Fesoterodine – USA

On Jan 11, 2019, Federal Circuit affirmed PTAB’s decision of upholding the compound patent on Pfizer Inc.’s Toviaz® drug in an IPR challenge from Amerigen Pharmaceuticals Ltd.

UCB Pharma owns U.S. Patent 6,858,650 (expiring on 07/03/2022) patent, which covers certain chemical derivatives of 3,3- diphenylpropylamines, including a compound called fesoterodine. Fesoterodine is an antimuscarinic drug marketed as Toviaz® to treat urinary incontinence. Fesoterodine is a prodrug of the active compound 5-hydroxymethyl tolterodine ("5-HMT"). 5-HMT is a metabolite of the compound tolterodine, an older antimusarinic drug sold under the trade name Detrol® to treat overactive bladder. Fesoterodine differ s from 5- HMT at the 2-position : 5-HMT has a hydroxy group, while fesoterodine has an isobutyryl ester. The issue before federal circuit was whether it would have been obvious to modify the 2-position hydroxy group of 5-HMT to an alkyl ester of six carbons or less as in fesoterodine.

   

             Fesoterodine                                           5-hydroxymethyl tolterodine ("5-HMT")

Mylan Pharmaceuticals Inc. petitioned for IPR of the ’650 patent, and the Board instituted review of claims 1–5 and 21–24 on two grounds: (1) obviousness over the Detrol Label, Postlind, Bundgaard, Bundgaard PCT, and Berge; and (2) obviousness over Brynne, Bundgaard, Bundgaard PCT, and Johansson. The references fall into three general categories. First, the Detrol Label, Postlind, and Brynne discuss tolterodine and its metabolism and pharmacokinetics. Second, Bundgaard and Bundgaard PCT focus on prodrug design principles. Third, Berge and Johansson relate to pharmaceutical salts. After institution, Amerigen and two other companies were joined as parties to the proceeding. In its obviousness analysis, the Board accepted that a person of ordinary skill would have chosen 5-HMT as a lead compound for development in order to reduce the number of potential metabolic steps and to avoid CYP2D6-related drug-drug interactions. However, after considering expert testimony from both the petitioners and UCB, the Board found that a person of ordinary skill would not have been motivated to modify 5-HMT to make a prodrug by replacing the 2- position hydroxy group with an alkyl ester of six or fewer carbons. Specifically, the Board found that a person of ordinary skill would not have been motivated to modify 5-HMT to improve its bioavailability. Petitioners’ expert, Dr. Patterson, testified that 5-HMT was insufficiently lipophilic because of its two hydroxy groups, and that its lipophilicity would cause bioavailability problems. UCB responded that no prior art reference suggested that 5-HMT would not be well-absorbed, and that the lipophilicity of 5-HMT relative to tolterodine, a known, well absorbed drug, did not show that 5-HMT had a bioavailability problem. Furthermore, UCB’s expert, Dr. Roush, conducted an analysis of 5-HMT using the “Rule of 5” discussed in a research article on drug delivery by Lipinski and concluded that none of them indicated that 5-HMT had a bioavailability problem. Dr. Patterson did not rebut this analysis. The Board thus credited Dr. Roush and determined that a person of ordinary skill would not have been motivated to modify 5-HMT because of bioavailability concerns.

Next, Board said that designing a prodrug was a complex endeavor, as toxicity, bioavailability, and other drug characteristics must be monitored for two compounds rather than just one. The Board also found that Bundgaard defined the prodrug form of a compound as inactive, but the petitioners did not demonstrate that esters of 5-HMT would be inactive. Moreover, the petitioners did not point to any prodrugs analogous to fesoterodine, for example, prodrugs in the same chemical class, with the same mechanism of action, or in the same field of treatment. The Board thus found that a person of ordinary skill would not have been motivated to develop a prodrug of 5-HMT. Even assuming that a person of ordinary skill would have been motivated to modify 5-HMT, the Board found that producing the specific claimed compounds would not have been a matter of routine optimization. Considering competing expert testimony, the Board determined that there were many possible molecular modifications of 5-HMT consistent with a prodrug design. For example, Bundgaard explained that diesters could be used in a prodrug. The Board credited Dr. Roush’s testimony that a person of ordinary skill would have considered esterifying the hydroxy groups at both the 2- and 5-positions. And even if a person of ordinary skill only considered esterifying the 2-position hydroxy group, the Board credited Dr. Roush’s testimony that there was no scientific justification to limit the ester to six carbons or fewer. Finally, even if the universe of possible esters was limited to alkyl esters of six carbons or fewer at the 2-position, that still left 86 possible monoesters. The Board found that it would not have been routine to test each one. Altogether, the Board held that the prior art did not suggest modifying 5-HMT to make the specific claimed compounds.

Amerigen appealed. During appeal Amerigen argued that the Board did not properly consider the evidence in support of obviousness. In particular, Amerigen alleges that: (1) the Board misunderstood Amerigen’s arguments concerning lipophilicity, and it should have recognized that a person of ordinary skill would have increased the lipophilicity of 5-HMT for its own sake; (2) the Board placed an excessive burden on Amerigen to show a motivation to make a 5-HMT prodrug; and (3) the Board failed to recognize that arriving at the specific claimed compounds would have been routine optimization.

On first issue, Federal Circuit held that Board correctly found that Dr. Roush better addressed the bioavailability issue and that the lipophilicity of 5-HMT relative to tolterodine did not demonstrate a bioavailability problem. Federal Circuit therefore agreed with UCB that a reasonable fact finder could have weighed Dr. Roush’s testimony over Dr. Patterson’s & concluded that substantial evidence supports the Board’s finding that a person of ordinary skill would not have been motivated to modify 5- HMT to increase its lipophilicity. Moreover, Amerigen does not point to a specific error in the Board’s findings, but generally argues that “there need not be a specific problem with bioavailability of 5-HMT for one of ordinary skill in the art to be motivated to modify 5-HMT to further improve its bioavailability. That may be true in some cases, but Amerigen’s conclusory argument is not sufficient to overcome the substantial evidence to the contrary underpinning the Board’s analysis.

On second issue, Amerigen argued that the Board imposed an “insurmountable burden” on petitioners. But Federal Circuit said that the Board sensibly found that a skilled artisan would “seek some degree of certainty that a prodrug of a particular molecule would be inactive before embarking on the process of attempting to create the prodrug,” and the petitioners failed to provide any such certainty. This deficiency is compounded by the Board’s second finding that the petitioners did not point to any prodrugs analogous to 5-HMT. Specifically, the Board found no evidence of prodrugs in the same chemical class, with the same mechanism of action, or in the same field of treatment. Therefore, Board just found that the absence of such evidence supported UCB’s argument that at the time of the invention skilled artisans had not considered “a prodrug of an antimuscarinic drug or any sort of overactive bladder drug.”

On third issue, Amerigen argued that Bundgaard disclosed esters as prototypical prodrug moieties and that modifying the 2-position alone would have been the most obvious choice. Federal Circuit said that while the Board considered Bundgaard’s disclosure of ester prodrugs, the Board also observed, citing Dr. Roush, that Bundgaard taught many other prodrug substitutions that a person of ordinary skill would have considered. Dr. Roush testified that these additional substitutions included ethers, carbamates, carbonates, phosphate esters, Mannich bases, and macromolecular prodrugs. Moreover, the Board also found that a person of ordinary skill would have considered modifications at the 5-position because the prior art did not indicate a preference for either the 2- or 5-position, and the inventors themselves considered modifying the 5-position. Moreover, Amerigen has demonstrated no discernible error in the Board’s technical analysis. Thus Federal Circuit concluded that substantial evidence supports the Board’s determination that the prior art did not suggest making the claimed monoester substitutions solely at the 2-position.

Altogether, the Board found that the petitioners neither established a general motivation to make a 5-HMT prodrug nor proved that the specific claimed modifications would have been obvious. Federal Circuit thus concluded that Amerigen’s factual challenges to the Board’s decision are without merit and that substantial evidence supports the Board’s findings.

Federal Circuit also touched upon issue related to standing to appeal. UCB argued that Amerigen lacks standing to appeal from the Board’s decision because USFDA will not approve Amerigen’s ANDA until the expiration of the ’650 patent, previously upheld in a separate suit in the District of Delaware, in 2022. Accordingly, UCB contends that Amerigen is foreclosed from infringing the ’650 patent, and without a possibility of infringement there can be no justiciable dispute. But Federal Circuit said that this case does not arise under the Hatch-Waxman Act, and the causes of action available under that Act do not necessarily control the standing inquiry in an appeal from an IPR decision. They do not control here because Amerigen does not rely on a risk of infringement liability as a basis for injury in fact; rather, it contends that the mere listing of the ’650 patent in the Orange Book inflicts a concrete commercial injury redressable by this court. And this court has previously recognized that listing a patent in the Orange Book may create a cognizable injury independent of the prospect of infringement liability. Moreover, The America Invents Act (“AIA”) and its provisions governing IPRs do not support an analogous statutory implication. Congress granted parties broad access to challenge patents through the IPR procedure. Any “party dissatisfied with the final written decision of the [Board] . . . may appeal the decision . . . .” The AIA thus provides no basis for us to premise standing in an appeal from an IPR decision on the availability of particular causes of action under the Hatch-Waxman Act. Rather, an appellant must demonstrate an injury consistent with the generally applicable requirements of Article III, i.e., a controversy “of sufficient immediacy and reality” to warrant the requested judicial relief. Federal Circuit further held that because Amerigen has demonstrated such a controversy traceable to UCB’s ’650 patent and redressable by this court, it has standing to appeal from the Board’s decision even though it may be incapable (as a Paragraph III filer) of maintaining a parallel Hatch-Waxman suit.