Methylnaltrexone - USA

On Apr. 08, 2020, Federal Circuit reversed district court’s summary judgment decision of non-obviousness & remanded case back for further consideration.

Valeant (Plaintiff) owns US 8,552,025 (expiring in Apr. 2024) patent, which claims stable methylnaltrexone pharmaceutical composition. Methylnaltrexone is unstable in aqueous solution, therefore, inventors of US’025 patent discovered optimum pH of 3 to 4 to stabilise the composition. This patent is listed in Orange Book against Valeant’s approved product, Relistor® (methylnaltrexone injection) which is used to treat constipation as a side effect of taking opioid medication. Mylan submitted ANDA with USFDA to market generic equivalent and then Valenant sued Mylan in New Jersey court subsequently.

Relevant here are claim 1 and claim 8 of the ’025 patent. Claim 8 depends from claim 1, which recites:

1. A stable pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation comprises a pH between about 3.0 and about 4.0.

8. The pharmaceutical preparation of claim 1, wherein the preparation is stable to storage for 24 months at about room temperature.

Before the district court, Valeant moved for summary judgment that claim 8 would not have been obvious, and the district court granted Valeant’s motion. The court rejected Mylan’s expert testimony and cited references as insufficient, largely because the references did not teach methylnaltrexone formulations but instead formulations of similar but different compounds, naloxone and naltrexone.

Mylan appealed.

During appeal, Mylan argued that the district court erred in at least two respects: (1) by failing to hold that Mylan established a prima-facie case that claim 8 would have been obvious because the pH range in the claim overlaps with pH ranges in the prior art for similar compounds and (2) by resolving disputed fact issues at summary judgment.

With respect to first point, Mylan argued that although cited references teach different compounds (naloxone & naltrexone) but they disclose formulations with pH ranges that overlap with the range recited in claim 8, pH between about 3 and about 4. And thus these references established a prima-facie case of obviousness. While no reference contemplates methylnaltrexone specifically, Mylan submitted that methylnaltrexone bears significant structural and functional similarity to both naloxone and naltrexone such that a person of skill in the art would seek to use prior disclosed pHs for naloxone and naltrexone when formulating solutions of methylnaltrexone. Valeant responded that overlapping ranges for different chemical compounds that fail to meet claim 8’s stability requirement do not establish obviousness. According to Valeant, the structural and functional similarities of the compounds are not relevant because claim 8 recites a solution of methylnaltrexone with a stability profile unrecognized and unattained in the prior art.

Court, however agreed with Mylan & said that a prima-facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art. However, here is a little difference, none of the references disclose the same drug as the one claimed. But that does not make much difference because for chemical compound claims, a prima facie case of obviousness “frequently turns on the structural similarities and differences between the compounds claimed and those in the prior art.” [Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010) (citing In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc))]. Moreover, an obviousness analysis can also rely on prior art compounds with similar pharmacological utility in addition to structural similarity [In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (holding that a person of skill in the art would have expected amitriptyline to resemble imipramine in the alleviation of depression in humans because of the drugs’ close structural similarity and similar use)].

Here, the prior arts teach stable formulations of naloxone, naltrexone, and methylnaltrexone. All these compounds are well-known opioid antagonists that operate by binding to the body’s opioid receptors without activating them. Each is an oxymorphone derivative, and the group mem-bers have remarkably similar structures, as indicated earlier. Because of the strong structural and functional similarity between the molecules, a person of skill could expect similar stability of the molecules at similar pH ranges in solution. Therefore, Mylan has at least raised a prima-facie case of obviousness. The district court erred by rejecting this inference as a matter of law at the summary judgment stage.

With respect to second point, Mylan argued that there were factual disputes precluding summary judgment. In Mylan’s view, the district court disregarded its obvious-to-try evidence because the pH ranges taught in the prior art were not sufficiently narrow. Mylan submitted that the adequacy of a prior art range is a classic question of fact and that the district court imposed a heightened predictability requirement. With respect to this argument, district court held that there was not a finite number of options between pH ranges falling between 3 and 7. As a matter of “basic math,” given any two unequal numbers, the quantity of number ranges falling between the two is infinite, not finite. The district court also rejected Mylan’s citations of expert testimony and prior art references because none of the references identified pH as the “first variable” that an experienced formulator would consider.

Federal circuit said that district court’s obvious-to-try analysis is inconsistent with precedent. The bounded range of pH 3 to 4 presents a finite number of narrower pH ranges for a skilled artisan to try. As a matter of math, there may be an infinite potential number of ranges within the range 3 to 4, but only if the realities of pH values (and the limitations of commercially available pH meters) are ignored. And in our view of basic math and based on the record, there is only one significant figure after the decimal point, in which case the range of pH variables is ten, or, if one considers two significant figures after the decimal point, one hundred, not an infinity. With respect to “first variable” requirement, Federal Circuit said that there is no requirement that for a variable to be obvious to try, it must be the first variable a person of skill would alter. And as to the stability limitation, a fact-finder could draw the inference from this record that trying a pH of 3–4 would lead to a methylnaltrexone formulation stable at room temperature. Absolute predictability that the proposed pH range would yield the exact stability parameters in the claim is not required. Moreover, it is important to note that pH is in fact the only variable in claim 8, not one of many variables that can be experimented with. Thus, the district court’s grant of summary judgment on Mylan’s obvious-to-try theory was in error.