Amerigen Pharm. Ltd. v. UCB Pharma GMBH

• Decision Date: 11 January 2019
• Docket Number: 2017-2596
• Citation: 913 F.3d 1076
• Parties: AMERIGEN PHARMACEUTICALS LIMITED, Appellant v. UCB PHARMA GMBH, Appellee
• Court: U.S. Court of Appeals — Federal Circuit

913 F.3d 1076

AMERIGEN PHARMACEUTICALS LIMITED, Appellant

v.UCB PHARMA GMBH, Appellee

2017-2596

United States Court of Appeals, Federal Circuit.

Decided: January 11, 2019

William Hare, McNeely Hare & War LLP, Princeton, NJ, argued for appellant. Also represented by Shyam Dixit, Dixit Law Firm, Tampa, FL.

Jeffrey J. Oelke, Fenwick & West, New York, NY, argued for appellee. Also represented by Ryan Johnson, Laura Moran, James Trainor.

Before Lourie, Chen, and Stoll, Circuit Judges.

Lourie, Circuit Judge.

Amerigen Pharmaceuticals Limited ("Amerigen") appeals from the decision of the United States Patent and Trademark Office Patent Trial and Appeal Board (the "Board") in an inter partes review ("IPR") holding that claims 1-5 and 21-24 of U.S. Patent 6,858,650 (the " ’650 patent") are not unpatentable as obvious. Mylan Pharm. Inc. v. UCB Pharma GmbH , No. 2016-00510, 2017 WL 3085867 (P.T.A.B. July 19, 2017) (" Decision "). We conclude that the Board did not err in its conclusions and affirm.

I. BACKGROUND

A.

UCB Pharma GmbH ("UCB") owns the ’650 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

.

The chemical structure of fesoterodine is depicted below:

On the upper left hand benzene ring above, we will refer to the position of the hydroxymethyl group as the 5-position, and the position of the isobutyryl ester as the 2-position.

Fesoterodine is a prodrug. Unlike a typical drug, a prodrug is an inactive molecule as-delivered and requires transformation within the body into its active therapeutic form. A prodrug may be employed when administering the active molecule itself is infeasible because of poor bioavailability (i.e. , the fraction of a drug dose that is absorbed into the bloodstream) or other drug delivery problems.

Fesoterodine is a prodrug of the active compound 5-hydroxymethyl tolterodine

("5-HMT"). 5-HMT is a metabolite of the compound tolterodine, an older antimuscarinic drug sold under the trade name Detrol ® to treat overactive bladder. In the body, tolterodine is converted to 5-HMT by cytochrome P450 2D6 ("CYP2D6"). The metabolite 5-HMT, like tolterodine, has antimuscarinic activity and thus contributes to the therapeutic effect of tolterodine. Such metabolites are known as active metabolites. The chemical structures of tolterodine and 5-HMT are shown below:

As depicted, CYP2D6 converts the methyl group at the 5-position of tolterodine

to a hydroxymethyl group in 5-HMT. Fesoterodine, on the other hand, differs from 5-HMT at the 2-position: 5-HMT has a hydroxy group, while fesoterodine has an isobutyryl ester. The issue before us is 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.¹

B.

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,² Postlind,³ Bundgaard,⁴ Bundgaard PCT,⁵ and Berge⁶ ; and (2) obviousness over Brynne,⁷ Bundgaard, Bundgaard PCT, and Johansson.⁸ After institution, Amerigen and two other companies were joined as parties to the proceeding. Only Amerigen has appealed.

1.

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. We will summarize each group in turn.

The Detrol

Label discloses the structure of tolterodine and its metabolism to 5-HMT via the enzyme CYP2D6. The metabolite 5-HMT is reported to have antimuscarinic activity similar to tolterodine and contribute to tolterodine’s therapeutic effect. The Detrol Label taught that a subset of the population (known as "poor metabolizers") lacks CYP2D6 activity and instead metabolizes tolterodine by means of the enzyme CYP34A. Since the CYP34A pathway metabolizes tolterodine more slowly than CYP2D6, poor metabolizers have higher concentrations of tolterodine and negligible concentrations of 5-HMT. However, because the sum of unbound tolterodine

and 5-HMT concentrations is similar in extensive (i.e. , patients with normal CYP2D6 activity) and poor metabolizers, the Detrol Label teaches that the net therapeutic activity of tolterodine would be similar between both groups.

Brynne is a research paper that describes the influence of patients’ varying CYP2D6 activity on tolterodine

activity. Like the Detrol Label, Brynne posits that "the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite." J.A. 301. However, Brynne did observe that "[t]olterodine is tenfold more lipophilic than 5-HM[T], and consequently tolterodine penetrates membranes more rapidly." J.A. 310. The reference suggests that this difference might contribute to poor metabolizers experiencing a slightly worse side effect than extensive metabolizers. But ultimately, Brynne concludes that the variation in CYP2D6 activity between poor and extensive metabolizers "does not appear to be of great pharmacodynamic importance." Id.

Postlind, another published research paper, focuses on tolterodine

metabolism. J.A. 296. Postlind cautions that tolterodine has a potential for drug-drug interactions because other drugs are metabolized by CYP2D6 and that CYP2D6 poor metabolizers could be particularly affected by such interactions.

Bundgaard describes prodrugs and their design principles. The reference defines a prodrug as "a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule." J.A. 316. Thus, "[t]he prodrug per se is an inactive species, and therefore, once its job is completed, intact prodrug represents unavailable drug." J.A. 319. Esters are listed as common prodrug substituents. Specifically, "[a]ctive drug species containing hydroxyl or carboxyl groups can often be converted to prodrug esters from which the active forms are regenerated by esterases within the body." J.A. 319; see J.A. 320 (listing ester prodrugs). Bundgaard further states that esters can be used to improve aqueous solubility of drugs containing a hydroxy group and that with esterification "it is feasible to obtain derivatives with almost any desirable hydrophilicity or lipophilicity." J.A. 321. Relatedly, Bundgaard PCT discloses an ester prodrug of morphine

that improves transdermal delivery and is more lipophilic than the parent drug.

Berge and Johansson both disclose pharmaceutical salts including fumarate salts.

2.

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. Decision , slip op. at 22. 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. Id. at 34-35, 40-41. This factual determination was premised on several subsidiary findings that Amerigen challenges on appeal. We summarize these findings here.

The Board found that a person of ordinary skill would not have been motivated to modify 5-HMT to improve its bioavailability. Decision , slip op. at 32-33. 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. In support, Dr. Patterson pointed to Brynne’s statement that tolterodine

is 10-fold more lipophilic than 5-HMT and could penetrate cell membranes more rapidly. 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.⁹ Dr. Patterson agreed that a person of ordinary skill would consider the Rule of 5. The Rule of 5 assesses four inherent properties of a compound that may help to predict whether it will have a bioavailability problem.¹⁰ Dr. Roush considered these properties as they pertained to 5-HMT 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. Decision , slip op. at 32-33.

Given its determination that 5-HMT did not have a bioavailability problem, the Board found that a person of ordinary skill would not have made a 5-HMT prodrug to solve a bioavailability problem that did not exist. Decision , slip op. at 35. Designing a prodrug was a complex endeavor, the Board found, as toxicity, bioavailability, and other drug characteristics must be monitored for two compounds rather than just one. Id. 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. Id. at 36. 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. Id. at 36-37. The Board thus found that a person of ordinary...