newer formulation. But if that is the case, it is only because the new formulation represents a significant medical advance, and thus a patent on the formulation is doing exactly what patents are intended to do, i.e., spur the development of improved modes of therapeutic treatment. Once the new formulation patents expire, generic companies will be free to sell versions of the new 0.01% formulation. Prior to their expiration, the market can decide 228 whether the improvement of the new formulation justifies the cost differential between it and generically available 0.03% formulation.