The U.S. Court of Appeals for the Federal Circuit recentlyrendered a decision in Ortho-McNeil Pharmaceutical Inc. v. LupinPharmaceuticals Inc. on the question ofwhether separate enantiomers can have "first commercial marketing or use"status for purposes of patent term extension under 35 U.S.C. § 156.
U.S. Patent No. 5,053,407, exclusively licensed toOrtho-McNeil Pharmaceutical, is directed to an enantiomer of a racemic compoundthat had previously been approved by the U.S. Food and Drug Administration(FDA). A district court agreed with the positions of the U.S. Patent andTrademark Office (PTO) and the FDA, and held that the statutory requirementsfor term extension were met for the '407 patent. The district court thenenjoined Lupin Pharmaceuticals from infringement during the extended term ofthe patent. Needless to say, Lupin was crestfallen and appealed, but thefederal circuit affirmed the district court's judgment.
The '407 patent is for an antimicrobial compound having the commonname levofloxacin. Levofloxacin is the levorotatory enantiomer (also designatedthe S(-) enantiomer) of the racemate ofloxacin, which is a known antimicrobialproduct. A racemate consists of equal amounts of spatial isomers calledenantiomers, molecules that are mirror images of each other.
Due to their spatial orientation, enantiomers are opticallyactive and are characterized by whether they rotate plane-polarized lightclockwise (dextrorotatory) or counter-clockwise (levorotatory). Although enantiomersand their racemates have the same chemical composition, they may differ intheir physical, chemical or biological properties.
The inventors determined that levofloxacin has propertiesthat are significantly superior to those of ofloxacin. The '407 patentdescribes this synthesis, and presents data showing that levofloxacin is moreeffective as an antimicrobial agent, more rapidly available for biologicaleffectiveness and has lower acute toxicity—and thus, may be administered inhigher doses than ofloxacin.
The PTO concluded that extension of the patent term waswarranted, and the PTO and FDA collaborated in calculation of the applicableextension of 810 days, in accordance with §156(d)(2)(A). Lupin the tried toblock the extension under 21 U.S.C. §355(j)(2)(A)(vii)(IV).
35 U.S.C. §156(a) states that: "The term of a patent whichclaims a product, a method of using a product or a method of manufacturing aproduct shall be extended in accordance with this section … if … (a)(4) theproduct has been subject to a regulatory review period before its commercialmarketing or use; (a)(5)(A) except as provided in subparagraph (B) or (C) [nothere relevant], the permission for the commercial marketing or use of theproduct after such regulatory review period is the first permitted commercialmarketing or use of the product under the provision of law under which suchregulatory review period occurred."
The term "drug product" means the active ingredient of a newdrug, antibiotic drug or human biological product … including any salt or esterof the active ingredient, as a single entity or in combination with anotheractive ingredient.
The issue was whether this was the first permittedcommercial marketing or use of levofloxacin, as required by 35 U.S.C.§156(a)(5)(A), as the racemate had previously been marketed. The district courtheld that the extension was in conformity with the practices of the PTO and theFDA with respect to enantiomers, and that the PTO's determination thatlevofloxacin is a different "product" than the racemate ofloxacin must beafforded "great deference."
Lupin argued that the PTO and the FDA incorrectlyinterpreted the statute, as enantiomer is half of its racemate, and that theenantiomer levofloxacin was an "active ingredient" or component of thepreviously marketed racemate ofloxacin. Thus, Lupin argued that levofloxacin isthe same "drug product" as ofloxacin, meaning that levofloxacin was not "thefirst permitted commercial marketing or use of the product" as required by§156(a)(5)(A).
Ortho countered that an enantiomer has consistently beenrecognized—by both the FDA and the PTO—as a different "drug product" from itsracemate. The FDA practices were explained by Dr. David Lin, a former actingdivision 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 FDAhas described a racemate as a single active ingredient, distinct from itsenantiomers and each enantiomer as a single active ingredient distinct from theother and from the racemate."
Lupin argued that the status of enantiomers with waslegislatively changed in 2007, in the statute that changed the FDA policyconcerning 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-racemicdrug containing as an active ingredient (including any ester or salt of theactive ingredient) a single enantiomer that is contained in a racemic drugapproved in another application" to, under certain conditions, "elect to havethe single enantiomer not be considered the same active ingredient as thatcontained in the approved racemic drug."
Lupin argued that by specificallyallowing an applicant to "elect" this separate treatment for enantiomers,Congress expressed its understanding that enantiomers were the same activeingredient as the racemate for all other purposes, including patent termextension.
The federal circuit said it couldn't find any support forthis theory in the legislative record, or elsewhere, and affirmed the districtcourt's ruling that the '407 patent on levofloxacin was properly granted thestatutory term extension, as the enantiomer is a different drug product fromthe racemate ofloxacin, and was subject to regulatory approval before it couldbe commercially marketed and used.
This case clarifies that separate enantiomers can obtainindependent 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 beinvalidated on obviousness grounds. So pharmaceutical companies that canshow (very?) good reasons thatseparation of enantiomers was not obvious can look forward to a much longerpatent term—for now.