## 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-appell ees. 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, G eorgia, argued for defendant-appellant Impax L aboratories, 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 ent ered 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 Astr azeneca AB, Aktiebolaget Hassle, KBI-E, Inc., KBI, Inc., and Astrazeneca LP (c ollectively, “Astra”) against a number of generic drug manufacturers for infringement ofAstra’s patents covering formulations of omeprazole, the active ingr edient in Prilosec, a drug designed to treat acid-related gastrointestinal disorders. The district court divided the defendant s into two separate “waves” for purposes of trial. For each wa ve, the district court held a consolidated bench trial. We decided appeals from the “f irst 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 Laborator ies, Inc., and judgment s 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 cour t’s judgments of infr ingement 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

2007-1414 2pharmaceutical preparations cont aining omeprazole, the active ingredient in Prilosec. Omeprazole is a potent inhibito r of gastric acid secretion, but it is susceptible to degradation in acid-reacting and neutra l media. Its stability is also affected by moisture and organic solvents. To prot ect omeprazole from gastric acid in the stomach, a pharmaceutical dosage can include an enteric coating that covers the drug core. Enteric coatings, however, contain acidiccompounds, 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 dos age over time. To increase the storage stability of a pharmaceutical dosage, al kaline reacting compounds (“ARCs”) may be added to the drug core. The addition of an A RC, however, can compromise the enteric coating. A conventional entericcoating allows for some diffusion of water from gastric juices into the drug core, but water enteri ng the drug core will disso lve the ARCs, which can in turn cause the enteric coating to dissolv e. ’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 disi ntegrates 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 t he 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

2007-1414 3(a) a core region comprising an effect ive amount of a material selected from the group consisting of omepr azole plus an alkaline reacting compound, an alkaline omeprazole sa lt plus an alkaline reacting compound and an alkaline omeprazole salt alone; (b) an inert subcoating which is solubl e 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 “acidlabile pharmaceutically active substance. ” Claim 1 of the ’230 patent recites: A pharmaceutical preparation comprising: (a) an alkaline reacting core compri sing an acid-labile pharmaceutically active substance and an alkaline reac ting 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 com pound different from said active substance; (b) an inert subcoating which rapidly di ssolves or disintegrates in water disposed on said core region, said subcoating comprising one or more layers comprising materials selected fr om 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 alkali ne reacting core from the enteric coating layer such that the stab ility 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 ofthe ’505 and ’230 pat ents under 35 U.S.C. § 271(e)(2)(A). Astra filed a second acti on against Impax after Impax amended its application to include a 40-mg product. In September 2004, t he FDA granted Impax

2007-1414 4final approval to market its 10- and 20-mg omeprazole products. Impax began marketing its approved products, which prom pted 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 unenfor ceability 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 counterclai ms 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 reso lution 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, Astr a 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 tria l with the other defendants. T he 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 Im pax with prejudice if the district court heard its claims against Impax in the consolidated benc h trial. Based on that stipulation, the cour t 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 hel d a 42-day bench trial. Fo llowing the trial and before the court issued its decision, the patents both expired. Impaxfiled 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 t hat motion, however, because the FDA had

2007-1414 5granted 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, enforc eable, and infringed by Impax. The court therefore set the effective dat e of Impax’s ANDA to October20, 2007, the end of Astra’s six-month period of market exclusivity. On appeal, Impax argues that t he 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 di strict 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 al ready dismissed its claims for damages, had no remaining claim for any possible relief to which it might be l egally entitled. The district court rejected that argument becaus e the FDA had granted Astra an additional six-month period of market exclusivity afte r Astra had agreed to t he FDA’s request that it perform pediatric testing of its product. T he court held that it had the authority to enforce Astra’s right to market exclusivity under the authority ofsection 271(e)(4)(A) and under its general equitabl e authority. We reject Impax’s argument as to the district court’s jurisdiction because we believe the di strict court correctly interpreted section 271(e)(4)(A) to provide a post-expiration remedy for infringement under section 271(e)(2).

2007-1414 6Section 271(e)(2)(A) makes it an act of in fringement to file “an application under section 505(j) of the Federal Food, Drug, and Cosmetic Ac t or described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of wh ich is claimed in a patent.” An application fil ed 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 contai n one of four certific ations 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 pr ovides 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 approv ing the ANDA for 30 months. 21 U.S.C. § 355(j)(5)(B)(iii). The FDA may approve the A NDA 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 in fringement of a valid patent resulting from the filing of an ANDA, section 271(e)(4) provides th ree remedies. Subparagraphs (B) and (C) provide the typical remedies for infr ingement: 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 t he district court to “order the effective date of any approval of t he drug or veterinary biological product involved in the

2007-1414 7infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed.” If t he FDA has not approved the ANDA before the district court determines that the patent has been infringed, t he FDA may not approve the ANDA until the effective date s pecified by the district cour t 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 effectiv e 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 pat ent 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 ex clusivity”) 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, authoriz es 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 pedi atric studies. If the NDA holder agrees to the request and performs t he pediatric studies, the period during which the FDA is barred from approving an ANDA filed by co mpeting drug manufactu rers is extended by six months. See 21 U.S.C. § 355a(b)-(c). Sect ion 355a specifically addresses situations in which a Paragraph IVcertification is submitted. In those cases, the period

2007-1414 8during which an ANDA may not be approv ed 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 (i ncluding 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 c hange 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 admi tting of specific relief through a decree of a conclusive character, as distinguished from an opi nion 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 expi red. 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 sugges t 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 9cases, 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 s upport for Impax’s position. The Pfizercourt relied on our decision in Kearns v. Chrysler Corp. , 32 F.3d 1541, 1549-51 (F ed. Cir. 1994), in which we held that a district court did not abuse its discretion in deny ing 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 avail ability of relief under section 271(e)(4)(A). The Pfizercourt’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 order ing the effective date of the defendant’s ANDA to be set to the date on which the six-month exclus ivity 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 infri nged.” 526 F. Supp. 2d at 1000. Here, Impax has not challenged the particular terms of the district c ourt’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 c hallenges 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 eit her the district court’s finding that Impax’s formulation contains an “effective amount” of omepraz ole and an ARC, or it s finding that the formulation has an inert subcoating. We reject both arguments.

1 This court continues to have juri sdiction 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 101 Limitation (a) of claim 1 of the ’505 patent requires: a core region comprising an effective am ount 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 dist rict court construed “effective amount” to apply to both the amount of omepraz ole and the amount of an ARC pr esent in the core. The court construed “alkaline reacting compound” as (1) a pharmaceutically acceptable alka line, 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 satisfie s 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 hav e been required to show that Impax’s formulation is stable without the use of a dessi cant. That argument is without merit. As the district court observed, the claims at issue do not r equire 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 st ability during storage that the water content of the final dosage form cont aining omeprazole (enteric coated tablets, capsules or pellets) is kept low, preferably not mo re 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 11where 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 t he 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 om eprazole. Based on its cons truction 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 creat ed 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 firs t wave litigation, the district court described the evidentiary requirement for the stabilization prong of it s construction of “alkaline reacting compound” bystating that “[a]s the s pecification 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 dist rict court that the specification supports that interpretation of “alkaline reacting compound.” Indeed, the description of the drug core states: Omeprazole is mixed with inert, pref erably water soluble, conventional pharmaceutical constituents to obtai n the preferred concentration of omeprazole in the final mixture and with an alkaline reacting, otherwise inert, pharmaceutically acceptable s ubstance (or substances), which creates a “micro-pH” around each omepraz ole particle of not less than pH=7, preferably not less than pH=8 , when water is adsorbed to the particles of the mixtur e 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 sa id subcoating layer, wherein the subcoating layer isolates the alkali ne reacting core from the enteric coating layer such that the stab ility of the preparation is enhanced. The district court, however, correctly c oncluded that enhanced stab ility 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 creat e 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 a ssertion, the requirement of “enhanced stability” was not “read out of the claims entirely.” Rather, for pr oof of the “enhanced stability” limitation, the distri ct court required Astra to demonstrate the presence of an inert subcoating and a drug core hav ing a micro-pH of not less than 7. That proof requirement is supported by t he specifications of the ’230 and ’505 patents, which teach that the result of using an inert s ubcoating 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 am ount of an alkali or alkaline earth metal carbonate to inhibit cycliz ation and discoloration.” The district court granted Warner-Lambert’s motion for summary judgment of infringement. We reversed

2007-1414 13after determining that Teva had pointed to a genuine issue of material fact “as to whether the magnesium carbonate in Teva's formu lation inhibits oxi dative discoloration.” Id. at 1342. By contrast, the di strict 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 formulati on met the “inert subcoating” limitation of both patents. Astra present ed evidence that in Impax’s product an inert subcoating forms in situ between the enteric coating and the dr ug core region. Astra’s evidence showed the presence, in Impax ’s product, of a hydroxypropyl methylcellulose phthalate (“HPMCP”) salt in the regi on 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 sa lt 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 eac h 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 pres ence 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 resu lts from a reaction between HPMCP in the enteric coati ng and dibasic sodium hydrogen ph osphate in the drug core. Second, Impax’s argument cha llenging the tests that were used to show the presence

2007-1414 14of the inert subcoating is misleading. Impax relies on the testimony of Dr. Davies that sodium atoms cannot be detected by att enuated total reflectance Fourier transform infrared spectroscopy (“ATR-FTIR”). Dr. Da vies, however, testifi ed that his ATR-FTIR data revealed the presence of a carboxylat e group, which indica ted the presence of HPMCP in the subcoating. Finally, with re spect 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 t herefore find that the record su pports 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 publicuse 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 theref ore April 20, 1986. Before that date, Astra commissioned f our 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 t herefore not public uses, of the cl aimed invention. Second, the court ruled that the patented formulation wa s not ready for patent ing until after the studies were completed. Impax challenges each of those findings.
1

2007-1414 15We agree with Impax that the district c ourt 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 w hen 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., concu rring). We therefore do not agree with the district court’s ruling that the exper imental use exception served to negate the public-use bar to patentability.
2 We may nevertheless affirm the district c ourt’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 patenti ng 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 16public use bar.”). The distri ct court found that the claim ed formulation was not reduced to practice before the clinical trials we re 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 afte r Astra’s predecessor had begun a research project to develop a drug capable of inhibiting gas tric acid secretion. 222 F. Supp. 2d at 434. Once the compound was dev eloped, 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 invent ors of the ’505 and ’230 patents. In the first hum an trials (the Phase I trials), Astra employed a buffered suspension to stabilize omeprazole in the ac idic environment of t he stomach. 222 F. Supp. 2d at 435. To create a dosage suitable for commercialization, Drs. Pilbrant and Lövgren added an enteric coating to an omepraz ole 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 in ventors decided to pr oceed with an entericcoated formulation. After testing various formulations with an enteric coating, t he inventors finally came up with a formulation that appeared sufficient ly promising to warrant testing in the Phase II clinical trials. That formulati on used an enteric coati ng 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 insuffici ent long-term shelf life. Drs. Pilbrant and

2007-1414 17Lövgren, along with other Astra scientists, t hen 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 e ffective 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 watersoluble subcoat, although they expected that the subcoat might prove ineffective because it would dissolve in t he water that leaked through the enteric coating. If that were the case, the omeprazole in the drug co re would degrade because of its sensitivity to water. Their laboratory experiments revealed, however , that the water-soluble subcoating increased gastric acid resistanc e and long-term stability. Based on those tests, the group decided to use t he formulation in the Phase III clinical trials. The results of those trials revealed gastric acid resist ance well in excess of Astra’s goal, together with three years of shelf stability. In Pfaff , the Supreme Court described two wa ys for a party to show that an invention was ready for patenti ng before the critical date of section 102(b): “by proof of reduction to practice before the cr itical 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 wa s ready for patenting,

2007-1414 18Impax has sought to show that the Phas e III formulation had been reduced to practice before Astra conducted the Phase III clinical trials. At trial, Impax bore t he burden of demonstrating byclear 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 woul d work for its intended purpose.” Id. (quoting Cooper v. Goldfarb , 154 F.3d 1321, 1327 (Fed. Cir. 1998)). “T esting is required to demonstrate reduction to practice in some instances because without such test ing there cannot be sufficient certainty that the invent ion 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 ev idence 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 formu lation still required extensive clinical testing and real-time stability testing to determine wh ether 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 commi tted 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 19whether the Board of Patent Appeals and Inte rferences erred in concluding that the junior party, Dentlinger, had reduced to prac tice 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 dat ed 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 s ubstantial 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 becaus e 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 e rror in finding, as a factual matter, that Drs. Pilbrant and Lövgren did not determine t hat the Phase III formulation would have sufficient in vivo and long-term stability before the Phase III tria ls. 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 thatthe Phase III formulation had been produced before the trials. The existence of the formulation, however, does not est ablish that the Astra scientists had determined that the invention would work for its intended purpose. Impax further asserts that the stab ility of the Phase III formulation had been confirmed in May 1983, before the Phase III tr ials were conducted. To support that assertion, Impax relies on the testimony of Dr . Pilbrant. Dr. Pilb rant confirmed that

2007-1414 20laboratory testing of the Phase III formulati on, conducted before the clinical trials, revealed that the Phase III formulation posse ssed significantly increased gastric acid resistance over the predecessor formulations. Dr. Pilbrant, however, further testified that as of May 1983 the As tra scientists did not have enough information to satisfy themselves that the Phase III formulation w ould work for its intended purpose. Instead, he testified that the Astra scientists t hought 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 porti on of Dr. Pilbrant’s test imony in which he stated that, before the trials, he knew“for sure that the stabilit y of the phase III formulation or the invention was better than the phase II formu lation.” That assertion also does not undermine the district court’s determination regar ding reduction to practice. The district court found that the Phase III fo rmulation 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 formu lation would be stable enough to provide an effective treatment. Impax points to the testimony of Dr. Carl sson 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 asse ss 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 re lied on that testimony in finding that the inventors had not determined t hat the Phase III formulation would have sufficient long2007-1414 21term and in vivo stability to produce a formulation e ffective 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 c ourt misapprehended the in tended purpose of the Phase III trials when it stat ed that the Astra scientists we re “still in the process of determining [during those tr ials] whether the Phase III formulation could safely and effectively be used as a ‘met hod of treatment of gastroint estinal 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 effe ctive 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 omepraz ole’s sensitivity to acidic environments, such as the stomach. Impax has not dem onstrated that, without conducting the Phase III clinical tests, the in ventors 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 di sease. 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 distri ct court’s order violated its Seventh Amendment right to a tr ial by jury because its antitrust counterclaims presented

2007-1414 22factual issues that were common to its in validity counterclaims. We rejected that argument when reviewing Impax’s petition fo r 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 circum stances that would justify our revisiting that decision. We therefore adhere to our prior ru ling 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 c ourt in any circumstance, although as a rule courts should be loath to do so in the absenc e 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 ri ght of trial by jury. . . . Consequently, denial of the petition for mandamus in th is matter is the law of the case.”). III We now turn to Apotex’s appeal. Like Impax, Apotex f iled an ANDA for 10-, 20-, and 40-mg generic omeprazole pr oducts 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 dist rict court during the same bench trial in which Astra’s claims against Impax were hear d. Based on testimonyfrom Dr. Davies, the district court ruled that Apotex’s formulation infringed both patents. The district court also rejected Apotex’s anticipation and obv iousness defenses. The court therefore ordered the effective dat e 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 23rulings on anticipation and obvious ness, 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 wa ter, methacrylic acid copolymer (“MACP”), and triethyl citrate. Even though Apotexdoes not apply a subcoating during the manufacturing process, Dr. Davies testifi ed that Apotex’s pellets infringe because a subcoating forms in situ from a reaction between the MA CP in the enteric coating and the PVP in the pellet core. Dr. Davies dem onstrated 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 reflec tance 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 enter ic coating. His CLSM fluorescence and reflectance images of the washed pellets lik ewise showed a fluorescent layer at the surface of the drug core. To determine t he 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 t he 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 24PVP spectrum shows a shift from 1670 cm -1 to 1630 cm -1 as a result of the formation of a complex between the carbony l 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, t he district court conc luded 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 regi on” within the meaning of the ’505 and ’230 patents because Apotex does not directly apply a subcoating during its manufacturing process. We rejected that ar gument in the appeal from the district court’s first wave trial based on our conclusion that the phrase “‘[d]i sposed on’ does not specify any method or structure involved in applicat ion 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. In terface 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 25Apotex next argues that the district court erred in concluding t hat the fluorescent band was formed by an MACP:PVP comple x and not by omeprazole and its degradation products. In maki ng that argument, Apotex re lies on evidence from its experts, Dr. Signorino and Dr. Cima. Dr. Signorino created “ANDA Reproduction Pellets” by following Apotex’s ANDA specif ication, 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 fluor escent band in the ANDA Reproduction Pellets, but no band in the modified pe llets that lacked omeprazole. The district court found that Dr. Si gnorino’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 sample s produced was smaller than the FDA would require for a pilot scale batch, the enteric coat ing 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 pelle ts for half as long as Apotex’s products, and he added more water than Apotex’s ANDA spec ified. The court further noted that the modified pellets lacking om eprazole had higher solid content than was called for by Apotex’s ANDA. Based on those differ ences between Dr. Signorino’s pellets and Apotex’s product, the district c ourt gave greater weight to t he testimony of Dr. Davies. That decision was reasonable and did not resu lt in a clearly erroneous finding of infringement. Apotex also asserts that Dr. Davies’s wash procedure undermines Astra’s claim that the subcoating was form ed by an MACP:PVP complex. Apotex argues that the

2007-1414 26MACP:PVP complex may have formed when Dr. Davies washed Apotex’s pellets in acetone:IPA. Apotex bases that argum ent 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 centigr ade for 25 minutes or drying the mixture in a vacuum for 11 hours. The court also observed that Dr. Cima’s AT R-FTIR data showed artifacts resulting from atmospheric suppression, a co rrection algorithm that suppresses spectral peaks from water vapor at the cost of introduc ing minor artifacts. Astra showed that when Dr. Cima’s data was ca lculated with atmospheric suppression turned off, Dr. Cima’s MACP:PVP spectral peaks disappeared. Apotex further argues that the district court shoul d have credited Dr. Cima’s Raman microspectroscopy evidence, whic h according to Apotex showed that omeprazole and its degradation pr oducts were present in the fluorescent band. The court, however, had ample reason to attach li ttle weight to Dr. Cima’s evidence. The court noted that Dr. Cima had normalized his data, leading to absur d 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 applicat ion. Dr. Signorino produced pellets both with and without omeprazole. In those samples Dr. Cima

2007-1414 27observed fluorescent bands in the pellets containing omeprazole while not observing any bands in the pellets that did not contain om eprazole. 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 Eur opean application. Even if the conditions used to make the pellets were irrelevant to whether omepr azole caused the observed fluoresence, the district court correctly not ed that evidence regarding infr ingement must compare the claims to the accused product. That omepr azole might cause fluorescence in the ’495 European application pellets does not refute As tra’s evidence that a different compound caused fluorescence in Apotex’s pellets. Finally, Apotex argues that Astra’s evi dence failed to show the presence of a continuous subcoating. Specif ically, Apotex points to Dr. Davies’s CLSM reflectance images of Apotex’s pellets that had been wa shed with acetone:IPA, and it argues that neither of those images show s the subcoating completely surrounding the pellet core. Dr. Davies, however, explained that w hat appears in a CLSM reflectance image depends on the angle of the surface of the pelle t 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 distri ct court’s conclusion that the inert subcoating in Apotex’s pellets is water sol uble. Dr. Davies prepared a video of a washed pellet disintegrating in an aqueous solution. Apotex argues that the video did not actually show the subcoat ing disintegrating but rather showed the disintegration of

2007-1414 28portions of the enteric coat ing that allegedly remained on the pellet after Dr. Davies washed the pellets in acetone:IPA. In reje cting Apotex’s argumen t, 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 thatthe 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, respective ly). The district court, however, struck the portion of Dr. Block’s testimony on whic h Apotex now relies because Dr. Block did

2007-1414 29not provide in his expert reports or in his deposition testimony his op inion that “alkaline salt” does not simply mean a salt with a basicpH. In any event, Apotex’s construction draws no support from the specification of t he ’230 patent, and it woul d contradict claim 8’s recitation of an ammonium salt as a possi ble alkaline salt. As ammonium salts do not fall within Apotex’s construction, the cl aims 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 Apot ex’s construction, and because Apotex does not challenge the distri ct 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 applicati on, 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 lab ile in acid media and that the district court erroneously imported an addi tional limitation requiring acid labile substances to have better stability in alkaline conditions. T he district court’s conclusion, however, was not based on that additional limitat ion. 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 testim ony that the goal of the ’815 European application was to release M-4 carboxylic ac id at low pH levels , implying that the

2007-1414 30compound is not labile in acid. We therefor e affirm the district c ourt’s ruling that the ’815 European application does not antici pate 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 combinat ion of the teachings of the ’495 European application with several other re ferences. The other references Apotex cites are the ’226 patent, the ’980 patent, the ’815 Eu ropean 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-toDate Pharmaceutical Technology Series No . 1 (Kiichiro Kakemi ed., 1969) (“Up-toDate”). Example 12 of the ’495 European applicat ion describes a tablet containing omeprazole magnesium salt with a cellulose acetate phthalat e enteric coating. The district court found that t he ’495 European application does not disclose tablets with any sort of subcoating or tablet s containing an ARC. The court further observed that the ’495 European application does not disclose orsuggest a negative interaction between the drug core and the enteric c oating. Apotex relies on a number of references that disclose the use of subcoatings in various pharmaceutical preparations in support of its argument that it woul d 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 obv ious to a person of skill in the art.

2007-1414 31Apotex 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 dist rict court, however, found that the ’495 European application does not di sclose or suggest a negative interaction between the drug core containing the magnesium omepraz ole 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 per son 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 t hat “[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, testifi ed 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 t hat 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 sk ill 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 32Cederburg, 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 fo rm, 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 woul d have recognized that there would be a negative interaction between the enteric coat ing 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 probl em. 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 resulti ng 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 syr up with an alkaline omeprazole salt, a liquid suspension of omeprazole wit h sodium bicarbonate, oromeprazole 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, s odium 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 33subcoating, since omeprazole is moisture -sensitive and needs to be delivered to the alkaline environment of the sm all intestine without degrading in the stomach. One of skill in the art would therefore have likely tr ied a non-soluble subcoat ing 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 prio r art references. Two of those references— the Eastman Brochures—were found not to be printed public ations. 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 East man 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 test imony from an employee of Eastman Chemical, the company that produced the br ochures. The employee could not, however, provide information about the circulation and availabilit y of the brochures in the 1960s or 1970s, the period during which the br ochures were produced. Apotex also asserts that t he district court erred by not addressing the testimony of Dr. Block, who stated t hat he received one of the Eastman Brochures in 1964. The evidence that Dr. Block received a single brochure from Eastm an Chemical in 1964 does little, if anything, to make up fo r the lack of evidence regarding Eastman Chemical’s distribution practice s. 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 Suprem e Court’s decision in KSR International Co. v. Teleflex Inc. , 127

2007-1414 34S. 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 dist rict 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 Exampl e 12 of the ’495 Eur opean application. The court’s finding was based on Apotex’s failure to demonstrate that a per son of skill in the art would conclude that a negative interact ion 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 ar gues that the district court erred in resetting the effective date of its ANDA to reflect Astra’s six-month period of mark et 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 ex piration 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 dec laring Astra’s patents enforceable, not invalid, and infringed are affirmed. We al so affirm the court’s ruling that it had

2007-1414 352007-1414 36 jurisdiction to reset the effective date of Im pax’s and Apotex’s ANDAs to reflect Astra’s period of market exclusivity. AFFIRMED

.