An ‘active ingredient’ of a drug must be present when the drug is administered

Author: Bart A. Gerstenblith (Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, Washington, DC)

PhotoCure ASA v Kappos, 603 F.3d 1372 (Fed. Cir. 2010), District Court, Eastern District of Virginia

Journal of Intellectual Property Law & Practice (2010) doi: 10.1093/jiplp/jpq188, first published online on 21 December 2010

The term ‘product’ in 35 USC §156(a) means the active ingredient that is present in a drug when administered, not necessarily the ‘active moiety’ of the drug.

Legal context

This appeal from a summary judgment decision of the US District Court for the Eastern District of Virginia concerns the interpretation of the patent term extension provisions of the Drug Price Competition and Patent Term Restoration Act 1984 (the ‘Hatch-Waxman Act’). These provisions are codified at 35 USC §156. In particular, this decision addresses the statutory meaning of the terms ‘product’ and ‘active ingredient’ in section 156, and whether ‘active ingredient’ is synonymous with ‘active moiety’. It also addresses the scope of deference to which an agency that is charged with administering a statute is entitled in these circumstances.


MAL hydrochloride and ALA hydrochloride
Methyl aminolevulinate hydrochloride (MAL hydrochloride) is the active ingredient in the drug Metvixia, which is used in photochemotherapy or photodynamic therapy to treat actinic keratoses—precancerous cell growths on the skin. When Metvixia is applied to the skin, MAL hydrochloride concentrates in the cells to be treated. The cells use MAL hydrochloride to form an excess amount of protoporphyrin IX (Pp), a naturally-occurring light sensitive compound. Pp is activated on exposure to light, and a chemical reaction ensues that kills the precancerous cells.

MAL Hydrochloride was patented as a new chemical compound in US Patent No. 6,034,267 (the '267 patent). Its patentability was based on its improved therapeutic properties as compared with aminolevulinic acid hydrochloride (‘ALA hydrochloride’), a known compound. ALA hydrochloride was previously reviewed and approved by the US Food and Drug Administration (FDA) for the same therapeutic uses as MAL hydrochloride. MAL is the methyl ester of ALA. The '267 patent describes the biological and physiological advantages of the MAL product over the ALA product, including that MAL is better able to penetrate skin and other tissues, is a better enhancer of Pp production than ALA, and provides improved selectivity for the target tissue to be treated.

FDA approval and PTO denial of patent term extension
Metvixia was considered a ‘new drug’ by the FDA and required full review and approval prior to its commercial marketing and use. Following FDA approval, PhotoCure applied for a patent term extension of the '267 patent under the Hatch-Waxman Act. The US Patent and Trademark Office (PTO) consulted with the FDA. The FDA advised the PTO that MAL hydrochloride is an ester of the previously FDA-approved ALA hydrochloride, and expressed its view that the requirements of 35 USC §156(a)(5)(A) were not met.

The PTO subsequently denied PhotoCure's requested term extension, stating that the ‘active ingredient’ in section 156(f)(2) does not mean the product that was approved by the FDA; rather, it means the ‘active moiety’ of that product. The PTO's view was based on its conclusion that MAL hydrochloride is the ‘same product’ as ALA hydrochloride because the ‘underlying molecule’ of MAL is ALA, and that ‘ALA is simply formulated differently in the two different drugs’. Accordingly, since the same ‘product’ was previously approved by the FDA, the subsequent approval of Metvixia was not the first commercial marketing or use of that ‘product’.

The District Court decision
The district court disagreed with the PTO. In particular, the court considered (1) the separate chemical composition, (2) the separate patentability, and (3) the separate FDA approval of the drugs. The district court found that MAL hydrochloride, not ALA hydrochloride, is the active ingredient in Metvixia® under section 156(f)(2)(A). Accordingly, the statutory requirements for patent term extension were satisfied because the MAL hydrochloride product was subjected to a full FDA regulatory review prior to its commercial marketing and use, under section 156(a)(4), and this FDA review permitted the first commercial marketing and use of the MAL hydrochloride product, under section 156(a)(5)(A). The district court thus held that the PTO's ruling was ‘not in accordance with law’, and that the '267 patent on MAL hydrochloride was subject to term extension.


The Director of the PTO appealed to the Federal Circuit, arguing that the district court incorrectly interpreted the statutory terms ‘drug product’ and ‘active ingredient’. The PTO asserted that (1) the statutory term ‘drug product’ means ‘active ingredient’, and ‘active ingredient’ means the ‘active moiety’ of the drug—the part responsible for the pharmacological properties—not the product that is actually present in the approved drug; and (2) that the agency's interpretation is entitled to deference.

The Federal Circuit rejected the PTO's arguments. Initially, it noted that the Patent Term Extension statute was enacted to restore a portion of the patent life lost during the lengthy procedures associated with FDA's regulatory review in order to preserve the economic incentive for development of new therapeutic products. It then reiterated its holding in Glaxo Operations UK, Ltd. v Quigg, 894 F.2d 392, 393 (Fed. Cir. 1990), that ‘product’ in section 156(a) means the product that is present in the drug for which federal approval was obtained. As explained by the district court, and repeated by the Federal Circuit, a compound can only qualify as the active ingredient of a drug if that compound itself is present in the drug when administered (see Hoechst-Roussel Pharms., Inc. v Lehman, 109 F.3d 756, 759 n.3 (Fed. Cir. 1997): ‘For purposes of patent term extension, this active ingredient must be present in the drug product when administered’). As correctly interpreted, the active ingredient of Metvixia was MAL hydrochloride, not ALA hydrochloride, since ALA was not present in the drug when administered. The Federal Circuit also noted that even under the PTO's incorrect statutory interpretation, the approval of Metvixia would meet the criteria for patent term extension because it was not disputed that (1) the pharmacological properties of MAL differ from those of ALA (as explained by the '267 patent); and (2) MAL hydrochloride is a different chemical compound from ALA hydrochloride. Those differences thus warranted separate patenting and separate regulatory approval even though their chemical structures are similar. Accordingly, the Federal Circuit held that they are different ‘products’ with different ‘active ingredients’ as those terms are used in section 156.

The Federal Circuit also addressed the PTO's argument that Pfizer Inc. v Dr. Reddy's Laboratories, Ltd., 359 F.3d 1361 (Fed. Cir. 2004), supported the PTO's statutory interpretation of ‘active ingredient’ as ‘active moiety’. Specifically, it noted that Pfizer did not concern the Glaxo holding that the active ingredient must be present in the drug product as administered. Rather, the issue in Pfizer was whether infringement of an extended patent on the drug amlodipine was avoided by changing the salt form of amlodipine. Also, Pfizer did not hold that an extension is not available when an existing product is substantively changed in a way that produces a new and separately patentable product having improved properties and requiring full FDA approval before commercial marketing and use. Rather, the disputed product in Pfizer was a salt that was included in Pfizer's patent claims and for which Pfizer had provided data to the FDA. Thus, according to the Court, its previous decision in Pfizer did not change the law of section 156 and did not concern a different, separately patented product requiring full regulatory approval.

Finally, the Court found that the PTO's erroneous statutory interpretation was not entitled to deference under Skidmore v Swift & Co., 323 US 134 (1944), or Chevron, USA Inc. v Natural Resources Defense Council, Inc., 467 US 837 (1984). Chevron did not apply because the statute is unambiguous and Skidmore deference was not warranted because the PTO's interpretation was neither persuasive nor consistent. Thus, even if some deference were owed to the PTO's interpretation, neither Chevron nor Skidmore permits a court to defer to an incorrect agency interpretation.

In sum, the Federal Circuit found that the PTO's statutory interpretation, which would have excluded MAL hydrochloride from patent term extension, was contrary to the statutory purpose because MAL hydrochloride is the active ingredient of a new and improved drug product. Accordingly, it affirmed the holding of the district court that the '267 patent on MAL hydrochloride is subject to term extension.

Practical significance

The Federal Circuit's decision endorses the meanings of the terms ‘product’ and ‘active ingredient’ as discussed by the Court in Glaxo. It also clarifies how its decision in Pfizer, which many (including the district court) felt was in conflict with Glaxo, should be understood going forward. The Court seemingly took a narrow view of its holding in Pfizer, by focusing heavily on several key facts in that case that were distinct from those presented here. Even with this narrowing, however, it is hard to rectify Pfizer's repeated endorsement of the term ‘active ingredient’ meaning ‘active moiety’ (see Pfizer, 359 F.3d at 1366, quoting the FDA's statutory interpretation of ‘active ingredient’ as ‘active moiety’ and the FDA's definition of ‘active moiety’), with the results of Glaxo and those reached here. As pointed out by PhotoCure's appellate brief, the result in Pfizer may be more reasonably understood as an issue of fairness rather than statutory interpretation.

In considering whether FDA approval of a new drug warrants patent term extension, this decision clearly places importance on (1) whether the new drug and an existing drug share similar properties, (2) whether the FDA required a full regulatory review of the new drug, (3) whether the PTO considered the new drug separately patentable, and (4) whether the active ingredient that is actually present in the new drug when administered is also present in a previously approved drug when administered.

1 comment:

  1. Aaradhana Sadasivam22 December 2010 at 07:42

    Thank you for the article. I realise active ingredient has not been defined in this context.