NJ District Court Affirms Enantiomer PTE Validity; Decision Quickly Appealed to the Federal Circuit

By Kurt R. Karst –      

In a recent unpublished opinion issued by the U.S. District Court for the District of New Jersey, the court ruled that the Patent Term Extension (“PTE”) granted by the U.S. Patent and Trademark Office (“PTO”) with respect to U.S. Patent No. 5,053,407 (“the ‘407 patent”) covering Ortho McNeil-Janssen Pharmaceutical, Inc.’s (“Ortho’s”) LEVAQUIN (levofloxacin) is valid.  Levofloxacin is an enantiomer in the previously approved Ortho racemate drug product FLOXIN (ofloxacin).  Lupin Pharmaceutical, Inc. (“Lupin”) challenged the ‘407 patent PTE in the context of ANDA Paragraph IV patent infringement litigation on the grounds that the PTE is invalid because FDA previously approved levofloxacin when the Agency approved ofloxacin.  Lupin appealed the decision to the U.S. Court of Appeals for the Federal Circuit only a few days after the New Jersey district court decision.  FDA and the PTO will likely closely follow the case as the agencies try to move forward on several pending PTE determinations for enantiomer patents.    

Under the PTE statute at 35 U.S.C. § 156(a)(5)(A), the term of a patent claiming a drug shall be extended from the original expiration date of the patent if, among other things, “the permission for the commercial marketing or use of the product . . . is the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred” (emphasis added).  (As we previously reported, this PTE criterion has been the subject of recent litigation.)  The term “product” is defined at 35 U.S.C. 156(f)(2) to mean, in relevant part, “the active ingredient of – a new drug, antibiotic drug, or human biological product . . . including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient” (emphasis added).  The term “active ingredient” is defined in FDA’s  regulations to mean “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure of any function of the body of man or of animals.”

In July 1997, FDA advised the PTO that the approval of NDA No. 20-634 for LEVAQUIN represented the first permitted commercial marketing or use of the product. In April 1998, FDA determined the regulatory review period for LEVAQUIN, and in March 2000, the PTO granted a PTE of 810 days with respect to the ‘407 patent, extending its term from October 1, 2008 to December 20, 2010.  FDA’s first permitted commercial marketing regulatory review determination and the PTO’s decision to grant a PTE were consistent with previous PTE decisions concerning a patent covering an enantiomer of a previously approved racemate.  For example, PTEs have been granted with respect to patents covering NEXIUM (esomeprazole magnesium), LEXAPRO (escitalopram oxalate), BETAXON (levobetaxolol HCl), XOPENEX (levalbuterol HCl), and REDUX (dexfenfluramine). 

Notwithstanding previous enantiomer patent PTE decisions, it is interesting to note that FDA has for decades treated single enantiomers of approved racemates as previously approved drugs not eligible for five-year new chemical entity exclusivity (but eligible for three-year new clinical investigation exclusivity).  For example, FDA stated in the preamble to its 1989 proposed regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.”  FDA still adheres to this policy today, although the 2007 FDA Amendments Act amended the FDC Act to add § 505(u), which permits the sponsor of an NDA for an enantiomer (that is contained in a previously approved racemic mixture) containing full reports of clinical investigations conducted or sponsored by the applicant to “elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug,” and thus be eligible for five-year new chemical entity exclusivity.

In challenging the validity of the ‘407 patent PTE, Lupin posited in its Motion for Summary Judgment that “[i]f levofloxacin is an ‘active ingredient,’ there is no dispute that levofloxacin was a component of a product (FLOXIN®, as an enantiomer in the racemic mixture) which was approved well prior to the approval and marketing of [Ortho’s] levofloxacin product (LEVAQUIN®), and thus the fifth requirement for a [PTE] would not be met.  In other words, the marketing of levofloxacin would not be the ‘first permitted commercial marketing or use’ of the active ingredient (levofloxacin) as either a single entity or in combination with another active ingredient.”  In establishing the “active ingredient” status of levofloxacin, Lupin cites the ‘407 patent, which asserts that levofloxacin exibits antimicrobial activity. 

Ortho asserts in its opposition papers (and Cross-Motion for Summary Judgment) that “Lupin’s attempt to overturn the decision to grant a [PTE] for the ‘407 patent should be rejected as a matter of law.”  Ortho argues, among other things, that levofloxacin “was not present in the previously approved Floxin®” (emphasis in original), “the PTO and the FDA acted in a manner consistent with their regular and longstanding practices in granting the term extension of the ‘407 patent,” and “ofloxacin and levofloxacin are entirely different therapeutic agents and, therefore, properly are considered to be different active ingredients.”  

In denying Lupin Motion for Summary Judgment and granting Ortho’s Cross-Motion for Summary Judgment, Chief District Judge Garrett Brown, Jr. declared the PTO’s ‘407 patent PTE to be valid and closed the case.  Relying heavily on previous FDA and PTO PTE decisions concerning patents covering an enantiomer of a previously approved racemate, Chief District Judge Brown reasoned that “[i]n each such case, the PTO and the FDA . . . have determined that the patent covering the enantiomeric product was entitled to extension, and have granted the [PTE] pursuant to 35 U.S.C. § 156. . . .  Thus, the undisputed facts clearly establish the PTO has determined that enantiomers are ‘products’ eligible for [PTEs] pursuant to 35 U.S.C. § 156, regardless of whether the patent term of the enantiomer’s racemate has also been extended. . . .  Lupin is not able to present clear and convincing evidence that the PTO’s decision to extend the term of the ‘407 patent is invalid.”

Within a few days after Chief District Judge Brown issued his decision, Lupin provided notice to appeal the decision to the U.S. Court of Appeals for the Federal Circuit.  Presumably FDA and the PTO will closely follow the case.  Based on a quick review of pending PTE applications for patents covering enantiomers of previously approved racemates, FDA appears to be (inexplicably) delaying making a first permitted commercial marketing or use determination in the context of the Agency’s regulatory review determination for PTE eligibility.