Methylnaltrexone - USA

On July 17, 2019, New Jersey court found formulation patent of Relistor® valid & infringed by Actavis.

Plaintiffs Bausch Health Companies Inc., Progenics Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc., and Wyeth LLC (“Plaintiffs”) sued Defendant Actavis for infringement of U.S. Patent No. 8,524,276 under Hatch-Waxman Act. Patent in suit relates to tablet composition comprising methylnaltrexone & sodium lauryl sulphate which forms ion pair when goes into solution. Inventor found this method of ion pairing basically to increase the permeation & bioavailability of methylnaltrexone. Actavis contended that claims 2 & 5 are invalid as obvious & non-infringement of claim 2.

1. A pharmaceutical composition for oral administration comprising a solid dosage of (i) methylnaltrexone, or a pharmaceutically acceptable salt thereof, and (ii) sodium dodecyl sulfate (SDS), wherein the composition is a tablet, and wherein the composition comprises from about 7% to about 75% methylnaltrexone cation and dodecyl sulfate anion, based upon the total weight of the composition.

2. The pharmaceutical composition of claim 1, wherein the methylnaltrexone, or a pharmaceutically acceptable salt thereof, and sodium dodecyl sulfate (SDS) form an ion pair when dissolved in solution.

5. The pharmaceutical composition of claim 1, wherein at least 50% of the composition dissolves in a dissolution apparatus with paddles at 100 rpm in 900 mL of 0.1 N HCl at 37° C. within about 15 minutes.

Obviousness:

The central issue was whether there was motivation in the prior arts to combine methylnaltrexone & SLS in order to increase permeation & bioavailability. Actavis begins its argument with the proposition that methylnaltrexone was known to have poor permeability and poor bioavailability. Court noted that the choice of adjective here matters: “poor” implies deficiency and a problem to be solved, whereas “low” does not. If Actavis’ theory contends that a low or lower level of permeability would have motivated the POSA to improve the permeability, the evidence must support the inference that the POSA would have recognized the level of permeability as a problem to be solved.

District court however, concluded that Actavis failed to show that prior arts recognized the problem of permeation. According to court the evidence clearly shows that the POSA would have believed that increasing plasma levels was undesirable, but it does not show what effect this belief had on beliefs about increasing permeation. The Court’s uncertainty about what the prior art understood about whether permeation could be increased without a concomitant increase in bioavailability does not weaken Plaintiffs’ argument that there was no motivation to increase the permeability of methylnaltrexone in the prior art. Plaintiffs expert said that for the potent drug like methylnaltrexone it is not necessary to have good permeability because less amount of drugs which is available in the blood is sufficient to elicit response. Court thus said that Actavis' primary argument regarding question to solve failed as there is nothing in the prior art which showed that permeability is a problem.  Moreover, the prior arts cited by Actavis are all addressing different problem ie increasing the bioavailability of methylnaltrexone. Actavis' argued that as per the specification,  inventor solved the question of bioavailability and based their whole theory on "accordingly" word. But court said that this word is ambiguous and one can not say firmly that this was the problem that inventor wanted to solve. Even assuming that this was the problem patent addressed, still there was nothing in the prior art, which disclosed n number of ways & excipients to achieve the bioavailability problem. Actavis can not cherry pick SLS as the preferred one. There is no motivation to combine methylnaltrexone & SLS in order to come with the invention as claimed.

Court held that in conclusion, Defendant’s obviousness theory has at least two large holes. The first hole is the failure to establish the fundamental proposition that the prior art believed that methylnaltrexone had poor permeability such that it was a problem to be solved. The second hole is the failure to show how it would have been obvious to the POSA, following the teachings of prior arts, to select SLS to combine with methylnaltrexone in an oral formulation. Lastly, Plaintiffs have shown, and Actavis has not disproven, that the prior art taught away from the inventive formulation, and that the inventive formulation produced unexpected results, supporting a conclusion of nonobviousness.

Infringement:

The central issue was whether Actavis product forms an ion pair in the solution. Plaintiff's Expert used the experimentation such as shake-flask method to determine apparent octanol/water partition coefficient (APC). Actavis argued that the experiments do not prove infringement of claim 2 on several grounds. Actavis cited the testimony of various Experts in support of the proposition that an increase in APC does not demonstrate ion pairing. Actavis next argued that APCs cannot be determined for ingredients within tablets. Actavis next points to the fact that there is only one example of the shake-flask method in the ’276 patent, and that it was performed on a pure compound, not tablets. It was also argued by Actavis that it is incorrect method as it is difficult to predict the APC of a particular tablet. It can be measured for API or its salt only. Becuase other excipients in the tablet may interface in the analysis. But court credited testimony of Plaintiff’s Expert & said that through experimentation it was observed that APC was less when there was no SLS in tablet composition blend compared to the tablet containing SLS. Plaintiffs have presented unrebutted evidence that, when SLS is removed from the tablet blend, the measured APC drops substantially.  The Court determined that, in the context of this case, the only explanation for this change is the presence or absence of ion pairing. Plaintiffs have also presented unrebutted evidence that the methylnaltrexone and SLS in the ANDA tablet, dissolved in solution, appear in the octanol phase in a 1:1 molar ratio. This supports the inference that the methylnaltrexone and SLS have formed ion pairs. Actavis has presented no useful experimental evidence.

The Court thus concluded that Plaintiffs have proven, by a preponderance of the evidence, that the methylnaltrexone and SLS in the Actavis ANDA product form an ion pair when dissolved in solution. Plaintiffs have proven, by a preponderance of the evidence, that the proposed ANDA product will infringe claim 2. Actavis has failed to prove, by clear and convincing evidence, that claims 2 or 5 of the ’276 patent are invalid as obvious.