Obviousness, Prodrugs and the Rule of 5: Amerigen Pharmaceuticals Limited v. UCB Pharma GmbH

Posted on 02/07/2019 by William Reid, in Articles, Patent Related Court Rulings, Patent Trends & Activity

In Amerigen Pharmaceuticals Limited v. UCB Pharma GMBH, 2017-2596 (Fed. Cir. January 11, 2019), the Federal Circuit upheld the Board’s IPR finding that claims 1-5 and 21-24 of UCB’s U.S. Patent 6,868,650 were not obvious.[1]  The patent claims cover Toviaz® (Fesoterodine), an antimuscarinic drug to treat urinary incontinence.[2]  Judge Lourie included a remark near the end of the Opinion that will warm the heart of anyone who has wrestled with an Examiner on an issue of hindsight analysis:

Any compound may look obvious once someone has made it and found it to be useful, but working backwards from that compound, with the benefit of hindsight, once one is aware of it does not render it obvious.[3]

The Opinion does a great job of summarizing the technical background involved.  Figure 1 below illustrates a prodrug, by which is meant an inactive molecule when administered that is transformed within the body into a therapeutically active form.[4]  Use of a prodrug is desirable when the active molecule has poor bioavailability.[5]  Fesoterodine itself is a prodrug for the compound 5-hydroxymethyl tolterodine (“5-HMT”)[6].  This is central to the obviousness question since the Board had ruled that a PHOSITA would not have been motivated to modify 5-HMT to improve its bioavailability, and develop a corresponding prodrug.[7]  In upholding the Board’s decision, the court referred to UCB’s expert, Dr. Roush, who had argued that there was no bioavailability problem with 5-HMT.[8]  Dr. Roush had cited an article by Lipinski et al. which outlined a “Rule of 5” that set forth several factors for determining whether poor absorption or permeation (poor bioavailability) would be present.[9]  The Rule of 5 factors are summarized in Table 1.

Table 1.
Rule of 5 Parameters[10]

1 There are more than 5 H-bond donors (expressed as the sum of OH’s and NH’s)
2 The MWT (molecular weight) is over 500
3 The Log P (indicator of lipophilicity) is over 5, or MLogP is over 4.15
4 There are more than 10 H-bond acceptors (expressed as the sum of N’s and O’s)
Compound classes that are substrates for biological transporters are exceptions to the rule.

According to Lipinski, if two or more of the above parameter conditions are present, then bioavailability problems could be present.[11].  However, in his testimony, Dr. Roush stated that 5-HMT did not violate any of the Lipinski rules[12].  Weighed against Amerigen’s argument that 5-HMT had a bioavailability problem based on 5-HMT’s lipophilicity compared to tolterodine (antimusarinic drug), the court found that substantial evidence supported the Board’s finding that no motivation existed to increase 5-HMT’s lipophilicity.[13]

Doubtless this decision is instructive to those having an interest in the validity of prodrug patent claims because of the clear reliance placed on the Rule of 5 parameters by both the Board and the court.  However, as mentioned above, it also disposed of an “impermissible hindsight” type argument with the same satisfying, cold efficiency that Indiana Jones displayed in his interaction with the master swordsman.

-William Reid

[1]  Slip Op., at 2.
[2]  Slip Op., at 2.
[3]  Slip Op., at 23.
[4]  Slip Op., at 2.
[5]  Slip Op., at 2.
[6]  Slip Op., at 3.
[7]  Slip Op., at 7.
[8]  Slip Op., at 18.
[9] Lipinski et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 23, 3-25 (1997).
[10]  Lipinski at 9.
[11]  Id.
[12]  Slip Op., at 18.
[13]  Slip Op., at 19.

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