Recently, the courts looked at the question of whether separate enantiomers can have “first commercial marketing or use” status for purposes of patent term extension under 35 U.S.C. § 156. The U.S. Patent and Trademark Office, after consulting with the FDA, had granted an extension for US Pat. No. 5,053,407, which is exclusively licensed to Ortho-McNeil Pharmaceutical and is directed to an enantiomer of a racemic compound.

Under the Hatch-Waxman Act, a patent term extension is permitted for a patent that claims a drug that required regulatory approval prior to being put on the market (the Drug Price Competition and Patent Term Restoration Act, codified in part at 35 U.S.C. § 156 et seq.).

The district court agreed with the positions of the Patent and Trademark Office and the FDA, and held that the statutory requirements for term extension were met for the ’407 patent. The court then prevented Lupin Pharmaceuticals from making and selling the drug during the extended term of the patent. Needless to say, Lupin was crestfallen and appealed but the US Court of Appeals for the Federal Circuit affirmed the district court’s judgment in Ortho-McNeil Pharma v. Lupin Pharma (09-1362).

The ’407 patent is for an antimicrobial compound having the common name levofloxacin. Levofloxacin is the levorotatory enantiomer (also designated the S(-) enantiomer) of the racemate ofloxacin, which is a known antimicrobial product. A racemate consists of equal amounts of spatial isomers called enantiomers, molecules that are mirror images of each other.

Due to their spatial orientation, enantiomers are optically active and are characterized by whether they rotate plane-polarized light clockwise (dextrorotatory) or counter-clockwise (levorotatory). Although enantiomers and their racemates have the same chemical composition, they may differ in their physical, chemical, or biological properties. It is often the case that one of the enantiomers possesses a substantially greater portion, if not all, of the biological activity of the racemic mixture. This raises the question of the status of separated enantiomers as “new drug products” and whether they can be “first commercial marketing or use” if the racemate has previously been granted market approval, pursuant to 35 U.S.C. § 156(a)(5)(A).

The inventors determined that levofloxacin has properties that are significantly superior to those of ofloxacin. The ’407 patent describes this synthesis, and presents data showing that levofloxacin is more effective as an antimicrobial agent, more rapidly available for biological effectiveness, and has lower acute toxicity and thus may be administered in higher doses than ofloxacin.

The PTO concluded that extension of the patent term was warranted, and the PTO and FDA collaborated in calculation of the applicable extension of 810 days, in accordance with §156(d)(2)(A). Lupin the tried to block the extension under 21 U.S.C. §355(j)(2)(A)(vii)(IV) (Paragraph IV certification).

The law, in 35 U.S.C. §156(a), states that:

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; . . .

The term “drug product” means the active ingredient of (A) 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.

The issue was whether this was the first permitted commercial marketing or use of levofloxacin, as required by 35 U.S.C. §156(a)(5)(A), for the racemate had previously been marketed. The district court held that the extension was in conformity with the practices of the PTO and the FDA with respect to enantiomers, and that the PTO’s determination that levofloxacin is a different “product” than the racemate ofloxacin must be afforded “great deference.”

Lupin argued that the PTO and the FDA incorrectly interpreted the statute as far as enantiomers are concerned. Lupin insisted that an enantiomer is half of its racemate, and thus that the enantiomer levofloxacin was an “active ingredient” or component of the previously marketed racemate ofloxacin. That is, the racemate was merely a composition containing two drugs: the R and the S enantiomers. Thus, levofloxacin is the same “drug product” as ofloxacin meaning that levofloxacin was not “the first permitted commercial marketing or use of the product” as required by §156(a)(5)(A).

Ortho countered that an enantiomer has consistently been recognized, by the FDA and the PTO, as a different “drug product” from its racemate. The FDA practices were explained by Dr. David Lin, a former acting Division Director in the FDA’s Division of New Drug Chemistry, declaring that “in each and every instance in which it has considered the question, the FDA has described a racemate as a single active ingredient, distinct from its enantiomers, and each enantiomer as a single active ingredient distinct from the other and from the racemate.”

Lupin tried arguing that the status of enantiomers with was legislatively changed in 2007, in the statute that changed the FDA policy concerning data exclusivity for new enantiomer products. 21 U.S.C. §355(u)(1) (Supp. II 2008). The new provision authorizes an applicant “for a non-racemic drug containing as an active ingredient (including any ester or salt of the active ingredient) a single enantiomer that is contained in a racemic drug approved in another application” to, under certain conditions, “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug.” Lupin felt that by specifically allowing an applicant to “elect” this separate treatment for enantiomers, Congress expressed its understanding that enantiomers were the same active ingredient as the racemate for all other purposes, including patent term extension.

The Federal Circuit said it couldn’t find any support for this theory in the legislative record, or elsewhere and affirmed the district court’s ruling that the ’407 patent on levofloxacin was properly granted the statutory term extension, for the enantiomer is a different drug product from the racemate ofloxacin, and was subject to regulatory approval before it could be commercially marketed and used.

This case clarifies that separate enantiomers can obtain independent patent protection and be entitled to patent term extension for “first commercial marketing or use” as new drug products. However, the Federal Circuit has said that patents for separated enantiomers can be invalidated on obviousness grounds.  So, pharmaceutical companies that can show (very?) good reasons that separation of enantiomers was not obvious can look forward to a much longer patent term – for now.

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  2. […] friend and patent law expert, Stephen Albainy-Jenei reviewed this decision in a May 19 post, so I refer you to that well-written comment for details. I would only add that, although the […]