After the US Patent and Trademark Office denied a patent term extension under 35 U.S.C. §156, to Metvixia® — with an active ingredient methyl aminolevulinate hydrochloride — Photocure ASA sought a do-over in district court under the Administrative Procedure Act, 5 U.S.C. §702.

The district court held that the PTO’s ruling was “not in accordance with law,” and that the patent on MAL hydrochloride is subject to term extension. The USPTO Director David Kappos appealed claiming that the district court did not correctly define or apply the statutory terms “drug product” and “active ingredient.”  The US Court of Appeals for the Federal Circuit sided with the district court.  Photocure ASA v. Kappos (09-1393).

The Patent Term Extension statute was enacted in recognition of the long procedures associated with regulatory review of a new drug product, for the patent term continues to run although the product cannot be sold or used until authorized by the Food and Drug Administration. The statute was designed to restore a portion of the patent life lost during the period of regulatory review, in order to preserve the economic incentive for development of new therapeutic products.

35 U.S.C. §156(a):

The term of a patent which claims a product, a method of using a product, or a method of manufacturing a product shall be extended in accordance with this section . . . , if– (a)(4) the product has been subject to a regulatory review period before its commercial marketing or use; (a)(5)(A) except as provided in subparagraph (B) or (C) [not here relevant], the permission for the commercial marketing or use of the product after such regulatory review period is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred;

A product includes a new drug, antibiotic drug, or human biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act), . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient.

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

MAL hydrochloride was a new chemical compound, and was patented in U.S. Pat. No. 6,034,267 on the basis of its improved therapeutic properties as compared with the known compound aminolevulinic acid hydrochloride. MAL is the methyl ester of ALA. ALA hydrochloride had previously received FDA approval for the same therapeutic use. The specification of the ’267 patent discusses and exemplifies the biological and physiological advantages of the MAL product over the ALA product; MAL is characterized as “better able to penetrate skin and other tissues,” as a “better enhancer[] of Pp production than ALA,” and as providing “improved selectivity for the target tissue to be treated.” ’267 patent col. 4 l.59–col. 5 l.

The product containing MAL hydrochloride was a “new drug” in terms of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §321(p), and required full FDA approval. The clinical and other tests for demonstration of safety and efficacy of the MAL hydrochloride product consumed four and a half years. After FDA approval was received, Photocure applied for the statutory extension of the term of the ’267 patent. The PTO consulted with the FDA, in accordance with the Memorandum of Understanding, 52 Fed. Reg. 17,830 (FDA May 12, 1987). The FDA advised that MAL hydrochloride had received regulatory approval for the designated use. The FDA also pointed out that MAL hydrochloride is an ester of the previously FDA-approved ALA hydrochloride, and proposed that the requirements of §156(a)(5)(A) were not met.

The PTO then denied the requested term extension, stating that “active ingredient” in §156(f)(2) does not mean the product that was approved by the FDA, but rather means the “active moiety” of that product. The PTO held that MAL hydrochloride is the “same ‘product’” as ALA hydrochloride because the “underlying molecule” of MAL is ALA, and the PTO stated that “ALA is simply formulated differently in the two different drugs.” Final Decision Regarding Patent Term Extension Application Under 35 U.S.C. §156 For U.S. Patent No. 6,034,267 at 3, 5 (May 13, 2008). The PTO held that since a drug product containing ALA hydrochloride was previously approved by the FDA, the FDA’s marketing approval of the MAL hydrochloride product was not the first commercial marketing or use of that “product.”

Applying the provisions of the patent term extension statute, the district court considered the separate chemical composition, the separate patentability, and the separate FDA approval of MAL, and held that MAL hydrochloride is the active ingredient of a new drug product that required FDA approval, §156(f)(2)(A); that the MAL hydrochloride product was subject to a full regulatory review period before commercial marketing and use was permitted, §156(a)(4); that this review permitted the first commercial marketing and use of the MAL hydrochloride product, §156(a)(5)(A); and therefore that the statutory requirements for term extension were met.

The PTO argued that the statutory term “active ingredient” does not mean the product that is present in the approved drug, but only the “active moiety” of the product, that is, the part responsible for the pharmacological properties. However, the Federal Circuit said that MAL would meet the criteria for term extension since the pharmacological properties of MAL differ from those of ALA, supporting the separate patentability of the MAL product. MAL hydrochloride is a different chemical compound from ALA hydrochloride, and it is not disputed that they differ in their biological properties, warranting separate patenting and separate regulatory approval, although their chemical structure is similar. Thus the district court held that MAL hydrochloride and ALA hydrochloride are different “products” with different “active ingredients,” as the terms are used in §156, explaining that “a compound can only qualify as the ‘active ingredient’ of a drug if that compound itself is present in the drug,” citing Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392, 393 (Fed. Cir. 1990). Photocure, 622 F. Supp. 2d at 347.  In Glaxo, the Federal Circuit held that “product” in §156(a) means the product that is present in the drug for which federal approval was obtained.

The Federal Circuit said that the district court correctly applied 35 U.S.C. §156 and that the patent on MAL hydrochloride is subject to term extension.

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    […] Photocure had developed and patented aminolevulinic acid (ALA), Levulan®, approved in 1999 to treat actinic keratoses — precancerous cell growth on the skin. In July 2004, Photocure obtained approval of methyl aminolevulinic hydrochloride (MAL) for the same indication. Photocure applied to the US Patent and Trademark Office (PTO) for an extension to the patent for ALA. The patent extension was based on the discovery that the methyl ester had better penetration characteristics than ALA. Despite the claimed differences, the PTO decided that MAL is the same as ALA because the “underlying molecule” is ALA. The Appeals court determined that the PTO erred because MAL was considered by FDA regulations to be a new drug, thus eligible for patent term extension under Hatch Waxman. For an in-depth legal analysis of this case see Stephen Albainy-Jenei’s post. […]