Full opinion text
MEMORANDUM OPINION BURKE, United States Magistrate Judge. INTRODUCTION Plaintiff, Bristol-Myers Squibb Company (“BMS”), markets a medication under the trade name Baraclude® for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication, and either evidence of persistent elevations in serum aminotransferases or histologically active disease. (D.I. 135, ex 1 (hereinafter “Uncontested Facts”) at ¶¶ 21-23) The medication contains 0.5 mg and 1 mg of the compound entecavir in tablet form. (Id. at ¶ 22) The United States Food and Drug Administration’s (“FDA”) Approved Drug Products with Therapeutic Equivalence Evaluations (“Orange Book”) lists United States Patent No. 5,206,244 (the “ '244 Patent”)'in connection with BMS’s Baraclude product. (Id. at ¶ 9) Defendant Teva Pharmaceuticals USA, Inc. (“Teva”) filed án Abbreviated New Drug Application (“ANDA”) seeking approval to market a generic version of Baraclude for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication, and either evidence of persistent elevations in serum aminotransferases or histologically active disease. (Id. at ¶¶ 2425) On September 22, 2010, BMS initiated this litigation against Teva in connéction with the Paragraph TV certification contained in Teva’s ANDA. (Id. at ¶ 34) On August 8, 2012, the parties jointly consented to the Court’s authority to conduct all proceedings in this case, including trial, the entry of final judgment, and all post-trial proceedings. (D.I. 132) The Court held a bench trial from October 15, 2012 to October 18, 2012.. (D.I. 142; D.I. 143; D.I. 144; D.I. 145 (collectively, “Tr.”)) At trial, Teva contended that claim 8 of the '244 Patent is invalid as obvious under 35 U.S.C. § 103 (“Section 103”). (D.I. 151 at ¶ 8) Teva also asserted that the '244 Patent is unenforceable based on inequitable conduct committed by certain former BMS employees before the U.S. Patent and Trademark Office (“PTO”). (Uncontested Facts at ¶ 37; D.I. 151 at ¶ 8) The parties completed post-trial briefing on December 17, 2012. (D.I. 150; D.I. 151; D.I. 156; D.I. 157) The 30-month stay imposed, by 21 U.S.C. § 355(j)(5)(B)(iii) on the FDA in relation to granting final approval of Teva’s ANDA expires.on or around February 12, 2013. (Uncontested Facts at ¶ 30) As. explained below, the Court finds in favor of Teva as to invalidity, finding that Teva has demonstrated by clear and convincing evidence that Claim 8 of the '244 Patent is invalid as obvious under Section 103. The Court finds in favor of BMS with respect to inequitable conduct, finding that Teva has not met its burden to prove that certain then-BMS employees committed inequitable conduct before the PTO regarding the application that led to the issuance of the '244 Patent. Pursuant to Federal Rule of Civil Procedure 52(a), the Court hereby presents its findings of fact and conclusions of law. FINDINGS OF FACT I. BACKGROUND A. Nature and Stage of Proceedings 1. BMS is the holder of New Drug Application (“NDA”) No. 21-797 for a medication in tablet form containing 0.5 mg and 1 mg of entecavir. (Uncontested Facts at ¶ 21) 2. On March 29, 2005, the FDA approved the marketing of the medication described in NDA No. 21-797 for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication, and either evidence of persistent elevations in serum aminotransferases or histologically active disease. (Id. at ¶ 22) 3. BMS sells the medication described in NDA No. 21-797 in the United States under the trade name Baraclude. (Id. at ¶ 23) 4. Teva has filed ANDA No. 202122 seeking approval to market a generic version of Baraclude. (Id. at ¶24) Teva’s ANDA application, containing a Paragraph TV certification, constituted an act of infringement of claim 8 of the '244 Patent under 25 U.S.C. § 271(e)(2), to the extent that claim was found to be valid and enforceable. (Id. at ¶ 39) 5. The thirty-month stay barring Teva from marketing its drug expires on or around February 12, 2013. (Id. at ¶ 30; 21 U.S.C. § 355(j)(5)(B)(iii); 21 C.F.R. § 314.107(b)(3)) B. Key Players 6. Dr. Robert Zahler is one’ of two named inventors on the '244 Patent. (JTX 1) Dr. Zahler received a Ph.D. in organic chemistry from the University of - California, Berkeley in 1977. He then completed four years of post-doctoral research in the areas of physical organic chemistry and synthetic methodologies and total synthesis of natural products at University College London and the California Institute of Technology. (JTX 51; Tr. 757:15-758:3) Dr. Zahler was hired by BMS’s predecessor, E.R. Squibb and Sons, Inc. (“Squibb”) in 1981, and worked there and at BMS until 2007, when he was laid off by BMS. (JTX 51; Tr. at 513:20-514:4) Dr. Zahler currently operates a consulting business. (JTX 51; Tr. 514:5-12) 7. Dr. William A. Slusarchyk is' the other named inventor on the '244 Patent. (JTX 1) Dr. Slusarchyk received a Ph.D. in organic 'Chemistry from Penn State in 1965. (Tr. 903:14-904:5) He was employed at Squibb, and then BMS following the merger, for approximately 37 years. (Tr. 904:13-23) 8. Stephen Venetianer was a patent prosecuting attorney at BMS from 1980 until December 1990. (Tr. 977:6-15) Mr. Venetianer filed U.S. Patent Application No.' 07/599,568 (the “ '568 Application”) on October 18, 1990 on behalf of Drs. Zahler and Slusarchyk; that application was the first application for the '244 Patent. (JTX 2.0004-107) 9. Stephen Davis was a patent prosecuting attorney at BMS from 1973 until his retirement in 2005. (Tr. 674:18-20) Mr. Davis was Mr. Venetianer’s successor in prosecuting the '568 Application. (Tr. 675:16-23) On September 20, 1991, Mr. Davis filed U.S. Patent Application 07/763,-033 (the “ '033 Application”) as a continuation-in-part of the '568 Application, which led to the issuance of the '244 Patent. (Tr. 677:12-16; JTX 1.0001; JTX 3.0001, .0244) 10. Dr. Clayton Heathcock is an expert witness proffered by Teva in the field of organic • and medicinal chemistry. (Tr. 120:5-7) Dr. Heathcock received a Ph.D. in organic chemistry from the University of Colorado in 1963 and completed one year of post-doctoral study at Columbia University. (JTX 149.0002; Tr. 100:4-11) He is an Emeritus Professor of Chemistry at the University of California, Berkeley, where he was hired as assistant professor in 1964. (JTX 149.0002; Tr. 98:20-23; 101:1-6) During the. course of his career, the primary area of Dr. Heathcock’s scientific research was synthetic organic chemistry, which is a field involving the making of complicated compounds. (Tr. 102:19-103:9; 109:6-7) Dr. Heathcock also completed projects in the field of medicinal chemistry and published in the area of physical organic chemistry. (Tr. 103:9-13) He has experience training medicinal chemists who went on to work for pharmaceutical companies. (Tr. 109:7-15) Since the 1960s, Dr. Heathcock has worked as a consultant for various pharmaceutical companies in regards to their medicinal chemistry programs. (Tr. 110:16-115:12) From approximately 1986-1991, Dr. Heathcock consulted with Abbott Laboratories concerning an antiviral nucleoside analog program. (Tr. 114:7-117:9) However, Dr. Heathcock has not otherwise focused 'his research or work on nucleoside analogs. (Tr. 243:17-23; 244:9-11; 244:18-20; 245:7-13) Although Dr. Heathcock has frequently testified about medicinal chemistry, this is the first case involving nucleoside analogs in which he has testified. (Tr. 247:11-19) 11. -Dr. Chloe L. Thio is an expert witness proffered by Teva in the area of hepatitis B infection and its treatment. (Tr. 394:18-20) Dr. Thio is a physician and Associate Professor of Medicine at John Hopkins University. (JTX 148; Tr. 384:11-14) She received an M.D. from Yale University in 1992. (Tr. 385:18-20) Dr. Thio predominantly treats patients with infectious diseases, specializing in the treatment of hepatitis and HIV infections. (Tr. 387:13-18) Her research focuses mainly on hepatitis B and HIV-hepatitis B co-infection. (Tr. 389:7-8) 12. Dr. Bud C. Tennant is an expert witness proffered by BMS in the 'areas of woodchuck hepatitis virus, woodchuck research, and the testing of antiviral drugs on woodchucks. (Tr. 988:13-17) Dr. Tennant received a Ph.D. in veterinary medicine from the University of California in 1959. (JTX 147; Tr. 983:14-18) He is currently the James Law. Professor of Comparative Medicine at Cornell University. (JTX 147; Tr. 985:3-9) For the past thirty years, Dr. Tennant’s primary research work has been done on the woodchuck model of hepatitis B infection. (Tr. 985:20-24) 13. Dr. Stewart Schneller is an expert witness proffered by BMS in the area of nucleoside analog research. (Tr. 1052:24-1053:3) Dr. Schneller received a Ph.D. in organic chemistry from Indiana University in 1968. (JTX 145; Tr. 1045:23-1046:7) He then, completed three years of postdoctoral work in organometallic chemistry. (JTX 145; ■ Tr. 1045:24-1046:12) Dr. Schneller is currently a Professor of Chemistry and Biochemistry at Auburn University. (JTX 145; Tr. 1047:6-8) His research is in the field of nucleoside chemistry, primarily carbocyclic nucleosides. (Tr. 1047:18-20) 14. Michael E. Tate is an expert witness proffered by BMS in the fields of financial and. economic analysis. (Tr. 1271:20-22) Mr. Tate received a M.S. in industrial administration from Purdue University in 1987. (JTX 146; Tr. 1269:6-10) He is currently the Vice President at Charles River Associates, an international business consulting firm. (JTX, 146; Tr. 1269:11-17) 15. Dr. Robert Gish is an expert witness proffered by BMS in the area of the treatment of hepatitis B. (Tr. 1324:11-13) Dr. Gish received an M.D. from the University of Kansas in 1980. (JTX 144.0002; Tr. 1317:16-19) He is a physician and is currently the co-director of the Center for Hepatobiliary Disease and Abdominal Transplantation, Chief of the Section of Hepatology, and Clinical Professor of Medicine at the University of California, San Diego. (JTX 144.0002; Tr. 1318:11-18) Dr. Gish treats patients with liver disease, including hepatitis B. (Tr. 1319:7-22) Dr. Gish’s research focuses on viral hepatitis, which includes hepatitis B and hepatitis C. (Tr. 1321:24-1322:9) Dr. Gish has consulted with several pharmaceutical companies regarding hepatitis B drugs, including BMS. regarding its development of entecavir. (Tr. 1322:10-1323:8) C. The '244 Patent and the Claimed Invention — Entecavir 16. The '244 Patent, entitled “Hydroxymethyl (Methylenecylopentyl) Purines and Pyrimidines,” issued on April 27, 1993, naming Dr. Zahler and Dr. Slusarchyk as the inventors, and listing Squibb as the assignee. (JTX 1; Uncontested Facts at ¶ 10) 17. The '244 Patent expires on February 21, 2015. (Uncontested Facts at ¶ 7) 18. The '244 Patent claims a.genus of chemical compounds known as nucleoside analogs. (PTX 1; D.I. 150 at ¶ 2; D.I. 151 at ¶ 2; Tr. 122:7-11) Natural nucleosides are chemical compounds made up of a sugar portion and a base portion and are part of the basic building blocks of DNA and RNA. (Tr. 130:10-24; 133:3-24; 1059:8-18) When the sugar portion contains five carbon atoms that are bonded to each other in a ring-like fashion, this is referred to as a “cyclopentane ring” (the “five-membered ring”). (Tr. 123:14-20) When this ring includes an attached oxygen atom, it is known as a “furanose ring.” (Tr. 165:19-166:14) 19. Natural nucleosides are the starting point for antiviral research. (Tr. 1065:21-1068:14) Nucleoside analogs are chemical compounds that are designed by chemists to mimic natural nucleosides, but have been modified in some way. (Tr. 136:18-137:12) Many antiviral drugs are nucleoside analogs. (Tr. 139:22-140:5; 1065:11-20) This is because nucleoside analogs interfere with the process by which a virus reproduces itself. (Tr. 139:1-21) 20. Guanosine is one of four common nucleosides. (Tr. 135:16-136:3; DDX 42) Guanosine is made up of a heterocyclic sugar portion (called ribose) and a hetero-cyclic base (called guanine). (Tr. 130:10-24; 131:1 — 9; • DDX 40) The remaining three common nucleosides are adenosine, uridine, and cytidiné. (Tr. 135:16-136:3; DDX 42) 21. The sugar portion of a nucleoside contains an oxygen at the 2 prime (also referred to as “2'”) position. (Tr. 133:5-9; DDX 41, 42) A 2' deoxynucleoside is a nucleoside that lacks an oxygen at the 2 prime position on the sugar portion of the compound, but is identical in other respects. (Tr. 133:5-19; DDX 41; PDX 531) There are four common deoxynucleosides involving adenine, guanine, thymine, and cytosine. (Tr. 136:3-17; DDX 43) Deoxynucleosides are the building blocks from which DNA is made, while nucleosides are the building blocks from which RNA is made. (Tr. 133:20-134:3) 22.The genus of purine nucleoside analogs claimed by the '244 Patent all must have what is referred to as an “exocyclic methylene group” at the 5 prime position of the sugar portion, which group is depicted in the circle below: (D.I. 150 at ¶ 2; JTX 1) “Exocyclic” means something that is attached outside of the five-membered ring; an exocyclic methylene group is a carbon-carbon double bond that is attached outside of that ring. (Tr. 210:16-17; 1077:2-18) 23.The only claim of the '244 Patent asserted in this case is claim 8, which covers the chemical compound enteeavir. (D.I. 150 at ¶ 2; 151 at ¶ 3) 24. Teva has stipulated to infringement of claim 8 of the '244 Patent, to the extent that claim 8 is found to be valid and enforceable. (Uncontested Facts at ¶¶ 39-JO; D.I. 135, ex. 7) 25. Enteeavir is a carbocyclic nucleoside analog. (Tr. 116:1-6) Enteeavir mimics the natural nucleoside 2' deoxyguanosine, in that the compounds have identical bases, but the sugar portion of enteeavir is different from that of the natural nucleoside. (D.I. 151 at ¶ 3; Tr. 137:13-24; 1074:7-11) While the sugar portion of 2' deoxyguanosine has an oxygen atom at the 5 prime position, enteeavir has a carbon-carbon double bond at the 5 prime position, instead of an oxygen atom. (D.I. 151 at ¶ 3; Tr. 137:20-24; 1077:2-1078:10; DDX 44) A chemical name for enteeavir is [IS — (1 a,-3 a,4 (3) ]-2-amino-l,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-me-thylene-cyclopentyl]-6H-purin-6-one. (Uncontested Facts at ¶ 16) The natural nucleoside 2' deoxyguanosine and entecavir can depicted as follows: (D.I. 150 at ¶ 3) 26. The Abstract of the '244 Patent states that “antiviral activity” is exhibited by the claimed compounds. (JTX 1) The patent’s specification states that the claimed compounds “are antiviral agents that can be used to treat viral infection in mammalian species such as ... humans ....” (JTX 1.0003, col. 3:62-66) The patent further states that the compounds are effective against particular viruses including herpes simplex virus 1 (“HSV-1”) and herpes simplex virus 2 (“HSV-2”), and that “[t]hey are also believed to be active against a variety of other” viruses including hepatitis B virus. {Id., col. 3:67-4:41) 27. The '244 Patent contains a table depicting in vitro test results for claimed compounds, including entecavir, displaying activity against herpes family viruses and HIV. (JTX 1.0027; Tr. 146:13-148:12) The patent does not include results from any in vivo testing against any virus. (Tr. 148:15-19) Nor does the patent include test results of any kind against hepatitis B. (Tr. 148:20-149:1; 455:3-13) 28. In 2005, entecavir, marketed by BMS as Baraclude, was approved by the FDA for the treatment of chronic hepatitis B virus infections. (Uncontested Facts at ¶¶ 21-23; DTX35; Tr. 140:6-11) II. FINDINGS OF FACT RELEVANT TO OBVIOUSNESS A. Approaches for Discovery of New Drugs 29. In the late 1980s, a medicinal chemist would generally take one of three approaches to attempt to discover new drugs. (DDX 29; Tr. 140:12-142:22) 30. The traditional approach — the easiest and probably the most common approach — was the modification of a known lead compound. (Tr. 140:24-141:8; 144:8-17) A chemist utilizing this approach makes changes to an existing compound, known as a “lead compound,” in an attempt to create a new compound with improved antiviral properties. (Tr. 140:24-141:10; 1147:2-12; 1149:2-23) This traditional approach is based upon a tenet known as “structure activity relationship” (“SAR”). (Tr. 145:4-19; 1146:13-1147:1) That is, a chemist working with a lead compound to make new compounds understands that if he has “two compounds that are similar in structure, [he will expect that] they will have similar activity.” (Tr. 145:4-14) At the beginning of this traditional SAR approach, a medicinal chemist typically does not know anything about “the mechanism of action of the drugs involved;” the idea is to learn about the compounds through the testing process. (Tr. 1150:4-14) 31. The second approach to discovering new drugs involves random screening of compounds against an in vitro assay to find a lead compound. (Tr. 141:11-142:7) 32. The. third approach to discovering new drugs, the most difficult, is known as the biological approach. (Tr. 142:8-22) This approach entails learning about the biology of a disease and, from there, attempting to design a drug that targets the disease. (Id.) B. The Invention of Entecavir 33. In 1985, Squibb made Dr. Zahler the leader of its effort to discover new antiviral drugs. (Tr. 763:12-14; 764:3-17) At this .time — the mid-1980s — Dr. Zahler had a Ph.D. in chemistry, a few years of medicinal chemistry experience, and no experience with nucleoside analogs. (Tr. 757:11-760:5; 763:12-764:17; 1447:12-1448:9) Dr. Zahler, along with other members of his team who worked the project with him, began by reading the scientific literature and patents in the antiviral nucleoside analog field. (Tr. 764:18-765:18) 34. While still reviewing the literature, Dr. Zahler and his team selected acyclovir as their lead compound. (Tr. 771:4-23) Acyclovir was chosen as a lead compound because it was a safe drug that was on the market and was effective in treating HSV-1, HSV-2 and varicella-zoster virus (“VZV”). (Tr. 772:3-7) Dr. Zahler and his team then spent a year making thirty to forty acyclic nucleoside analogs, using acyclovir as a lead compound. (Tr. 776:20-777:6; PTX 181-225, 234, 235) None of the analogs showed enough antiviral activity to support further development as a drug candidate. (Tr. 779:17-780:13; PTX 181-225, 234, 235) 35. Using the traditional drug discovery approach — making structural changes to lead compounds that exhibited antiviral activity — Dr. Zahler had invented a carbocyclic nucleoside analog called lobucavir (also known as “BMS 180194” and “SQ-33054”) with a four-membered carbocyelie ring in the place of a sugar. (Tr. 560:5-9; 801:23-24; 882:20-884:5; PTX 622.0006-07) 36. By 1989, after his team had failed to succeed using the traditional drug discovery approach, Dr. Zahler decided to try a different approach, which led to his conception of enteeavir. (Tr. 571:22-572:9; 787:11-19) 'Dr. Zahler first came up with the idea for enteeavir in his head and drew it out on paper. (Tr. 552:6-16; 811:12-23) Then, because he tended to think in “three dimensions,” Dr. Zahler used what are known as “Dreiding models” in order to further develop his idea and to see if “what [he] had in [his] mind was somehow evident in that physical model.” (Tr. 552:12-16; 796:2-22; 811:17-812:11; PDX 531) The use of these models caused Dr. Zahler to solidify his thinking as to the structure of enteeavir and to determine that it may be a “useful structure” because enteeavir overlapped “quite nicely” with the Dreiding model for 2'-deoxyguanosine (with the exception of the exocyclic methylene group). (Tr. 812:12-813:20) 37. After Dr. Zahler used the Dreiding models to conceive of enteeavir, his team then used a proprietary, computer-based computational model in order to better predict entecavir’s preferred conformations (or preferred shapes), the purpose of which was to see if entecavir’s conformation was similar to those compounds that had antiviral properties, including lobucavir. (Tr. 553:1-554:16; 559:1-10; 562:9-18; 651:20-652:19; 804:9-811:8; 812:12-813:24; PTX 622.0007-09) In 1989, using computer-based molecular modeling in the drug discovery process was an approach that was “unheard of’ at the time in nucleoside drug discovery programs. (Tr. 806:13-807:1; 810:23-811:8) Thus, Dr. Zahler did not invent enteeavir utilizing one of the three general drug discovery approaches. (Tr. 1141:6-11) 38. At this point in the process of discovering enteeavir, in Dr. Zahler’s mind, the factor that distinguished enteeavir from 2'-deoxyguanosine was the addition of the exocyclic methylene group to the five-membered ring. (Tr. 812:18-23; 815:13-16) However, Dr. Zahler had concern about what the impact would be of adding the exocyclic methylene group to the natural nucleoside. (Tr. 814:1-815:16) Dr. Zahler therefore had members of his team, including Dr. Joseph Tino and Dr. Val Goodfellow, perform the computer modeling discussed above; this modeling process demonstrated that enteeavir did indeed “overlap nicely” with 2'-deoxygua-nosine, which motivated Dr. Zahler to attempt to make (or synthesize) enteeavir. (Tr. 553:14-555:4; 816:23-817:10; 969:14-19) 39. In performing this computer modeling in May 1990, Dr. Zahler’s team selected several different compounds to compare to enteeavir via computer modeling and to help “validate” the computer model. (Tr. 559:1-561:11; 563:3-564:3; 573:4-9; 658:3-9; 969:20-970:14) The compounds used in this process included lobucavir, the natural nucleoside 2'-deoxyguanosine, and another carbocyclic nucleoside analog of 2'-deoxyguanosine (“2'-CDG” or “CDG”). (Tr. 559:11-561:11; 654:7-655:7; 670:23-671:22; 975:15-18) The only two compounds used in this computer modeling and validation process that were not compounds originally synthesized at BMS were (1) 2'-deoxyguanosine; and (2) 2'-CDG. (Tr. 560:14-18; 658:10-15) 2'-CDG was chosen for use in this process as a “positive control,” in that it had shown antiviral activity. (Tr. 564:4-13; 569:22-570:4) As BMS continued this modeling process, they refined the model; eventually the results showed that both enteeavir and 2'-CDG demonstrated similar conformations to lobucavir, and that enteeavir might have similar antiviral properties to lobucavir. (Tr. 658:19-660:20) Dr. Zahler was aware of these testing procedures and results, as he was “heavily involved” in this testing process. (Tr. 660:21-24) 40. Once the computer modeling showed that enteeavir could have promising antiviral properties, Dr. Zahler’s team set out to synthesize enteeavir. (Tr. 817:2-818:8) Dr. Zahler went to Dr. Slusarchyk with his conception, and Dr. Slusarchyk (along with an associate of his at BMS) began the synthesization process. (Tr. 503:10-24) Dr. Slusarchyk, as he explained a good chemist would, “had [] a very good idea” of how to synthesize enteeavir right away. (Tr. 503:10-506:20) Nevertheless, according to Dr. Zahler, the synthesis of enteeavir was not an easy process, as the compound turned out to be harder to make than Dr. Zahler would have thought. (Tr. 818:4-8) After six months, Dr. Slusarchyk and his associate at BMS were able to synthesize enteeavir. (Tr. 822:11-823:15; 912:6-17) 41. Shortly thereafter, enteeavir was tested for antiviral activity. (Tr. 827:12-14) Those test results showed that enteeavir had modest but real activity against HSV-1, HSV-2 and VZV. (Tr. 828:1-5) Entecavir’s activity against HSV-1 was fourfold less than that of acyclovir, the standard in the field. (Tr. 828:1-5; 829:2-4) Enteeavir was not tested against hepatitis B, because BMS did not have a hepatitis B assay at the time. (Tr. -828:6-15) Due to its modest initial test results for herpes activity and against VZV, BMS did not take steps to further develop enteeavir; instead, the compound was “put on the shelf’ at BMS for a number of years. (Tr. 828:16-829:1) C. The Person of Ordinary Skill in the Art to Which the '244 Patent Is Directed 42-. Teva’s expert, Dr. Heathcock, defined a person of ordinary skill in the art to which the '244 Patent is directed as “a medicinal chemist” who has a Ph.D. in organic chemistry or in medicinal chemistry (though Dr. Heathcock said that the former is more likely than the latter). (Tr. 151:22-152:6; 152:20-153:1) According to Dr. Heathcock, the person of ordinary skill has been working for two or three years as a medicinal chemist, and can apply the tools of organic chemistry to design and make compounds. (Tr. 152:7-153:9) Alternatively, the person of ordinary skill has a bachelor’s degree or master’s degree in organic or medicinal chemistry and has been working in the field for 10-15 years. (Tr. 153:13-19; DDX 47) 43. While BMS’s expert, Dr. Schneller, testified at trial that the person of ordinary skill in the art would “be defined a little differently” than the person defined by Dr. Heathcock, Dr. Schneller did not testify at trial as to the nature of these specific credentials. (Tr. 1139:3-13) In his expert report, Dr. Schneller defined a person of ordinary skill in the art as having “a Ph.D. and at least five years’ experience in synthetic organic chemistry and at least three years’ experience with nucleoside analogs (including carbocyclic nucleoside analogs), synthetic experience at the bench, familiarity with the work of other nucleoside analog scientists (through reading the literature and/or attendance at meetings), and presentation of papers or posters.” (DTX 239.0017 at ¶ 51) At trial, when asked whether it mattered whether the Court utilized his definition of a person of ordinary skill in the art, or that put forward by Dr. Heathcoek, Dr. Schneller opined that it did not, as “a person of ordinary skill can be defined in a number of ways,” all of which would be “acceptable” to Dr. Schneller. (Tr. 1139:14-20) 44. Dr. Heathcoek stated that Dr. Sehneller’s position as to the level of the person of ordinary skill in the relevant art is a person of “more than ordinary skill.” (Tr. 153:24-154:14) Dr. Heathcoek disagreed with Dr. Schneller’s view that a person of ordinary skill would have some experience with nucleoside analogs because “medicinal chemists are quite versatile.” (Tr. 154:15-17) Citing specific examples of medicinal chemists he had encountered as a consultant throughout the years, Dr. Heathcoek explained that such chemists can move among projects in various therapeutic areas with ease, and do not “need to work three years [in a particular therapeutic area within medicinal chemistry] before they could begin to be considered ordinary.” (Tr. 154:15— 156:9) 45. Both Dr. Heathcoek and Dr. Schneller stated that regardless of which definition of the person of ordinary skill in the art is found to be correct, their opinions as to the validity of the patent would remain the same. (Tr. 157:14-158:5; 1139:3-1140:1) 46. In its opening post-trial brief, BMS appears to adopt Dr. Heathcock’s definition of a person of ordinary skill in the relevant art, stating that in 1985, when Dr. Zahler began working on nucleoside analogs at BMS, he “had the exact credentials possessed by a person of ordinary skill in the art: a Ph.D. in chemistry, a few years of experience in medicinal chemistry, and no experience with nucleoside analogs.” (D.1.150 at ¶ 8) (emphasis added) 47. Accordingly, the Court adopts Teva’s definition of the person of ordinary skill in the art. D. Nucleoside Analogs and the Scope and Content of Prior Art References Relating to Nucleoside Analogs 48. BMS’s and Teva’s experts, as well as Dr. Zahler, all identified three classes of nucleoside analogs that were in existence at the time of entecavir’s invention: nucleoside analogs with a furanose (or carbohydrate) ring (also called “furanosides”), acyclic nucleoside analogs (also called “acyelics”), and carbocyclic nucleoside analogs (also called “carbocyclics”). (Tr. 158:11-160:1; 767:5-769:4; 1111:24-1112:7; D.I. 150 at ¶ 23; PDX 58-1; DDX 48) 1. Furanosides 49. In 1959, a furanoside known as cytosine arabinoside (“Ara-C”) was developed and was ultimately approved by the FDA as an anticancer agent. (Tr. 160:2-161:4; DDX 49) In 1960, a nucleoside analog in this category known as adenine arabinoside (“Ara-A”) was developed and eventually approved by the FDA as an antiviral agent to treat the herpes virus. (Tr. 161:5-15; 176:7-14; DDX 49) 50. Furanosides are straightforward to synthesize. (Tr. 773:23-24; 1115:6-9) 51. Furanosides were a “fairly well developed field” at the time of entecavir’s invention (and prior to it), having been the focus of the previous twenty-five years of research. (Tr. 773:23-774:2) 2. Acyclics 52. The “classic example” of an acyclic nucleoside analog is acyclovir, which was discovered in 1977, (JTX 66.001), and eventually became approved by the FDA to treat the herpes virus. (Tr. 162:9-13) Acyclovir is an analog of the natural nucleoside 2' deoxyguanosine. (Tr. 161:21-162:9; DDX 51) In 1988, the developers of acyclovir were awarded the Nobel Prize. (Tr. 1113:5-12) 53. There were additional acyclic nucleoside analogs in the prior art. (Tr. 162:19-163:4) One paper reported “several dozen” such compounds. (Tr. 163:1-2) These compounds generally all contained a guanine ring, and their differences could be found on the sugar portion of the compound because it was “not very difficult” to make changes to the “side chain.” (Tr. 163:2-20) Thus, acyclics are easy to make. (Tr. 773:22-23; 774:3-4; 1114:16-19) 54. Many acyclics showed antiviral activity. (Tr. 164:2-3) Accordingly, several acyclic compounds were put into clinical development. (Tr. 164:2-5) 55. Ganciclovir is another example of an acyclic nucleoside analog. (Tr. 772:22-24; 1112:13-24) Ganciclovir was active against the herpes virus and was on its way to being FDA approved at the time of enteeavir’s invention. (Tr. 772:8-10; 1112:19-1113:3) 56. At the time of entecavir’s invention, acyclics were “a crowded field,” as many scientists had worked with acyclics and made many such compounds. (Tr. 168:13-20) Even so, there were plenty of researchers who were still using acyclic nucleoside analogs as lead compounds during this time. (See, e.g., JTX 87.0001; Tr. 284:17-287:1) 3. Carbocyclics and 2'-CDG a. Use of Carbocyclics in the Late 1980s and Early 1990s 57. A carbocyclic is an analog that has a base portion, and a sugar/carbohydrate portion with a carbon atom instead of an oxygen atom at the 5 prime position. (Tr. 165:8-11; DDX 53) 58. One example of a carbocyclic that existed in the prior art is aristeromycin, which is an analog of the nucleoside adenosine. (Tr. 164:24-165:12) Aristeromycin was first synthesized in 1966 ■ by Dr. Y. Fulmer Shealy and a group of researchers with whom Dr. Shealy worked. (Tr. 165:11-16; DTX 41) The base portion of aristeromycin is an adenosine ring and the sugar portion (also known as the furanose ring) has a carbon instead of an oxygen at the 5 prime position. (Tr. 165:1-12; DDX 53) 59. While a few compounds in the other above categories had been FDA approved at the time of enteeavir’s invention, no carbocyclics had been FDA approved. (Tr. 1114:1-3) 60. Carbocyclics take a long time to synthesize. (Tr. 1114:7-13) Despite this, chemists were, in fact, regularly synthesizing carbocyclics in the late 1980s and the beginning of the 1990s. For example, even BMS’s expert, Dr. Schneller, who testified as to the difficulty in synthesizing carbocyclics, oversaw students in his laboratory synthesizing’ carbocyclics during this time period, and noted that “it was most of what we did.” ‘ (Tr. 1071:15-1072:7; 1183:8-12; 1194:4-11) Dr. Schneller also confirmed that other groups including researchers at the Southern Research Institute (“SRI”), Glaxo Group Research Ltd. (“Glaxo”), Syntex Research (“Syntex”), and even BMS itself were synthesizing carbocyclic nucleosides during the relevant time period, in spite of the difficulty of this process. (Tr. 1194:8-1195:8) 61. Accordingly, in the late 1980s, the ordinary medicinal chemist would and did explore the field of carbocyclic nucleosides in attempting to develop antiviral drugs. As Teva’s expert Dr. Heathcoek explained, carbocyclics was a group “that people would notice as a ... fertile place to go to look for a new drug.” (Tr. 168:20-169:7) By this time, the areas of furanosides and acyclics were crowded, (Tr. 168:13-20; 773:23-774:2), while the area of carbocyclic nucleoside analogs was “a fertile field that hadn’t been plowed very much yet.”- (Tr. 168:20-24) Dr. Schneller, for his part, confirmed on cross-examination that by the 1980s, there was a growing interest in the area of carbocyclic nucleoside analogs, in part due to the work that Dr. Shealy and SRI were doing with those ■ analogs. (Tr. 1154:5-1155:10) 62. A 1986 article by Victor E. Marquez & Mu-111 Lim entitled “Carbocyclic Nucleosides” (“Marquez”), published in Medical Research Reviews, notes generally that carbocyclic nucleosides “are endowed with an interesting range of biological activities, especially in the areas of antiviral and anticancer chemotherapy,” and concludes that “good antiviral activity appeared to be the rule rather than the exception among carbocyclic nucleosides.” {Id. at 171.0004,171.0038) 63. An article by researchers at Glaxo in the U.K: including Keith Biggadike (“Biggadike” or the “Biggadike article”) was published in 1987. (DTX 150) The article, inter alia, stated that “[t]here is considerable current interest in the synthesis of carbocyclic nucleosides in our laboratories and elsewhere [citing to the work of Dr. Shealy and others] due to the high levels of selective antiviral activity displayed by some members of this group [citing in part to a 1984 article by Dr. Shealy that is more fully discussed below].” {Id.) 64. An article by G.V. Bindu Madhavan (“Madhavan” or the “Madhavan reference”) and others with Syntex published in the Journal of Medicinal Chemistry in 1988 revealed that the researchers at Syntex were developing carbocyclic nucleoside analogs and analyzing the antiviral activity of such analogs. (JTX 81; 1194:12-1195:8) 65. And BMS itself wa's working in the carbocyclics field in the late 1980s, having invented lobucavir prior to the invention of entecavir. (Tr. 883:12-884:13; 887:3-6) In September 1989, at a scientific conference, Dr. Zahler and- others at BMS reported on the promise of lobucavir (referred to as “SQ-33054”) as a “novel, synthetic nucleoside analog with excellent activity” against HSV-1 and HSV-2, human cytomegalovirus, and VZV. (PTX 443.0003; Tr. 894:14-20; 1156:14-20) In fact, the testing results that the BMS group obtained on lobucavir proved it to be “superior to acyclovir, and comparable to ganciclovir” against the above viruses. - (Tr. 896:9-17; PTX 445.0003) 66. Two other groups, Abbott Laboratories and Nippon Kayaku, had also independently developed the carbocyclic analog that BMS called lobucavir. (Tr. 884:10-885:24; 887:22-888:12; PTX 622.0006) 67. An article summarizing the antiviral research to date by Dr. J.A. Montgomery of SRI was published in October 1989 (“Montgomery 1989”). (DTX 172.0003-04) Dr. Montgomery concluded that of the compounds identified by SRI with promising antiviral activity, “[b]y far the most active and selective agents are carbocyclic nucleoside analogs.... ” (DTX 172.0004; Tr. 189:3-12) Dr. Heathcock noted that such a statement by a “very well regarded” chemist served as a “pretty open invitation ... to medicinal chemists to look at that class of compounds as leads.” (Tr. 188:19; 189:3-15) b. 2'-CDG 68. Another carbocyclic nucleoside analog that existed and was described in the prior art at the time of entecavir’s invention was 2'-CDG. (Tr. 166:21-167:15; 531:1-6) Indeed, Dr. Zahler was aware of 2'-CDG and the work that chemists at SRI had done with the compound before he began his development of entecavir. (Tr. 531:6-22) In that regard, as is discussed more fully below, 2-CDG was cited as prior art in applications for other patents on which Dr. Zahler was listed as an inventor, including patent applications filed in December 1988 and July 1990 (before the first application - for the '244 Patent was filed in October 1990). (Tr. 622:2-627:19; JTX 103; DTX 163) 69.Dr. Shealy of SRI invented 2'-CDG in 1984. (Tr. 168:24-169:4; DTX 126) 2'-CDG is a carbocyclic nucleoside analog of the natural nucleoside 2' deoxyguanosine. (Tr. 167:1-11; 533:5-12; DDX 54) 2'-CDG mimics the natural nucleoside 2' deoxyguanosine in that the compounds have identical bases, but the sugar/carbohydrate portion of 2'-CDG has a carbon atom at the 5 prime position, instead of an oxygen atom. (Tr. 167:1-8; 533:5-12; DDX 54) 2'-CDG can be depicted as follows: HO" (D.1.151 at ¶ 45) 70. 2'-CDG was singled out as a promising compound in the carbocyclics field, (Tr. 171:19-173:18), in that it demonstrated “very good” antiherpes activity. (Tr. 168:24-169:3; 173:20-174:1) 71. For example, Dr. Shealy’s synthesis of 2'-CDG was published in a six-page article in the Journal of Medicinal Chemistry in 1984: “Synthesis and Antiviral Activity of Carbocyclic Analogues of 2'-Deoxyribofuranosides of 2-Amino-6-sub-stituted-Purines and of 2-Amino-6-Substituted-8-Azapurines” (“Shealy 1984”). (Tr. 172:1-172:19; DTX 126) 72. Shealy 1984 discusses testing results regarding a number of carbocyclic analogs of nucleosides, including 2'-CDG. (DTX 126.0001) The article reported that 2'-CDG showed better activity in in vitro testing against the herpes virus (both HSV-1 and HSV-2) than did Ara-A, the FDA-approved drug in the furanoside family used to treat the herpes virus. (Tr. 174:2-176:1; 176:15-22; DTX 126.0002) The article went on to note that “[i]n these tests vs. HSV-1, the carbocyclic analog[] of 2'-deoxyguanosine (12) [along with three other compounds] were the most potent compounds .... The carbocyclic analog of 2'-deoxyguanosine (12) showed excellent activity (VR, 3.7) and high potency (MIC50, .0.8 mcg/mL) against strain MS of HSV-2.” (DTX 126.0002) 73. Dr. Shealy obtained a U.S. Patent No. 4,543,255 entitled “Carbocyclic Analogs of Purine 2'-Deoxyribofuranosides” for 2'-CDG and a family of related compounds, which issued and was published in September 1985 (“Shealy '255 Patent”). (Tr. 177:1724; DTX 151) The Shealy '255 Patent discloses the invention of a number of compounds, including 2'-CDG, that are carbocyclic analogs of purine 2'-deoxyribo-furanosides, explaining that these compounds are useful in the treatment of viral infections. (DTX 151) The patent describes 2'-CDG as one of two compounds that was “markedly more effective than was- [the FDA approved drug] Ara-A.” (Tr. 178:13-18; DTX 151.0008) 74. 2-CDG is also one of a number of carbocyclic nucleosides referenced in the Marquez article;' it is referred to in the article'twice, and neither time by name. Instead, in one instance, a tautomer (a type of structural isomer) of 2'-CDG appears as an entry (entry number 37d) in a table of a large number of different carbocyclic purine nucleosides. (DTX 171.0010) In the other instance, in the third paragraph of Section III.A.b. of the article, 2'-CDG is referenced by entry number (along with other compounds). The reference notes, citing to Shealy 1984, that 2'-CDG showed activity against HSV-1 and demonstrated that it was more potent against HSV-2 than certain other carbocyclic nucleosides. (DTX 171.0017-18 (referencing 2'-CDG in group of nucleoside analogs listed as entry numbers “37c-f”)) 75. Another Shealy article, a five-page 1987 article in the Journal of Medicinal Chemistry, was titled “Synthesis and Antiviral Evaluation of Carbocyclic Analogues of 2-Amino-6-substituted-purine 3'-Deox-yribofuranosides” (“Shealy 1987”). The-article focuses on the synthesis and antmral properties of carbocyclic analogs of 2-amino-6-substituted-purine 3 '-dexoyribofuranosides. (DTX 125) While Shealy 1987 is, therefore, not an article primarily about 2'-CDG, as part of its discussion of these other carbocyclic analogs, the article discloses that 2'-CDG showed in vivo activity against both HSV-1 and- HSV-2. (Tr. 181:13-182:3; DTX 125.0002) 76. Additional testing was conducted on 2'-CDG in the 1980s. 2-CDG is a chiral compound, meaning there are two different ways to arrange the atoms of the compound and achieve the same overall connectivity. (Tr. 183:6-12; DDX 55) These two different forms are called enantiomers; they are non-superimposable mirror images of one another. (Tr. 182:15-24; 183:14-18) In drug compounds that are chiral, generally only one of the two enantiomers are responsible for the.drug’s biological activity. (Tr. 184:3-5) Dr. Shealy and other researchers at SRI did additional work on 2'-CDG to determine which enantiomer triggered its biological activity. (Tr. 185:12-186:5; DTX 173) Their testing proved that the enantiomer of 2-CDG responsible for its activity is that corresponding to the natural nucleoside, 2'-de-oxyguanosine. (Tr. 185:23-186:14; DTX 173) 77. Other researchers outside of SRI engaged in additional testing of 2'-CDG. (See, e.g., DTX 152) Peter M. Price and other researchers with the Mount Sinai School of Medicine published the results of testing of 2'-CDG against the hepatitis B virus in an November 1989 article (the “Price- article”). (Id.) Price reported that 2'-CDG showed excellent activity against the hepatitis B (“HBV”) virus. (Tr. 186:22-187:10; DTX 152 (“Treatment of 2.2.15 cells (10) with as little as 25 ng of 2-CDG per-ml resulted in the almost complete disappearance of replicating HBV .... ”)) The group’s testing also demonstrated that 2'-CDG “was nontoxic in concentrations up to 200 times the minimum effective inhibitory concentration.” (DTX 152; Tr. 187:16-19) According to Dr. Heathcock, Price’s testing demonstrated that 2'-CDG “had a very good therapeutic window [because] [i]t was effective at a level, much lower than its toxic level.” (Tr. 187:2124) E. Selection of 2'-CDG as a Lead Compound 78. As noted above, the earliest priority date for the '244 Patent is October 18, 1990. (JTX 1; Uncontested Facts at ¶¶ 3, 6) As of this time frame, 2'-CDG would have been chosen as a lead compound by the person of ordinary skill in the art; indeed, researchers at other companies actually utilized 2-CDG as a lead compound. (Tr. 191:11-20) 79. Dr. Heathcock testified that 2'-CDG would have been noticed and recognized as “a very good lead compound” during the relevant time frame. (Tr. 199:811) In support of this opinion, Dr. Heathcock cited to the facts that (1) 2'-CDG is structurally related to the natural nucleoside deoxyguanosine, only differing by the change from one oxygen atom into a carbon atom on the five-membered ring; (2) it showed excellent activity against the herpes virus and had in vivo potency; and (3) it had actually, been selected as a lead compound by researchers. (Tr. 199:8-24; 200:15-21) 80. In his 1989 article that identified carbocyclics as “the most active and selective” of the antiviral compounds, Dr. Montgomery singled out 2-CDG as a promising compound in the carbocyclics field: “By far the most promising carbocyclic purine nucleosides for the treatment of herpes infections are in the 2'-deoxyribo series ... (Shealy et al., 1984b). Of these the most likely compounds appear to be the 2'-deoxyguanosine analog (CDG, 32) and its prodrug forms.” (DTX 172.0014; Tr. 190:7-15) Further, Dr. Montgomery stated that 2'-CDG was “five to six times as potent as acyclovir against” HSV-1 and HSV-2 “in plaque reduction assays in human foreskin fibroblasts.” (Tr. 1181:10-15; DTX 172.0016) Thus, the Montgomery 1989 article was a “lamp post that really. illuminate[d] 2'-CDG as [ ] a very exciting lead compound to work from.” (Tr. 191:5-10) 81. The testimony of BMS’s own expert, Dr. Schneller, supports the conclusion that 2'-CDG would have been (and was) chosen as a lead compound in this time period. In his trial testimony, upon direct examination, Dr. Schneller first stated that 2'-CDG wás “on the list” (along with hundreds of other compounds) as a possible lead compound for antiviral drug research. (Tr. 1111:1-16; 1113:13-17) Qn cross-examination, however, Dr. Schneller agreed that the Glaxo researcher^ had considered 2'-CDG to be a lead compound. (Tr. 1175:21-1176:6; 1210:13-23) He also agreed that researchers at SRI had treated 2'-CDG as a promising compound. (Tr. 1181:16-20) Furthermore, Dr. Schneller conceded that he did not “completely disagree” with Dr. Heathcock’s opinion that 2'-CDG would have been and was used as a lead compound, (Tr.. 1164:15-19), and clearly acknowledged that in the relevant time period other “talented” chemists did in fact treat 2'-CDG as a lead compound. (Tr. 1166:3-15; 1167:4-10) 82. As noted above, some of those other chemists include the group led by Keith Biggadike at Glaxo. Biggadike and other researchers at Glaxo published the 1987 Biggadike article that described their synthesis of 2'-CDG. (Tr. 191:18-192:18; DTX 150) The article notes that their interest in the compound was triggered by the “high levels of selective antiviral activity” displayed by 2'-CDG (as well as other members of the carbocyclics family). (Tr. 192:19-193:4; DTX 150) The fact that Glaxo invested efforts to make 2'-CDG is, as Dr. Heathcock put it, “evidence that Glaxo had selected CDG as a lead structure to work from.” (Tr. 194:3-10) 83. Indeed, in 1988, Glaxo researchers (led by Alan D. Borthwick, and including Keith Biggadike), published an article (the “Borthwick article”) reporting that they had made a compound identical to 2'-CDG but -with one addition: they attached a fluorine atom to the carbon atom at the 2 prime position of the sugar portion. (Tr. 194:13-195:10; 1214:11-1215:14; DTX 170-170.0002; DDX 56) The researchers reported that the compound that they created had good potency against HSV-1 and HSV-2. (Tr. 195:12-14; DTX 170) In fact, the new compound was found to be approximately thirty times more active than acyclovir — a drug FDA-approved to treat herpes at the time — against HSV-1. (Tr. 195:18-196:1; DTX 170) The new compound also showed “extremely high levels of activity” against HSV-2. (DTX 170; Tr. 196:19-21) This group’s synthesis of an analog of 2'-CDG demonstrates that the chemists “took the clues from probably the Shealy papers ... and they selected 2'-CDG as their lead compound. They made an analog and it was active ... even more active than acyclovir.” (Tr. 197:23-198:3; accord 273:1320; 1216:1020) In other words, the Borthwick group- “took [2'— CDG] and improved it by adding the fluorine.” (Tr. 276:22-24) On cross-examination at trial, Dr. Schneller agreed that this article is evidence that “people of skill in the art looked at 2'-CDG and made changes to the sugar portion” — and thus is evidence that people were using 2-CDG as a lead compound, a starting point, at the relevant time. (Tr. 1213:19-24; 1215:9-11; 1216:10-18) 84. Dr. Schneller himself wrote an article that discussed 2'-CDG: “(± )-Carbocyclic 5'-Nor-2'-deoxyguanosine and Related Purine Derivatives: Synthesis and Antiviral Properties,” published in the Journal of Medicinal Chemistry in June 1992. (DTX 178;. Tr. 1182:14-1183:7) The article states that the authors prepared “derivatives” of, among other compounds, “carbocyclic 2'-deoxyguanosine.” (DTX 178.0003; Tr. 1185:1-10) The article further states that “[r]acemic and Dcarbocyclic 2'-deoxyguanosine [2-CDG] (represented as [compound] 1) have shovim significant antiviral activity 'as a result of selective- conversion to their 5'-triphosphate derivatives,” citing to, inter alia, Shealy 1984. (DTX 178.0003; Tr. 1189:20-1191:11) Dr. Schneller disputes that the article’s use of the term “derivative[]” means that he used 2'-CDG as a lead compound, noting that he may have “misspoken” in using the term “derivative” in the article. (Tr. 1185:11-20) However, it is at the very least clear that Dr. Schneller had read about Shealy’s invention of 2'-CDG, noted that 2-CDG had shown significant antiviral activity, and wrote about 2'-CDG while synthesizing carbocyclics and investigating their antiviral activity. (DTX 178.0003; Tr. 1189:17-1193:8) 85. Even considering the track records of acyclics and furanosides, 2'-CDG could easily have been viewed by a person of skill in the art as a more promising lead compound than compounds in those classes, because researchers were reporting during the relevant time that 2'-CDG showed better antiviral activity than both Ara-A, an FDA-approved furanoside, (Tr. 174:2-176:1; 176:15-22; 178:13-18; DTX 126.0002), and acyclovir, an FDA-approved acyclic. (Tr. 1181:10-15; DTX 172.0016) 86. An later article published in Current Pharmaceutical Design in April 1997 (the “Mansour and Storer article”) appears to confirm that 2-CDG was used in the past in the role of a lead compound, stating that “[t]he carbocyclic analogue of 2'-deox-yguanosine ... has played a pivotal role in providing a . template for the development of carbocyclic nucleoside analogue pro-grammes.” (DTX 154.0017) Dr. Schneller agreed that this description “sounds like [the authors] think ... 2'-CDG was a lead compound,” noting that “[t]hat’s what [the authors] say” in the article. (Tr. 1245:23-1246:1) 87. Any toxicity then-associated with 2'-CDG as of October 1990 would not have deterred the person of ordinary skill in the art from selecting 2'-CDG as a lead compound, because at that time, 2'-CDG was not then known (as it would later come to be known) as being associated with a high toxicity. (DTX 126.0002; DTX 172.0014; DTX 152.0001) 88. For example, the Shealy 1984 article did not provide clear indication that 2'-CDG was toxic. Table III of the article contains anticancer data, including references to the results of testing as to the relative toxicity of a number of compounds, including 2'-CDG (referenced in the table as compound 12), which results were reported on day five of a nine-day trial. (DTX 126.003; Tr. 266:3-8) A footnote in that table explains that a “dose is considered to be toxic (t) if T/C < 85% or the weight-change differential is greater in magnitude than Ag.” (DTX 126.003, tbl.III & n.d) However, by that criteria, the data listed in Table III did not suggest that 2'-CDG was toxic, as to the dosage.reported for 2-CDG. (100 milligrams per kilogram per day). (DTX 126.0003; Tr, 375:22-378:3) Dr. Heathcock testified on cross examination that one possible interpretation of this data for 2'-CDG — had its test results been reported on day nine of the trial or were they based on a dosage of 200 milligrams per day — was that the authors of the article would have had to report toxicity issues. (Tr. 267:12-23) However, Dr. Heathcock also said that this was a “pretty hypothetical” conclusion, and that if the authors believed there were toxicity issues with 2'-CDG, they “would have said something like that in the paper.” (Id.) Dr. Schneller, for his part, did not opine that the Shealy. 1984 article provided any indication that 2'-CDG was toxic. 89.In the 18-page Montgomery 1989 article, there is a table ■ (table 6.) on one page of the article that reports on the activity of 2'-CDG (and other compounds) in mice that were infected with HSV-1. (DTX 172.0015) One column (titled “Uninfected toxicity controls (survivors/total)”) of that table reports on the. number of mice in a control group (a group that were not infected with HSV-1) that survived the testing; the results in this column shows that all of those mice did, in fact, survive. (Id.) Another column of the table notes how many virus-infected mice survived 21 days-worth of testing, and notes that the number of such survivor mice decreased as the dosage of 2'-CDG rose above 2.5 mg/ kg/day. (Id.) However, nowhere in the table (nor in the article) do the authors cite 2'-CDG as a toxic compound. (Id.) Instead, as noted above, on the page of the article just prior to table 6, the authors instead call out 2'-CDG’s “promising” antiherpetic properties. (DTX 172.0014) Dr. Schneller, for his part,, did not opine that the Montgomery 1989 article provided any indication that 2'-CDG was toxic. 90. An article by Lee Bennett, Shealy and others at SRI published in 1990 (“the Bennett ^article”) did note that 2'-CDG appeared to have cytotoxic effects. (JTX 90.0007) While the Bennett article also states that “[c]ellular DNA polymerases may also be inhibited to some extent” by 2'-CDG, the article’s abstract highlights that “2'-CDG apparently is a good substrate for the virus-coded kinase and a very poor substrate for cellular phosphorylating enzymes.” (JTX 90, 90.0007) Dr. Heathcock noted that this discussion about cytotoxicity and 2'-CDG was largely couched in “tentative” terms, and would not automatically steer the ordinary medicinal chemist away from selecting 2'-CDG as a lead compound. (Tr. 257:4-259:4; 259:14-15; JTX 90.0007) Dr. Heath-cock explained that the abstract of the Bennett article suggests that 2'-CDG has a “greater effect on the virus than ... on the cell itself,” which would be interpreted to mean that 2'-CDG “would not be especially toxic” because it “influencies] the cell more than it influences the virus.” (Tr. 373:9-374:18) While the Bennett article was accepted for publication on March 13, 1990, and was published at some point in 1990, it is not clear from the record as to whether it was published prior to October 18, 1990. (JTX 90.0001; Tr. 256:14-19; 371:16-372:12) 91. While Dr. Schneller’s expert report opines that 2'-CDG was a less fruitful lead than other carbocyclics because it “came to be understood as cytotoxic,” two supporting citations for this proposition come from 1992 (after the October 1990 priority date regarding the patent). (DTX 239.0013 & n. 16) The third is the 1990 Bennett article which, as explained above, is tentative in the way it describes the impact of cytotoxicity associated with 2'-CDG. (Id.) 92. Testimony from BMS’s own expert, Dr. Bud Tennant, illuminates that the toxicity of 2'-CDG was not well known as of October 1990. Dr. Tennant explained that woodchucks are an animal model used to test potential hepatitis B drugs before they are tested in humans, because the woodchuck hepatitis virus is similar to the human hepatitis B virus. (Tr. 462.T0-21) Dr. Tennant tested 2'-CDG on his woodchuck colony to .determine the effects of the compound against the woodchuck hepatitis virus. (Tr. 988:22-989:12; JTX 141) This testing occurred in 1990 and 1991. (Tr. 989:21-22; JTX 141) Dr. Tennant was “absolutely not aware” of any toxicity of 2'-CDG before he started the testing' and noted that, had such toxicity data been available, he would have considered it. (Tr: 1022:16-1028:6) Had Dr. Tennant known that 2'-CDG was toxic at this time, he would not have done the studies “the way they were done.” (Tr. 1022:16-21) Indeed, Dr. Tennant’s July 30, 1991 report summarizing his testing (which was never published) characterized the “high fatality rate ... associated with 2'-CDG treatment” as “unanticipated.” (Tr. 1023:7-12; 1027:21-23; JTX 141.0007) 93.As was stated above, the 1989 Price article reported that 2'-CDG “was nontoxic in concentrations up to 200 times the minimum effective inhibitory concentration.” (DTX 152; Tr. 187:16-19) And, in a later 1992 article, the authors wrote that “[n]either we nor Shealy et al. (20) found that 2'-CDG was cytotoxic in vitro (21) or toxic in vivo. ” (DTX 185.0005) 94. Even if some evidence did exist prior to October 1990 indicating that 2'-CDG was associated with toxicity, such evidence was limited, and would not have discouraged the ordinary medicinal chemist from using 2'-CDG as a lead compound. Indeed, Dr. Slusarchyk, the medicinal chemist who designed the synthesis for entecavir, testified that toxicity data about nucleoside analogs that he was making “wouldn’t deter ,[him] from making more compounds in the area to investigate further” as he was a “medicinal chemist,” not a “toxicologist.” (Tr. 508:8-19) F. Similarities and Differences Between the Claimed Invention and 2-CDG 95.’ The only structural difference between entecavir and 2'-CDG is the addition of one carbon atom at the 5 prime position of the ribose portion'of entecavir. (Tr. 211:222; 219:19-220:7; DDX 60) 2'-CDG has a single carbon atom at the 5 prime position while entecavir has an exocyclic methylene group (a “carbon-carbon double bond”) at the 5 prime position. (Tr. 220:2-7; 1249:13-19; DDX 62) The remaining structural features of entecavir and 2'-CDG are the same (both have a carbocyclic core, a guanine base, a hydroxyl (OH) group at the 3 prime position and a hydroxymethyl (CH2OH) at the 4 prime position. (Tr. 1247:19-1249:11) As previously illustrated, the compounds 2'-CDG and entecavir can be depicted as follows: HO'' entecavir (D.1.151 a^45) 96.It is clear, as Dr. Heathcock opined, that the two compounds would have been deemed “structurally very similar” by a person of ordinary skill in the art. (Tr. 219:5-220:8) In his testimony at trial, Dr. Zahler, who “think[s] in three dimensions,” characterized the compounds “as both structurally similar and dissimilar.” (Tr. 547:6-8; 608:16-19) However, a July 1997 article authored by BMS scientists, including Dr. Zahler, illuminates how BMS viewed entecavir and 2'-CDG well before this litigation. (JTX 107) In a discussion of entecavir’s (referred to in the article as “BMS-200475”) activity against the hepatitis B virus, the authors state that “2'-CDG, a structurally similar guanine-based nucleoside in which the natural furanose oxygen is also replaced by a carbon, has been shown to inhibit hepadnaviral reverse transcription in this fashion.” (JTX 107.0003; Tr. 612:5-6; 613:8-18) (emphasis added) In his trial testimony, Dr. Zahler claimed that the words “structurally similar” in the article are used “[l]oosely” and are “not [his] words,” yet it is clear that he is listed as an author of this article. (Tr. 614:14-19) Another 1998 article authored by BMS scientists again calls out the structural similarity between 2'-CDG, entecavir and lobucavir (another carbocyclic analog) in their triphosphate forms: “To date, the only truly effective priming inhibitors appear to be BMS-200475-TP [entecavir] and lobucavir-TP ... and the structurally related compound 2'-CDG-TP.” (JTX 108.0008) (emphasis added) As Dr. Zahler confirmed, papers authored by BMS chemists prior to this litigation discussed the “activity” of 2.'-CDG as well as its “structural similarities” with entecavir. (Tr. 616:14-24; 617:10-13) These papers did not, on the other hand, discuss “structural differences” between the two compounds. (Tr. 617:1-9) 97. As was previously noted above, under Dr. Zahler’s direction, BMS engaged in computer modeling of nucleoside analogs in three dimensions — entering data into the computer- about a compound to determine its three dimensional shape (i.e., its conformation). (Tr. 553:4-554:22) Through this computer modeling, Dr. Zahler and his team confirmed that entecavir and 2'-CDG should have similar antiviral activity. (DTX 120.0001) Specifically, BMS plotted three-dimensional conformations of nucleoside analogs, and identified a boundary (that resembled a “Pac-Man” shape) showing which of those conformations would be “expectfed] to have activity.” (DTX 120.0001; Tr. 565:6-566:4; 656:24-657:9) Both entecavir and 2'-CDG were within that boundary. (Tr. 566:11— 567:3; 658:16-659:11; DTX 120.0001) Thus, both entecavir and 2'-CDG had similar three dimensional conformations because both conformations were in the boundary that BMS used to predict bioactivity. (Tr. 659:12-660:18) 98. While' it is true that entecavir’s ex-ocyclic methylene group “affects the three-dimensional structure” of the compound, giving it a less flexible carbocyclic ring than 2'-CDG, (Tr. 1080:3-1082:23), Dr. Zahler pointed out that many chemists do not analyze structural similarity between compounds by thinking in three dimens