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Distinct Enantiomers Are Different “Drug Products” and Properly Subject to Statutory Term Extensions

May 10, 2010

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Last Month at the Federal Circuit - June 2010

Judges: Newman (author), Rader, Linn

[Appealed from: D.N.J., Chief Judge Brown]

In Ortho−McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc., No. 09−1362 (Fed. Cir. May 10, 2010), the Federal Circuit affirmed the district court’s grant of SJ sustaining the term extension of U.S. Patent No. 5,053,407 (“the ’407 patent”) because the enantiomer levofloxacin is a different drug product from its racemate ofloxacin.  In addition, the Federal Circuit affirmed the district court’s injunction enjoining Lupin Pharmaceuticals, Inc. and Lupin Ltd. (collectively “Lupin”) from infringement during the extended term of the ’407 patent. 

The ’407 patent, assigned to Daiichi Sankyo Co. (“Daiichi”) and exclusively licensed to Ortho−McNeil Pharmaceutical, Inc. and Ortho−McNeil, Inc. (collectively “Ortho”), claims levofloxacin.  Levofloxacin is the levorotatory enantiomer of the racemate ofloxacin, an antimicrobial drug previously approved by the FDA.  Enantiomers are compounds that are nonsuperimposable mirror images of each other and are distinguished by the direction in which they rotate plane−polarized light.  Enantiomers that rotate
plane−polarized light clockwise are called dextrorotatory, while those that rotate plane−polarized light counterclockwise are called levorotatory.  A racemate contains equal amounts of the dextrorotatory and levorotatory enantiomers.  Although enantiomers and their racemates have the same chemical composition, they may differ in their physical, chemical, or biological properties.  Slip op. at 2. 

The inventors at Daiichi worked for several years to separate the dextrorotatory and levorotatory enantiomers of ofloxacin, but were never successful.  Ultimately, they were able to obtain the pure enantiomers by stereospecific synthesis rather than separation.  Upon studying the pure enantiomers, the inventors found that levofloxacin has properties significantly superior to those of ofloxacin.  Id. at 3.  In particular, as described in the ’407 patent, 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.  See id. (citing Ortho−McNeil Pharm. Inc. v. Mylan Labs., Inc., 348 F. Supp. 2d 713, 754 (N.D.W. Va. 2004)). 

The ’407 patent issued on October 1, 1991.  In 1996, the FDA approved levofloxacin for commercial marketing and use.  In accordance with 35 U.S.C. § 156, Daiichi then applied for patent term extension.  After consulting with the FDA, the PTO concluded that extension of the term of the ’407 patent was warranted and, in collaboration with the FDA, calculated an extension of 810 days.  

Lupin then invoked the litigation procedures of 21 U.S.C. § 355(j)(2)(A)(vii)(IV).  In the district court, Lupin stipulated to the validity, enforceability, and infringement of the ’407 patent, contesting only whether the ’407 patent was entitled to the term extension.          

The relevant statutory provision regarding patent term extension provides that the term of a patent which claims a drug product shall be extended if the drug product has been subject to a regulatory review period before its commercial marketing or use.  See id. at 4 (citing 35 U.S.C. § 156(a)).  The statute also requires that “the permission for the commercial marketing or use of the [drug] product after such regulatory review period is the first permitted commercial marketing or use of the [drug] product under the provision of law under which such regulatory review period occurred.”  See id. (emphasis added) (quoting 35 U.S.C. § 156(a)(5)(A)).  The term “drug product” means the active ingredient of a new drug, antibiotic drug, or human biological product as a single entity or in combination with another active ingredient.  See id. at 5. 

The ’407 patent claims levofloxacin, a drug product, and levofloxacin underwent regulatory review by the FDA prior to its commercial marketing and use.  However, the issue that arose here was whether this was the first permitted commercial marketing or use of levofloxacin, since levofloxacin is a component enantiomer of the previously approved ofloxacin. 

Lupin argued in the district court, and on appeal, that because enantiomers compose half of racemates, levofloxacin was an active ingredient of ofloxacin and thus the same “drug product” as ofloxacin.  Since ofloxacin had been previously approved, the commercial marketing and use of levofloxacin was not its first, rendering the ’407 patent ineligible for term extension.

Ortho responded, and the Federal Circuit agreed, that the FDA and PTO have consistently recognized pure enantiomers as different drug products than their racemates, noting in support that levofloxacin required full regulatory approval by the FDA and was viewed as separately patentable by the PTO.  Ortho also supported their argument with a declaration by Dr. David Lin, a former acting Division Director in the FDA’s Division of New Drug Chemistry, who stated 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.”  Id. at 6.  The Federal Circuit concluded that it could “discern no basis for challenging these established FDA and PTO practices,” and that “[t]he FDA and PTO practices are in accordance with Glaxo, where the court held that ‘product’ as used in § 156(a) is the active ingredient present in the drug.”  Id.

Lupin also argued that the eligibility of patents directed to enantiomers for patent term extension was legislatively changed in 2007 by an amendment to the new product exclusivity provisions.  The amendment allowed “an applicant ‘for a non−racemic drug containing as an 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.’”  Id. at 6−7 (quoting 21 U.S.C. § 355(u)(1) (Supp. II 2008)).  Lupin asserted that by allowing applicants to elect a separate treatment for enantiomers with regard to new product exclusivities, Congress intended to treat enantiomers as the same active ingredient as the racemate for all purposes, including patent term extension.      

The Federal Circuit found no support for Lupin’s theory in the legislative record, or elsewhere, and stated that “Lupin’s interpretation would change the long−standing term−extension policy of the FDA and the PTO.”  Id. at 7.  The Federal Circuit concluded that “such a far−reaching change is not achieved by legislative silence.”  Id.                

Thus, the Federal Circuit affirmed the district court’s ruling that the ’407 patent was properly granted statutory term extension because the enantiomer levofloxacin is a different drug product from its racemate ofloxacin.   

Lastly, Lupin argued that the injunction imposed by the district court enjoining them from making, using, offering to sell, selling, or importing levofloxacin in bulk or tablet form during the extended term of the ’407 patent was improperly broad, because patent term extension only applies to the sale and use of the patented product, not to any other exclusionary patent rights, such as making or importing the patented product. 

The Federal Circuit “recognized that an extended patent term does not apply to unrelated uses of an FDA−approved product.”  Id. at 8 (citing Pfizer Inc. v. Dr. Reddy’s Labs., Ltd., 359 F.3d 1361, 1366 (Fed. Cir. 2004)).  However, because Lupin did not assert any nonpharmaceutical uses for levofloxacin, the Federal Circuit concluded that “[t]he district court did not abuse its discretion in issuing an injunction commensurate with the patent rights of exclusion.”  Id


Summary authored by Marya K. Jones, Ph.D., student associate at Finnegan.