In Re Omeprazole Patent Litigation

United States Court of Appeals for the Federal Circuit
IN RE OMEPRAZOLE PATENT LITIGATION

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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

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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

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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

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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).

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 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

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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

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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

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 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.

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’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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