Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW YOUNG, District Judge. TABLE OF CONTENTS FINDINGS OF FACT I.The Parties.830 II.Background in the Relevant Field Prior to the Prosecution of the ’382 Patent.831 A. Schizophrenia.831 B. Early Drug Treatment — Typical Antipsychotic Drugs.831 C. Clozapine: The First Atypical Antipsychotic.832 D. The Search for a Safe, Atypical Antipsychotic Drug.832 E. Lilly’s Attempts to Discover a Safe, Atypical Antipsychotic Drug.832 F. The Discovery of Olanzapine .834 III. Prosecution History of the ’382 Patent.835 A. The ’143 Patent Application .835 B. The ’348 Continuation Application.837 IV. The Validity of the ’382 Patent.841 A. Anticipation.841 1. Anticipation by Chakrabarti 1980a.841 2. Anticipation by Schauzu .843 B. Obviousness.844 1. The Scope and Content of the Prior Art.844 a. Clozapine and Clozapine-Like Molecules .844 b. The’574 Patent .844 c. The Chakrabarti Articles.845 (1) Chakrabarti 1980a .845 (2) Chakrabarti 1982.845 (3) Chakrabarti 1989.846 d. The Sullivan and Franklin Article .846 2. Ordinary Skill in the Art.846 3. The Differences Between the Claimed Invention and the Prior Art.847 4. Motivation Provided by the Prior Art to Make Olanzapine.847 a. Compound ’222 as the Beginning Compound.847 (1) Compound ’222’s Activity.847 (2) Hydrogen as a Preferred Substituent.848 (a) Compound 6 .848 (b) Compound 36 .848 (c) Compound 34 .849 b. Changing the 2-ethyl in Compound ’222 to a 2-methyl.849 c. Replacing the Fluorine Atom in Flumezapine with a Hydrogen Atom.850 5. Reasonable Expectation of Success.850 6. Composition and Method Claims .851 7. Secondary Considerations. 00 or to a. Long-Felt Need. 00 cn co b. Failure of Others. 00 cn co c. Commercial Success . 00 cn co d. Industry Acclaim. 00 en co e. Unexpected Differences Between Compound ’222 and Olanzapine — The Dog Studies. Principles Toxicology. (2) Lilly’s and Defendants’ Dog Toxicology Studies .... (a) Lilly’s D07290 Dog Study. (b) Zenith’s Dog Study — The MPI Study. (c) DRL’s Dog Study — The Calvert Study. (3) Criticisms of Lilly’s Dog Study Evidence. (a) The Dog as a Model.. (b) Total Cholesterol as a Tested Parameter. (e) Randomization. (d) The Length of the Study. (e) The Number of Dogs and Analysis by Sex. (f) The Dosage Used. (g) The Use of Equal Doses of Olanzapine and Compound ’222 . O <0 00 (h) How the Study Was Conducted. O ZD 00 i) Good Laboratory Practices Were Followed O ZD 00 ii) Double Rations . O ZD 00 (i) The Results of Lilly’s and Zenith’s Studies. 1-1 SO 00 i) Statistics Experts for All of the Parties Found a Statistically Significant Cholesterol Increase in the Compound ’222-Treated Dogs. 00 ii) The Repeated Measures Analysis Was Appropriate. 00 iii) Dunnett’s Test Does Not Show that the Effect of Compound ’222 Is Small. iv) Dr. Gibbons’ UPL Test Does Not Show that the Effect of Compound ’222 Is Small . (j) The Cholesterol Results. i) The Increase in Cholesterol Is Biologically Significant. 00 ii) The Increase in Cholesterol Was Not Caused by Other Factors. 00 a) The Female Estrous Cycle. 00 b) Double Rations . 00 c) The Alleged Hypothyroid Dog. 00 iii) The Reference Range. 00 iv) Other Statistically Significant Changes. 00 v) Dog Data Excluded from the Study Did Not Effect the Study Findings. 00 f. Prolactin' as a Previously Unconsidered Unexpected Result 00 (1) The Results of the MPI Study. 00 00 00 (3) Olanzapine’s Effect on Prolactin. o t— oo g. Unexpected Differences Between Olanzapine and Flumezapine. o 00 (1) Liver and Muscle Enzyme Test Results from the Flume-zapine Clinical Trials . t-00 (2) Liver and Muscle Enzyme Test Results from Olanzapine Clinical Trials. oo -3 > — (3) Dr. Diamond’s Opinion. oo -q CO C. Double Patenting. 00 «<3 co D. Public Use. 00 —-3 oo E. Inequitable Conduct. OO —q cr 1. Lilly’s Statements to the PTO Did Not Contradict Prior Statements It Made to the Swedish Board of Health. 00 —3 or 2. Lilly Did Not Believe that It Was Necessary to Compare Olanza-pine and Compound ’222 in a Second Species. 3. Dr. McGrath Believed the Effect of Compound ’222 on Cholesterol Was Significant Before Dr. Symanowski Performed a Statistical Analysis. c— oo 4. Dr. McGrath’s Draft Definition of “Clinical Pathological Significance” Was Not Lilly’s Standard for Clinical Significance. CO 00 5. Dr. Emmerson Did Not Mislead the Patent Examiner Regarding the Significance of the Results of the D07290 Study. 00 -q co 6. Lilly Did Not Mislead the PTO Regarding the Relation Between the D07290 Study in Dogs and the Potential Effects of Cholesterol in Humans. 00 00 a. Lilly’s Representations in the Response After Final. 00 00 b. Dr. Scruby’s Declaration . 00 CO c. Dr. Means’ Declaration. 00 00 d. Dr. Tye’s Declaration. 00 00 7. Lilly Did Not Mislead the PTO by Withholding Individual Dog Data. CO 00 CR 8. Nonprotocol Bleed Data from Moribund Dog 240712 and from Dog 240692 After the End of the Study Taken in Connection with a Bone Marrow Biopsy Are Not Material. oo 00 05 9. A Statement in the Response After Final That There Was No Cholesterol Elevation in “Any” of the Olanzapine-Treated Dogs Was Not Intentionally Misleading. 00 00 -q 10. Individual Data from the Control Dogs Does Not Contradict Lilly’s Arguments to the PTO. 00 00 00 11. Individual Data from Two Dogs Offered Double Rations Did Not Confound the Study Results. 00 00 CO 12. The Change in the Statistical Analysis Protocol from Dunnett’s Test to Repeated Measures Was Proper. 00 00 CO 13. Dr. Symanowski Did Not Withhold Results Inconsistent with the Results He Presented to the PTO . f — i 05 00 14. There Was Nothing Misleading About the Use of the Standard Error in Figure 3 of Dr. Symanowski’s Declaration. 00 CO to 15. Other Parameters Did Not Show Olanzapine to Be More Toxic than Compound ’222 . 00 CO CO 16. The Reference Range for Cholesterol Is Not Material and Was Not Intentionally Withheld from the PTO . CO 05 00 17. There Was No Inequitable Conduct Regarding the Failure to Disclose the Phase I Clinical Trials. 05 00 18. There Was No Inequitable Conduct Regarding Lilly’s Failure to Disclose the ’574 Patent and the Chakrabarti Articles. 00 a. Chakrabarti 1980a and the ’574 Patent. ^ 00 b. Chakrabarti 1982 and Chakrabarti 1989 . LO 00 CONCLUSIONS OF LAW I. Controlling Authority. AO 0*5 00 A. Jurisdiction. ÍO 05 00 B. Federal Circuit Law Applies. CO 05 00 C. The Presumption of Validity. CO -05 00 D. Selection Inventions. 05 CO II.- The Validity of the ’382 Patent. 1> 05 00 A. Anticipation — Lack of Novelty under 35 U.S.C. § 102. t> 05 00 1. ChakrabaHi 1980a Does Not Anticipate the Claims of the ’382 Patent. 00 05 00 a. Chakrabarti 1980a Does Not Disclose a Genus . 05 05 00 b. The Preferences Expressed in Chakrabarti 1980a Do Not Lead a Person of Ordinary Skill in the Art to Envision Olanzapine. CD o o 2. Schauzu Does Not Anticipate the Claims of the ’382 Patent... CD O o B. Obviousness. rH O 05 1. The Prima Facie Case . CO O 05 a. It Would Not Have Been Obvious to Start with Compound ’222 . rtf O 05 b. It Would Not Have Been Obvious to Modify Compound ’222 to Arrive at Olanzapine. ^ O 05 c. It Would Not Have Been Obvious to Modify Flumezapine . ^ O 05 d. There Was No Reasonable Expectation of Success. LO O 05 2. Objective Evidence of Nonobviousness — The Secondary Considerations. LO a. Long-Felt Need. CO b. Failure of Others. CD c. Commercial Success . CD d. Industry Acclaim. t> e. Unexpected Results. C> 3. Conclusion Regarding Obviousness. 05 o C. Double Patenting. 1. Domination. 05 0 O rH 2. The Double Patenting Issue . D. Public Use. 1. The HGAA, HGAB, and HGAC Phase I Clinical Trials Were Not a Public Use of Olanzapine .912 2. The HGAA, HGAB, and HGAC Phase I Clinical Trials Were Not a “Use” of the Claimed Invention.913 3. The HGAA, HGAB, and HGAC Phase I Clinical Trials Were “Experimental Uses” of Olanzapine.913 E. Inequitable Conduct rH 05 1.Materiality . rH 05 2.Intent to Deceive.•. 915 3. Lilly Did Not Commit Inequitable Conduct During the Prosecution of the ’382 Patent. CD rH 05 a. Lilly’s Nondisclosure of Prior Art Does Not Constitute Inequitable Conduct. CD i — 1 05 b. Dr. McGrath Believed the Cholesterol Results of the D07290 Study Were Significant. tH 05 c. Dr. Symanowski Did Not Conceal or Misrepresent the D07290 Study Data. 00 r — t 05 (1) The Use of the Repeated Measures Analysis. 00 i — I 05 (2) The Failure to Include Individual Dog Data. co rH 05 (3) The Failure to Include Nonprotocol Bleed Data. 00 tH 05 (4) The Failure to Inform the PTO of the Results of the Robustness Cheek. CD CD (5) Figure 3 of Dr. Symanowski’s Declaration. CD CD (6) The Failure to Disclose the Results of Other Parameters CD CD d. Statements Made by Other Lilly Representatives Do Not Constitute Inequitable Conduct. CD (1) Lilly’s Response to the Swedish Board of Health .... CD (2) Dr. Emmerson’s Statement to the Examiner. CD (3) Lilly’s Representations in the Response After Final.. CD (4) Dr. Scruby’s Declaration. CD (5) Dr. Means’ and Dr. Tye’s Declarations. CD (6) Lilly’s Other Failures to Disclose Were Not Material CD e. Conclusion Regarding Inequitable Conduct. CD III. Summary of Conclusions. .922 Plaintiffs, Eli Lilly and Company and Lilly Industries Ltd., filed suit against the Defendants, Zenith Goldline Pharmaceuticals, Inc., Dr. Reddy’s Laboratories, Ltd., and Teva Pharmaceuticals USA, Inc. (collectively “Defendants”), for infringement of United States Patent No. 5,229,382 (“’382 patent”). The parties tried this case before the court from January 26, 2004, through February 12, 2004. Following the trial, the parties filed proposed findings of fact and conclusions of law, and responses thereto. The parties also filed post-trial briefs, which the court found helpful given the breadth and complexity of the disputed issues. The majority of the relevant briefing was submitted by May 12, 2004, with final submissions filed in February 2005. Being duly advised, the court finds that Defendants have failed to prove by clear and convincing evidence that the ’382 patent is invalid, as anticipated under 35 U.S.C. § 102, as obvious under 35 U.S.C. § 103, under the doctrine of double patenting, or as barred by prior public use under 35 U.S.C. § 102. The court further finds that Defendants have failed to prove by clear and convincing evidence that the ’382 patent is unenforceable due to inequitable conduct. The court now issues its findings of fact and conclusions of law pursuant to Federal Rule of Civil Procedure 52(a): FINDINGS OF FACT I.The Parties 1. Eli Lilly and Company is an Indiana corporation engaged in the business of research, development, manufacture, and sale of pharmaceutical products throughout the world. 2. Lilly Industries Ltd., located in England, is a subsidiary of Eli Lilly and Company (the Plaintiffs are hereinafter collectively and individually “Lilly”). 3. Zenith Goldline Pharmaceuticals, Inc. (“Zenith”) is a Florida corporation having its corporate offices and principal place of business at 4400 Biscayne Boulevard, Miami, Florida 33137. Zenith’s Amended Answer to Complaint for Patent Infringement, Affirmative Defenses and Counterclaims, filed August 7, 2002, ¶ 3. 4. Dr. Reddy’s Laboratories, Ltd. (“DRL”) is a public limited liability corporation having its principal place of business at 7-1-27 Ameerpet, Hyderabad 500 016, India. DRL’s Amended Answer and Counterclaim, filed July 29, 2002, ¶ 3. 5. Teva Pharmaceuticals USA, Inc. (“Teva”) is a Delaware corporation with its principal place of business at 650 Cathill Road, Sellersville, Pennsylvania. Answer of Defendant Teva Pharmaceuticals USA, Inc., filed on March 18, 2003, ¶ 3. 6. On July 20, 1993, the United States Patent and Trademark Office (“PTO”) issued the ’382 patent which is entitled “2-Methyl-Thieno-Benzodiazepine.” The ’382 patent was assigned to, and is owned by, Lilly. TX 1000; TX 1360. 7. The ’382 patent claims, inter alia, the chemical compound known as olanza-pine and methods of using olanzapine to treat schizophrenia. TX 1000, col. 12, claims 1, 2, 3, 7, 8, and 15. 8. Olanzapine, sold by Lilly under the trademark ZYPREXA® (“Zyprexa”), was approved by the United States Food and Drug Administration (“FDA”) in late 1996. Paul Tr. 139:16-19. 9. Zenith, DRL, and Teva filed Abbreviated New Drug Applications (“ANDAs”) under the Drug Price Competition and Patent Term Restoration Act of 1984, 98 Stat. 1585 (popularly known as the Hatch-Waxman Act), seeking approval to market generic copies of Lilly’s olanzapine products prior to the expiration of the ’382 patent. 10. Pursuant to 21 U.S.C. § 355(j)(2)(B)(ii), Zenith, DRL, and Teva sent letters to Lilly to notify it that they had filed ANDAs for olanzapine in various dosages. 11. Lilly filed suit against Zenith, DRL, and Teva alleging infringement of the ’382 patent under 35 U.S.C. § 271(e)(2)(A). The court consolidated Lilly’s suits against Zenith, DRL, and Teva into this single action. See e.g., Entries of February 15, 2002; April 11, 2002; November 1, 2002; and March 14, 2003. 12. Lilly seeks an order (1) prohibiting FDA approval of the Defendants’ generic olanzapine products prior to the expiration of the ’382 patent, in accordance with 35 U.S.C. § 271(e)(4)(A); and (2) enjoining the Defendants from the commercial manufacture, use, offer to sell, sale, or importation of their olanzapine products, in accordance with 35 U.S.C. § 271(e)(4)(B). Complaint, filed April 2, 2001, Prayer for Relief. 13. After the commencement of the suit, Zenith and DRL stipulated that “if the Court finds the ’382 patent valid and enforceable, then their actions constitute infringement.” Entry, December 2, 2003 at 2. The parties further stipulated that the only method-of-use claims to be tried in this case are claims 7 and 8 of the ’382 patent relating to the treatment of schizophrenia. Stipulation and Order entered on July 31, 2003 at p. 3. Therefore, the issues before the court are the validity and enforceability of claims 1, 2, 3, 7, 8, and 15 of the ’382 patent. 14. Teva did not participate in the trial but agreed to be bound by the decision of the court herein. Entry on Joint Stipulation and Staying Actions, July 16, 2003. II. Background in the Relevant Field Prior to the Prosecution of the ’382 Patent A. Schizophrenia 15. Schizophrenia is a chronic, debilitating mental illness that appears during late adolescence or early adulthood and essentially lasts the lifetime of the patient. Paul Tr. 109:17-110:1. 16. Some of the symptoms of schizophrenia include, but are not limited to, “positive” symptoms and “negative” symptoms. “Positive” symptoms include hallucinations, delusions, and thought disorders. See, e.g., video clip at TX 1446.1. “Negative symptoms” include loss of emotional and mental functioning, loss of motivation, loss of normal emotional response to other people, slowness of thinking, memory deficits, changes in speech (speaking in a dull monotone), and difficulties with cognition, sustained attention, decision-making, and mental flexibility. Paul Tr. 108:2-25, 109:1-16; Schulz Tr. 2972:1-5. B. Early Drug Treatment — Typical Antipsychotic Drugs 17. Prior to the discovery of antipsy-chotic medications in the 1950s, most schizophrenic patients were isolated from society and kept in large asylums. Paul Tr. 110:10-19. This pattern of lifetime institutionalization for ' schizophrenic patients began to change in 1952 with the introduction of chloropromazine and continued through the later introduction of haloperidol in the 1960s. TX 1398 at 746; Paul Tr. 111:2-9. These early antipsy-chotic medications (known as “typical” an-tipsychotics) showed substantial reduction of positive symptoms and allowed a number of patients to leave institutional settings. TX 1398 at 746; Paul Tr. 111:12-112:4. 18. However, the typical antipsychotic medications did little to treat the symptoms of schizophrenia and also induced a number of “sometimes severe and intolerable neurological side effects.” TX 1398 at 746; Paul Tr. 112:8-13. Such side effects associated with so-called extrapyramidal symptoms or “EPS” led to gross movement disorders, such as disfiguring tremors, stiffness, tics, and writhing. A particularly severe form of EPS, called “tardive dyskinesia,” persisted even after medications were withdrawn. Paul Tr. 113:22-114:1. In addition, patients experienced elevation of the hormone prolactin that led to breast engorgement and milk production in both male and female patients. Paul Tr. 112:5-115:12. C. Clozapine: The First Atypical An-tipsychotic 19. In the late 1960s and early 1970s, it became apparent that a drug called “cloza-pine” could treat the psychotic symptoms without EPS or prolactin elevation, causing it to be recognized as the first “atypical” antipsychotic. Paul Tr. 116:6-117:2; Nichols Tr. 2743:9-13. 20. In 1975, clozapine was withdrawn from the market in many countries because it was found to cause an often fatal blood disorder called “agranulocytosis” in approximately one percent of patients. This effect, and resulting withdrawal of the drug from the market, prompted people in the pharmaceutical industry to start looking for a drug like clozapine, but without the same side effect profile. Nichols Tr. 2743:14-2744:9; Paul Tr. 131:8-11; Schulz Tr. 3004:15-20. , D. The Search for a Safe, Atypical Antipsychotic Drug 21. The general failure for many years to find a clozapine replacement was reflected in the scientific literature. TX 1356, Nichols Tr. 2750:17-2752:2. The literature contains many reports of promising compounds which failed either for lack of efficacy or because -of toxic side effects. TX 1356; TX 1383; TX 1593; TX 1594; TX 1595; Nichols Tr. 2751:5-2769:24; see also Tupper Tr. 242:22-243:10, 246:9-247:8; TX 1595 (summarizing various scientific publications that reported the efforts of major pharmaceutical companies to find safe and effective antipsychotic medications). 22. In late 1989, the FDA approved clozapine for limited use in the United States notwithstanding its adverse side effects, as a therapy of last resort to be used only with careful blood monitoring. Paul Tr. 117:25-118:13. 23. In 1991, the New England Journal of Medicine reported that, “[djespite the extensive developmental effort in- this area, no alternative to clozapine has been identified that has clinical antipsychotic efficacy and no extrapyramidal neurologic side effects, but has a low risk of inducing other important toxic effects (bone marrow suppression' or seizures).” TX 1398 at 747. 24. Clozapine and certain other “typical” antipsychotics on the market such as chlorpromazine and haloperidol, had a “neuroleptic substituent,” an electron withdrawing group believed to be important for antipsychotic activity. The most common neuroleptic substituent has a halogen atom. The term “halogen” refers to either a fluorine or a chlorine atom. Tupper Tr. 414:9-418:18, 487:13-488:1. E.Lilly’s Attempts to Discover a Safe, Atypical Antipsychotic Drug 25. In the late' 1970s and early 1980s, Lilly produced a novel class of compounds called thienobenzodiazepines. Tupper Tr. 428:23-429:25. Thienobenzodiazepines are tricyclic compounds having “thieno,” “ben-zo,” and “diazepine” rings fused together. 26. In 1975, Lilly filed a patent application related to these compounds. In 1978, the PTO issued two patents, U.S. Patent No. 4,115,568 (“the ’568 patent”), TX 1408, and U.S. Patent No. 4,115,574 (“the ’574 patent”), TX 3129, having identical technical disclosures, but different claims. Tup-per Tr. 429:16-20, 431:4-19. Dr. Jibán Chakrabarti (“Dr. Chakrabarti”) and Dr. David Tupper (“Dr. Tupper”) are listed as the named inventors on the ’568 patent and the ’574 patent. TX 1408; TX 3129. 27. The ’568 and ’574 patents described the members of this class of new compounds as “useful in the treatment of ... certain kinds of psychotic conditions ...” TX 3129, col. 13, 11. 62-66; TX 1408, col. 14,11. 41-42. 28. The ’574 patent identifies the characteristics of the most preferred class of compounds within this family. TX 3129, col. 4, 11. 27-29. From this most preferred class, the patent identifies one particularly active compound as 2-ethyl-7-fluoro-10-(4’-methyl-l’-piperazinyl)-4H-thieno[2,3-b][l,5]benzodiazepine, known throughout this trial as “ethyl flumeza-pine.” Tupper Tr. 431:20-432:8. 29. Lilly, like many others in the field, modeled its lead candidates after cloza-pine, having a halogen atom in the molecule. Nichols Tr. 2751:5-2757:14; TX 1356 at 806; Tupper Tr. 413:21-414:9, 503:20-21; Pullar Tr. 200:20-201:3. Clozapine has a chlorine atom (Cl) at a position analogous to the fluorine atom (F) in ethyl flumezapine. 30. Other than the broad genus claimed in claim 1, Lilly’s ’574 patent claimed only compounds with a halogen. TX 3129, col. 39, claims 2-7; Tupper Tr. 433:5-14; Nichols Tr. 2749:5-9. 31. Beginning in the fall of 1974, Lilly made a compound like ethyl flumezapine, but without the fluorine atom, which corresponds to ethyl olanzapine, a compound otherwise known as “compound ’222”. Tup-per Tr. 426:23-427:10; TX 1205. 32. From the very earliest tests of the ethyl flumezapine and compound ’222 molecules, it was apparent that the fluorine-containing molecule (ethyl flumezapine) was much more active in tests believed to be relevant to potential antipsychotic activity than the molecule without the fluorine (compound ’222). Tupper Tr. 428:9-15. 33. After a year and a half of preclinical development work aimed at taking ethyl flumezapine into human clinical trials, disaster struck. In a six-month toxicology study with dogs, conducted at 4, 8, and 12 mg/kg using three dogs of each sex at each dose level, blood disorders, reminiscent of the potentially fatal blood disorder seen with clozapine in humans, were seen in dogs at all dose levels. TX 1035; TX 3421; Pullar Tr. 175:14-176:23. In particular, the toxicology tests in dogs showed widespread neutropenias in all dose groups and one anemia. Neutropenia is a reduction of white blood cells. Some of the dogs had reductions as much as 75% of their normal value. TX 3421; Emmerson Tr. 542:6-21. 34. In an effort to find a compound in the class free of this problem, Lilly conducted a comparative toxicology test between ethyl flumezapine and a closely related compound called “flumezapine.” TX 1003; Pullar Tr. 177:23-178:14. The difference between ethyl flumezapine and flumezapine is that in the two position on the thiophene ring where ethyl flumeza-pine has an ethyl group (-CH2-CH3), flumezapine has a methyl group (-CH3). Pullar Tr. 178:1-7. 35. During the comparative dog study, two of the ethyl flumezapine-treated dogs, but none of the flumezapine-treated dogs, developed blood problems. Pullar Tr. 180:11-19; TX 1003, 1004. As a result, Lilly terminated the development of ethyl flumezapine and commenced the development of flumezapine in early 1978 under the guidance of Dr. Ian Pullar (“Dr. Pul-lar”). Pullar Tr. 180:23-181:1; Hotten Dep. 71:12-72:10. 36. Lilly spent the next four years developing flumezapine through preclinical testing and initial safety testing in normal human volunteers. Pullar Tr. 185:20-188:12; TX 1008; TX 1010. Among other tests, Lilly conducted a six-month dog study of flumezapine, Emmerson Tr. 544:23-545:24; TX 1005, and a safety trial in normal human volunteers. TX 1010 at ZYP 177 1715-19. Then, in the spring of 1982, during the first trial of flumezapine in actual schizophrenic patients, administered at and below therapeutic doses, several patients experienced elevations in the muscle enzyme creatinine phosphokinase (ór “CPK”) and in a variety of liver enzymes. Pullar Tr. 188:13-189:14, 195:15-198:16; TX 1015 at ZYP 177 1998-99; Hotten Dep. 70:14-71:11. 37. The findings were reported by telephone to the FDA. TX 3259. That afternoon, Dr. Paul Leber in the Division of Neuropharmacology Drug Products at the FDA, halted U.S. clinical testing when he “advised that patients be withdrawn from the drug as soon as possible.” TX 3260. 38. Similarly, the British regulatory authority “expressed surprise at the magnitude of the increases in liver enzymes and especially the levels of CPK,” noting that- they “had not experienced anything similar.” TX 1615. After Lilly informed the agency of these results, the agency withdrew the United Kingdom (“U.K.”) authorization for clinical testing, and Lilly terminated the flumezapine clinical trials. Pullar Tr. 190:20-194:11; TX 1042. 39. Neither the failure of the flumeza-pine clinical trials nor the reasons for it (muscle or liver enzyme elevations) were publicly reported. Reith Tr. 927:9-11; Nichols Tr. 2776:18-2777:3; TX 1356 at 809. F. The Discovery of Olanzapine 40. After the failure of flumezapine in clinical trials, a team led by Dr. Tupper at Lilly created another group of compounds in the same series in an effort to find another compound that could be developed as a clozapine replacement and that would not meet the same fate in the clinic as flumezapine. Tupper Tr. 441:23-443:2, 446:2-447:17; TX 1229-40. 41. The cause of flumezapine’s toxicity Was unknown. Tupper Tr. 443:3-20. Speculation abounded inside Lilly regarding possible causes, including reactions involving the “piperazine nitrogen” and the fluorine atom. The distal piperazine nitrogen is dem-ethylated and the nitrogen and adjacent carbon oxidised as with other N-methylpiperazinyl compounds. If this is the source of the toxicity it is unlikely that it can be reduced without losing the neuroleptic activity. The 7-fluorine is replaced by hydroxy and methylthio groups .... [wjhether the source of this toxicity is the reduction in glutathione levels, a metabolic intermediate or the methylthio metabolite itself is at present, unknown. The hydroxylation metabolic pathway could also be implicated. TX 3657 at ZY 80 94. 42.' Compounds with ethyl groups (like ethyl flumezapine and ethyl olanzapine (compound ’222)) were not considered for further development because the ethyl group was believed by some at Lilly to produce agranulocytosis in dogs. TX 3657 at ZY 80 94; Tupper Tr. 443:6-444:20; Hotten Dep. 79:6-80:8, 81:11-19. 43. Several fluorinated and unfluorinat-ed alternatives were made and tested, including the compound known as olanzapine (then known simply as “LY170053”). Hot-ten Dep. '42:5-16, 43:20-44:8, 45:1-17. Olanzapine was first synthesized in the U.K. by Terrence Hotten (“Mr. Hotten”), a research chemist at Lilly, on April 29, 1982. Tupper Tr. 446:2-14; TX 1229. 44. Olanzapine differs from flumeza-pine by having a hydrogen atom (conventionally not shown on structural diagrams) where flumezapine has a fluorine atom. Pullar Tr. 199:16-24; Hotten Dep. at 42:21-43:6. A number of people doubted that olanzapine would work because it lacked the halogen atom then known to be important to the activity of clozapine and believed to be important for activity in this series of compounds as well. Pullar Tr. 200:20-201:3; Tupper Tr. 451:7-20. Indeed, olanzapine was believed, based on a variety of preclinical tests, to be only about half as potent as flumezapine. Pullar Tr. 201:10-18; Tye Dep. 71:21-72:21, 75:21-76:12; TX 3657 at ZY 80 100-101, 103 (comparing two compounds). 45. In 1983, Lilly began by testing olanzapine in dogs — first in a three-month study and later in a one-year study. Em-merson Tr. 546:23-547-6, 552:14-17. During each of the studies, one dog developed a blood problem. Emmerson Tr. 546:19-24, 552:18-553:7. After extensive testing, Lilly determined that the effect in dogs appeared to be an immune response and “idiosyncratic” in nature, meaning it occurred due to the unusual sensitivity in individual dogs. Emmerson Tr. 549:22-550:23, 554:18-555:15. Only then did Lilly determine that it might cautiously proceed with human trials of olanzapine. Emmer-son Tr. 550:14-551:8, 555:6-15. 46. In 1986 and 1987, Lilly conducted Phase 1 clinical trials of olanzapine in healthy human volunteers in Indianapolis, Indiana. Goldberg Tr. 307:9-21; TX 3741; TX 3742; TX 3744. At the conclusion of these trials, Lilly proceeded to the litmus test of olanzapine — a clinical trial to test the compound’s efficacy in actual schizophrenic patients. Goldberg Tr. 326:25-327:20. These clinical trials took place in the U.K. TX 1058; TX 1064. 47. Toward the end of 1989, the clinical trials were promising. In the first test of the drug in actual schizophrenic patients, olanzapine appeared to be a safe and effective, atypical antipsychotic drug having a more favorable side effect profile than typical antipsychotics in terms of EPS and not producing the blood disorders in patients. Goldberg Tr. 335:19-20, 344:14-22, 345:6-9; TX 1063; TX 1064 at ZYP 520 983-84. 48. On January 18, 1990, the olanza-pine project team reported the success of the clinical trial to Lilly’s Research Management Staff (“RMS”), and the RMS agreed to “product commitment.” TX 1063 at ZYP 449 1132. After the project team report, the project was referred to with words like “AAA priority” and the “Manhattan Project” (in reference to the scientific push to develop the atom bomb), TX 3532, and Lilly scientists made plans for expanded clinical trials on the compound. Goldberg Tr. 338:21-340:7; TX 1063 at ZY 449 1128. 49. In the fall of 1990, Lilly conducted another comparative dog toxicology study prior to filing a patent application with the PTO. The study was designated D07290, and is known throughout this litigation as the “D07290 Dog Study” or “D07290 Study.” 50. The purpose of the D07290 Study was to determine over the course of a chronic treatment period whether there was a difference in the toxicity profile between olanzapine and compound ’222. Symanowski Tr. 664:4-665:13, 668:24-669:4, 2077:9-18; TX 3439 at ZYP 187 713, Item 4. 51. At the conclusion of the D07290 Study, Lilly claimed that the results of the study showed that olanzapine was unexpectedly superior to compound ’222 in that olanzapine did not cause a significant elevation in average mean cholesterol versus compound ’222. TX 1001.1 at FH 17-18. 52. The D07290 Dog Study is at the heart of this case and is discussed at length in this opinion. III. Prosecution History of the ’382 Patent A. The T43 Patent Application 53. On April 23, 1991, Lilly filed U.S. Application Serial No. 690,143 (“the Y43 application”). TX 1000, col. 1,11. 4-5. 54. Lilly had previously filed a patent application in the U.K. on April 25, 1990, and perfected the priority date. Pursuant to 35 U.S.C. § 119, Lilly is entitled to the April 25, 1990 date for purposes of determining the relevant scope and content of the prior, art. Killworth Tr. 769:15-770:16, TX 1000. 55. As part of the 143 patent application, Lilly was required to fill out an Information Disclosure Statement (“IDS”) to inform the Patent Examiner (“Examiner”) of the most closely related prior art. In Lilly’s IDS, Charles Ashbrook (“Mr. Ash-brook”), Assistant General Patent Counsel at Lilly, represented that the most closely related prior art was the matter claimed in the ’568 patent. TX 1001.1 at FH 44-45. 56. Though the patent applicants did not cite the Examiner to either the ’574 patent or Chakrabarti et ah, k-Piperazi-nyl-10H-thieno[2,3-b][l, 5Jbenzodiaze-pines as Potential Neuroleptics, J. Med. Chem. 23:878-84 (1980) (“Chakrabarti 1980a ”), the Examiner performed a search of the prior art, found those references, and cited them in the Office Action. ' TX 1001.1at FH 48-53. 57. In the 1991 IDS, Lilly told the Examiner that compound ’222, described in the ’568 patent, is the adjacent homolog to olanzapine, but that olanzapine is patentable over the disclosure in the ’568 patent because of the “surprising biological differences of the 2-methyl derivative (olanzapine) over the 2-ethyl derivative (compound ’222).” TX 1001.1 at FH 44. 58. Also in the 1991 IDS, the patent applicants told the Examiner that flumeza-pine, which is the 7-fluoro derivative of olanzapine, “caused significant adverse effects when administered to humans” and that olanzapine “has an unexpectedly superior therapeutic profile.” TX 1001.1 at 45. 59. In the ’143 application, the applicants represented that: “In dog toxicity studies with a closely analogous compound 2-ethyl-10-(4-methyl-l-piperazinyIMH-thieno[2,3-b][l,5] benzodiazepine [compound ’222], at a dosage of 8 mg/kg, it was observed that four out of eight dogs showed a significant rise in cholesterol levels, whereas the compound of the invention did not show any rise in cholesterol levels.” TX 1001.1 at FH 17-18. This text corresponds to col. 3, 11. 29-36 of the ’382 patent, TX 1000, col. 3, 11. 29-36, and is a reference to the D07290 Dog Study. Plaintiffs’ Reply to Amended Answer to Complaint for Patent Infringement, Affirmative Defenses, And Counterclaims of Zenith Goldline Pharmaceuticals, Inc. (filed September 20, 2002) (“Lilly’s Reply”), ¶ 19. 60. In the ’143 application, Lilly stated that seventeen patients received flumeza-pine before the clinical trial was terminated after consultation with the FDA because of an unacceptably high incidence of raised enzyme levels in the treated patients. Specifically, “creatinine phosphoki-nase (CPK) and the liver enzymes, serum glutamate oxalacetic transmaninase (SGOT) and serum glutamate pyruvate transaminase (SGPT), estimated in the blood samples from the patients, were substantially in excess of normal values, indicating the possibility of toxicity.” TX 1001.1at FH 15. With respect to olanza-pine, Lilly stated only that “there is a low incidence of only mild and transient elevation of liver enzymes in patients treated with therapeutic doses, and plasma levels of ... CPK are lower than with flumeza-pine, indicating a lower adverse effect on muscular tissue.” TX 1001.1 at FH 17. 61. The Examiner reviewed the claims for compliance with the enablement requirement of 35 U.S.C. § 112, the definiteness requirements of 35 U.S.C. § 112, for novelty under 35 U.S.C. § 102, for nonob-viousness under 35 U.S.C. § 103, and for obviousness-type double patenting. TX 1001.1at FH 49-51, 53; Killworth Tr. 778:10-24, 779:5-21, 781:13-19. 62. On November 25, 1991, the Examiner issued an Office Action with respect to the ’143 application rejecting all of the claims. TX 1001.1 at FH 48-53. 63. In evaluating novelty, the Examiner rejected Lilly’s claims under 35 U.S.C. § 102(b) as being “anticipated” by the ’574 patent, citing a portion of the text of the ’574 patent that was shared by the ’568 patent cited by Mr. Ashbrook in his IDS. Killworth 778:20-779:3; TX 1001.1 at FH 50. 64. The Examiner rejected all of the claims under 35 U.S.C. § 103 as obvious over the ’574 patent in view of Chakrabarti 1980a. TX 1001.1 at FH 51-53. The Examiner stated that “[i]t would have been obvious to one with ordinary skill in the art to replace the 2-ethyl substituent on the homologous species [compound ’222] taught in [the ’574 patent] with the 2-methyl substituent in order to obtain the instant compound [olanzapine] because [Chakrabarti 1980a ] specifically suggests to one with ordinary skill in the art that this type of substituent is preferably [sic ] to increase [central nervous system] activity.” TX 1001.1 at FH 51-52. 65. The Examiner considered the description of the unexpected cholesterol results in the application to be “insufficient” because “1) [n]o controls were run, 2) there is no evidence that such data is statistically significant and 3) that such data is necessarily showing a significant beneficial effect to the patient.” TX 1001.1 at FH 52; Killworth Tr. 780:10-17.' 66. Finally, the Examiner rejected Lilly’s claims under the judicially created doctrine of “obviousness-type double patenting” as being unpatentable over the claims of the ’574 patent in view of Chakrabarti 1980a for the same reasons that the claims were alleged to be obvious from the text of the ’574 patent in view of Chakrabarti 1980a under 35 U.S.C. § 103. TX 1001.1 at FH 53; Killworth Tr. 781:13-782:12. B. The ’348 Continuation Application 67. Lilly responded to the Office Action on May 22, 1992, by filing a file wrapper continuation application to extend the time period for response to the rejection. TX 1001.1 at FH 98-100; Killworth Tr. 782:16-783:13. This application was assigned the application serial number 890,-348 (the “ ’348 application”). TX 1001.1 at FH 98. 68. The ’348 application contained the same disclosure, including the claims, as the 143 application. In accordance with standard PTO procedure, the ’348 application was assigned to the same Examiner who had examined the 143 application. Killworth Tr. 782:16-783:25; TX 1001.1 at FH 98-100. 69. On September 11, 1992, the Examiner issued another Office Action rejecting the claims for the same reasons set forth in the prior Office Action in the 143 application. Killworth Tr. 784:1-22; TX 1001.1 at FH 102. 70. On December 10,1992, three representatives of Lilly conducted a personal interview with the Examiner in the ’348 application. The Lilly representatives were Macharri Yorndran-Jones (“Ms. Vorndran-Jones”) and Joseph Jones (“Mr. Jones”) from Lilly’s legal department, and Dr. James Emmerson (“Dr. Emmerson”), a Lilly toxicologist. TX 1001.1 at FH 109-10. 71. At the interview, Lilly presented eight declarations of Lilly employees to the Examiner extensively describing the results of comparative tests of olanzapine and compound ’222, including the D07290 Dog Study. TX 1001.1 at FH 125-54. 72. These declarations were submitted by Dr. Nicholas Tye (“Dr. Tye”), Dr. Pul-lar, Dr. Nicholas Moore (“Dr. Moore”), Dr. Jeffrey Means (“Dr. Means”), Dr. Emmer-son, Dr. David Wong (“Dr. Wong”), Dr. David Scruby (“Dr. Scruby”), and Dr. James Symanowski (“Dr. Symanowski”). TX 1001.1 at FH 125-27 (Tye), FH 128-30 (Pullar), FH 131-34 (Moore), FH 135-39 (Means), FH 140-42 (Emmerson), FH 143-45 (Wong), FH 146-48 (Scruby), FH 149-54 (Symanowski). Dr. Tye, Dr. Pul-lar, and Dr. Moore are pharmacologists; Dr. Means is a pharmacologist and toxicologist; Dr. Emmerson, as stated earlier, is a toxicologist; Dr. Wong is a biochemist; Dr. Scruby is a Lilly physician; and Dr. Symanowski is a statistician. 73. All declarations were submitted under 37 C.F.R. § 1.132 and all declarants swore that the statements made therein were true. TX 1001.1 at FH 125-54. 74. Dr. Moore’s declaration analyzed the results of behavioral tests in which animals were administered olanzapine or compound ’222. TX 1001.1 at FH 131-34. Dr. Moore concluded that in the conditioned avoidance response (“CAR”) test, olanzapine was more active. TX 1001.1 at 132. He also concluded that out of the four tests he conducted — the apomorphine-induced climbing and hypothermia tests in mice, the CAR test in rats, the catalepsy-induction in rats, and the locomotor activity in rats — “both compounds have very similar dopamine antagonist activity in vivo,” TX 1001.1 at 134. 75. Dr. Pullar presented the results of in vitro testing of olanzapine and compound ’222 using binding assay tests. The results were presented in two tables showing the respective IC60 values for each compound in each of the tests. No argument was made that the compounds could be differentiated based on the results of these tests. TX 1001.1 at FH 128-30. 76. Dr. Tye’s declaration discussed his examination of the data set out by Dr. Moore and Dr. Pullar and his views on the D07290 Dog Study carried out by Dr. Means and the results thereof. TX 1001.1 at FH 124-27. Dr. Tye concluded that: (1) the data of Dr. Moore and Dr. Pullar suggested “little difference in the properties of [olanzapine and compound ’222]”; (2) the data from the dog toxicology study “show[ed] significantly increased levels of cholesterol in the case of [compound ’222],” (3) raised cholesterol levels resulting from compound ’222 are a serious disadvantage because cholesterol is a factor in coronary heart disease in humans, and (4) olanza-pine “is clearly and significantly superior to [compound ’222] so far as it has been shown in the toxicity study by Dr. Means to lack any tendency to raise cholesterol levels.” TX 1001.1 at FH 126. 77. Dr. Wong’s declaration evaluated data obtained from radioligand and binding studies of olanzapine and compound ’222. TX 1001.1 at FH 143-45. In part, Dr. Wong concluded that “both olan-zapine and [compound] ’222 can produce functional responses at 5-HT10 and 5-HT2 receptors.” TX 1001.1 at FH 145. 78. Dr. Emmerson oversaw the Lilly D07290 Dog Study. He stated in his declaration that he believed that “olanzapine displayed an unexpected and significant superior toxicological benefit over compound ’222” with respect to the elevation of serum cholesterol in female dogs dosed with 8 mg/kg of compound ’222 compared with dogs similarly dosed with olanzapine and the control dogs. TX 1001.1 at FH 142. Dr. Emmerson believed that this toxicological benefit was a critical property to consider in the safety analysis of the two compounds and that he “would not recommend the clinical development of a compound which significantly increases the serum cholesterol levels in dogs when there is a compound with similar activity which does not affect serum cholesterol levels.” TX 1001.1 at FH 142. 79. Dr. Means was the study director for Lilly’s D07290 Dog Study. His declaration summarized the design, conduct, and findings of the study. TX 1001.1 at FH 134-39. a. Dr. Means stated that “[sjuprisingly serum cholesterol levels in females of the 8 mg/kg-’222 treatment group were significantly increased when compared to the cholesterol levels of females in either the 8 mg/kg-olan-zapine treatment group or the control group.” TX 1001.1 at FH 137. b. Dr. Means also stated that “[n]o significant differences in serum cholesterol levels were detected among the olanzapine treatment and control groups.” TX 1001.1 at FH 137. c. Dr. Means concluded that “the toxicity of olanzapine and compound ’222 in beagle dogs is similar in many respects,” but that “[a]n unexpected difference between olanzapine and compound ’222 was the significant increase of serum cholesterol concentrations with time in female dogs given 8 mg/kg/day of compound ’222 compared to the cholesterol values in female dogs given 8 mg/kg/day [of] olanzapine and compared to the cholesterol values in female control dogs.” TX 1001.1 at FH 139. 80. Dr. Scruby stated that he reviewed Dr. Means’ and Dr. Symanowski’s declarations, and that those declarations provided the basis for Dr. Scruby’s clinical statements concerning the dog toxicology studies. TX 1001.1 at FH 146-48. a. In his declaration, Dr. Scruby discussed his knowledge of the risk associated with elevated total cholesterol in humans and stated that “any factor which leads to an increase in serum lipids [] can have a significant deleterious effect on [cornary artery disease and the progression of atherosclerosis].” TX 1001.1 at FH 147-48. b. Dr. Scruby concluded that based on the findings of the study in which the serum cholesterol female dogs treated with compound ’222 after 60 days averaged nearly 260mg/dl and “[i]n view of the overwhelming evidence in the literature that serum cholesterol in excess of 240 mg/dl is a significant contributor to the genesis of atherosclerosis,” he believed that “the significant elevation of serum cholesterol observed in female dogs treated with the ’222 compound could provide a marked clinical difference in the pathogenesis of coronary artery disease.” TX 1001.1 at FH 148. 81.Dr. Symanowski’s declaration summarized the statistical tests used in the D07290 Study. TX 1001.1 at FH 149-54. He reported that cholesterol levels in 8 mg/kg compound ’222 female dogs were noticeably elevated after day 25 of treatment and that statistical analysis indicated that these levels increased significantly over time when compared to both the 8 mg/kg olanzapine female dogs and the control group, whereas none of the olanza-pine-treated groups were statistically significantly different from control. TX 1001.1 at FH 150-51. He presented three graphs illustrating mean cholesterol levels over time. Figure 1 presented the group mean cholesterol values throughout the study for all of the groups of female dogs. TX 1001.1 at FH 152. Figure 2 presented the same information for the groups of male dogs. TX 1001.1 at FH 153. The data presented by Dr. Symanowski showed no significant difference between olanza-pine and compound ’222 with respect to cholesterol in male or low-dose female dogs. Figure 3 illustrated the mean values plus and minus one standard error for the cholesterol levels in female dogs dosed with 8 mg/kg of compound ’222 and olanza-pine, as well as the female control group. TX 1001.1 at FH 154. 82. Following the interview, the Examiner prepared a short, handwritten summary of the interview indicating that the Lilly representatives and the Examiner discussed the declarations. TX 1001.1 at FH 109. The Examiner reported in his summary that while “the reviewed data looked sufficient pending final review and analysis of the complete set of data,” an agreement was not reached as to patenta-bility. TX 1001.1 at FH 109. 83. Following the interview, the patent applicants presented to the PTO a document entitled “Response After Final.” TX 1001.1 at FH 112-24. 84. In the Response After Final, the patent applicants argued that “olanzapine exhibits the significant beneficial property of preserving the natural balance of cholesterol 'synthesis in the treatment of schizophrenia and schizophreniform disorders.” TX 1001.1 at FH 119-20. 85. In the Response After Final, the patent applicants also argued that Lilly’s “probative evidence of olanzapine’s superiority in one or more properties is sufficient to overcome the jprima facie obviousness rejection.” TX 1001.1 at FH 120. 86. To overcome a prima facie obviousness rejection, a patent applicant can respond to the rejection or the applicant can attempt to overcome the rejection by filing declaratory evidence. Sofocleous Tr. 959:15-960:6; Killworth Tr. 789:4-16. 87. While Lilly did not acquiesce to the Examiner’s determination that the claims were prima facie obvious, it did not advance specific argument to challenge this finding. TX 1001.1 at FH 117, 124 (indicating Lilly’s intent not to admit prima facie obviousness); Vorndran-Jones Tr. 1611:3-7; Killworth Tr. 789:4-790:2; Sofo-cleous Tr. 789:15-22. 88. In the Response After Final, Lilly made several significant statements. a. “Dr. Means’ Declaration demonstrates that the blood cholesterol levels of female dogs treated with the ’222 derivative were significantly elevated when compared to the blood cholesterol levels of dogs treated with the 2-methyl (olanza-pine) compound.” TX 1001.1 at FH 120-21. b. “No significant increase in cholesterol levels was observed in either the olanzapine treated dogs or the control dogs.” TX 1001.1 at FH 120. c. “[Vjalid controls were included in the study as substantiated by Dr. Means’, Dr. Emmerson’s, and Dr. Symanowski’s Declarations.” TX 1001.1 at FH 121. . d. “Statistically significant elevated blood cholesterol levels occurred in the ’222 treated dogs, as demonstrated by Dr. Symanowski’s Declaration.” TX 1001.1 at 121. e. “Dr. Tye declares that pharmacolog-ically there is little difference between olanzapine and ’222; however, he states that olanzapine is clearly and significantly superior to the ’222 compound based on olanzapine’s toxicological benefit.” TX 1001.1 at FH 122. 89. On December 17, 1992, the Examiner issued a Notice of Allowability of all of the pending claims of the ’382 patent, meaning that he had determined that the requirements for patentability had been met and that all previous rejections were withdrawn. TX 1001.1 at FH 156. 90. The Examiner noted that the Notice of Allowability was in response to “Amendment B [Lilly’s Response After Final] and the declarations filed 12/10/92.” TX 1001.1 at FH 156; Killworth Tr. 792:16, 793:16. 91. On July 20, 1993, the PTO issued the ’382 patent. TX 1000; TX 1360. The named inventors are Dr. Chakrabarti, Dr. Tupper, and Mr. Hotten. IV. The Validity of the ’382 Patent A. Anticipation 1. Anticipation by Chakrabarti 1980a 92. Defendants argue the claims of the ’382 patent are anticipated by Chakra-barti 1980a. One of the authors of that scientific article is Dr. Chakrabarti of Lilly. TX 3465. 93. The Chakrabarti 1980a publication describes several variations of the 4-piper-azinyl-10H-thieno[2,3-b][l,5]benzodiaze-pine family of compounds and examines specifically three areas on the structure of the family of molecules. TX 3465; Reith Tr. 820:14-821:10; 827:18-828:3. 94. All compounds .examined in Chak-rabarti 1980a had a common structural nucleus with different substitutions at three places: the piperazine ring, the benzene ring, and the thiophene ring. TX 3465; Reith Tr. 827:18-828:3. The authors labeled these three areas for substitution “R”, “Rj”, and “R2”. TX 3465. 95. Only particular substituents for each disclosed compound are listed in a table. TX 3465 at 880-82. 96. In total the authors examined forty-five specific compounds (as opposed to a genus of compounds) in the 4-piperazinyl-10H-thieno[2,3-b][l,5]benzodiazepine family and 14 analogous 5-piperazinyl-substi-tuted 4H-thieno[2,3-b][l,4]benzodiaze-pines, created “[t]o compare the activity.” TX 3465 at 879, 880-82. Significantly, olanzapine was not one of the compounds the authors examined. TX 3465; Reith Tr. 828:7-9. 97. To arrive at their conclusions about which compounds were preferred, the authors tested the compounds by using three different animal behavioral tests: the mouse hypothermia test, the CAR test, and the rat catalepsy (“CAT”) test. TX 3465; Reith Tr. 821:16-826:5. Of these, the tests of special interest were the CAR and the CAT test. Pullar Tr. 254:4-11. 98. The CAR test evaluates the inhibition of a behavioral response in rats. Reith Tr. 822:19-823:13. In this test, inhibition is expressed on a scale from zero to five where a score of zero' reflects minor inhibition, and a score of five represents severe inhibition. Reith Tr. 823:8-13. 99. The CAR test was the only measure of potential antipsychotic activity, and if the compound did not achieve a CAR score of three or four at a dose of less than 30 mg/kg, it was not considered active. Nichols Tr. 2768:16-2769:11. 100. A “good score” in the CAR test— a three or four — indicates a desirable blockade of dopamine receptors. Reith Tr. 823:22-24; Pullar Tr. 222:25-223:1. Clozapine, the benchmark compound, had a ■ CAR score of three. LaVoie Tr. 1568:11-15. 101. The CAT test evaluates cataleptic behavior in rats following administration of a compound. The scores in this test reflect group scores, with a group consisting of eight animals. The higher the score the more catalepsy observed in the group. Reith Tr. 824:8-825:16. 102. Generally, for purposes of determining whether a compound has the potential to be an effective atypical antipsy-chotic, a scientist would like to see a “separation of activity” — i.e., a good score on the CAR test at a dose that would not get a high score on the CAT test. Reith Tr. 826:6-23; Pullar Tr. 254:4-15. 103. However, a separation between the CAR and CAT scores only came into play if the first condition — a good CAR score — was met. Moore Dep. 82:5-22, 83:9-84:6, 86:5-14. The separation of activity between the CAR and CAT scores was thought to be relevant to the potential absence of EPS at an active or potentially therapeutic dose. The separation, by itself, is not a measure of activity. Moore Dep. 83:9-84:6, 86:5-14. 104. Chakrabarti 1980a identified five specific compounds (9, 12, 17, 29, and 34) that were “found to be more potent than clozapine and show similar, if less marked, separation of activity in [the CAR and CAT] tests.” TX 3465 at 878, 883. 105. The five preferred compounds had a CAR score of three or better. LaVoie Tr. 1568:16-18. 106. With respect to these five preferred compounds, the authors expressed a preference for specific, complete compounds; they did not express a preference for a genus of compounds having any and all combinations of the individual substitu-ents on those molecules. Nichols Tr. 2779:2-8 (“[A] preferred compound would have a combination of different substitu-ents that would lead it to have optimal activity. Removing one or more of those substituents would destroy that preference. So the compound would be taken as a whole.”); LaVoie Tr. 1567:11-19. 107. Four of the five preferred compounds (9, 12, 17, and 29) have a fluorine at the 7-position of the benzene ring (compound 29 contains two fluorine atoms, one at the 7-position and one at the 8-posi-tion). Tupper Tr. 437:4-11; Nichols Tr. 2749:9-18, 2780:2-9; TX 3465 at 880-81. The fifth, compound 34, does not contain a fluorine on the benzene ring, but contains a hydroxyethyl group on the piperazine ring. Tupper Tr. 437:12-16; Nichols Tr. 2749:9-18, 2780:11-19; TX 3465 at 881. These two components were generally recognized at the time of the publication of Chakrabarti 1980a to enhance antipsychotic activity. LaVoie Tr. 1564:6-1565:4; Nichols Tr. 2785:18-2787:22; TX 3123 at 396-97. Olanzapine does not include either of these substituents. Reith Tr. 902:5-8; LaVoie Tr. 1564:16-18. 108. The authors did not list compound 6, the freebase of compound ’222, as a preferred compound. TX 3465. Compound 6 had a CAR score of two. TX 3465 at 880; LaVoie Tr. 1568:11-15. 109. In addition to the preferred compounds, the authors discussed the authors’ preferred substituents. Reith Tr. 897:6-12. For example, the authors expressed a preference for position 7 by stating that “[t]he substitution of the phenyl ring with a halogen atom (Cl, F) at position 7 enhanced the activity” and that the “7,8-difluoro compound (29) retained good activity.” TX 3465 at 879, col. 2. The text never states a preference for a hydrogen at position 7, as is required for olanzapine. In addition, the authors mentioned three specific substituent groups thought to be helpful: three R groups (methyl, hydrox-yethyl, and hydroxypropyl), three Rx substitutions (7-F, 7-C1, 7,8-di-F, explained above), and three R2 groups (2-methyl, 2-ethyl, and 2-isopropyl). TX 3465 at 879. No possible combination of these preferred substituents, i.e., a preferred R with a preferred Rj and a preferred R2, would generate olanzapine because all of these combinations contain a fluorine (F) or a chlorine (Cl) atom at position 7 where olanzapine has only a hydrogen. Reith Tr. 897:16-898:21; LaVoie Tr. 1566:2-12; Nichols Tr. 2777:4-2778:6; TX 3465 at 879. 110. Because none of the forty-five specific compounds disclosed in Chakrabarti 1980a include olanzapine, none of the five preferred compounds disclosed in Chakra-barti 1980a include olanzapine, and none of the preferred substituents include a hydrogen at position 7 as is required for olanza-pine, the court finds Chakrabarti 1980a does not describe olanzapine. 111. The court further finds that one of ordinary skill in the art, applying the preferences expressed in Chakrabarti 1980a, would not envision olanzapine. 112. The composition and method claims of the ’382 patent are directed to dosage forms containing specified amounts of olanzapine (e.g., claim 15) and methods of treating patients suffering from schizophrenia with specified doses of olanzapine (e.g., claim 8). Such dosage forms and methods are not described in Chakrabarti 1980a for any of the compounds disclosed in that article. See Findings of Fact ## 183-84. 2. Anticipation by Schauzu 113. DRL also argues that olanzapine is described as compound 11 in a scientific article entitled Schauzu, H.G. and Mager, P.P., A Free-Wilson Study of k-Piperazi-nyl-1 OH-thienobenzodiazepine Analogues, 38 Die PhaRmazie 562 (1983) (“Schauzu ”). 114. The biological data in Schauzu comes from Chakrabarti, J.K., et al., Effects of Conformationally Restricted lp-Pi-perazinylr-lOH-thienobenzodiazepine Neuroleptics on Central Dopaminergic and Cholinergic Systems, J. Med. Chem. 1133(1982) (“Chakrabarti 1982 ”). Nichols Tr. 2793:20-2794:9; LaVoie Tr. 1506:9-18; Reith Tr. 902:9-20. 115. The compounds disclosed in Chak-rabarti 1982 were fluorinated piperazine compounds. This means that the compounds had a fluorine in the 7-position and two nitrogens in the top ring (the pipera-zine ring). Nichols Tr. 2793:7-16. 116. The structure drawn in Schauzu is not a fluorinated piperazine compound because it is missing both a fluorine atom at the 7-position and one of the nitrogen atoms in the top ring. Nichols Tr. 2792:22-2795:19. Thus, the structure drawn in Schauzu is a piperidine compound- — not a piperazine as the title of the article otherwise sets forth. LaVoie Tr. 1532:5-19; Nichols Tr. 2789:3-23. 117. A piperidine compound has one nitrogen in the top ring (the piperidine ring), whereas a piperazine compound, as noted above, includes a second nitrogen substituent in the top ring (the piperazine ring). Nichols Tr. 2789:16-2790:1; LaVoie Tr. 1500:16-1501:10. 118. Schauzu was abstracted by both Chemical Abstracts and Beilstein as disclosing piperidine compounds. Nichols Tr. 2791:10-2792:18; LaVoie Tr. 1532:3-1535:17. 119. Olanzapine is a piperazine compound. Nichols Tr. 2795:12-16. 120. The structure drawn in Schauzu does not include olanzapine since the structure does not include a second nitrogen in the top ring. Nichols Tr. 2792:22-2795:19. 121. The biological data from Chakra-barti 1982 does not include olanzapine because olanzapine is an unflominated pi-perazine compound. Nichols Tr. 2789:24-2790:1, 2795:12-16. 122. In order to find that olanzapine is described as compound 11 in Schauzu, one with ordinary skill in the art would have to mentally insert a nitrogen atom into the structure depicted in Schauzu, thereby converting it into a piperazine compound (in this case, olanzapine), yet ignore the fact that the biological data reported in the Schauzu article was from Chakrabarti 1982, which discussed only fluorinated compounds. Compare LaVoie Tr. 1500:20-1501:2, 1504:4-1507:5, with Nichols Tr. 2793:20-2794:9, 2789:16-2790:1; Reith Tr. 902:9-20. 123. Olanzapine is not described as compound 11 in Schauzu. Nichols Tr. 2789:3-5. B. Obviousness 124. Lilly contends the discovery of olanzapine and its unique properties represent a nonobvious selection invention within the broad genus of compounds disclosed in the ’574 and ’568 patents. In other words, the ’382 patent, which specifically claims olanzapine, is a “species” falling within the broad “genus” claimed in the ’574 patent. Defendants contend that the claims of the ’382 patent are obvious under 35 U.S.C. § 103 over the disclosure of olanzapine in the ’574 patent in combination with Chakrabarti 1980a. They also contend the claims of the ’382 patent are obvious over the disclosure of flumezapine in the ’574 patent in combination with Chakrabarti 1980a and the Sullivan and Franklin article discussed infra., Findings of Fact § TV.B.l.d. 1. The Scope and Content of the Pri- or Art a. Clozapine and Clozapine-Like Molecules 125. The prior art included numerous failures to find a safe, atypical antipsychotic drug. See Findings of Fact § II.D. 126. As mentioned, clozapine, the first atypical antipsychotic, was withdrawn from the market in 1975. Thus, the challenge was to find a clozapine-like molecule that produced the benefits of clozapine without the adverse side effects. Nichols Tr. 2743:14-2744:9; Paul Tr. 131:8-11; Schulz Tr. 3004:15-20. 127. The prior art confirmed that small structural changes in clozapine-like molecules led to unpredictable changes in properties. Changing the position of the chlorine atom in clozapine changed it from an atypical antipsychotic to a typical antipsy-chotic. TX 3465 at 878 (“[Clozapine’s] 2-chloroisomer HF-2046 behaves like a classical neuroleptic ...”); Nichols Tr. 2796:16-2797:3; LaVoie Tr. 1543:23-1544:11; LD 45; LD 94. Changing the ring structure of clozapine led to variable and unpredictable toxicities. Tilozepine caused seizures. TX 1356, compound 3; TX 1365 at