Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW KENT A. JORDAN, Circuit Judge. TABLE OF CONTENTS I. INTRODUCTION.........................................................332 II. FINDINGS OF FACT .....................................................332 A. The Parties...........................................................332 B. Procedural Background................................................333 C. Pharmaceutical Background ............................................334 i. Tramadol....................... 334 ii. Controlled Release Formulations....................................336 iii. Plaintiffs ’ Development of the Claimed Inventions.....................338 iv. The Asserted Claims...............................................340 D. Therapeutic Effect of Par’s Tablets......................................342 i. Bioequivalence of Ultram ER and Par’s Tablets.......................342 ii. Ultram IR .......................................................342 iii. Bioequivalence of Ultram IR and Ultram ER.........................344 iv. Therapeutic Effect of Ultram ER....................................346 E. Prosecution History of the Patents-in-Suit — Chapter I.....................347 i. Background References............................................348 ii. The Merck/Bondi Reference ........................................348 iii. Issuance of the Patents-in-Suit .....................................349 F. References Not Before the PTO.........................................350 i. U.S. Patent No. 5,580,578 (“Oshlack”)................................350 ii. U.S. Patent No. 5,^,78,577 (“Kaiko”) .................................351 G. Commercial Success of Ultram ER ......................................351 H. Par’s Copying of Ultram ER............................................352 I. Prosecution History of the Patents-in-Suit — Chapter II.....................354 i. The Malkowska I Declaration ......................................354 ii. World Congress of Pain............................................356 iii. EP '866 Opposition Proceedings and the Malkowska II Declaration.....356 iv. Napp Repeat Experiments .........................................358 III. CONCLUSIONS OF LAW..................................................361 A. Infringement..........................................................362 i. '887 Patent.......................................................363 ii. 'ISO Patent.......................................................366 B. Validity..............................................................367 C. Inequitable Conduct...................................................374 i. Materiality.......................................................375 ii. Intent to Deceive................................. 378 iii. Balancing Materiality and Intent.................. 380 IV. SUMMARY OF CONCLUSIONS..... 380 1. INTRODUCTION This is a patent infringement case. Purdue Pharma Products L.P. (“Purdue”) and Napp Pharmaceutical Group Ltd. (“Napp”) (collectively “Plaintiffs”) have sued Par Pharmaceutical, Inc. and Par Pharmaceutical Companies, Inc. (collectively “Par”), in connection with Par’s Abbreviated New Drug Application (“ANDA”) and its manufacture, use, and intent to sell generic versions of Ultram ® ER (“Ultram ER”). Ultram ER is an extended-release tramadol hydrochloride pain relief medication. (Uncontroverted Facts, D.I. 326 at ¶ III.C.(27), (29).) Plaintiffs allege infringement of U.S. Patent No. 6,254,887 (the “'887 patent”), entitled “Controlled Release Tramadol,” and seek a declaratory judgment of infringement of U.S. Patent No. 7,074,430 (the “'430 patent”), entitled “Controlled Release Tramadol Tramadol [sic] Formulation.” Par denies infringement and responds in defenses and counterclaims that the asserted claims of the patents-in-suit are invalid and are unenforceable due to inequitable conduct. A five-day bench trial was held in this action from April 16 to April 22, 2009. The following, issued pursuant to Federal Rule of Civil Procedure 52(a), are my findings of fact and conclusions of law on the issues of infringement, validity, and enforceability of the patents-in-suit. For the reasons that follow, I conclude that Par has infringed the asserted claims of the patents-in-suit but that those claims are obvious and therefore invalid. I also conclude that Par has not carried its burden of showing by clear and convincing evidence that the patents-in-suit are unenforceable due to inequitable conduct. II. FINDINGS OF FACT A. The Parties 1. Purdue is a limited partnership organized and existing under the laws of the State of Delaware, having a place of business at One Stamford Forum, 201 Tresser Boulevard, Stamford, Connecticut 06901-3431. (Uncontroverted Facts, D.I. 326 at ¶ III.A.(1).) Napp is a limited company organized and existing under the laws of England, having a place of business at Cambridge Science Park, Milton Road, Cambridge, CB4 OGW, United Kingdom. (Id. at ¶ III.A.(2).) 2. Purdue and Napp were assigned the patents-in-suit on May 4, 2007 by EuroCeltique S.A. (Id. at ¶¶ III.E.(48), F.(60).) 3. Par Pharmaceutical, Inc. is a corporation organized and existing under the laws of the State of Delaware, having a place of business at One Ram Ridge Road, Spring Valley, New York 10977. (Id. at ¶ III.A.(5).) Par Pharmaceutical Companies, Inc. is a corporation organized and existing under the laws of the State of Delaware, having a place of business at 300 Tice Boulevard, Woodcliff Lake, New Jersey 07677. Par Pharmaceutical, Inc. is a wholly owned subsidiary of Par Pharmaceutical Companies, Inc. (Id. at ¶ III.A.(6).) B. Procedural Background 4. Biovail Laboratories International, SRL (“Biovail”) submitted New Drug Application (“NDA”) 21-692 to the Food and Drug Administration (“FDA”) on December 31, 2003. (Uncontroverted Facts, D.I. 326 at ¶ III.C.(29)-(30).) Biovail’s NDA was for a controlled release tramadol formulation for once-daily dosing, under the proposed trade name “Ralivia ER.” The FDA approved the application on September 8, 2005; the trade name for the drug was later changed to Ultram ER. (Id. at UIII.C.(29), (30), (32); Trial Transcript [“Tr.”] 699:10-700:10; Plaintiffs’ Trial Exhibit [“PTX”]-879.) 5. Ultram ER is indicated for “the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.” (PTX-650 at 2.) The label also provides that Ultram ER should be taken “once daily.” (Id. at 4.) 6. In compliance with 21 U.S.C. § 355(b)(1), Biovail certified to the FDA as a part of its NDA that the '887 patent claims cover Ultram ER. (Uncontroverted Facts, D.I. 326 at ¶ III.E.(49).) Accordingly, the FDA lists Ultram ER as being associated with the '887 patent in a publication entitled “Approved Drug Products with Therapeutic Equivalence Evaluation,” which is generally called the “Orange Book.” (Id.) 7. Ortho-McNeil, Inc. (now Ortho-McN eil-Janssen-Pharmaeeuticals, Inc.) (“Ortho”) sells Ultram ER in the United States pursuant to an agreement with Biovail. (Nature of the Case, D.I. 326 at ¶ 1.2; Incontroverted Facts, id. at ¶ III.C.(33).) The parties have assumed that Ortho is a licensee of the patents-in-suit. (Nature of the Case, id. at ¶ 1.2.) 8. Par has submitted ANDA No. 78-783 to the FDA, pursuant to 21 U.S.C. § 355®, seeking approval to market generic extended-release tramadol hydrochloride tablets (“Tramadol ER tablets” or “Par’s tablets”). Specifically, Par’s ANDA seeks FDA approval for the commercial manufacture, use, or sale of Tramadol ER tablets in 100, 200, and 300 mg dosage strengths. (Uncontroverted Facts, D.I. 326 at ¶ III.B.(7).) Par’s ANDA contains a “Paragraph IV Certification,” see 21 U.S.C. § 355(j)(2)(A)(vü)(IV), which alleges that the claims of the '887 patent are invalid and/or will not be infringed by Par’s tablets. (Uncontroverted Facts, D.I. 326 at ¶ III.E.(52)). 9. Par notified Plaintiffs of its ANDA filing, and Plaintiffs responded by filing this action, alleging infringement of the '887 patent under 35 U.S.C. § 271(e)(2). (Id. at ¶¶ III.B.(8), E.(50).) Plaintiffs also seek a declaratory judgment that the manufacture, use, and substantial preparations for the offering for sale of Par’s tablets will constitute infringement, contributory infringement, and active inducement of infringement of the '430 patent. (D.I. 78 at 7.) Par’s Second Amended Answer and Counterclaims allege that the claims of the patents-in-suit are invalid, unenforceable, and not infringed. (Uncontroverted Facts, D.I. 326 at ¶ III.E.(53), F.(62).) C. Pharmaceutical Background 10. At claim construction, I determined that a person of ordinary skill in the art at the time of the invention was one with experience as a formulator (one who makes a drug), a pharmaeokineticist (one who researches and characterizes the drug), and a clinician (one with experience in treating pain). Purdue Pharma Prods. L.P. v. Par Pharm., Inc., 584 F.Supp.2d 664, 670 n. 12 (D.Del.2008) (“Claim Construction Opinion”). The parties do not dispute that determination, and I find that it continues to be the appropriate standard. i. Tramadol 11. The patents-in-suit relate to oral controlled release tramadol formulations. (’887 patent, L22-25.) Tramadol is categorized as a weak opioid analgesic used to relieve moderate to moderately severe pain. (Grond, Tr. 981:1-14, 1025:13-17.) It is comparable in potency to codeine. (Id. at 1025:13-17.) An opioid is a drug that has been synthesized from material in the opium poppy and which binds to opioid receptors in the body in order to provide an analgesic response. (Smith, Tr. 15:3-6.) 12. Tramadol has been used to treat moderate to severe pain for many years. ('887 patent, 1:12-23.) It was first synthesized in the early 1960s and was made available for pain treatment in Germany beginning in the late 1970s in immediate release forms. (Grond, Tr. 1023:16-1025:6; Smith, Tr. 12:11-22.) Although tramadol was patented in the United States in 1972 by Grünenthal GmbH (“Grünenthal”), it was not widely available for patient use outside of Germany until the mid-1990s. (Defendants’ Trial Exhibit [“DTX”]-458; Kaiko, Tr. 209:2-4; Smith, Tr. 12:18-13:4.) Tramadol was not added to the World Health Organization (‘WHO”) guidelines for cancer pain management until 1996. (Grond, Tr. 1051:14-16; Smith, Tr. 13:5-16:7; PTX-557 at 18-19, 50-51.) 13.Tramadol has the chemical name (+)-trans-2-[ (dimethylamino)methyl]-l(3-methoxyphenyl) cyclohexanol ('887 patent, 1:10-12), which explains the need for a good nickname like “tramadol.” The drug is a racemic compound, in other words a 50%-50% mixture of two compounds that have identical chemical formulas but are mirror images of each other. (Weinberger, Tr. 858:1-6; Grond, Tr. 983:8-22, 987:22-988:15.) Each of the two compounds is called an enantiomer and is given the designation of either ( + ) or (-); each compound has a different mechanism of action similar to that of antidepressents. (Weinberger, Tr. 858:1-5, 859:21-23; Grond, Tr. 983:8-984:14, 987:22-988:15.) The compound ( + )-tramadol acts mainly in the spinal cord as a seratonin reuptake inhibitor. (Weinberger, Tr. 859:21-860:8; Grond, Tr. 986:4-10.) The compound (-)- tramadol also works in the spinal column but as a norepinephrine reuptake inhibitor. (Weinberger, Tr. 859:22-23; Grond, Tr. 986:11-12.) Both seratonin and norepinephrine are neurotransmitters, and blocking their reuptake inhibits the transmission of pain sensations. (Weinberger, Tr. 859:21-860:8.) Both (-f)-tramadol and (-)- tramadol are metabolized by the liver into metabolites, at least one of which, the Mx metabolite, is important to the effect of the drug. (Weinberger, Tr. 858:10-859:20.) The Mi metabolite has activity at the |x opioid receptor, similar to morphine. (Id.) 14. All three mechanisms — ( + )-tramadol, (-)-tramadol, and the Mx metabolite— add together to produce analgesia. (Id. at Tr. 859:15-860:8.) All of them work in the central nervous system and must therefore cross the blood-brain barrier, a physiological barrier that prevents certain materials in the blood from entering the brain and the spinal cord. (Grond, Tr. 984:19-987:11.) 15. In part because of the complexity of the drug, there is no established blood plasma level above which tramadol can be expected to provide analgesia in the average patient. (Smith, Tr. 19:10-21:9; Grond, Tr. 985:8-987:21.) In other words, a minimum effective concentration (“MEC”) for tramadol has not been thoroughly established. (Smith, Tr. 19:10— 21:9; Grond, Tr. 987:3-993:3; 1036:3-1037:4.) For that reason, it is, and was at the time of the filing of the application for the parent to the patents-in-suit, more difficult to estimate the analgesic effect of tramadol than other opioids, such as fentanyl, morphine, hydromorphone, and oxycodone. (Grond, Tr. 1028:18-1029:10.) Nonetheless, a relationship is known to exist between the concentration of tramadol in a patient’s blood and the pain relief experienced by that patient. (Weinberger, Tr. 885:20-887:8, 922:19-923:11; Katz, Tr. 621:9-622:8.) The patents-in-suit describe tramadol formulations that preferably maintain a drug concentration in the blood “within the therapeutic range” for 12 hours or more. ('887 patent, 1:38-40.) ii. Controlled Release Formulations 16. Conventional release, or immediate release, preparations of tramadol are typically administered four to six times per day. ('887 patent, 1:12-18; Grond, Tr. at 1048:12-20; PTX-844 at 3.) Controlled release preparations, in contrast, achieve a slow release of a drug over an extended period of time. (’887 patent, 1:34-36.) The patents-in-suit are directed to controlled release preparations of tramadol that are to be taken one or two times daily. (Id. at 1:23-25.) 17. Controlled release delivery systems are known to offer advantages over conventional dosage forms, including increased patient compliance with prescriptions, decreased total drug delivery, and decreased side effects. (DTX-107 at 5; Palmieri, Tr. 1267:25-1268:20.) Those advantages were well known as early as 1980, when one of the inventors of the patents-in-suit, Stewart Leslie, published an article entitled “Continus Controlled Release Preparations” (the “Leslie article”), which describes the benefits of controlled release dosage forms. (DTX-107.) More particularly, the Leslie article detailed the advantages of a specific system or template for formulating controlled release drugs. The system, known as the Continus ® (“Continus”) controlled release system, was used by Napp researchers beginning in the 1980s. (DTX-107 at 1, 7.) Plaintiffs acknowledge that Leslie obtained a U.S. patent on the Continus system, No. 3,965,256, which issued on June 22, 1976. (D.I. 334 at ¶ 122; DTX-302.) The patents-in-suit employ the Continus controlled release system. (Miller, Tr. 1233:24-1234:2,1241:15-18.) 18.Controlled release oral dosage forms are made with excipients (i.e., inert ingredients) that have certain chemical characteristics. (Palmieri, Tr. 1289:13-22, 1287:11-1288:14, 1291:14-1291:25, 1298:12-16; DTX-839.) Pharmaceutical formulators have been manipulating mixtures, structures, and coatings to make controlled release dose forms since 1955. (Palmieri, Tr. 1286:14-20.) Commercial controlled release products began to appear on the market in the United States in 1960. (Id. at 1286:21-1287:10.) Basic textbooks such as Introduction to Pharmaceutical Dosage Forms (1981) describe “delayed action dosage forms,” (DTX-476 at 390; Palmieri, Tr. 1290:13-1291:7), and textbooks such as the Handbook of Pharmaceutical Excipients (1986) describe excipients appropriate for controlled release formulations. (DTX-839; Palmieri, Tr. 1288:6-1289:25.) Examples of oral controlled release delivery systems include permeable coatings (Palmieri, Tr. 1264:5-13), controlled release matrices surrounded by cosmetic coatings (id. at 1265:2-15), and osmotic pumps that use semi-permeable coatings (id. at 1265:25-1266:11). 19. The Leslie article explains that controlled release delivery systems generally rely on at least one of four general principles: osmotic pressure, ion exchange, dissolution, and diffusion. (DTX-107 at 6.) The Continus system uses dissolution and diffusion. (Id. at 7.) “Dissolution” is a reference to the water solubility of the drug and/or the coating as a means to control the delivery of the drug. (Id.) For example, a salt formation can decrease the solubility of a drug with an otherwise high dissolution rate, making it more suitable for use in a controlled release formulation. (Id.) “Diffusion” refers to the movement of drug molecules from a region of high concentration to one of lower concentration, through a water insoluble polymer, for example, again as a means of controlling drug delivery. (Id; Palmieri, Tr. 1264:5-13.) The Leslie article teaches that the Continus system may be used to realize diffusion and dissolution over a period of 12 hours in vivo, and it provides a sample in vitro dissolution rate for a tablet, with aminophylline as the active ingredient, that is controlled to give even release over a period of six hours. (DTX-107 at 7-8.) 20. Through routine experimentation, a formulator can substitute a different active ingredient with a similar physical chemical profile into a once-a-day controlled release formulation and produce a formulation that has a dissolution rate similar to the original formulation. (Palmieri, Tr. 1287:11-1288:5; DTX-107 at 7.) Par’s formulation expert, Dr. Anthony Palmieri, testified that, in order to make a once-a-day dose formulation using a given active ingredient, a formulator would start by evaluating controlled release forms that have active ingredients with similar physical chemical profiles, prepare prototype formulations with reference to the list of excipients that were available, and do dissolution work to optimize the formulation using “routine ordinary quite frankly often dull laboratory experiments.” (Palmieri, Tr. 1255:24-1256:2, 1287:11-1288:5.) For example, Dr. Palmieri testified that a formulator could decrease or increase the thickness of the coating or use different excipients to obtain the desired controlled release profile. (Id. at 1323:21-1324:15.) The Leslie article also explained that, by varying the amounts of the different excipients used, “it is possible to vary the rate of drug diffusion through the matrix and subsequent rate of dissolution.” (DTX-107 at 7.) A formulator would then interact with clinicians through an iterative process to tweak the dose form if needed. (Palmieri, Tr. 1292:1-13, 1323:21-1324:6.) In rebuttal, Plaintiffs’ expert testified that a formulator “couldn’t expect to simply transpose one drug for another into a pharmaceutical ] controlled release formulation and expect to achieve the same dissolution profile, the same pharmacokinetic data and, of course, the same pharmacodynamic data.” (Davies, Tr. 1489:16-23.) But Plaintiffs failed to address Par’s main point: the alterations that are needed to achieve a successful controlled release formulation would be the result of routine experimentation. 21. The patents-in-suit describe controlled release matrices as preferred embodiments for the claimed controlled release tramadol, along with suitable ex-cipients for inclusion in such matrices. ('887 patent, 3:39-68.) Normal release matrices having a coating that provides for controlled release of tramadol are also described, along with suitable excipients. ('887 patent, 3:45-47, 4:24-55.) It is undisputed that Par’s tablets have a controlled release coating over a normal release matrix, rather than a controlled release matrix. (Incontroverted Facts, D.I. 326 at ¶ III.B.(25); Davies, Tr. 661:10-20; PTX-166 at PAR015917.) iii. Plaintiffs’ Development of the Claimed Inventions 22. Before detailing the development of the claimed inventions, it will be helpful to define some terms used in the art to characterize the properties of drugs and drug formulations. As noted earlier, the “minimum effective concentration” of a therapeutic drug, or “MEC,” is the minimum amount of drug per unit volume of blood plasma needed to provide a therapeutic effect in the average patient. (Findings of Fact [“FF”] ¶ 15.) “Onset of action” is the time at which a drug formulation begins to provide a therapeutic effect. (Davies, Tr. 695:10-697:1.) Plaintiffs use the term “onset concentration” to mean the blood plasma level of a drug at the onset of action. (D.I. 331 at 15-16.) For convenience, I will use that term as well. As used at trial, the term “trough concentration” refers to the blood plasma level of a drug at the end of a dosing interval. (Grond, Tr. 1056:4-24.) “Steady state” refers to the point at which the average blood plasma level over a dosing interval does not change with each successive dose. See Purdue Pharma L.P. v. Boehringer Ingelheim GmbH, 98 F.Supp.2d 362, 373-76 (S.D.N.Y.2000). “Cmax” refers to the peak blood plasma level of a drug following administration, and “W50” is the duration of time over which the plasma concentrations are equal to or greater than 50% of Cmax. (D.I. 247 at 10.) “Tmax” is the time it takes to get to Cmax. (Palmieri, Tr. 1314:23-1315:5.) 23.Scientists at Napp, including Smith, were involved in the development of a twice-a-day tramadol preparation in the early 1990s. (Smith, Tr. 12:3-10.) In August 1991, Dr. Derek Prater, a director of technical development at Mundipharma Research Ltd. (“Mundipharma Research”) and a named inventor of the patents-in-suit, suggested that, based on data obtained during the twice-a-day development, Smith should look into a once-a-day formulation. (Prater, Tr. 82:5-83:6; PTX-50 at NAPP0342385.) 24. In April 1992, Smith calculated theoretical dissolution rates and blood plasma profiles for a once-daily formulation. Smith’s calculations were based, in part, on a published 1986 paper by Dr. W. Lintz, et al., entitled “Bioavailability of Enteral Tramadol Formulations” (“Lintz”), which evaluated an oral immediate release preparation of tramadol. Smith relied on the MEC assumed in Lintz, which was 100 ng/ml. (Smith, Tr. 18:5-26:21; PTX-594 at NAPP0041240-41; PTX-42 at NAPP0096248.) Lintz also reported that tramadol has good water solubility, is rapidly absorbed, has a long half-life, and has high bioavailability relative to other centrally acting analgesics. (PTX-594 at NAPP0041240, NAPP0041245.) Thus, Lintz concluded that “the duration of analgesia of tramadol is likely to be longer with equianalgesie doses and equal pain intensity than that of pentazocine and codeine.” (PTX-594 at NAPP0041245.) 25. Smith disclosed his calculated theoretical dissolution rates and blood plasma profiles in a memo to Leslie and Prater dated April 24, 1992. (PTX-42.) To calculate his theoretical data Smith used the “favourable]” elimination half-life that had been reported for tramadol, along with the high bioavailability, and determined the rate at which tramadol would need to enter the blood stream in order to maintain a plasma concentration above the 100 ng/ml level for 24 hours. (Id. at NAPP009624849.) After discussing his calculations, Smith concluded that “albeit at an early (and purely theoretical) stage, I think we can be hopeful that a once-a-day preparation is a realistic target.” (Id. at NAPP0096249.) 26. In late 1993, formulators supervised by Prater and co-inventor Sandra Malkowska, the Assistant Director of Formulation Laboratories at Napp, created a once-daily tramadol formulation using Smith’s theoretical release data. Napp formulators chose hydrogenated vegetable oil (“HVO”) to slow the dissolution rate after trying and rejecting several other waxes. They made and tested tablets containing different ratios of tramadol to HVO and determined that an equal amount of tramadol hydrochloride (“tramadol Hcl”) and HVO seemed most promising for a once-daily formulation that would also be suitable in size for patients to swallow. (Malkowska Tr. 1064:3-10, 1160:3-61:2; Prater Tr. 79:3-13, 84:6-86:25, 92:3-93:22; PTX-71 at NAPP0096234; PTX-69 at NAPP0371891 [F474/07], NAPP0371895 [F474/15], NAPP0371903 [F474/30].) 27. In March 1994, Smith supervised TRAM.PKIN4, the first PK pilot study on the once-daily formulation that Prater and Malkowska had developed. TRAM.PKIN4 was a single dose study that compared blood plasma levels produced by 200 mg of the Napp controlled release formulation to a single 100 mg dose of a commercial immediate release tramadol formulation. As Smith explained, a once-daily dose of 200 mg is comparable to 50 mg of an immediate release dose taken four times daily, which is a typical dosing regimen for immediate release tramadol that was known to provide pain relief. (Smith, Tr. 27:3-35:2, 73:4-15; Katz, Tr. 500:2-506:9, 512:17-513:18; Grond, Tr. 1048:15-20, 1051:14-25; PTX-844 at 3.) Accordingly, Smith compared the plasma levels of the Napp controlled release formulation to one-half the plasma levels of the 100 mg immediate release control dose, i.e., the plasma levels that would be achieved by a 50 mg dose. TRAM.PKIN4 showed that the Napp controlled release formulation maintained plasma concentrations for more than 24 hours above the six-hour trough concentration, i.e., a trough concentration occurring at six hours after administration of a 50 mg dose. That gave Smith confidence that Napp had successfully made a once-daily formulation. (Smith Tr. 27:3-37:5; PTX-18 at NAPP0093094-95, NAPP0093111; Grond Tr. 1056:4-25.) 28. TRAM.PKIN4 also showed that the W50 of the controlled release formulation was greater than the W50 for the immediate release formulation. Smith took that larger WB0 to mean that the controlled delivery of the formulation was “very strong.” (Smith Tr. 38:7-40:11; PTX-18 at NAPP0093103.) 29. The TRAM.PKIN4 study and its results were included as Example 8 and Figure 2 in the specifications of the patents-in-suit. ('887, patent, Fig. 2, 11:35-12:14; Weinberger, Tr. 917:4-16; Smith, Tr. 47:2-20.) 30. Ronald Miller, one of the inventors of the patents-in-suit and the person to whom another inventor, Leslie, reported, testified that, when development began, he expected to successfully create a controlled release formulation of tramadol. (Miller, Tr. 1232:24-25, 1237:1-5.) Napp scientists used the Continus system to develop their controlled release formulation of tramadol (FF ¶ 17) because they believed that it was “reliable” and that it would lead to a successful result. (Miller, Tr. 1236:11-25, 1237:15-1238:12.) That belief was well founded. Napp had used the Continus system to develop various controlled release drugs at Napp for at least six different therapeutic indications. (Id. at 1233:24-1234:21.) Even with aminophylline, an active ingredient that was “an awkward substance to handle pharmaceutically,” Napp had used the Continus system to achieve a controlled release formulation that is “highly effective” and “very stable.” (Miller, Tr. 1234:22-1236:25.) Similarly, inventor Udo Hahn testified that he had no reason to think that tramadol could not be used with the Continus system. (Hahn, Tr. 1231:21-23.) iv. The Asserted Claims 31. Plaintiffs are asserting claims 3, 13, 27, and 29 of the '887 patent and claims 5, 7, and 11 of the '430 patent. (D.I. 280.) Those claims all relate to controlled release oral formulations of tramadol suitable for dosing every 24 hours. 32. Specifically, the asserted claims of the '887 patent relate to preparations or tablets of tramadol, or its salt, that are covered by a controlled release coating made out of certain excipients, that have a certain dissolution rate under certain conditions when tested in vitro and that have various pharmacokinetic properties. ('887 patent, 12:50-64, 13:53-14:6, 16:1-5, 12-15; Smith, Tr. 23:21.) The claimed formulations are designed to provide pain relief for approximately 24 hours. ('887 patent, 12:32-34,14:5-6.) 33. Claim 1 of the '887 patent, from which claim 3 depends, reads: A controlled release oral pharmaceutical preparation suitable for dosing every 24 hours comprising a substrate comprising a pharmaceutically effective amount of tramadol or a salt thereof; said substrate coated with a controlled release coating; said preparation having a dissolution rate in vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0, 1 N hydrochloric acid at 37° C. and using UV detection at 270 nm, between 0 and 50% tramadol released after 1 hour; between 0 and 75% tramadol released after 2 hours; between 3 and 95% tramadol released after 4 hours; between 10 and 100% tramadol released after 8 hours; between 20 and 100% tramadol released after 12 hours; between 30 and 100% tramadol released after 16 hours; between 50 and 100% tramadol released after 24 hours; and greater than 80% tramadol released after 36 hours, by weight, said preparation providing a therapeutic effect for about 24 hours after oral administration. (Id. at 12:16-35.) 34. Dependent claim 3 provides narrower in vitro dissolution ranges than claim 1. (Id. at 12:50-64.) In other words, the range of dissolution percentages at certain time points is smaller. For example, claim 3 requires between 35% and 100% tramadol released after 8 hours, rather than the 10% to 100% called for in claim 1. (Id. at 12:62.) 35. Independent claim 13 claims a pharmaceutical “tablet” rather than a “preparation” and requires that the coated tablet provide “a W50 in the range of 10 to 33 hours when orally administered”; otherwise, claim 13 is identical to claim 1. (Id. at 13:53-14:6.) 36. Dependent claim 27 reads: A controlled release preparation in accordance with claim 1, wherein said controlled release coating comprises a material selected from the group consisting of a water insoluble wax, a water insoluble polymer, a water insoluble cellulose and mixtures of any of the foregoing. (Id. at 16:1-5.) 37. Claim 29 is similar to claim 27 but depends from claim 13 rather than claim 1. (Id. at 16:12-16.) 38. The asserted claims of the '430 patent are similar to those asserted in the '887 patent but define the structure of the controlled release formulation with more detail. 39. Specifically, claim 1 of the '430 patent, from which the asserted claims depend, reads: A solid controlled release oral dosage form, comprising, a therapeutically effective amount of tramadol or a pharmaceutically acceptable salt thereof incorporated into a normal release matrix, said matrix overcoated with a controlled release coating comprising a polymethacrylate or a water insoluble cellulose, said dosage form providing a therapeutic effect for at least about 24 hours. ('430 patent, 12:41-51.) 40. With respect to the duration of therapeutic effect, the '887 patent uses the phrase “about 24 hours” and the '430 patent uses “at least about 24 hours.” ('887 patent, 12:33; '430 patent, 12:49-50.) As will become apparent, the difference between those two phrases is irrelevant to the issues as I have decided them. Therefore, I. will simply refer to the duration of therapeutic effect required by all the asserted claims as “approximately 24 hours.” 41. Claim 3, from which asserted claim 5 depends, requires the controlled release coating to comprise a water insoluble cellulose. ('430 patent, 12:54-57.) Claim 5 requires the controlled release coating to further comprise a polyvinylpyrrolidone. (Id. at 12:61-63.) 42. Claim 7 adds to claim 1 the same narrow in vitro dissolution rate as claim 3 of the '887 patent. (Id. at 13:1-12; '887 patent, 12:50-64.) Although claim 7 adds the term “about” to the dissolution ranges — claiming, for example, “about 0 to about 50% tramadol released after 1 hour” rather than the “0-50” provided in claim 3 of the '887 patent — that difference is immaterial to this case. 43. Claim 11 adds to claim 1 “a W50 in the range of 10 to 33 hours.” ('430 patent, 14:11-12.) D. Therapeutic Effect of Par’s Tablets 44. Plaintiffs’ infringement theory as to whether Par’s tablets provide a therapeutic effect for approximately 24 hours relies on a comparison of the PK data of Ultram ER to a 50 mg dose of Ultram IR, the latter of which, Plaintiffs say, has an onset of action at 30 minutes. (D.I. 331 at 15-17; see FF ¶ 22.) Plaintiffs contend that, because the PK studies for Ultram ER reveal blood plasma concentrations of tramadol for approximately 24 hours above the onset concentration of 50 mg Ultram IR, and because Par’s tablets and Ultram ER produce substantially similar PK values and are “therapeutically equivalent,” Par’s tablets meet the 24-hour limitation in the asserted claims. (D.I. 331 at 18.) 45. Plaintiffs’ theory requires me to make a number of factual findings, namely, whether 50 mg Ultram IR has an onset of action at 30 minutes, whether a dose of 50 mg Ultram IR can be used to measure the efficacy of Ultram ER, how the onset concentrations of Ultram IR compare to the blood plasma concentrations observed with Ultram ER, and the similarity of Ultram ER to Par’s tablets. i. Bioequivalence of Ultram ER and Par’s Tablets 46. Taking the last issue first, I find that the therapeutic effect of Par’s tablets will be the same as that provided by Ultram ER. Indeed, Par readily concedes this point: “Par’s product will have the same efficacy as Ultram ER because its PK profile is the same throughout the entire curve.... ” (D.I. 337 at 4; see PTX-214 at PAR011462-66; Davies, Tr. 681:16-83:11; Weinberger, Tr. 841:8-17, 873:17-76:17; Grond, Tr. 997:6-21, 1000:3-8; PTX-166 at PAR015918; Elvin, Tr. 452:10-54:14; Katz Tr. 517:23-18:8.) Thus, a demonstration of the therapeutic effect of Ultram ER is necessarily a demonstration of the therapeutic effect of Par’s tablets. ii. Ultram IR 47. Moving to the therapeutic effect of Ultram IR, I find for the following reasons that 50 mg Ultram IR provides a therapeutic effect and that onset of action of that dose occurs at 30 minutes. 48. Plaintiffs’ clinical expert, Dr. Warren Katz, testified that, in his experience prescribing Ultram IR to thousands of patients since the product was released in 1995, many of his patients tell him that they have at least some pain relief within the first 30 to 60 minutes of taking a 50 mg pill. (Katz, Tr. 491:9-492:23.) In line with that testimony, Dr. Katz published a peer-reviewed article in 1996 that reported that the onset of action following administration of 50 mg of Ultram IR occurred within one hour. (PTX-857 at 39; Katz, Tr. 495:7-497:7.) Dr. Katz also highlighted another article from the same journal (the “Lee article”) that reported that an additional dose of 50 mg immediate release tramadol may be given if pain relief is inadequate at 30 to 60 minutes after the first dose. (PTX-858 at 336; Katz, Tr. 497:12-499:18.) From that statement, Dr. Katz reasonably surmised that some patients did have an adequate response to the first dose of tramadol in 30 minutes. (Katz, Tr. 498:19-24.) 49. Clinical studies support Dr. Katz’s testimony. The NDA for Ultram IR contained twenty single dose pain trials. (PTX-883 at BVF00022012; Davies, Tr. 695:1-698:8; Grond, Tr. 1016:14-17:14.) Twelve of those twenty studies investigated the 50 mg dose of Ultram IR, six in dental pain models and six in surgical pain models. (PTX-883 at BVF00022012-16.) In ten of those twelve studies, 50 mg Ultram IR produced a mean onset of pain relief in about 30 minutes. Specifically, mean onset of action was 22 minutes in the 6-hour dental study TE/TE2 (id. at BVF00022029); 38 minutes in the 6-hour dental study TF (id. at BVF00022036); 30 minutes in the 6-hour dental study TG, (id. at BVF00022050); 24 minutes in the 8-hour dental study TH (id. at BVF00022057); 37 minutes in the 8-hour dental study TI (id. at BVF00022064); 21 minutes in the 8-hour post-surgical study TA (id. at BVF00022100); 20 minutes in the 6-hour post-surgical study TC (id. at BVF00022107); 19 minutes in the 6-hour post-surgical study TJ (no placebo) (id. at BVF00022114); 36 minutes in the 6-hour post-surgical study TW (id. at BVF00022122); and 16 minutes in the 6-hour cesarean section study TV (id. at BVF00022166). Of the remaining two studies, one, TF3, had a mean onset of action of 62 minutes (id. at BVF00022043); and the results of the other, TB, were not analyzed due to insufficient enrollment (id. at BVF00022016). In an efficacy test sponsored by Purdue for a separate NDA, the median time to perceptible pain relief following administration of 50 mg Ultram IR was found to be 69 minutes (a mean time is not given); the median time to “meaningful pain relief’ was found to be 3.1 hours. (Grond, Tr. 1046:16-1048:11, 1018:2-11.) Taking the reported summary from each of the analyzed studies, the average time to at least some pain relief was 33 minutes. 50. At trial, Par’s expert, Dr. Stefan Grond, dismissed the significance of those clinical studies. Relying on a report from an FDA reviewer that concluded that tramadol 50 mg was “positive” in only one of eight of the trials (PTX-883 at BVF00022017; Grond, Tr. 1017:2-8), Dr. Grond testified that, “in my opinion, the FDA concluded ... that 50 mg of Tramadol immediate release has marginal efficacy, and in my opinion, you cannot take only one of eight studies and, using that, ... make an assumption of analgesic efficacy at between 30 minutes and six hours.” (Grond, Tr. 1017:9-14.) 51. However, the FDA reviewer’s conclusion on which Dr. Grond relies does not address onset of action. Although the clinical studies measured both pain intensity and pain relief (e.g., PTX-833 at BVF00022025, 26), the FDA reviewer based his one-of-eight conclusion on pain intensity measurements alone. Specifically, the FDA reviewer looked at the pain intensity differences from baseline (“PID”), measured after the first half hour and hourly thereafter, and summed those differences for the first three hours (“3-hour SPID”). (Id. at BVF00022012.) The reviewer considered a drug to be “positive” in a given study if the 3-hour SPID for the drug beat placebo. (Id. at BVF00022013-16.) In contrast to the 3-hour SPID measurements, the mean pain relief measurements show that 50 mg tramadol was greater than placebo at the first half hour in all but two of the studies. (Id. at BVF00022025, 32, 39, 46, 53, 60, 88, 96, 103,118,162.) 52.Furthermore, although Dr. Grond is clearly well-credentialed and a recognized authority in his field of anesthesia and pain management, I do not agree with him that the FDA endorsed a conclusion that a 50 mg dose was only marginally effective. To the contrary, the FDA approved the use of an initial 50 mg dose of Ultram IR for the American public where “rapid onset of analgesic effect is required.” (PTX-844 at 3.) Apparently, the FDA did not require that 50 mg Ultram IR provide some pain relief in 30 minutes for all patients before deeming it effective, and there is no basis for me to hold Ultram IR to a more exacting efficacy standard than did the FDA. The Ultram IR label insert states, “Onset of analgesia in humans is evident within one hour after administration”; the FDA approved that label following the submission of the clinical studies. (PTX-844 at 3; PTX-883A at BVF00021883; Katz, Tr. 493:18-94:12; Davies, Tr. 685:9-20, 697:2-9, 698:9-14.) The FDA’s approval, the clinical studies, Dr. Katz’s clinical experience, Dr. Katz’s article, and the Lee article that he referenced in his testimony (FF 1148) all lead me to conclude that Plaintiffs have established, by a preponderance of the evidence, that 50 mg Ultram IR can and frequently does provide an analgesic effect at 30 minutes after oral administration. iii. Bioequivalence of Ultram IR and Ultram ER 53. Par disputes whether the FDA allowed Biovail to rely on the efficacy of Ultram IR to establish the efficacy of Ultram ER, with the implication being that, if the FDA did not allow Biovail to do so, I should not allow Plaintiffs to do so either. (D.I. 337 at 4-5; D.I. 336 at 4 n. 1.) 54. Biovail’s Ultram ER NDA was submitted pursuant to § 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (codified at 21 U.S.C. § 355(b)(2)) and relied on efficacy and safety data for Ultram IR. (Uncontroverted Facts, D.I. 326 at ¶ III.C.(31); PTX-879 at BVF00144032.) In its draft “Guidance for Industry,” the FDA has stated that a 505(b)(2) application is appropriate for a controlled release product that is bioequivalent to a previously approved drug where “1. [t]he proposed product is at least as bioavailable as the approved pharmaceutically equivalent product ... or 2.[t]he pattern of release of the proposed product, although different, is at least as favorable as the approved pharmaceutically equivalent product.” (DTX-479 at 6.) 55. Biovail initially sought FDA approval to market Ultram ER for the treatment of “moderate to moderately severe pain,” which would encompass both chronic and acute pain. (PTX-833 at BVF00021887.) That was the same indication for which Ultram IR had been approved in 1995. (Weinberger Tr. 889:5-891:4; PTX-750 at BVF00117572.) As a part of the Ultram ER approval process, Biovail submitted multiple clinical studies comparing the PK data for a single 200 mg Ultram ER tablet to data for a 50 mg Ultram IR dose taken four times a day at regular and at irregular intervals. (PTX-750 at BVF00117578-93.) 56. In October 2004, Biovail received an “approvable” letter from the FDA that identified questions about Biovail’s proposed labeling and studies and stated that “upon review of the data presented in [the] NDA, [Ultram ER] is not bioequivalent to the reference listed product.” (PTX-884 at BVF00529849 (emphasis added).) The letter requested an additional trial demonstrating “robust evidence of efficacy.” (Id. at BVF00529850.) The FDA also issued two clinical reviews recommending that Biovail’s NDA 21-692 not be approved, “based on lack of efficacy in conjunction with the high rate of adverse events.” (DTX-354 at SBA 208; DTX-353 at SBA 134.) 57. On March 7, 2005, Biovail submitted a “Complete Response” letter to the FDA, in which Biovail limited the proposed indication for Ultram ER to “chronic pain” and submitted new analyses of its previously conducted clinical studies to explain how those studies revealed that Ultram ER was, indeed, bioequivalent to Ultram IR. (PTX-770 at BVF00160624, BVF00160636.) Biovail did not conduct additional clinical trials. (Id. at BVF00160630, BVF00160635.) 58. Following Biovail’s response, the division director responsible for dealing with Biovail’s NDA, Dr. Robert Rappaport, issued a “Division Director Review and Basis for Approval Action,” in which he noted that he disagreed with the clinical review team and that he had concluded that Biovail had “provided adequate evidence of efficacy in support of [its] marketing application for [Ultram ER].” (PTX-746 at SBA 49.) Following a review of Biovail’s March 7 Complete Response, additional FDA reviewers concluded that, although there were still some questions as to the efficacy of Ultram ER at steady state, “the [bioequivalence] of [Ultram ER] to Ultram [IR] was demonstrated after [a] single daily dose in all [of Biovail’s] studies.” (DTX-356 at SBA 478.) Those reviewers, like Rappaport, concluded that Biovail’s application was acceptable. (Id. at SBA 477.) The FDA ultimately approved Ultram ER, on September 8, 2005, and authorized it to be labeled for “moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.” (PTX-747 at BVF00190805, 816, 840.) 59.Based on the foregoing record, and contrary to Par’s assertion, it appears that the FDA ultimately did conclude that the PK data submitted by Biovail was sufficient to establish bioequivalency. Although the FDA initially asked for direct clinical evidence of efficacy, it did not finally require more studies for approval. Par highlights Plaintiffs’ statement in post-trial briefing that the FDA considered bioequivalence at steady state, rather than after an initial dose. (D.I. 337 at 5 n. 1 (citing D.I. 331 at 14).) But that statement is not inconsistent with Plaintiffs’ argument that PK data from Ultram IR can be used to measure the efficacy of Ultram ER. That Biovail only established bioequivalence as to steady state merely reflects the threshold showing that the FDA required for approval of Ultram ER for chronic pain. In other words, just because Biovail may not have needed to establish a single pill equivalency before the FDA does not mean that it could not have. In fact, quite the opposite appears to be true in light of the reviewer comments that “the [bioequivalence] of [Ultram ER] to Ultram [IR] was demonstrated after [a] single daily dose in all [of Biovail’s] studies.” (DTX-356 at SBA 478 (emphasis added).) 60. I conclude that Plaintiffs have shown by a preponderance of the evidence that a single dose of 200 mg Ultram ER is bioequivalent to a 50 mg Ultram IR dose taken four times a day and that the efficacy of Ultram IR is a proper basis on which to judge the efficacy of Ultram ER. iv. Therapeutic Effect of Ultram ER 61. Biovail’s Study 2551, submitted as a part of its NDA, compared the PK profile of four 50 mg Ultram IR tablets taken every six hours to one 200 mg Ultram ER tablet. (Davies, Tr. 700:12-02:22; PTX-750 at BVF00117589-93). That study reveals a 30-minute blood plasma concentration for 50 mg Ultram IR of 40 ng/ml. (Davies, Tr. 703:23-04:19; PTX-750 at BVF00117590.) Plaintiffs’ formulation expert, Dr. Martyn Davies, estimated that, based on the same study, a 200 mg dose of Ultram ER provided blood plasma concentrations above that 40 ng/ml level for about 32 hours. (Davies, Tr. 704:13-23; PTX-750 at BVF00117590; DTX-685 at BVF00123144.) 62. With respect to the 300 mg Ultram ER tablet, the plasma concentrations of tramadol will increase proportionally from the 200 mg Ultram ER tablet. (Grond, Tr. 1028:3-8.) Based on dose proportionality (see supra note 28), Dr. Davies determined that, because 200 mg Ultram ER is therapeutically effective for about 24 hours as shown by its plasma levels, the 300 mg Ultram ER tablet has at least the same duration of efficacy given its higher plasma levels. (Davies Tr. 707:5-708:11; PTX-750 at BVF00117609). 63. With respect to the 100 mg Ultram ER tablet, Dr. Davies relied on Biovail’s single dose PK Study 2677, also submitted as a part of its NDA, to determine the duration of efficacy. Study 2677 graphed the blood plasma levels provided by a target formulation of 100 mg Ultram ER against those provided by a 100 mg Ultram IR control. Using Study 2677 and the 40 ng/ml onset concentration at 30 minutes from Study 2551 as a reference point, Dr. Davies determined that a 100 mg dose of Ultram ER maintains therapeutic plasma levels above that known therapeutic concentration for about 25 hours. (Davies Tr. 708:17-10:13; PTX-750 at BVF00117643; PTX-878 at BVF00127709.) 64. Par does not argue that the 30-minute onset concentration for 50 mg Ultram IR was inaccurately measured or that the various dosage strengths of Ultram ER fail to provide blood plasma concentrations above that concentration level for approximately 24 hours. Rather, its argument is pinned on the concept that onset of action for 50 mg Ultram IR does not occur at 30 minutes. I have rejected that position. (FF ¶ 52.) Par also vigorously disagrees with the general notion that 40 ng/ml represents an effective concentration of tramadol. However, as already discussed (FF ¶ 60), and as further explained in my Conclusions of Law [“CL”], infra, ¶¶ 8-12, I am persuaded that the 40 ng/ml blood plasma concentration is a proper marker at which the duration of therapeutic effect can begin to be measured. Thus, Plaintiffs have sufficiently established that the 100 mg, 200 mg, and 300 mg dosage strengths of Ultram ER — and, because of their bioequivalency to Ultram ER, the same dosage strengths of Par’s tablets (FF ¶ 46) — provide a therapeutic effect for approximately 24 hours. E. Prosecution History of the Patents-in-Suit — Chapter I 65. The prosecution history of the patents-in-suit is relevant to issues of both obviousness and inequitable conduct. At this point, I will discuss the portion of the prosecution history that relates most directly to the question of obviousness. 66. The application that issued as the '887 patent, Application No. 08/677,798 (the “'798 application”), was filed on July 10, 1996. ('887 patent, cover page.) The 798 application was filed as a division of Application No. 08/241,129 (the “'129 application”), which was filed May 10, 1994 and issued as U.S. Patent No. 5,591,452 (the “'452 patent”) on January 7, 1997. ('452 patent, cover page.) 67. The application that issued as the '430 patent, Application No. 09/800,204 (the “'204 application”), was filed on March 6, 2001. ('430 patent, cover page.) The '204 application was filed as a continuation of the application for the '887 patent. (Id.) 68. The '887 patent and its parent, the '452 patent, claim priority to four foreign patent applications filed from May 10,1993 to March 14, 1994. ('887 patent, cover page.) Under 35 U.S.C. § 119, the claims set forth in a United States application are entitled to the benefit of a foreign priority date if the corresponding foreign application provides a sufficient written description of what is claimed in the United States patent. In re Gosteli, 872 F.2d 1008, 1010-11 (Fed.Cir.1989). The earliest of those claimed priority documents is German Patent Application No. DE 4315525 (the “German priority document”). (Uncontroverted Facts, D.I. 326 at ¶ III.G.(64).) ■ 69. The German priority document does not disclose any PK data, any product having a 24-hour therapeutic effect, any of the dissolution ranges stated in the asserted patents to be suitable for once daily administration, controlled release coatings of tablets suitable for once-a-day dosing, or any W50 values. (DTX-21; Grond, Tr. 997:22-998:20; Palmieri, Tr. 1271:22-73:12.) Moreover, PK study TRAM. PKIN4, which underlies Figure 2 and Example 8 of the patents-in-suit, was conducted in March 1994, almost a year after the filing ■ of the German priority document. (FF ¶¶ 27-29.) Thus, I agree with Par (D.I. 339 at ¶ 240) that the asserted claims of the '887 patent are not supported in the German priority document and are not entitled to that document’s May 10, 1993 filing date. 70. Plaintiffs are silent as to whether the German document entitles them to a foreign priority date. However, they do not dispute that the references raised by Par are prior art. (See D.I. 331 at 27.) i. Background References 71. The references described in this subsection were all before the U.S. Patent Office (“PTO”) during the prosecution of the patents-in-suit. ('887 patent at p. 2; '430 patent at pp. 1-2.) 72. U.S. Patent No. 4,844,909 (the “'909 patent”), filed October 26, 1987 and issued July 4, 1989, discloses controlled release formulations of 1 to 100 mg of hydromorphone. (DTX-24 at cover page, 2:41^44; Palmieri, Tr. at 1308:11-1309:7.) The '909 patent provides dissolution release rates and plasma profiles (DTX-24 at 1:8-26; Palmieri, Tr. 1314:18-21); it describes a Tmax (see FF ¶ 22) between 4 to 8 hours (DTX-24 at 2:11-16; Palmieri, Tr. 1314:18-1315:9); it describes water insoluble cellulose coatings, such as ethylcellulose coatings (DTX-24 at 4:42; Palmieri, Tr. 1315:11-15); and it describes a normal release matrix having a coating that controls the release of the drug (DTX-24 at 3:64-66). Hydromorphone has similar water solubility, molecular weight, and dose size as tramadol. (Palmieri, Tr. 1317:4-20.) 73. U.S. Patent No. 5,266,331 (the “'331 patent”), filed November 27, 1991 and issued November 30, 1993, discloses controlled release formulations of 1 to 50 mg of oxycodone. (DTX-22 at cover page, 2:46-48.) Even though the '331 and '909 patents specify different active ingredients, they both disclose the identical dissolution release rate profiles, which are within the ranges of the asserted claims. (Palmieri, Tr. 1316:5-22.) 74. U.S. Patent No. 5,286,493 (the “'493 patent”), filed January 27, 1992 and issued February 15, 1994, discloses controlled release compositions of a variety of analgesics: hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, “and the like.” (PTX-609 at 7:31-37.) The '493 patent discloses controlled release coatings (PTX-609 at 2:67-3:5), including Eudragit ®, which is a polymethacrylate (Palmieri, Tr. 1317:23-1318:9); it discloses a dissolution profile within the claimed ranges (PTX-609 at 4:57-67; Palmieri, Tr. 1312:24-1314:11); and it describes a substrate covered by a controlled release coating (PTX-609 at 9:23-30). ii. The Merck/Bondi Reference 75. On June 7, 2000, the PTO issued an office action rejecting the pending claims of the '887 patent as anticipated by or obvious in light of European Patent No. 147,780 (the “Merck/Bondi reference”). (PTX-2 at PLIR1109663.) 76. The Merck/Bondi reference discloses using a polyvinyl alcohol (“PVA”) coating, which is a water insoluble polymer, to control the release of active pharmaceutical ingredients. (DTX-16 at NAPP0045471; DTX-1456.) It lists tramadol as one of hundreds of possible agents that may be used with PVA coating. {Id. at NAPP0045468.) The possible agents in the Merck/Bondi reference are listed in 12 different classes identified by letters (a) through (I), each of which lists multiple agents within the class. {Id. at NAPP0045466-70.) Tramadol, which is an opioid analgesic, is listed in Merck/Bondi as a preferred agent, but is misclassified as one of about 60 different agents in the non-steroidal anti-inflammatory drug (“NSAID”) class. {Id. at NAPP0045468; Palmieri, Tr. 1355:5-17, 1397:10-1400:8.) The reference discloses that the amount of PVA coating can range from 1% to 15% by weight of the entire drug delivery device, with 3% to 10% PVA preferred. (DTX-16 at NAPP0045471.) Sixty-four different examples of controlled release formulations are disclosed in Merck/Bondi, using various active agents and different PVA concentrations. None of the 64 examples uses tramadol. (Id. at NAPP0045472-77.) Claim 2 of Merck/Bondi claims tramadol as one of twelve potential NSAID active ingredients, where the PVA coating constitutes from 2% to 5% of the composition weight. (Id. at NAPP0045478-79.) iii. Issuance of the Patents-in-Suit 77. In the PTO’s June 7, 2000 office action, the examiner stated that the MercfyBondi reference teaches a slow releasing composition of tramadol and that “[a]ny differences are minor modifications and are obvious because a skilled artisan would be motivated to make minor changes ... in order to determine optimal conditions.” (PTX-2 at PUR1109664.) 78. The examiner then held a personal interview with the applicants, after which the examiner noted that he “agreed that the large scope of listed compounds in [the Merck/Bondi reference] did not establish a prima facie case of obviousness.” (PTX-2 at PUR1109665; Davidson, Tr. 258:15-259:12.) 79. According to the applicants’ subsequent submission to the PTO, the prior art before the examiner also was discussed during the interview and generally categorized as follows: (a) prior art directed to pharmaceutical formulations that list tramadol in a long list of possible drugs to be included in such formulations but do not exemplify any tramadol formulations, namely the [Merck/Bondi reference] relied upon by the Examiner in the last Office Action; (b) prior art directed to controlled release formulations of narcotic opioid analgesics ...; and (c) prior art patents directed to controlled release formulation technology (where tramadol was not mentioned) and their applicability to the claimed invention. (PTX-2 at PUR1109672.) 80. The '798 application matured into the '887 patent, which issued on July 3, 2001. ('887 patent, cover page.) 81. The '204 application, which ultimately issued as the '430 patent, was filed on March 6, 2001. ('430 patent, cover page.) 82. The same primary examiner reviewed both the '798 application and the '204 application. ('887 patent, cover page; '430 patent, cover page.) On April 23, 2002, after the '887 patent had issued, the examiner rejected the pending claims in the '204 application, stating that it would have been obvious to use the controlled release method taught in the Merck/Bondi reference for making an oral composition of tramadol. (PTX-5 at PUR11100011110002.) The examiner noted that “[t]he claims drawn to specific amounts, specific dosage forms, specific dissolution rates etc., are all obvious since a skilled artisan would reasonably be expected to tweak the controlled release form of tramadol to meet a variety of needs.” (Id. at PUR1110002.) 83. In response, the applicants argued that one skilled in the art would not be motivated to select tramadol from the large number of active ingredients disclosed in the Merck/Bondi reference. (Id. at PUR1110110.) They also argued that the prior art did not teach the “24 hour therapeutic effect” limitation of the asserted claims. (Id. at PUR1110112-15.) 84. The examiner maintained his rejection until the applicants amended the claims to limit the claimed “controlled release coating” to one “comprising a polymethacrylate or a water insoluble cellulose.” (Id. at PUR1110125, PUR1110145, PUR1110416.) The applicants argued that the Merck/Bondi reference did not disclose such a controlled release coating. (Id. at PUR1110416.) The claims were then allowed, subject to a terminal disclaimer with respect to the '887 patent. See In re Goodman, 11 F.3d 1046, 1052 (Fed.Cir. 1993) (“To prevent extension of the patent right beyond statutory limits, the doctrine of obviousness-type double patenting rejects application claims to subject matter different but not patentably distinct from the subject matter claimed in a prior patent.”); 37 CFR § 1.321(c) (specifying procedures for disclaiming the portion of the patent term following the expiration of a commonly owned patent that fits the description provided by In re Goodman). 85. The '430 patent issued on July 11, 2006. ('430 patent, cover page.) F. References Not Before the PTO i. U.S. Patent No. 5,580,578 (“Oshlack”) 86. Benjamin Oshlack, former Vice President of Pharmaceutics at Purdue, is an inventor of U.S. Patent No. 5,580,578 (the “'578 patent” or “Oshlack”), filed July 27, 1993, as a continuation in part of the application for the '493 patent (see FF ¶ 74) and issued December 3, 1996. (Oshlack, Tr. 171:7-21, 189:16-19.) Oshlack is directed to a method of increasing the shelf life of solid controlled release formulations. (PTX-601 at 3:3-41; Oshlack, Tr. 186:18-187:10, 189:12-21.) Oshlack teaches that an increased shelf life can be obtained by curing (heating) the controlled release formulation for an extended period. (PTX-601 at 3:41-64; Oshlack, Tr. 186:18-187:10.) 87. Oshlack describes various controlled release oral dosage formulations that are even closer to the asserted claims than is Merck/Bondi. Oshlack discloses specific examples of controlled release formulations that use morphine, hydromorphone, and acetaminophen as the active ingredients, but the reference broadly claims that it is applicable to controlled release dosage forms containing “systemically active therapeutic agent[s].” (PTX-601 at 20:12-39:26, 43:48-44:19; Oshlack, Tr. 187:17-24, 190:4-14.) Tramadol is claimed as one of 14 different “opioid analgesics” that qualify as appropriate therapeutic agents. (PTX-601 at 44:10-19, 29-36.) 88. Oshlack further describes controlled release coatings comprising either hydrophobic (water-insoluble) acrylic polymers (PTX-601 at 7:37-39) or polymethacrylates such as Eudragit® (Id. at 9:30-41; Palmieri, Tr. 1318:1-12, 1336:24-1337:7). 89. Claim 43 of Oshlack (“Claim 43”) describes a dissolution profile through eight hours that falls within th