A Fresh Look At The Lead Compound Analysis
I previously wrote about the standing issue addressed in Amerigen Pharmaceuticals v. UCB Pharma GMBH. In this article, I look at the lead compound analysis that led the USPTO Patent Trial and Appeal Board (PTAB) to uphold the claims against an obviousness challenge, including a factor that doesn’t always get much attention.
The Patent At Issue
The patent at issue was UCB’s U.S. Patent 6,858,650, which claims the active ingredient of Toviaz® (fesoterodine), an antimuscarinic drug used to treat urinary incontinence. Fesoterodine is a prodrug of 5-hydroxymethyl tolterodine (5-HMT), which itself is a metabolite of tolterodine, which is the active ingredient of Detrol®, an antimuscarinic drug used to treat overactive bladder.
The PTAB’s Lead Compound Analysis
The patent was challenged in an Inter Partes Review (IPR) proceeding originally brought by Mylan, and joined by Amerigen and two others after institution. At issue was whether it would have been obvious to modify 5-HMT to arrive at fesoterodine.
The PTAB cited the Federal Circuit decision in Otsuka Pharm. Co., Ltd., v. Sandoz, Inc., 678 F.3d 1280 Fed. Cir. 2012), as setting forth a “two prong inquiry” for determining whether a new chemical compound would have been obvious:
- whether one of ordinary skill would have selected one or more lead compounds for further development and,
- whether the prior art would have supplied sufficient motivation to modify a lead compound to arrive at the compound claimed with a reasonable expectation of success.
This framework is referred to as a “lead compound analysis.”
As summarized in the PTAB’s Final Written Decision, Petitioners asserted that it would have been obvious for one of ordinary skill in the art to:
- identify 5-HMT as a lead compound for drug development;
- recognize that 5-HMT could have adverse effects due to its metabolism and poor oral bioavailability due to its lipophilicity profile
- address such concerns regarding adverse effects and poor oral bioavailability by esterifying 5-HMT to create a prodrug having increased lipophilicity and, subsequently, optimizing the ester moiety to
arrive at a compound having a short-chain mono-ester derivative at only the
5-hydroxyl position; and
- select an acid-addition salt that provides the desired product stability.
The PTAB agreed with Petitioners on the first point, but disagreed that they had shown that there would have been a motivation to modify HMT, as asserted for the second point. In particular, the PTAB found that Petitioners had not shown that the CYP2D6 metabolism known to occur with tolterodine was a concern for HMT, or that HMT would have been expected to exhibit poor bioavailability.
The PTAB also disagreed that a person of ordinary skill would have pursued a prodrug of HMT. On this point, it credited Patent Owner’s argument that developing a prodrug can be more complicated than developing a drug:
As Patent Owner points out, and as we agree, “prodrug development requires monitoring the toxicity, bioavailability, receptor affinity, pharmacokinetics, and pharmacodynamics of not only one, but two, compounds – the prodrug and the desired active compound – making the development process even more complex, time consuming, and expensive.”
Further, the PTAB found “inadequate evidence in the record” that the prior art “would have suggested making the specific molecular modification necessary to achieve fesoterodine.” Rather, the PTAB credited the testimony of Patent Owner’s expert regarding “[t]he sheer number of possibilities available to the person of ordinary skill in the art at each stage of the process.” On this point, the PTAB was “not persuaded” by Petitioners’ arguments “that it would have been ‘routine optimization’ to test all 86 possible phenolic esters, particularly in view of the inventors’ testimony in the district court litigation that those experiments yielded unpredictable results.”
Even on the last point, which Petitioners supported by citation to Berge et al., Pharmaceutical Salts, 66(1) J. PHARM. SCI. 1–19 (1977), the PTAB was persuaded by Patent Owner’s evidence of the unpredictability of identifying a suitable salt of fesoterodine in particular. The PTAB noted that “the inventor of the ’650 patent screened more than 70 salts of fesoterodine,” but discovered “only two viable stable, pure, and crystalline salt forms.” (The Federal Circuit did not address this finding, on the basis that it was “not necessary to the Board’s judgment”.)
Thus, the PTAB determined that the Petitioners had not carried their burden of demonstrating obviousness.
The Federal Circuit’s Lead Compound Analysis
The Federal Circuit decision was authored by Judge Lourie and joined by Judges Chen and Stoll.
Before addressing the PTAB’s decision on the merits, the Federal Circuit noted that it reviews the PTAB’s factual findings for “substantial evidence,” which only requires that “a reasonable mind might accept the evidence as adequate to support the finding.” With that standard of review in mind, the Federal Circuit found no error in how the PTAB weighed conflicting expert testimony or in the conclusions reached.
Considering the first prong of the PTAB’s lead compound analysis, the Federal Circuit expressly commented on the PTAB’s decision that “a person of ordinary skill would have considered prodrug development to involve trade-offs,” and found no error in the PTAB determination “that a person of ordinary skill would not have turned to a prodrug approach ‘to solve an undefined problem.'”
Considering the second prong of the PTAB’s lead compound analysis, the Federal Circuit found the PTAB decision rested on three main findings:
- Petitioners presented no evidence that an ester of 5-HMT would be inactive, as required for a prodrug.
- Petitioners did not point to any prodrugs analogous to 5-HMT (e.g., “in the same chemical class, with the same mechanism of action, or in the same field of treatment”)
- It would not have been routine to make the claimed molecular modifications to 5-HMT to produce the claimed compounds.
On the first two points, the Federal Circuit drew a line between requiring Petitioners to prove those points and finding “the absence of such evidence” to supported non-obviousness. On the third point, the court noted:
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.
Thus, the Federal Circuit affirmed the PTAB decision.
A Fresh Look at the Lead Compound Analysis
One thing I found interesting about this case was the issue raised under the first prong of the lead compound analysis–whether there was a motivation to modify HMT. Often the issue under this prong is whether the cited prior art compound would have been viewed as a “lead” compound, with motivation to improve the prior art compound being assumed.
Another thing interesting about this case is the argument that the existence of a patent on HMT in and of itself would have motivated a person of ordinary skill to develop a different compound. The PTAB dismissed this argument based on its “untimely development,” the “absence of factual underpinnings,” and the “lack of legal precedent. The Federal Circuit also gave it short shrift, because “even accepting, for the sake of discussion, that a patent on 5-HMT would provide a commercial motivation for a skilled artisan to modify 5-HMT,” Amerigen still had to show that the “specific molecular modifications” were obvious.
KSR imbued a person of ordinary skill in the art with “ordinary creativity.” Will a person of ordinary skill in the art next be defined as having an ordinary profit motive?