United States Court of Appeals for the Federal Circuit
IN RE OMEPRAZOLE PATENT LITIGATION
----------------------------------------------------------------
2007-1414, -1416, -1458, -1459
ASTRAZENECA AB, AKTIEBOLAGET HASSLE,
KBI-E, INC., KBI, INC., and ASTRAZENECA LP,
Plaintiffs-Appellees,
v.
APOTEX CORP., APOTEX, INC.,
and TORPHARM, INC.,
Defendants-Appellants,
and
IMPAX LABORATORIES, INC.,
Defendant-Appellant.
Errol B. Taylor, Milbank, Tweed, Hadley & McCloy, LLP, of New York, New York,
argued for plaintiffs-appellees. Of counsel were Fredrick M. Zullow, John M. Griem, Jr.,
Lawrence T. Kass, David C. Haber, Claire A. Gilmartin, and Emily J. Kunz.
Robert B. Breisblatt, Katten Muchin Rosenmann LLP, of Chicago, Illinois, argued
for defendants-appellants Apotex Corp., et al. With him on the brief were Robert S.
Silver, Bruce J. Chasan, Allan H. Fried, William C. Youngblood, and Marc B. Bassler,
Caesar, Rivise, Bernstein, Cohen & Pokotilow, Ltd., of Philadelphia, Pennsylvania.
Jeffrey J. Toney, Sutherland Asbill & Brennan LLP, of Atlanta, Georgia, argued
for defendant-appellant Impax Laboratories, Inc. With him on the brief were John L.
North, N.E.B. Minnear, Jackie L. Toney, and Kristin M. Timm, of Atlanta, Georgia, and
Blair M. Jacobs, of Washington, DC. Of counsel was Leslie S. Thomasson.
Appealed from: United States District Court for the Southern District of New York
Judge Barbara S. Jones
United States Court of Appeals for the Federal Circuit
IN RE OMEPRAZOLE PATENT LITIGATION
----------------------------------------------------------------
2007-1414, -1416, -1458, -1459
ASTRAZENECA AB, AKTIEBOLAGET HASSLE,
KBI-E, INC., KBI, INC., and ASTRAZENECA LP,
Plaintiffs-Appellees,
v.
APOTEX CORP., APOTEX, INC.,
and TORPHARM, INC.,
Defendants-Appellants,
and
IMPAX LABORATORIES, INC.,
Defendant-Appellant.
Appeals from the United States District Court for the Southern District of
New York in case no. 01-CV-9351, 00-CV-7597, 01-CV-2998, and M21-81,
Judge Barbara S. Jones.
___________________________
DECIDED: August 20, 2008
___________________________
Before LOURIE, BRYSON, and GAJARSA, Circuit Judges.
BRYSON, Circuit Judge.
Apotex Corp., Apotex, Inc., and Torpharm, Inc., (collectively, “Apotex”) and
Impax Laboratories, Inc., appeal judgments entered against them by the United States
District Court for the Southern District of New York. Apotex and Impax were defendants
in a multidistrict litigation initiated by plaintiffs Astrazeneca AB, Aktiebolaget Hassle,
KBI-E, Inc., KBI, Inc., and Astrazeneca LP (collectively, “Astra”) against a number of
generic drug manufacturers for infringement of Astra’s patents covering formulations of
omeprazole, the active ingredient in Prilosec, a drug designed to treat acid-related
gastrointestinal disorders. The district court divided the defendants into two separate
“waves” for purposes of trial. For each wave, the district court held a consolidated
bench trial.
We decided appeals from the “first wave” litigation in In re Omeprazole Patent
Litigation, 84 Fed. App’x 76 (Fed. Cir. 2003), and In re Omeprazole Patent Litigation,
483 F.3d 1364 (Fed. Cir. 2007). The present appeals arise from the “second wave”
litigation. In the second wave cases, the district court entered judgment of
noninfringement with respect to Mylan Laboratories, Inc., and judgments of infringement
against Apotex and Impax. Astra appealed the judgment of noninfringement in the
Mylan case, and we recently affirmed that judgment in In re Omeprazole Patent
Litigation, 2008 WL 2369864 (Fed. Cir. June 10, 2008). In this consolidated appeal,
Apotex and Impax challenge the district court’s judgments of infringement against each
of them. Because we find no error in the district court’s decision, we affirm.
I
The patents involved in this appeal are U.S. Patent No. 4,786,505 (“the ’505
patent”) and U.S. Patent No. 4,853,230 (“the ’230 patent”). The two patents relate to
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pharmaceutical preparations containing omeprazole, the active ingredient in Prilosec.
Omeprazole is a potent inhibitor of gastric acid secretion, but it is susceptible to
degradation in acid-reacting and neutral media. Its stability is also affected by moisture
and organic solvents. To protect omeprazole from gastric acid in the stomach, a
pharmaceutical dosage can include an enteric coating that covers the drug core.
Enteric coatings, however, contain acidic compounds, which can cause the omeprazole
in the drug core to decompose while the dosage is in storage, resulting in discoloration
and decreasing omeprazole content in the dosage over time. To increase the storage
stability of a pharmaceutical dosage, alkaline reacting compounds (“ARCs”) may be
added to the drug core. The addition of an ARC, however, can compromise the enteric
coating. A conventional enteric coating allows for some diffusion of water from gastric
juices into the drug core, but water entering the drug core will dissolve the ARCs, which
can in turn cause the enteric coating to dissolve. ’505 patent, col. 1, line 33, to col. 2,
line 4.
The inventors of the ’505 and ’230 patents solved that problem by adding an inert
subcoating that rapidly disintegrates in water. The subcoating increases storage
stability and provides sufficient gastric acid resistance to prevent omeprazole from
degrading in the stomach. Once the dosage reaches the small intestine, the solubility of
the subcoating allows for rapid release of the omeprazole in the drug core. ’505 patent,
col. 5, ll. 19-68.
The ’505 patent covers a pharmaceutical preparation containing omeprazole.
Claim 1 recites:
An oral pharmaceutical preparation comprising
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(a) a core region comprising an effective amount of a material selected
from the group consisting of omeprazole plus an alkaline reacting
compound, an alkaline omeprazole salt plus an alkaline reacting
compound and an alkaline omeprazole salt alone;
(b) an inert subcoating which is soluble or rapidly disintegrating in water
disposed on said core region, said subcoating comprising one or more
layers of materials selected from among tablet excipients and polymeric
film-forming compounds; and
(c) an outer layer disposed on said subcoating comprising an enteric
coating.
The ’230 patent more broadly covers a preparation containing an “acid-
labile pharmaceutically active substance.” Claim 1 of the ’230 patent recites:
A pharmaceutical preparation comprising:
(a) an alkaline reacting core comprising an acid-labile pharmaceutically
active substance and an alkaline reacting compound different from said
active substance, an alkaline salt of an acid labile pharmaceutically active
substance, or an alkaline salt of an acid labile pharmaceutically active
substance and an alkaline reacting compound different from said active
substance;
(b) an inert subcoating which rapidly dissolves or disintegrates in water
disposed on said core region, said subcoating comprising one or more
layers comprising materials selected from the group consisting of tablet
excipients, film-forming compounds and alkaline compounds; and
(c) an enteric coating layer surrounding said subcoating layer, wherein the
subcoating layer isolates the alkaline reacting core from the enteric
coating layer such that the stability of the preparation is enhanced.
II
On December 31, 1999, Impax sought approval from the Food and Drug
Administration (“FDA”) to sell 10- and 20-mg generic versions of Prilosec. In response,
Astra filed suit for infringement of the ’505 and ’230 patents under 35 U.S.C.
§ 271(e)(2)(A). Astra filed a second action against Impax after Impax amended its
application to include a 40-mg product. In September 2004, the FDA granted Impax
2007-1414 4
final approval to market its 10- and 20-mg omeprazole products. Impax began
marketing its approved products, which prompted Astra to amend its complaint to
include claims for damages under 35 U.S.C. § 271(a)-(c). Impax filed an answer to
Astra’s second amended complaint in which it asserted counterclaims for fraud and
sham litigation, for a declaration of unenforceability as to the two patents, and for
declarations of noninfringement and invalidity as to all the claims of both patents. Impax
demanded a jury trial for all of its counterclaims and for Astra’s claims of infringement.
At that time, Astra’s claims for damages and willful infringement had been
severed and stayed pending the resolution of the liability issues in the case. Astra and
Impax had also agreed in 2003 to sever and stay Impax’s antitrust counterclaims. At a
hearing on December 1, 2005, Astra asked the court to sever its claims of infringement
under section 271(a)-(c) from its claims under section 271(e), for which it did not seek
damages, so that the district court could consolidate its claims against Impax under
section 271(e) in a bench trial with the other defendants. The district court requested
briefing on whether Impax was entitled to a jury trial. In response, Astra stipulated that
it would agree to dismiss its demand for damages against Impax with prejudice if the
district court heard its claims against Impax in the consolidated bench trial. Based on
that stipulation, the court denied Impax’s demand for a jury trial and consolidated the
section 271(e) claims against Impax with the claims against the other defendants.
The district court then held a 42-day bench trial. Following the trial and before
the court issued its decision, the patents both expired. Impax filed a motion to dismiss
Astra’s claims against it as moot because Astra had dismissed its claims for damages
against Impax. The district court denied that motion, however, because the FDA had
2007-1414 5
granted Astra a six-month period of market exclusivity following the expiration of the
’505 and ’230 patents. On May 31, 2007, the district court issued its decision, holding
that Astra’s patents were valid, enforceable, and infringed by Impax. The court
therefore set the effective date of Impax’s ANDA to October 20, 2007, the end of Astra’s
six-month period of market exclusivity.
On appeal, Impax argues that the district court erred in denying its demand for a
jury trial and in denying its motion to dismiss Astra’s claims as moot. It also challenges
the sufficiency of the evidence of infringement, and it further claims that the district court
committed clear error by not finding the claims of the two patents invalid under the
public-use bar of 35 U.S.C. § 102(b).
A
We first address Impax’s argument that the district court lost jurisdiction over the
case after the patents expired on April 20, 2007. Impax argues that on that date the
case became moot because Astra, having already dismissed its claims for damages,
had no remaining claim for any possible relief to which it might be legally entitled. The
district court rejected that argument because the FDA had granted Astra an additional
six-month period of market exclusivity after Astra had agreed to the FDA’s request that
it perform pediatric testing of its product. The court held that it had the authority to
enforce Astra’s right to market exclusivity under the authority of section 271(e)(4)(A)
and under its general equitable authority. We reject Impax’s argument as to the district
court’s jurisdiction because we believe the district court correctly interpreted section
271(e)(4)(A) to provide a post-expiration remedy for infringement under section
271(e)(2).
2007-1414 6
Section 271(e)(2)(A) makes it an act of infringement to file “an application under
section 505(j) of the Federal Food, Drug, and Cosmetic Act or described in section
505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a
patent.” An application filed under section 505(j) of the Federal Food, Drug, and
Cosmetic Act, codified at 21 U.S.C. § 355(j), is known as an Abbreviated New Drug
Application (“ANDA”). An ANDA must contain one of four certifications regarding each
patent that covers the application’s drug:
(I) that such patent information has not been filed,
(II) that such patent has expired,
(III) of the date on which such patent will expire, or
(IV) that such patent is invalid or will not be infringed by the manufacture, use, or
sale of the new drug for which the application is submitted.
21 U.S.C. § 355(j)(2)(A)(vii). If the applicant provides a Paragraph IV certification, the
patent holder may file suit under section 271(e)(2)(A). If the patent holder files suit
within 45 days, the FDA is barred from approving the ANDA for 30 months. 21 U.S.C.
§ 355(j)(5)(B)(iii). The FDA may approve the ANDA after that period, or earlier if the
applicant succeeds in showing non-infringement of the patent or in proving the patent’s
invalidity. Id. § 355(j)(5)(B)(iii)(I).
If the patent holder proves infringement of a valid patent resulting from the filing
of an ANDA, section 271(e)(4) provides three remedies. Subparagraphs (B) and (C)
provide the typical remedies for infringement: injunctive relief and damages.
Subparagraph (A), however, provides an additional type of relief after a finding of
infringement under section 271(e)(2) by requiring the district court to “order the effective
date of any approval of the drug or veterinary biological product involved in the
2007-1414 7
infringement to be a date which is not earlier than the date of the expiration of the patent
which has been infringed.” If the FDA has not approved the ANDA before the district
court determines that the patent has been infringed, the FDA may not approve the
ANDA until the effective date specified by the district court under section 271(e)(4)(A).
See 21 U.S.C. § 355(j)(5)(B)(iii)(II)(bb). If the FDA has already approved the ANDA, the
district court’s order would alter the effective date of the application, thereby converting
a final approval into a tentative approval. See Ortho-McNeil Pharm., Inc. v. Mylan
Labs., Inc., 520 F.3d 1358, 1366 (Fed. Cir. 2008); Mylan Labs., Inc. v. Thompson, 389
F.3d 1272, 1281-82 (D.C. Cir. 2004); see also S. Rep. No. 98-547, at 46 (1984), as
reprinted in 1984 U.S.C.C.A.N. 2647, 2679 (“In the case where an ANDA had been
approved, the order would mandate a change in the effective date.”).
In most circumstances, the effective date in a district court’s order under section
271(e)(4)(A) will be the date of patent expiration, including any patent extensions. In
this case, however, Astra was entitled to an additional six-month period of market
exclusivity (sometimes known as a period of “pediatric exclusivity”) under the Food and
Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296. A
provision of that Act, codified at 21 U.S.C. § 355a, authorizes the Food and Drug
Administration to make a written request to the holder of an approved new drug
application (“NDA”) for the holder to perform pediatric studies. If the NDA holder agrees
to the request and performs the pediatric studies, the period during which the FDA is
barred from approving an ANDA filed by competing drug manufacturers is extended by
six months. See 21 U.S.C. § 355a(b)-(c). Section 355a specifically addresses
situations in which a Paragraph IV certification is submitted. In those cases, the period
2007-1414 8
during which an ANDA may not be approved under section 355(j)(5)(B) “shall be
extended by a period of six months [i.e., the period of pediatric or market exclusivity]
after the date the patent expires (including any patent extensions).” Id.
§§ 355a(b)(2)(B), 355a(c)(2)(B).
Impax does not argue that the district court was altogether foreclosed from
enforcing Astra’s period of market exclusivity. Rather, Impax argues that Astra’s claim
of infringement became moot once the ’505 and ’230 patents expired, and therefore the
district court lacked authority to order a change in the effective date of Impax’s ANDA.
We reject that argument. For a claim to be justiciable, “[i]t must be a real and
substantial controversy admitting of specific relief through a decree of a conclusive
character, as distinguished from an opinion advising what the law would be upon a
hypothetical state of facts.” Aetna Life Ins. Co. v. Haworth, 300 U.S. 227, 240-41
(1937). Impax does not dispute that, if the district court had issued its decision before
the patents expired, section 271(e)(4)(A) would have authorized the district court to
order the effective date of Impax’s ANDA to be October 20, 2007, the date on which
Astra’s period of market exclusivity expired. Impax argues that once the patents
expired, section 271(e)(4)(A) no longer provided a remedy because the patents’
expiration rendered the claim of infringement moot. That argument simply assumes its
conclusion; Impax offers no reason to suggest that section 271(e)(4)(A) provides no
remedy after patent expiration other than to assert that no remedy is available after
patent expiration.
In support of its position that the district court may not grant relief relating to the
period of market exclusivity after a patent has expired, Impax relies on two district court
2007-1414 9
cases, Pfizer, Inc. v. Mylan Labs., Inc., 2006 WL 2990398 (W.D. Pa. Oct. 18, 2006), and
Roche Palo Alto LLC v. Apotex, Inc., 526 F. Supp. 2d 985 (N.D. Cal. 2007). Neither of
those cases provides persuasive support for Impax’s position. The Pfizer court relied
on our decision in Kearns v. Chrysler Corp., 32 F.3d 1541, 1549-51 (Fed. Cir. 1994), in
which we held that a district court did not abuse its discretion in denying injunctive relief
after the patent in suit had expired. Kearns, however, addressed the availability of relief
under 35 U.S.C. § 283; it did not address the availability of relief under section
271(e)(4)(A). The Pfizer court’s reliance on Kearns was therefore misplaced. In Roche,
the court addressed the proper language to be used in an order entered under section
271(e)(4)(A). Instead of ordering the effective date of the defendant’s ANDA to be set
to the date on which the six-month exclusivity period would end, the court adopted the
language of the statute, ordering the effective date to be “not earlier than the date of the
expiration of the patent which has been infringed.” 526 F. Supp. 2d at 1000. Here,
Impax has not challenged the particular terms of the district court’s order; it has
challenged the availability of any relief at all under section 271(e)(4)(A). 1
B
On the issue of infringement, Impax challenges the sufficiency of the evidence
that its formulation infringes the claims of the ’505 and ’230 patents. Impax argues that
the record does not support either the district court’s finding that Impax’s formulation
contains an “effective amount” of omeprazole and an ARC, or its finding that the
formulation has an inert subcoating. We reject both arguments.
1
This court continues to have jurisdiction in the Impax case because of the
pending claim for attorney fees under 35 U.S.C. § 285. In the Apotex case, claims for
damages are at issue, so the expiration of the patents does not render that case moot.
2007-1414 10
1
Limitation (a) of claim 1 of the ’505 patent requires:
a core region comprising an effective amount of a material selected from
the group consisting of omeprazole plus an alkaline reacting compound,
an alkaline omeprazole salt plus an alkaline reacting compound and an
alkaline omeprazole salt alone.
In the first wave trial in this case, the district court construed “effective amount” to apply
to both the amount of omeprazole and the amount of an ARC present in the core. The
court construed “alkaline reacting compound” as
(1) a pharmaceutically acceptable alkaline, or basic, substance having a
pH greater than 7 that (2) stabilizes the omeprazole or other acid labile
compound by (3) reacting to create a micro-pH of not less than 7 around
the particles of omeprazole or other acid labile compound.
Impax argues that Astra’s evidence satisfies only the first and third of those three
requirements because Astra did not introduce evidence of comparative stability testing
to prove the second. Impax maintains that without stability testing Astra’s evidence was
deficient in two respects.
First, Impax argues that Astra should have been required to show that Impax’s
formulation is stable without the use of a dessicant. That argument is without merit. As
the district court observed, the claims at issue do not require that omeprazole be
stabilized without the use of a desiccant. In fact, the patents teach the use of a
desiccant as a preferred, additional means of stabilizing the claimed product. The
description of the final dosage form states:
It is essential for the long term stability during storage that the water
content of the final dosage form containing omeprazole (enteric coated
tablets, capsules or pellets) is kept low, preferably not more than 1.5% by
weight. As a consequence the final package containing hard gelatin
capsules filled with enteric coated pellets preferably also contain a
desiccant, which reduces the water content of the gelatin shell to a level
2007-1414 11
where the water content of the enteric coated pellets filled in the capsules
does not exceed 1.5% by weight.
’505 patent, col. 5, line 63, to col. 6, line 5 (emphasis added).
Second, Impax asserts that Astra’s evidence does not assess the individual
contribution of the ARC to the stability of omeprazole in the drug core. Even so, the
district court did not err in concluding that Astra’s evidence was sufficient to
demonstrate the stability of omeprazole. Based on its construction of the claim term
“alkaline reacting compound,” the district court found that Astra proved that limitation to
be met by showing that a basic compound created a “micro-pH” in the drug core of not
less than 7. Impax argues that, in doing so, the district court strayed from the
construction it had applied in the first wave litigation.
We reject Impax’s argument. In the first wave litigation, the district court
described the evidentiary requirement for the stabilization prong of its construction of
“alkaline reacting compound” by stating that “[a]s the specification discloses, that
stabilization is achieved by using an ARC in the core to create a micro-pH around the
omeprazole particles of not less than pH 7.” Astra Aktiebolag v. Andrx Pharms., Inc.,
222 F. Supp. 2d 423, 464 (S.D.N.Y. 2002). That is the same evidentiary burden that the
district court placed on Astra in this case, and we agree with the district court that the
specification supports that interpretation of “alkaline reacting compound.” Indeed, the
description of the drug core states:
Omeprazole is mixed with inert, preferably water soluble, conventional
pharmaceutical constituents to obtain the preferred concentration of
omeprazole in the final mixture and with an alkaline reacting, otherwise
inert, pharmaceutically acceptable substance (or substances), which
creates a “micro-pH” around each omeprazole particle of not less than
pH=7, preferably not less than pH=8, when water is adsorbed to the
particles of the mixture or when water is added in small amounts to the
mixture.
2007-1414 12
’505 patent, col. 3, ll. 38-47. We therefore find no clear error in the district court’s
conclusion that Astra’s pH data proved the presence of an “effective amount” of an ARC
in Impax’s ANDA formulation.
Impax presents similar arguments with respect to the “enhanced stability”
requirement of the ’230 patent. Limitation (c) of claim 1 of the ’230 patent requires
an enteric coating layer surrounding said subcoating layer, wherein the
subcoating layer isolates the alkaline reacting core from the enteric
coating layer such that the stability of the preparation is enhanced.
The district court, however, correctly concluded that enhanced stability is the intended
result of using an inert subcoating around a drug core containing an amount of an ARC
in the drug core sufficient to create a micro-pH of not less than 7. See Syntex (U.S.A.)
LLC v. Apotex, Inc., 407 F.3d 1371, 1378 (Fed. Cir. 2005) (“the term ‘in a stabilizing
amount’ simply describes the intended result of using the weight to volume ratios recited
in the claims.”). Contrary to Impax’s assertion, the requirement of “enhanced stability”
was not “read out of the claims entirely.” Rather, for proof of the “enhanced stability”
limitation, the district court required Astra to demonstrate the presence of an inert
subcoating and a drug core having a micro-pH of not less than 7. That proof
requirement is supported by the specifications of the ’230 and ’505 patents, which teach
that the result of using an inert subcoating and an ARC is increased stability.
Finally, we reject Impax’s argument that this court’s decision in Warner-Lambert
Co. v. Teva Pharmaceuticals USA, Inc., 418 F.3d 1326 (Fed. Cir. 2005), requires
reversal of the district court’s finding of infringement. In that case, Warner-Lambert
sued Teva for infringement of a claim that required “a suitable amount of an alkali or
alkaline earth metal carbonate to inhibit cyclization and discoloration.” The district court
granted Warner-Lambert’s motion for summary judgment of infringement. We reversed
2007-1414 13
after determining that Teva had pointed to a genuine issue of material fact “as to
whether the magnesium carbonate in Teva's formulation inhibits oxidative discoloration.”
Id. at 1342. By contrast, the district court in this case, acting as finder of fact, made a
factual determination based on the evidence presented at trial that Impax’s inert
subcoating and ARC increased the stability of its formulation.
2
Impax’s second challenge to the district court’s decision on infringement is based
on the court’s finding that Impax’s formulation met the “inert subcoating” limitation of
both patents. Astra presented evidence that in Impax’s product an inert subcoating
forms in situ between the enteric coating and the drug core region. Astra’s evidence
showed the presence, in Impax’s product, of a hydroxypropyl methylcellulose phthalate
(“HPMCP”) salt in the region between the enteric coating and the drug core. Impax
argues that Astra’s evidence was insufficient to establish infringement because Astra
did not prove the mechanism by which the salt forms; because the test Astra used to
detect the presence of HPMCP salt is incapable of detecting sodium; and because the
tests showed traces of omeprazole.
The district court correctly rejected each of those arguments. First, to prove
infringement Astra did not need to identify the process by which the infringing
subcoating was produced; it was sufficient for it to show the presence of the claimed
structure. In any event, the district court credited testimony by Dr. Davies, Astra’s
expert, in which he stated that the HPMCP salt layer results from a reaction between
HPMCP in the enteric coating and dibasic sodium hydrogen phosphate in the drug core.
Second, Impax’s argument challenging the tests that were used to show the presence
2007-1414 14
of the inert subcoating is misleading. Impax relies on the testimony of Dr. Davies that
sodium atoms cannot be detected by attenuated total reflectance Fourier transform
infrared spectroscopy (“ATR-FTIR”). Dr. Davies, however, testified that his ATR-FTIR
data revealed the presence of a carboxylate group, which indicated the presence of
HPMCP in the subcoating. Finally, with respect to the evidence of the presence of
omeprazole in the test results, Dr. Davies testified that the omeprazole peaks in his
spectral data could be explained in two ways: Omeprazole may have entered the
subcoating but only in trace amounts allowed by the claims; or the ATR-FTIR may have
picked up weak signals from the omeprazole in the drug core. The district court
credited that testimony. We therefore find that the record supports the district court’s
determination that Impax’s formulation infringes Astra’s patents.
C
Finally, Impax challenges the district court’s findings with respect to the public-
use bar under section 102(b). Astra filed its applications for the ’505 and ’230 patents
on April 20, 1987. The critical date of the patents is therefore April 20, 1986. Before
that date, Astra commissioned four large clinical studies to determine the safety and
efficacy of its formulation in order to obtain FDA approval. At trial, Impax argued that
the studies involved the public use of Astra’s claimed formulation. The district court
ruled against Impax on two grounds. First, the court ruled that the studies constituted
experimental uses, and therefore not public uses, of the claimed invention. Second, the
court ruled that the patented formulation was not ready for patenting until after the
studies were completed. Impax challenges each of those findings.
1
2007-1414 15
We agree with Impax that the district court misapplied this circuit’s law with
respect to the experimental use exception. The district court found that, even if Astra’s
formulation had been reduced to practice before or during the clinical studies, the
studies were experimental and therefore negated the public-use bar to patentability.
Impax correctly points out, however, that it is clear from this court’s case law that
experimental use cannot negate a public use when it is shown that the invention was
reduced to practice before the experimental use. See Cargill, Inc. v. Canbra Foods,
Ltd., 476 F.3d 1359, 1371 n.10 (Fed. Cir. 2007); Allen Eng’g Corp. v. Bartell Indus., Inc.,
299 F.3d 1336, 1354 (Fed. Cir. 2002); New Railhead Mfg., LLC v. Vermeer Mfg. Co.,
298 F.3d 1290, 1299 (Fed. Cir. 2002); EZ Dock, Inc. v. Schafer Sys., Inc., 276 F.3d
1347, 1357 (Fed. Cir. 2002) (Linn, J., concurring); Zacharin v. United States, 213 F.3d
1366, 1369 (Fed. Cir. 2000); Baxter Int’l, Inc. v. COBE Labs, Inc., 88 F.3d 1054, 1060
(Fed. Cir. 1996). But see Atlanta Attachment Co. v. Leggett & Platt, Inc., 516 F.3d
1361, 1368-69 (Fed. Cir. 2008) (Prost, J., concurring). We therefore do not agree with
the district court’s ruling that the experimental use exception served to negate the
public-use bar to patentability.
2
We may nevertheless affirm the district court’s conclusion that the claims were
not invalid under section 102(b) based on the court’s factual determination that the
claimed formulation was not ready for patenting until after the clinical studies were
completed. See Pfaff v. Wells Electronics, Inc., 525 U.S. 52, 67 (1998); Invitrogen
Corp. v. Biocrest Mfg., L.P., 424 F.3d 1374, 1380 (Fed. Cir. 2005) (“the ready for
patenting component of Pfaff’s two-part test [is] another necessary requirement of a
2007-1414 16
public use bar.”). The district court found that the claimed formulation was not reduced
to practice before the clinical trials were completed, and we uphold that finding.
According to the undisputed facts of this case, omeprazole was first created by
Astra’s scientists in 1979, 12 years after Astra’s predecessor had begun a research
project to develop a drug capable of inhibiting gastric acid secretion. 222 F. Supp. 2d at
434. Once the compound was developed, a team of Astra’s scientists turned their focus
to developing an oral dosage form of the drug, a task that proved difficult because of
omeprazole’s unstable nature in certain environments. Two scientists on that team
were Drs. Ake Pilbrant and Kurt Lövgren, two of the named inventors of the ’505 and
’230 patents. In the first human trials (the Phase I trials), Astra employed a buffered
suspension to stabilize omeprazole in the acidic environment of the stomach. 222 F.
Supp. 2d at 435. To create a dosage suitable for commercialization, Drs. Pilbrant and
Lövgren added an enteric coating to an omeprazole drug core. After performing studies
that showed that the enteric coating did not cause the omeprazole to degrade any more
than was caused by other excipients, the inventors decided to proceed with an enteric-
coated formulation.
After testing various formulations with an enteric coating, the inventors finally
came up with a formulation that appeared sufficiently promising to warrant testing in the
Phase II clinical trials. That formulation used an enteric coating of hydroxypropyl
methylcellulose phthalate to cover a drug core containing omeprazole combined with
ARCs and other excipients. The Phase II formulation ultimately proved to have
insufficient gastric acid resistance and insufficient long-term shelf life. Drs. Pilbrant and
2007-1414 17
Lövgren, along with other Astra scientists, then set out to develop a formulation that
would solve both of those problems.
That task proved difficult because the two goals seemingly conflicted. Increasing
shelf life required stabilizing omeprazole in an alkaline environment. Yet the acidic
enteric coating would be less effective at providing gastric acid resistance when in
contact with alkaline compounds. The scientists tried a number of modifications to the
Phase II formulation until Drs. Pilbrant and Lövgren decided to use a subcoating
between the enteric coating and the drug core. They attempted inserting a water-
soluble subcoat, although they expected that the subcoat might prove ineffective
because it would dissolve in the water that leaked through the enteric coating. If that
were the case, the omeprazole in the drug core would degrade because of its sensitivity
to water. Their laboratory experiments revealed, however, that the water-soluble
subcoating increased gastric acid resistance and long-term stability. Based on those
tests, the group decided to use the formulation in the Phase III clinical trials. The results
of those trials revealed gastric acid resistance well in excess of Astra’s goal, together
with three years of shelf stability.
In Pfaff, the Supreme Court described two ways for a party to show that an
invention was ready for patenting before the critical date of section 102(b): “by proof of
reduction to practice before the critical date; or by proof that prior to the critical date the
inventor had prepared drawings or other descriptions of the invention that were
sufficiently specific to enable a person skilled in the art to practice the invention.” 525
U.S. at 67-68. In attempting to demonstrate that the invention was ready for patenting,
2007-1414 18
Impax has sought to show that the Phase III formulation had been reduced to practice
before Astra conducted the Phase III clinical trials.
At trial, Impax bore the burden of demonstrating by clear and convincing
evidence that the Phase III formulation had been reduced to practice before the testing
began. See z4 Techs., Inc. v. Microsoft Corp., 507 F.3d 1340, 1352 (Fed. Cir. 2007).
To demonstrate reduction to practice, a party must prove that the inventor (1)
“constructed an embodiment or performed a process that met all the limitations” and (2)
“determined that the invention would work for its intended purpose.” Id. (quoting Cooper
v. Goldfarb, 154 F.3d 1321, 1327 (Fed. Cir. 1998)). “Testing is required to demonstrate
reduction to practice in some instances because without such testing there cannot be
sufficient certainty that the invention will work for its intended purpose.” Id. (quoting Slip
Track Sys., Inc. v. Metal-Lite, Inc., 304 F.3d 1256, 1267 (Fed. Cir. 2002)). We review
the district court’s factual determinations as to the necessity and sufficiency of testing
for clear error.
The district court found that the Phase III formulation was not reduced to practice
before the trials because the evidence showed that at that time the inventors believed
only that the formulation “might solve the twin problems of in vivo stability and long-term
storage.” The district court found that “the Phase III formulation still required extensive
clinical testing and real-time stability testing to determine whether it could treat gastric
acid diseases safely and effectively.”
Relying on Tasket v. Dentlinger, 344 F.3d 1337 (Fed. Cir. 2003), Impax argues
that the district court committed clear error in finding that the inventors had not reduced
their formulation to practice before the Phase III clinical trials. In Taskett, the issue was
2007-1414 19
whether the Board of Patent Appeals and Interferences erred in concluding that the
junior party, Dentlinger, had reduced to practice the limitation “obtaining financial
authorization” when the record indicated that Dentlinger had not commercially tested
that feature of his invention. Id. at 1341-42. The Board relied on the testimony of two of
Dentlinger’s employees and a dated test receipt to conclude that Dentlinger had proved
reduction to practice by a preponderance of the evidence. This court affirmed, finding
the Board’s decision to be supported by substantial evidence based on the employees’
testimony and the test receipt relied on by the Board, in addition to evidence in the
record that the limitation had been well tested in the field. Id. at 1342.
Taskett provides limited support for Impax because in this case the district court
found that there was insufficient evidence to support a factual determination that the
Phase III formulation had been reduced to practice. Impax must therefore show that the
district court committed clear error in finding, as a factual matter, that Drs. Pilbrant and
Lövgren did not determine that the Phase III formulation would have sufficient in vivo
and long-term stability before the Phase III trials. Impax has not made that showing.
Impax’s challenge to the district court’s finding begins with its assertion that the
Astra scientists had conceived and produced the Phase III formulation before the
clinical trials. It is not disputed that the Phase III formulation had been produced before
the trials. The existence of the formulation, however, does not establish that the Astra
scientists had determined that the invention would work for its intended purpose.
Impax further asserts that the stability of the Phase III formulation had been
confirmed in May 1983, before the Phase III trials were conducted. To support that
assertion, Impax relies on the testimony of Dr. Pilbrant. Dr. Pilbrant confirmed that
2007-1414 20
laboratory testing of the Phase III formulation, conducted before the clinical trials,
revealed that the Phase III formulation possessed significantly increased gastric acid
resistance over the predecessor formulations. Dr. Pilbrant, however, further testified
that as of May 1983 the Astra scientists did not have enough information to satisfy
themselves that the Phase III formulation would work for its intended purpose. Instead,
he testified that the Astra scientists thought the Phase III formulation “had a good
possibility to be used as a marketing drug” but that the team did not have long-term
stability data and had “no experience of how it performed in clinical studies.”
Impax also relies on the portion of Dr. Pilbrant’s testimony in which he stated
that, before the trials, he knew “for sure that the stability of the phase III formulation or
the invention was better than the phase II formulation.” That assertion also does not
undermine the district court’s determination regarding reduction to practice. The district
court found that the Phase III formulation still required testing to determine whether that
formulation would be sufficiently stable to treat gastrointestinal disease effectively. The
Phase III formulation may have been more stable than the Phase II formulation, but that
does not establish that the Phase III formulation would be stable enough to provide an
effective treatment.
Impax points to the testimony of Dr. Carlsson in support of its contention that the
Phase III formulation was adopted in 1983. Dr. Carlsson testified, however, that the
purpose of the Phase III trials was to assess the formulation’s safety and efficacy,
stating that it was not until all Phase III trials were completed that safety and efficacy
could be documented. The district court relied on that testimony in finding that the
inventors had not determined that the Phase III formulation would have sufficient long-
2007-1414 21
term and in vivo stability to produce a formulation effective to treat gastrointestinal
disease. Impax has not pointed to any evidence showing that the clinical trials were not
necessary to allow the Astra scientists to conclude that the Phase III formulation would
have sufficient long-term and in vivo stability to serve as an effective treatment.
Impax contends that the district court misapprehended the intended purpose of
the Phase III trials when it stated that the Astra scientists were “still in the process of
determining [during those trials] whether the Phase III formulation could safely and
effectively be used as a ‘method of treatment of gastrointestinal disease.’” Impax
argues that it was known in 1979—the year Astra filed its first patent application for
omeprazole—that omeprazole could provide a safe and effective treatment.
Impax’s argument misses the point. The Astra scientists had long understood
that omeprazole could provide a safe and effective treatment for certain gastrointestinal
diseases. The challenge they faced was developing a formulation to deliver omeprazole
to the small intestine, a challenge that was made difficult by omeprazole’s sensitivity to
acidic environments, such as the stomach. Impax has not demonstrated that, without
conducting the Phase III clinical tests, the inventors knew that the Phase III formulation
would achieve the goals of long-term stability and in vivo stability such that it would be
effective as a treatment for gastrointestinal disease. We therefore find no clear error in
the district court’s finding on this issue.
D
Finally, we address Impax’s challenge to the district court’s order denying
Impax’s demand for a jury trial. Impax argues that the district court’s order violated its
Seventh Amendment right to a trial by jury because its antitrust counterclaims presented
2007-1414 22
factual issues that were common to its invalidity counterclaims. We rejected that
argument when reviewing Impax’s petition for a writ of mandamus on this issue two
years ago. In re Impax Labs., Inc., 171 Fed. App’x 839 (Fed. Cir. 2006). Impax has not
pointed to any extraordinary circumstances that would justify our revisiting that decision.
We therefore adhere to our prior ruling as the law of the case. See Christianson v. Colt
Indus. Operating Corp., 486 U.S. 800, 817 (1988) (“A court has the power to revisit prior
decisions of its own or of a coordinate court in any circumstance, although as a rule
courts should be loath to do so in the absence of extraordinary circumstances such as
where the initial decision was ‘clearly erroneous and would work a manifest injustice.’”);
Maldonado v. Flynn, 671 F.2d 729, 732 (2d Cir. 1982) (“Mandamus is the accepted
method to review an order denying a claimed right of trial by jury. . . . Consequently,
denial of the petition for mandamus in this matter is the law of the case.”).
III
We now turn to Apotex’s appeal. Like Impax, Apotex filed an ANDA for 10-, 20-,
and 40-mg generic omeprazole products and certified in its application that the ’505 and
’230 patents were invalid or not infringed. Astra filed suit against Apotex, and Astra’s
claims against Apotex were heard by the district court during the same bench trial in
which Astra’s claims against Impax were heard. Based on testimony from Dr. Davies,
the district court ruled that Apotex’s formulation infringed both patents. The district court
also rejected Apotex’s anticipation and obviousness defenses. The court therefore
ordered the effective date of Apotex’s ANDA to be October 20, 2007, to reflect Astra’s
period of market exclusivity. Apotex challenges the findings of infringement, the court’s
2007-1414 23
rulings on anticipation and obviousness, and the court’s order to set the effective date to
the end of Astra’s exclusivity period.
A
Apotex’s formulation contains a pellet core consisting of omeprazole, povidone
(“PVP”), magnesium hydroxide, and mannitol. Apotex applies to the pellet core an
enteric coating made from a solution of water, methacrylic acid copolymer (“MACP”),
and triethyl citrate. Even though Apotex does not apply a subcoating during the
manufacturing process, Dr. Davies testified that Apotex’s pellets infringe because a
subcoating forms in situ from a reaction between the MACP in the enteric coating and
the PVP in the pellet core. Dr. Davies demonstrated the presence of a subcoating in
Apotex’s pellets with confocal laser scanning microscopy (“CLSM”) fluorescence and
reflectance images. Dr. Davies’s CLSM fluorescence images showed a fluorescent
band in Apotex’s accused pellets. When Dr. Davies’s CLSM fluorescence images were
overlaid with his CLSM reflectance images, the fluorescent band was shown to lie at the
surface of the drug core and to have a thickness of about 2 to 6 microns.
Additionally, Dr. Davies washed some of Apotex’s pellets in acetone and
isopropanol (“acetone:IPA”) to remove the enteric coating. His CLSM fluorescence and
reflectance images of the washed pellets likewise showed a fluorescent layer at the
surface of the drug core. To determine the composition of the fluorescent band, Dr.
Davies used ATR-FTIR data. Most pertinent to the district court’s finding of
infringement, he compared the spectrum of the surface of the washed pellets to the
spectrum of a MACP:PVP reference. The spectrum of the washed pellets’ surface
showed a peak at 1633 cm-1. Dr. Davies testified that when PVP reacts with MACP, the
2007-1414 24
PVP spectrum shows a shift from 1670 cm-1 to 1630 cm-1 as a result of the formation of
a complex between the carbonyl groups of PVP and the carboxyl groups of MACP. Dr.
Davies additionally showed that the properties of the MACP:PVP complex were different
from PVP and MACP alone by performing pH testing on the three compounds. Based
on the evidence from Dr. Davies’s testing, the district court concluded that Apotex’s
pellets have a continuous, water-soluble subcoating that is formed in situ. Apotex
challenges the sufficiency of that evidence.
1
Apotex first argues that, even if a subcoating forms in situ, the subcoating is not a
“subcoating . . . disposed on said core region” within the meaning of the ’505 and ’230
patents because Apotex does not directly apply a subcoating during its manufacturing
process. We rejected that argument in the appeal from the district court’s first wave trial
based on our conclusion that the phrase “‘[d]isposed on’ does not specify any method or
structure involved in application of the subcoating.” 84 Fed. App’x 76, 80 (Fed. Cir.
2003). We reject that argument in this appeal for the same reason.
Apotex also argues that its manufacturing process merely practices the prior art,
citing European Patent Application No. EP 124,495 A2 (“the ’495 European
application”). It is well established, however, that “practicing the prior art” is not a
defense to infringement. Tate Access Floors, Inc. v. Interface Architectural Res., Inc.,
279 F.3d 1357, 1365-69 (Fed. Cir. 2002); Baxter Healthcare Corp. v. Spectramed, Inc.,
49 F.3d 1575, 1583 (Fed. Cir. 1995).
2
2007-1414 25
Apotex next argues that the district court erred in concluding that the fluorescent
band was formed by an MACP:PVP complex and not by omeprazole and its
degradation products. In making that argument, Apotex relies on evidence from its
experts, Dr. Signorino and Dr. Cima. Dr. Signorino created “ANDA Reproduction
Pellets” by following Apotex’s ANDA specification, along with a series of “modified
ANDA Reproduction Pellets,” one version of which was made without omeprazole. Dr.
Cima then obtained UV fluorescent images of the ANDA Reproduction Pellets and the
modified pellets. His images showed a fluorescent band in the ANDA Reproduction
Pellets, but no band in the modified pellets that lacked omeprazole.
The district court found that Dr. Signorino’s reproduction pellets were not
comparable to Apotex’s accused products. The court reached that conclusion for a
number of reasons: the size of the samples produced was smaller than the FDA would
require for a pilot scale batch, the enteric coating of the pellets was half the size of the
coating of Apotex’s ANDA samples, Dr. Signorino did not know the temperature at
which his pellets were made, he coated his pellets for half as long as Apotex’s products,
and he added more water than Apotex’s ANDA specified. The court further noted that
the modified pellets lacking omeprazole had higher solid content than was called for by
Apotex’s ANDA. Based on those differences between Dr. Signorino’s pellets and
Apotex’s product, the district court gave greater weight to the testimony of Dr. Davies.
That decision was reasonable and did not result in a clearly erroneous finding of
infringement.
Apotex also asserts that Dr. Davies’s wash procedure undermines Astra’s claim
that the subcoating was formed by an MACP:PVP complex. Apotex argues that the
2007-1414 26
MACP:PVP complex may have formed when Dr. Davies washed Apotex’s pellets in
acetone:IPA. Apotex bases that argument on experiments performed by Dr. Cima,
which Apotex argues show that MACP and PVP can react in acetone:IPA. The district
court found that Dr. Cima’s experiments were flawed because Dr. Cima was able to
create a reaction in acetone:IPA only under extreme conditions, including heating the
mixture at 100 degrees centigrade for 25 minutes or drying the mixture in a vacuum for
11 hours. The court also observed that Dr. Cima’s ATR-FTIR data showed artifacts
resulting from atmospheric suppression, a correction algorithm that suppresses spectral
peaks from water vapor at the cost of introducing minor artifacts. Astra showed that
when Dr. Cima’s data was calculated with atmospheric suppression turned off, Dr.
Cima’s MACP:PVP spectral peaks disappeared.
Apotex further argues that the district court should have credited Dr. Cima’s
Raman microspectroscopy evidence, which according to Apotex showed that
omeprazole and its degradation products were present in the fluorescent band. The
court, however, had ample reason to attach little weight to Dr. Cima’s evidence. The
court noted that Dr. Cima had normalized his data, leading to absurd results. His
normalized data showed mannitol, an ingredient in the drug core, distributed equally
throughout the entire pellet, and it showed more omeprazole in the enteric coating than
in the drug core, while Dr. Cima’s non-normalized data showed mannitol and
omeprazole concentrated in the drug core.
Apotex also argues for reversal based on evidence from pellets produced by Dr.
Signorino according to the teachings of the ’495 European application. Dr. Signorino
produced pellets both with and without omeprazole. In those samples Dr. Cima
2007-1414 27
observed fluorescent bands in the pellets containing omeprazole while not observing
any bands in the pellets that did not contain omeprazole. Apotex argues that the district
court erred when it discounted that evidence based on Dr. Signorino’s failure to follow
the teachings of the ’495 European application. Even if the conditions used to make the
pellets were irrelevant to whether omeprazole caused the observed fluoresence, the
district court correctly noted that evidence regarding infringement must compare the
claims to the accused product. That omeprazole might cause fluorescence in the ’495
European application pellets does not refute Astra’s evidence that a different compound
caused fluorescence in Apotex’s pellets.
Finally, Apotex argues that Astra’s evidence failed to show the presence of a
continuous subcoating. Specifically, Apotex points to Dr. Davies’s CLSM reflectance
images of Apotex’s pellets that had been washed with acetone:IPA, and it argues that
neither of those images shows the subcoating completely surrounding the pellet core.
Dr. Davies, however, explained that what appears in a CLSM reflectance image
depends on the angle of the surface of the pellet to the light. At certain angles, the
pellet will reflect light away from the detector for a portion of the image. The district
court credited Dr. Davies’s explanation of the CLSM evidence, and doing so did not
render its ultimate finding clearly erroneous.
3
Apotex also appears to challenge the district court’s conclusion that the inert
subcoating in Apotex’s pellets is water soluble. Dr. Davies prepared a video of a
washed pellet disintegrating in an aqueous solution. Apotex argues that the video did
not actually show the subcoating disintegrating but rather showed the disintegration of
2007-1414 28
portions of the enteric coating that allegedly remained on the pellet after Dr. Davies
washed the pellets in acetone:IPA. In rejecting Apotex’s argument, the district court
relied on Dr. Davies’s CLSM reflectance and fluorescence images, which showed that
no portions of the enteric coating remained after the washing procedure. Because we
have found no error in the district court’s reliance on Dr. Davies’s CLSM images, we
affirm the court’s conclusion that Dr. Davies’s video demonstrated the water solubility of
the inert subcoating.
B
Apotex next argues that the claims of the ’230 patent were anticipated by U.S.
Patent No. 2,991,226 (“the ’226 patent”), U.S. Patent No. 4,470,980 (“the ’980 patent”),
and European Patent Application No. EP 122,815 A1 (“the ’815 European application”).
The district court found that those three references do not disclose an “acid labile
pharmaceutically active substance,” which the court construed to refer to compounds
that are unstable in acidic conditions and have better stability in alkaline conditions. The
court further found that the ’226 and ’980 patents do not disclose formulations that use
an “alkaline salt.” Apotex does not challenge the district court’s factual findings, but
rather argues that the district court’s constructions of “acid labile” and “alkaline salt” are
incorrect.
The district court construed “alkaline salt” to mean a salt with a basic pH. Citing
the testimony of its expert Dr. Block, Apotex argues that the phrase should be construed
to mean a salt having an element from Groups I or II of the periodic table (the alkali
metals and the alkaline earth metals, respectively). The district court, however, struck
the portion of Dr. Block’s testimony on which Apotex now relies because Dr. Block did
2007-1414 29
not provide in his expert reports or in his deposition testimony his opinion that “alkaline
salt” does not simply mean a salt with a basic pH. In any event, Apotex’s construction
draws no support from the specification of the ’230 patent, and it would contradict claim
8’s recitation of an ammonium salt as a possible alkaline salt. As ammonium salts do
not fall within Apotex’s construction, the claims of the ’230 patent themselves do not
support Apotex’s proposed construction. See Phillips v. AWH Corp., 415 F.3d 1303,
1314 (Fed. Cir. 2005) (en banc) (“Because claim terms are normally used consistently
throughout the patent, the usage of a term in one claim can often illuminate the meaning
of the same term in other claims.”). We therefore reject Apotex’s construction, and
because Apotex does not challenge the district court’s findings under the court’s
construction, we affirm the district court’s determination that the ’226 and ’980 patents
do not anticipate the claims of the ’230 patent.
With respect to the ’815 European application, Apotex argues that the district
court’s determination was based on an erroneous construction of the phrase “acid labile
pharmaceutically active substance.” Apotex argues that the phrase should be
construed to mean a pharmaceutical that is labile in acid media and that the district
court erroneously imported an additional limitation requiring acid labile substances to
have better stability in alkaline conditions. The district court’s conclusion, however, was
not based on that additional limitation. Rather, the district court found that the active
substance in the ’815 European application—M-4 carboxylic acid—is stable in acid.
That finding was supported by expert testimony that the goal of the ’815 European
application was to release M-4 carboxylic acid at low pH levels, implying that the
2007-1414 30
compound is not labile in acid. We therefore affirm the district court’s ruling that the
’815 European application does not anticipate the claims of the ’230 patent.
C
Apotex next argues that all the claims of both the ’230 and ’505 patents would
have been obvious in light of the combination of the teachings of the ’495 European
application with several other references. The other references Apotex cites are the
’226 patent, the ’980 patent, the ’815 European application, and two articles—
Pharmaceutical Manufacturing Methods, in 1 Basic Course in Drug Development XI
(Kyosuke Tsuda & Hsashi Nogami eds., 1971) (“Tsuda”), and Drug Coatings, in Up-to-
Date Pharmaceutical Technology Series No. 1 (Kiichiro Kakemi ed., 1969) (“Up-to-
Date”).
Example 12 of the ’495 European application describes a tablet containing
omeprazole magnesium salt with a cellulose acetate phthalate enteric coating. The
district court found that the ’495 European application does not disclose tablets with any
sort of subcoating or tablets containing an ARC. The court further observed that the
’495 European application does not disclose or suggest a negative interaction between
the drug core and the enteric coating. Apotex relies on a number of references that
disclose the use of subcoatings in various pharmaceutical preparations in support of its
argument that it would have been obvious to one of skill in the art to apply an inert
subcoating to Example 12 of the ’495 European application. None of the references on
which Apotex relies, however, undermine the trial court’s conclusion that the claims of
the ’230 and ’505 patents would not have been obvious to a person of skill in the art.
2007-1414 31
Apotex was required to show by clear and convincing evidence that a person of
skill in the art would have appreciated the need to include a subcoating in Example 12
of the ’495 European application. The district court, however, found that the ’495
European application does not disclose or suggest a negative interaction between the
drug core containing the magnesium omeprazole salt and the enteric coating in
Example 12. The court further found that a person of ordinary skill in the art would not
have inferred from the ’495 European application that a negative interaction would
occur. Based on those findings, the court concluded that a person of ordinary skill
would have had no reason to apply a subcoating to the tablets shown in Example 12 of
the ’495 European application.
To overcome that shortcoming of the ’495 European application, Apotex relies on
testimony from Dr. Block that “[a] person of ordinary skill would understand that
cellulose acetate phthalate has free carboxylic acid groups and could interact with the
omeprazole magnesium salt, the omeprazole being acid-labile.” The district court was
presented with ample evidence to support the contrary conclusion, however. Dr.
Langer, Astra’s expert, testified that the ’495 European application does not suggest
any problem relating to the interaction of the enteric coating and the drug core.
Furthermore, Dr. Langer and Apotex’s expert, Dr. Signorino, agreed that the disclosure
in the ’495 European application does not suggest any need to stabilize omeprazole
beyond using the salt form. Dr. Langer also testified that a 1985 article by Dr. Pilbrant,
one of the named inventors of the ’230 and ’505 patents, provided further support for
the view that a person of skill in the art would not have believed that an enteric coating
would create a problem resulting from contact with omeprazole. See Pilbrant, A. &
2007-1414 32
Cederburg, C., Development of An Oral Formulation of Omeprazole, 20 Scandinavian J.
Gastroenterology, suppl. 108, at 113 (1985). The Pilbrant & Cederburg article states
that “an enteric-coated dosage form, which does not release the active ingredient for
dissolution and absorption until it has been transported down to the neutral reacting part
of the small intestine, offers the best possibilities.” Based on that evidence, the district
court reasonably concluded that a person of ordinary skill in the art would not have seen
any need to apply to Example 12 of the ’495 European application the teachings of the
references disclosing subcoatings.
Even if a person of skill in the art would have recognized that there would be a
negative interaction between the enteric coating and the drug core, the district court
found that it would not have been obvious to try applying a water-soluble subcoating as
a means of solving that problem. The district court gave lengthy consideration to the
multiple paths that would have faced a person of ordinary skill in the art who recognized
the stability problem resulting from a directly applied enteric coating. First, one
recognizing the problem might have decided to abandon the enteric coating altogether.
The prior art shows formulations using a syrup with an alkaline omeprazole salt, a liquid
suspension of omeprazole with sodium bicarbonate, or omeprazole granules
administered with an antacid. See ’495 European application (Example 11); Pilbrant &
Cederburg, at 114, 118-20. Second, one might instead have modified the enteric
coating, for instance, by removing monomers and small acidic pieces from the coating,
or by using an inert coating. Third, one might have altered the drug core by adding an
antioxidant such as cysteine, sodium ascorbate, or sodium sulfite. Finally, even if one
had decided to use a subcoating, one would not necessarily have used a water-soluble
2007-1414 33
subcoating, since omeprazole is moisture-sensitive and needs to be delivered to the
alkaline environment of the small intestine without degrading in the stomach. One of
skill in the art would therefore have likely tried a non-soluble subcoating or a subcoating
containing a fatty acid.
Apotex further argues that the claims of the ’505 and ’230 patents would have
been obvious in light of a list of 15 other prior art references. Two of those references—
the Eastman Brochures—were found not to be printed publications. Apotex does not
identify any clear error in the district court’s conclusion with regard to those references.
Apotex was required to show that the Eastman Brochures were accessible to members
of the public interested in the prior art. See In re Hall, 781 F.2d 897, 899 (Fed. Cir.
1986). Apotex presented testimony from an employee of Eastman Chemical, the
company that produced the brochures. The employee could not, however, provide
information about the circulation and availability of the brochures in the 1960s or 1970s,
the period during which the brochures were produced.
Apotex also asserts that the district court erred by not addressing the testimony
of Dr. Block, who stated that he received one of the Eastman Brochures in 1964. The
evidence that Dr. Block received a single brochure from Eastman Chemical in 1964
does little, if anything, to make up for the lack of evidence regarding Eastman
Chemical’s distribution practices. With respect to the 13 other references, Apotex has
not indicated how those references demonstrate that the claims of the ’505 and ’230
patents would have been obvious.
Finally, Apotex argues that the district court’s analysis conflicts with the analysis
required by the Supreme Court’s decision in KSR International Co. v. Teleflex Inc., 127
2007-1414 34
S. Ct. 1727 (2007), because the district court insisted on absolute predictability instead
of a reasonable expectation of success and because the district court failed to
recognize that adding a subcoating would be “obvious to try,” a standard referred to in
KSR. Apotex, however, mischaracterizes the district court’s decision. The court found
that a person of skill in the art would not have seen a reason to insert a subcoating in
the prior art formulation shown in Example 12 of the ’495 European application. The
court’s finding was based on Apotex’s failure to demonstrate that a person of skill in the
art would conclude that a negative interaction would take place between the enteric
coating and the drug core.
In sum, based on the district court’s thorough analysis of the prior art and the
nature of the problem, we find no error in the court’s findings of fact and conclusions of
law on the question of obviousness.
D
Like Impax, Apotex also argues that the district court erred in resetting the
effective date of its ANDA to reflect Astra’s six-month period of market exclusivity. As
we discussed with respect to Impax’s appeal, the district court had jurisdiction to provide
relief under section 271(e)(4)(A) despite the expiration of Astra’s patents. And even if
the district court’s order were defective in some other way, Apotex’s challenge to the
merits of that order would be moot because Astra’s period of exclusivity has lapsed.
IV
The judgments of the district court declaring Astra’s patents enforceable, not
invalid, and infringed are affirmed. We also affirm the court’s ruling that it had
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jurisdiction to reset the effective date of Impax’s and Apotex’s ANDAs to reflect Astra’s
period of market exclusivity.
AFFIRMED.
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