By Kevin E. Noonan —

In Ortho-McNeil Pharmaceutical, Inc. v. Lupin
Pharmaceuticals, Inc., the Federal Circuit has rendered a decision on 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 Hatch-Waxman regime for patent term extension
(the Drug Price Competition and Patent Term Restoration Act, codified in part
at 35 U.S.C. § 156 et seq.) permits an extension of a patent that claims
a drug that required regulatory approval prior to being put on the market.  One of the limitations on patents
entitled to the extension is that regulatory approval be the "first
commercial marketing or use"of the drug.  It is known that certain drugs exist as racemic mixtures of
enantiomers, molecules that differ structurally by being mirror image arrangements
of the same component atoms, and that these enantiomers can have differ
physical, chemical, and biological properties.  Differences in the biological properties of these molecules
can be striking:  due to the
enantiomeric nature of biological molecules in a patient, it can be (and has
frequently been) the case that one of the enantiomers possesses substantially
all of the biological activity of the racemic mixture while the other
enantiomer is far less biologically active (and can be totally inactive).  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).  An example of one such situation is
Prilosec® (racemic omeprazole) and Nexium® (the S enantiomer
thereof).  The Federal Circuit
answered this question in the affirmative in its decision rendered on May 10th.

This case involves the antibiotic levafloxicin (marketed
as Levaquin®), which is the stereospecifically-synthesized levorotatory
enantiomer of ofloxacin, a racemic mixture.  Daiichi Sankyo, owners of the patent in suit (U.S. Patent
No. 5,053,407) and their licensee filed suit against Lupin in response to Lupin's
ANDA filing, pursuant to 35 U.S.C. § 271(e)(2).  Lupin stipulated to infringement, validity, and
enforceability of the '407 patent, contending only that the Patent Office and
FDA had improperly granted Daiichi an 810 patent term extension under § 156 of
the patent statute.  Relevant to
the District Court's decision in Daiichi's favor, and the Federal Circuit's
affirmance, the '407 patent specifically claims levafloxicin (i.e., this
enantiomer was determined to be patentable over the existence of ofloxacin in
the prior art) and the FDA required Daiichi to satisfy the requirements of an
NDA for levafloxacin as for a new chemical entity (NCE).  The District Court accorded "great
deference" to the PTO's determination that levafloxacin was a different
drug product than ofloxacin under the terms of the statute, pursuant to the
regulatory framework upheld in Glaxo Operations UK Ltd. v. Quigg, 894
F.2d 392, 399 (Fed. Cir. 1990), where patent term was
extended on a patent claiming a new ester of a previously-approved drug
comprising salts of the same acid.

Both at trial and in the appeal, Lupin argued that
since levafloxacin was the "active ingredient" of ofloxacin, and was
present in the racemate, it was in essence the "same" drug product
both as levafloxacin and ofloxacin, and thus the patent claiming levafloxacin
(the '407 patent) should not be entitled to patent term extension.  Daiichi argued, and the Federal
Circuit agreed, that both the PTO and FDA had consistently treated separate
enantiomers to be different drug products than racemic mixtures thereof.  That the FDA required Daiichi to obtain "full
regulatory approval" and that the PTO found levafloxacin to be
independently patentable over ofloxacin were used by Daiichi to support its
argument.  The argument was
supported by expert testimony of Dr. David Lin, a former FDA official (Director
of the Division of New Drug Chemistry at the FDA), 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,' Lin Decl. ¶20, J.A.
1280 (including examples and Orange Book descriptions, at Lin Decl. Ex. C, J.A.
1278-1439)

The Federal Circuit, in an opinion by Judge Newman
joined by Judges Rader and Linn, agreed with Daiichi and the District Court
that the '407 patent term was properly extended because levafloxacin was the "first
commercial marketing or use" of this drug regardless of its existence as a
component (even the active component) of previously approved and marketed
ofloxacin.  "We discern no basis for challenging these established FDA
and PTO practices.  The 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."  The Court also held that amendments to the statute enacted in 2007,
wherein "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'" did not mandate that the PTO or FDA change their practices
regarding approval of separate enantiomers and patent term extensions of
patents specifically claiming such enantiomers.  This interpretation, according to Judge Newman's opinion, "would
change the long-standing term-extension policy of the FDA and the PTO; such a
far-reaching change is not achieved by legislative silence."

In addition to clarifying (or at least
putting the Federal Circuit's imprimatur upon) the status of separate
enantiomers to obtain independent patent protection and be entitled to patent
term extension for "first commercial marketing or use"
as new drug products, the Court's decision may
provide a boon to "evergreening" efforts by pharmaceutical companies
marketing drugs comprising racemic mixtures of enantiomers.  This is not a panacea, of course, at
least because in the wake of the Supreme Court's KSR v. Teleflex
decision the Federal Circuit has determined that patents for separated
enantiomers can be invalidated on obviousness grounds (compare, for
example, Aventis Pharma Deutschland GmbH v. Lupin, Ltd. with Sanofi-Synthelabo v. Apotex, Inc.).  But under
the right circumstances (for example, as here where separation of the
enantiomers is difficult or impossible), the capacity for separate enantiomer
patents to be eligible for patent term extension provides more incentives for
companies marketing drugs comprising racemic mixtures of enantiomers to expend
R&D (and marketing) efforts and capital on such separations (or
stereospecific syntheses).  In a
world of finite resources, these efforts can be expected to siphon resources
away from new drug development.  While this may be smart business (and in view of the unpredictability of
new drug development, drug companies may not be able to spurn such
opportunities), it may not be in the best interest of further pharmaceutical
innovation.

Ortho-McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc. (Fed. Cir. 2010)
Panel:  Circuit Judges Newman, Rader, and Linn
Opinion by Circuit Judge Newman