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When Does “A Little” Equal “Enough”?
Development and filing of an ANDA to market a generic drug requires many
considerations. One important consideration concerns the evaluation of the patent
landscape protecting the brand name product. An initial patent evaluation typically
begins with patents listed in the Orange Book for the brand name product. Patents listed
in the Orange Book may be directed to: i) the “drug substance” (active ingredient); ii) the
“drug product” (formulation and composition); and iii) the approved method(s) of use. It
is recommended that the generic company also search for and analyze any non-Orange
Book patents (i) owned by the brand manufacturer (which may include process patents,
method of treatment patents for non-approved uses, and patents directed to alternative
formulations), and (ii) patents owned by third parties which might be relevant to the
Typically, the generic drug company is not manufacturing the active
pharmaceutical ingredient (API) that is to be included in its proposed generic product.
Instead, it obtains the API from a third party source and relies on that third party to have
sufficiently characterized its API and evaluated and cleared its API with respect to any
At the same time, in many situations the NDA holder is the brand manufacturer
who undertook the initial development of the API and still produces the API for inclusion
in the brand product(s). A natural consequence is that the brand manufacturer has had a
long period of time to characterize and study the API, and may have obtained patents
directed not only to the chemical structure of the API, but also to polymorphs,
metabolites, pro-drugs, isomers, anhydrates and hydrates, and different salt forms, for
example. This is particularly the case where the patents covering the chemical entity
itself are either expired or will expire in the foreseeable future, leaving the valuable brand
name product with less than optimal patent coverage. In response to such patents, third
party manufacturers of the API may seek to design around such patents. Examples of
design around strategies would include using a different polymorph, or a different
hydrate of a specifically claimed polymorph or hydrate of the API in question.
What if the API in the ANDA product contains substantially all API in a non-
infringing form, but also may contain minor amounts of API in a form that falls within
the claim of a patent (and even more critically, an Orange Book patent)? Can an ANDA
product be found to infringe a patent that claims a specific species of the API where the
ANDA filer’s proposed generic formulation contains small amounts, trace amounts or
even undetectable amounts of the claimed species of the API? This question demands
serious consideration by companies during the development of an ANDA product.
Trace Amount of a Claimed Species of API
The issue of whether a trace amount of a claimed species of API contained in a
proposed ANDA product would infringe the NDA holder’s Orange Book patent that
specifically claims that species has recently been considered. SmithKline Beecham
Corporation and Beecham Group PLC v. Apotex Corp., Apotex, Inc., and Torpharm Inc.,
365 F.3 1306 (Fed. Cir. 2004).
In this case, SmithKline Beecham ( “SKB”) sued
Apotex for patent infringement under Hatch-Waxman1 asserting that Apotex’s ANDA
filing for generic paroxetine constituted an infringement of SKB’s U.S. Patent No.
4,721,723 directed to crystalline paroxetine hydrochloride hemihydrate.
Paroxetine was developed in the 1970’s and was the subject of U.S. Patent No.
4,007,196 that claimed certain 3-substituted 4-phenylpiperidines and salts thereof. The
‘196 patent was owned by a British Company, Ferrosan, that developed the process for
the preparation of crystalline paroxetine hydrochloride. The ‘196 patent technology was
later licensed to SKB who eventually developed a new crystalline form of paroxetine
believed to be more stable than the hydrochloride form. This new crystalline form was
crystalline paroxetine hydrochloride hemihydrate, which became the subject matter of
U.S. Patent No. 4,721,723 assigned to SKB. The ‘723 patent, which was not set to expire
until June 29, 20072 contained claims directed to the hemihydrate salt, a process for its
preparation, an antidepressant formulation and to a method of treating depression. The
‘723 patent was Orange Book listed as covering SKB’s marketed paroxetine
Apotex filed an ANDA for generic paroxetine identifying the active ingredient as
paroxetine hydrochloride anhydrate
. Apotex submitted a paragraph IV certification in
view of the Orange Book listed ‘723 patent asserting that the ‘723 patent was invalid or
non-infringed by Apotex’s proposed formulation. SKB subsequently filed an
infringement action against Apotex asserting that Apotex’s paroxetine hydrochloride
anhydrate “necessarily contain[ed], by a conversion process… at least trace amounts of
PHC [paroxetine hydrochloride] hemihydrate.”3
1. Crystalline paroxetine hydrochloride hemihydrate.
The District Court records indicated that during the litigation, the court considered claim
1 of the ‘723 patent to be indefinite and therefore considered claim 1 to be limited to
commercially significant amounts of the hemihydrate.4 The District Court based this
decision on uncontested testimony that a paroxetine hydrochloride anhydrate-
hemihydrate composition would require “high double digits” of the hemihydrate in order
for the composition to have any commercial value.5
On Appeal, the Court of Appeals for the Federal Circuit (“CAFC”) disagreed with
the District Court. The CAFC held the language of claim 1 is not ambiguous and that the
record showed skilled artisans would understand the meaning of the claim to embrace
2 The patent term of the ‘723 patent was extended 6-months for pediatric exclusivity.
3 SmithKline Beecham Corporation and Beecham Group PLC v. Apotex Corp., Apotex, Inc., and TorpharmInc., 365 F.3 1306 at 1309, April 23, 2004 (CAFC)).
4 Id. at 1310.
paroxetine hemihydrate without further limitation.6 The CAFC further noted that nothing
in the specification limited the hemihydrate to commercial applications and that “nothing
in the prosecution history defined the invention in terms of commercially significant
In an important aspect of its decision, the CAFC maintained that indefiniteness of
a claim “does not depend on a potential infringer's ability to ascertain the nature of its
own accused product to determine infringement, but instead on whether the claim
delineates to a skilled artisan the bounds of the invention.”8 The Court appears to be
taking the position that it may be permissible for the patent holder to evaluate the accused
ANDA product using new or more sensitive technology to determine the presence of the
In the end, the CAFC held that Apotex’s proposed paroxetine hydrochloride
anhydrate formulation infringed claim 1 of the ‘723 patent. However, the CAFC also
held that claim 1 of the ‘723 patent was invalid in view of SKB’s public use more than
one year prior to the filing of the application that issued as the ‘723 patent.10,11 This
result leaves open the possibility that a proposed ANDA product could be held to infringe
a patent claiming a species of the API, even if that ANDA product contains trace amounts
In determining whether trace amounts of a claimed API species are present in an
alleged infringing compound, the presence of such a substance can only be excluded up
to the relevant limit of detection. The burden of proving the presence of such trace
amounts rests upon the patent holder.12 Consider the situation where the API as tested by
6 Id. at 1313.
8 Id. at 1315.
9 See the District Court’s decision in SmithKline Beecham Corporation and Beecham Group PLC v. ApotexCorp.
, 247 F.Supp.1011, 1032 (D.Ill. 2003), aff’d, SmithKline Beecham Corporation and Beecham GroupPLC v. Apotex Corp., 365 F.3rd 1306 (Fed. Cir. 2004).
10 35 U.S.C. § 102(b)11 See my previous article in the July/August issue of Drug Delivery Technology entitled “Loss of PatentRights: “Experimental Use” Versus On-Sale Bar/Public Use”.
12 Glaxo Inc., v. Novopharm Limited, 931 F. Supp 1280 at 1286
the ANDA filer (or its supplier) does not contain any detectable amount of the claimed
API species. Could the patent holder nevertheless contend that the API species is still
present and bring a Hatch-Waxman (ANDA) litigation? That remains to be seen, but it is
not hard to imagine that such a situation (e.g., where the patent holder alleges some basis
for its contention) may indeed lead to the initiation of an ANDA litigation.
In addition to its contention that the Apotex product directly infringed the ‘723
patent, SKB also had contended that ingestion of Apotex’s paroxetine hydrochloride
anhydrate formulation by a patient would ultimately result in conversion of the anhydrate
to the claimed hemihydrate. The CAFC never decided this issue as they held claim 1 to
be invalid for public use. However, the CAFC in a 1993 decision held that a claim to a
compound (descarboethoxyloratidine) was anticipated because evidence showed that a
prior art substance (loratidine) was metabolized into the claimed compound upon
ingestion by a patient. Schering Corp. v. Geneva Pharmaceuticals, Inc., 339 F.3d 1373
Companies that are seeking to bring generic products to the market should focus
on the possible assertion of any and all patents which may be pertinent to the ANDA
formulation. This focus should include the API itself. In situations where patents exist
on specific forms of the API, the advice of patent counsel concerning the applicability of
such patents to the API should be sought. These issues should optimally be addressed
early in the development process of a generic product rather than later.
By: Cliff Davidson, Esq.
Rich Zanzalari, Esq.
Davidson, Davidson & Kappel, LLC 485 Seventh Avenue, New York, NY 10018 Telephone: (212) 736-1940 Facsimile: (212) 736-2427
Email: firstname.lastname@example.org www.ddkpatent.com
Introduction In general, there is a paucity of research in the field of pediatric psychopharmacology. Many practices are considered “off-label,” meaning there is no FDA approval. This is also true of many non-psychiatric medications and their uses in children (perhaps half or more medication interventions in children are “off-label”). This does not mean that such practices are not supp
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