FeSSIF/FaSSIF Dissolution: If you Understand What is Written Above You Should Read this Article

A part of any complete study for a pre-clinical candidate (PCC) pharmaceutical compound is a dissolution study in Fed and Fasted Simulated Stomach and Intestinal Fluids (FeSSIF and FaSSIF) for the active pharmaceutical ingredient (API) and the complete formulation. These studies are later implemented in the human studies. Both are conducted to gauge the effect of the drug when the patient’s stomach is empty or full as stomach and gastric pH levels will fluctuate.

Now, what does this have to do with patent law? The United States Court of Appeals for the Federal Circuit issued an opinion on December 3, 2014 in the case of Par Pharm., Inc. v. TWi Pharms., Inc., 2014 U.S. App. LEXIS 22737 (Fed. Cir. Dec. 3, 2014) further clarifying a long line of cases on inherency in regard to the obviousness of pharmaceutical formulations. In this opinion the patentee may have avoided invalidation by claiming specific limitations to the Cmax difference between fed and fasted states.

In Par Pharm., Inc. v. TWi Pharms, the case involved methods of use of nanosized formulations of the drug megestrol acetate (“megestrol”). After a bench trial, the U.S. district court for the District of Maryland found the asserted claims of the U.S. Patent No. 7,101,576 (“’576’ patent”) invalid as obvious pursuant to 35 U.S.C. §103(a). The claim at issue recites:

A method of increasing the body mass in a human patient suffering from anorexia, cachexia, or loss of body mass, comprising administering to the human patient a megestrol formulation, wherein:
(a) the megestrol acetate formulation is a dose of about 40 mg to about 800 mg in about a 5 mL dose of an oral suspension;

(b) the megestrol acetate formulation comprises megestrol particles having an effective average particle size of less than about 2000 nm, and at least one surface stabilizer associated with the surface of the megestrol particles; and

(c) the administration is once daily;

wherein after a single administration in a human subject of the formulation there is no substantial difference in the Cmax of megestrol when the formulation is administered to the subject in a fed versus a fasted state,

wherein fasted state is defined as the subject having no food within at least the previous 10 hours, and wherein fed state is defined as the subject having a high-calorie meal within approximately 30 minutes of dosing.

To substantiate the obviousness TWi presented prior art showing: (1) the pharmacokinetic properties of megestrol; and (2) nanoparticle technology in drug formulation decreasing food effects. Id. at 7. Par argued that the prior art failed to disclose a known food effect in in megestrol, to which the district court agreed but relied on inherency to supply the missing claim limitation. Id. at 12. The district court concluded that “[t]he claimed pharmacokinetic parameters with respect to a food effect . . . are inherent properties of the obvious nanoparticulate formulation.” Par Pharms., Inc. v. Twi Pharms., Inc., No. CCB-11-2466, 2014 U.S. Dist. LEXIS 21704, 2014 WL 694976, at *13.

The Court of Appeals for the Federal Circuit agreed with the district court’s finding that the prior art failed to disclose a known food effect for Megesterol, but concluded that the district court erred in applying the inherency analysis under the Federal Circuit’s current precedent. Par Pharm., Inc. v. TWi Pharms., Inc., 2014 U.S. App. LEXIS 22737 at 18. The Federal Circuit reiterated the current law which establishes that:

A party must … meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art. Id. at 21.

The Federal Circuit found that the district court did not require that TWi present evidence sufficient to prove inherency under this standard. Id. at 21. Instead, TWi presented evidence only showing that improvement in bioavailability decreases the food effect. However, the district court’s analysis ignored the claim limitation that specifically recites “no substantial difference in Cmax” between the fed and fasted states be within an enumerated percentage difference as recited in Claim 4. The Federal Circuit held that:

While it may be true that a reduction in particle size naturally results in some improvement in the food effect, the district court failed to conclude that the reduction in particle size naturally results in “no substantial difference” in the food effect. Id. at 22.

Accordingly, the Federal Circuit held that TWi failed to present evidence sufficient to demonstrate that the claimed food effect limitations are necessarily present in the prior art combinations and vacated the district court’s inherency analysis and remanded the case back to the district court to determine if TWi presented clear and convincing evidence that demonstrates the food effect as claimed is necessarily present in the prior art combination. Id. at 23.

As we wait for the district courts findings in the remanded hearing, it is important to understand at this point that the “natural result flowing” standard appears to be directed at general properties of the questioned function. As such, the patentee should take care to incorporate specific limitations that require a certain amount of experimentation to determine beyond what the properties of the component parts can impart. However, this issue will not be fully understood until the factual findings from the district court are presented and challenged.

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