Full opinion text
OPINION STARK, United States District Judge: Plaintiffs — UCB, Inc., UCB BioPharma SPRL, Research Corporation Technologies, Inc., and Harris FRC Corporation (collectively, “Plaintiffs”) — allege that Defendants — Accord Healthcare, Inc., Intas Pharmaceuticals Ltd., Alembic Pharmaceuticals, Ltd., Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of New York, LLC, Aurobindo Pharma Ltd., Auro-bindo Pharma USA, Inc., Breckenridge Pharmaceutical, Inc., MSN Laboratories Pvt. Ltd., Sun Pharma Global FZE, Sun Pharmaceutical Industries, Ltd., Watson Laboratories, Inc. — Florida (n/k/a Actavis Laboratories FL, Inc.), Watson Pharma, Inc. (n/k/a Actavis Pharma, Inc), Actavis, Inc., Apotex Corp., Apotex, Inc., Mylan Pharmaceuticals Inc., Mylan, Inc., Zydus Pharmaceuticals (USA) Inc., and Cadila Healthcare Limited (collectively, “Defendants”) — infringe United States patent No. RE38,551 (JTX-1 (“the ’551 patent” or “the patent-in-suit”)). (D.I.l) The ’551 patent generally relates to “an-ticonvulsant drugs,” which “control and prevent[ ] seizures associated with epilepsy or related central nervous system disorders.” (’551 patent at 1:26-29) Each of the Defendants has filed an Abbreviated New Drug Application (“ANDA”) with the U.S. Food and Drug Administration (“FDA”) seeking approval to market generic versions of Plaintiffs’ pharmaceutical product Vimpat®, which is an embodiment of claims of the patent-in-suit. The Court construed the disputed claim terms in May 2015. (D.I. 240) In December 2015, the Court conducted a bench trial. (See D.I. 264-267 (“Tr.”)) The parties completed post-trial briefing on February 8, 2016. (D.I. 263, 271, 274, 277) In connection with the briefing, the parties submitted proposed findings of fact (D.I. 262, 270, 273) as well as a Stipulation of Uncontested Facts (“SUF”) (D.I. 272). On May 23, 2016, the Patent Trial and Appeal Board (“PTAB”) instituted an inter partes review of the validity of claims 1-13 of the ’551 patent. (See D.I. 294, 294-1) On June 16, 2016, the U.S. Patent and Trademark Office (“PTO”) instituted an ex parte reexamination of the same claims. (See D.I. 300, 300-1) Pursuant to Federal Rule of Civil Procedure 52(a), and after having considered the entire record in this case and the applicable law, the Court concludes that: (1) Defendants have stipulated that their proposed products infringe claims 9, 10, and 13 of the ’551 patent, and (2) Defendants have failed to prove that any of claims 9, 10, and 13 of the ’551 patent are invalid for obviousness-type double patenting, obviousness, anticipation, indefiniteness, or improper reissue. The Court’s findings of fact and conclusions of law are set forth in detail below. I.FINDINGS OF FACT This section contains the Court’s findings of fact for issues raised by the parties during trial. Certain findings of fact are also provided in connection with the Court’s conclusions of law. A. The Parties 1. Plaintiff UCB, Inc. is a corporation organized and existing under the laws of Delaware, having a principal place of business at 1950 Lake Park Drive, Smyrna, Georgia 30080. (SUF ¶ 1) 2. Plaintiff UCB BioPharma SPRL (together with UCB, Inc., “UCB”), is a corporation organized and existing under the laws of Belgium, having a principal place of business at Allee de la Recherche 60, Brussels, 1070, Belgium. (SUF ¶ 2) 3. Plaintiff Research Corporation Technologies, Inc. (“RCT”) is a corporation organized and existing under the laws of Delaware, having a principal place of business at 5210 East Williams Circle, Suite 240, Tucson, Arizona 85711-4410. ■ (SUF ¶ 3) 4. Plaintiff Harris FRC Corporation (“Harris”) is a corporation organized and existing under the laws of New Jersey, having a principal place of business at 2137 State Highway 35, Holmdel, New Jersey 07733. (SUF ¶4) 5. Defendant Accord Healthcare, Inc. is a corporation organized and existing under the laws of North Carolina, having a principal place of business at 1009 Slater Road, Ste. 210-B, Durham, North Carolina 27703. (SUF ¶ 5) 6. Defendant Intas Pharmaceuticals Ltd. is a corporation organized and existing under the laws of India, having a principal place of business at Chinubhai Centre, off Nehru Bridge, Ashram Road, Ahmedabad 380009, Gujarat, India. (SUF ¶ 6) 7. Defendant Alembic Pharmaceuticals Ltd. is a corporation organized and existing under the laws of India, having a principal place of business at Alembic Road, Vadodara-390003, Gujarat, India. (SUF ¶ 7) 8. Defendant Amneal Pharmaceuticals, LLC is a corporation organized and existing under the laws of Delaware, having a principal place of business at 400 Crossing Boulevard, 3rd Floor, Bridgewater, New Jersey 08807. (SUF ¶ 8) 9. Defendant Amneal Pharmaceuticals of New York, LLC is a corporation organized and existing under the laws of Delaware, having a principal place of business at 85 Adams Avenue, Hauppauge, New York 11788. (SUF ¶ 9) 10. Defendant Aurobindo Pharma Ltd. is a corporation organized and existing under the laws of India, having a principal place of business at Plot # 2, Maitrivihar, Ameerpet, Hyderabad-500038, Telagana, India. (SUF ¶ 10) 11. Defendant Aurobindo Pharma USA, Inc. is a corporation organized and existing under the laws of Delaware, having a principal place of business at 6 Wheeling Road, Dayton, New Jersey 08810. (SUF ¶ 11) 12. Defendant Breckenridge Pharmaceutical, Inc. is a corporation organized and existing under the laws of Florida, having a principal place of business at 6111 Broken Sound Parkway NW, Suite 170, Boca Raton, Florida 33487. (SUF ¶ 12) 13. Defendant Vennoot Pharmaceuticals, LLC is a corporation organized and existing under the laws of Georgia, having a principal place of business at 11009 Estates Circle, Alpharetta, Georgia 30022. (SUF ¶ 13) On August 1, 2016, the Court granted the parties’ stipulation to substitute MSN Laboratories Ptv. Ltd. for Ven-noot. (D.I. 311) 14. Defendant Sun Pharma Global FZE is a corporation organized and existing under the laws of the United Arab Emirates, having a principal place of business at Executive Suite #43, Block Y, SAIF-Zone, P.O. Box 122304, Sharjah, U.A.E. (SUF ¶ 14) 15. Defendant Sun Pharmaceutical Industries, Ltd., is a corporation organized and existing under the laws of India, having a principal place of business at SUN HOUSE, CTS No. 201 BA, Western Express Highway, Goregaon (E), Mumbai 400063, India. (SUF ¶ 15) 16. Defendant Watson Laboratories, Inc. — Florida (nA</a Actavis Laboratories FL, Inc) is a corporation organized and existing under the laws of Florida, having a principal place of business at 4955 Orange Drive, Fort Lauderdale, Florida 33314. (SUF ¶ 16) 17. Defendant Watson Pharma, Inc. (n/ k/a Actavis Pharma, Inc) is a corporation organized and existing under the laws of Delaware, having a principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey 07054. (SUF ¶ 17) 18. Defendant Actavis, Inc. is a corporation organized and existing under the laws of Nevada, having a principal place of business at Morris Corporate Center III, 400 Interpace Parkway, Parsippany, New Jersey 07054. (SUF ¶ 18) 19. Defendant Apotex Corp. is a corporation organized and existing under the laws of Delaware, having a principal place of business at 2400 North Commerce Parkway, Suite 400, Weston, Florida 33326. (SUF ¶ 19) 20. Defendant Apotex, Inc. is a corporation organized and existing under the laws of Canada, having a principal place of business at 150 Signet Drive, Toronto, Ontario, Canada M9L 1T9. (SUF ¶ 20) 21. Defendant Mylan Pharmaceuticals Inc. is a corporation organized and existing under the laws of West Virginia, having a principal place of business at 781 Chestnut Ridge Road, Morgantown, West Virginia 26505. (SUF ¶ 21) 22. Defendant Mylan, Inc. is a corporation organized and existing under the laws of Pennsylvania, having a principal place of business at 1500 Corporate Drive, Canons-burg, Pennsylvania 15317. (SUF ¶ 22) 23. Defendant Zydus Pharmaceuticals (USA) Inc. is a corporation organized and existing under the laws of New Jersey, having a principal place of business at 73 Route 31 North, Pennington, New Jersey 08534. (SUF ¶ 23) 24. Defendant Cadila Healthcare Limited is a corporation organized and existing under the laws of India, having a principal place of business at Zydus Tower, Satellite Cross Roads, Ahmedabad, 380015, Gujarat, India. (SUF ¶ 24) B. Testifying Witnesses 25. Dr. Clayton Heathcock testified on behalf of Defendants. Dr. Heathcock is an Emeritus Professor of Chemistry at the University of California, Berkeley. He has more than 50 years of experience in organic and medicinal chemistry, and has evaluated antiepileptic drugs for the National Institutes of Health. (Heathcock Tr. at 68-69, 71-72; DTX-2184) Dr. Heathcock has never been involved in the development of anticonvulsant drugs generally or for epilepsy specifically. (Heathcock Tr. at 169) 26. Dr. Samuel J. Pleasure testified on behalf of Defendants. Dr. Pleasure is a Professor of Neurology at the University of California, San Francisco (“UCSF”), School of Medicine and is a practicing physician with over 20 years of experience treating epilepsy patients. (Pleasure Tr. at 220-25, 316; DTX-2455) Dr. Pleasure is neither board certified in epilepsy nor focused on epilepsy in his research or clinical practice. (Pleasure Tr. at 291-93,1012) He does not see patients at UCSF’s Epilepsy Center, nor is he listed as an epileptologist on the UCSF Epilepsy Center website. (Pleasure Tr. at 292-93) He has not been an investigator in any trials for approval of an epilepsy drug. (Pleasure Tr. at 1013) 27. Dr. Harold Kohn testified on behalf of Plaintiffs. Dr. Kohn is the inventor of the ’551 patent. (See JTX-1) He possesses a Ph.D. in chemistry and worked as a professor at the University of Houston for over 20 years. (Kohn Tr. at 370-71) Dr. Kohn' later worked as a professor at the University of North Carolina at Chapel Hill. (Kohn Tr. at 371) Over the course of his career, Dr. Kohris research focused on functionalized amino acids. (See, e.g., JTX-7; JTXr9; JTX-10; JTX-11; JTX-40) 28. Dr. Roush was called at trial by Plaintiffs. Dr. William Roush is a professor at the Scripps Institute in Jupiter, Florida, and the Executive Director of the Scripps Institute’s internal drug discovery program. (Roush Tr. at 550-51; JTX-71) For the-past ten years he has focused on drug development. (Roush Tr. at 550-53) Dr. Roush has authored over 330 peer-reviewed papers, is an. associate editor for the Journal of the American Chemical Society, and has received numerous honors for his work. (Roush Tr. at 553-54; see also JTX-71) 29. Dr. Carl Bazil testified on behalf of Plaintiffs. Dr. Bazil is a Professor of Neurology and the Director of the Comprehensive Epilepsy Center at Columbia University New York Presbyterian Hospital. (JTX-59; Bazil Tr. at 753-63) He is board certified in epilepsy, has treated epilepsy patients for more than 30 years, and has overseen the care of thousands of epilepsy patients. (Bazil Tr. at 758-60) Dr. Bazil has overseen FDA-required phase III and IV trials for three anti-epileptic drugs. (Bazil Tr. at 755-56) 30. Dr. Christopher Vellturo is an economist who has performed a .wide variety of economic and econometric analyses in the context of mergers and acquisitions, intellectual property, antitrust litigation, and regulatory disputes. (See JTX-73) Dr;-Vell-turo has expertise in pharmaceutical economics based on consulting for clients in the pharmaceutical industry for more than 20 years. (See id.; see also Vellturo Tr. at 898-901) Dr. Vellturo was called at trial by Plaintiffs. 31. Dr. DeForest McDuff is an economist with more than ten years of experience in consulting, finance, and economic research. (DTX-2188) He has performed economic analyses on more than 100 professional engagements and in a wide variety of subject matters, including pharmaceuticals, biotechnology, diagnostics, consumer electronics, semiconductors, and finance. (See id) Dr. McDuff was called at trial by Defendants. 32. Dr. Henrik Klitgaard is a vice president and research fellow in the Neurosci-ences Therapeutic Area at UCB. (Klit-gaard Tr. at 873) Dr. Klitgaard has been involved in drug development for over 25 years and has published several papers on epilepsy and epilepsy drug development. (Id. at 874-75) Dr. Klitgaard conducted UCB’s assessment of lacosamide in 1997. (Id at 879-81) C. Person Having Ordinary Skill in the Art 33. As concerns the ’551 patent, the parties agree that a person having ordinary skill in the art (“POSA”) would have had knowledge and experience both in medicinal or organic chemistry and in the development of potential drug candidates. (Heathcock Tr. at 95-96; Roush Tr. at 562-63) This includes knowledge and experience in assessing the toxicology, pharmacology, and clinical utility of such candidates. (Heathcock Tr. at 95-96; Roush Tr. at 562-63) 34. “A medicinal chemist is someone who has been trained in organic or medicinal chemistry_” (Heathcock Tr. at 95) This person would “[u]sually” have “at least a master’s or bachelor’s degree” but, “[m]ore likely ... a Ph.D. degree and then a few years of actually doing medicinal chemistry and learning how medicinal chemistry does drug discovery” — “including developing drug candidates.” (Heathcock Tr. at 95-96) 35. “[Bjecause drug discovery involves a multi-disciplinary approach, a medicinal chemist may interface or consult with individuals having [other] specialized expertise, for example, a physician with experience in the administration of dosing and efficacy of drugs for the treatment of epilepsy or other central nervous system disorders.” (Pleasure Tr. at 315) D. Epilepsy and Its Treatment 36. Epilepsy is a chronic neurological disorder that afflicts about one percent of the population. (Bazil Tr. at 765-66) It is characterized by uncontrolled seizures that can be life-threatening or life-limiting, impacting the patient’s quality of life. (See Pleasure Tr. at 226, 228, 255; Bazil Tr. at 769-72) 37. Epilepsy is a heterogeneous disorder. (Bazil Tr. 766-68) The cause of most cases of epilepsy is unknown, making the development of antiepileptic drugs (“AEDs”) challenging and unpredictable. (Bazil Tr. 767-69; see DTX-2249 at DEF_7606; JTX-63 at PLS-V1M667) 38. The manifestations of epilepsy also vary greatly, as seen in the different types of seizures that patients suffer, which can involve the whole brain (generalized seizure) or a part of the brain (partial seizure). (Bazil Tr. at 766-67; Pleasure Tr. at 255-56) 39. As a result, epilepsy treatments must be individualized to the specific patient. (Bazil Tr. at 768-69) Although a particular treatment may be effective for one patient, it may not work for another and may “be completely absurd to try” as a treatment choice for some patients. (Bazil Tr. at 768-69; see also id at 772-73) 40. Before March 15, 1996, more than 20 AEDs had been marketed to patients in the United States, including phenobarbital, mephobarbital, phenytoin, trimethadione, mephenytoin, paramethadione, phenythe-nylate, phenacemide, metharbital, benzch-loropropionamide, aminoglutethimide, ace-tazolamide, phensuximide, primidone, methsuximide, ethotoin, methazolamide, ethosuximide, diazepam, carbamazepine, clonazepam, lorazepam, valproic acid, clo-razepate, felbamate, gabapentin, and lamo-trigine. (SUF ¶ 83) E. UCB’s Vimpat® 41. UCB is the holder of New Drug Application (“NDA”) Nos. 022-253, 022-254, and 022-255, which cover an anti-epileptic drug known by the trade name Vimpat®. (SUF ¶ 25) 42. The active ingredient of Vimpat® is a compound called lacosamide. (SUF ¶ 26) 43. On October 28, 2008, NDA Nos. 022-253, and 022-254 were approved by the FDA to authorize the commercial marketing of Vimpat® tablets and injections as an adjunctive (i.e., add-on AED to be used with other AEDs) therapy in patients ages 17 years or older for partial on-set seizures. (SUF ¶ 28) Injection is indicated as a short-term replacement when oral administration is not feasible in these patients. (SUF ¶ 27) 44. On April 20, 2010, NDA No. 022-255 was approved by the FDA to authorize the commercial marketing of Vimpat® oral solution as an adjunctive therapy in patients ages 17 years or older for partial on-set seizures. (SUF ¶ 27) 45. In August 2014, NDA Nos. 022-253, 022-254, and 022-255 were further approved as a monotherapy in patients ages 17 years or older for partial on-set seizures. (SUF ¶ 29) 46. Vimpat® first launched in the U.S. market in 2008. (SUF ¶ 84) 47. Lacosamide had been formerly identified by or referred to as SPM 927, ADD 234037, or harkoseride. (SUF ¶ 85) 48. Vimpat® has the features needed in an AED for chronic treatment of epilepsy: high anticonvulsant activity, minimal neurological toxicity, and a high margin of safety. (See JTX-1 at 3:14-55; Bazil Tr. 788-93) It also causes little to no liver toxicity, making it suitable for chronic administration. (See JTX-1 at 3:36-38) 49. In Dr. Bazil’s experience, lacosamide is a “very important option” for a “large number of patients,” including those whose serious seizures could not be controlled with other AEDs. (Bazil Tr. at 816-17; see also Pleasure Tr. at 990 (agreeing with Dr. Bazil)) F. Applicable Principles of Medicinal Chemistry 50. “Enantiomeric compounds,” also known as “enantiomers” or “stereoisom-ers,” are molecules that “have the same connectivity” — ie., the same atoms connected to each other in the same way — but are mirror images of each other in three-dimensional space. (See Heathcock Tr. at 82-83) With the exception of three-dimensionality, enantiomers share “the same structure.” (Roush Tr. at 714-16) This relationship is called “chirality.” (See id.) A 50-50 mixture of two enantiomers is called a “racemate” or “racemic mixture.” (Heath-cock Tr. at 83) 51. Racemic compounds and enantiom-ers are different compounds having different properties. (See Roush Tr. at 624-30; Kohn Tr. at 403-05) Racemic compounds have different crystal forms, melting points, solubilities, optical rotations, spectroscopic properties, and biological effects than do enantiomeric compounds. (Roush Tr. at 625-28; Kohn Tr. at 403-05) Race-mates and enantiomers each receive different registration numbers from the Chemical Abstracts Services (“CAS”). (Kohn Tr. at 404-05; Roush Tr. at 627-28) 52. In this case, the two enantiomers that make up a racemic mixture can be called either “R” and “S,” or “D” and “L.” (Heathcock Tr. at 85-86; see also Roush Tr. at 695) “[F]or ... compounds that we are concerned with ... D is synonymous with R and L is synonymous with S.” (Heathcock Tr. at 86) 53. During the relevant period, medicinal chemists evaluated drugs for their anti-convulsant activity based on “ED60” values obtained in the “maximal electroshock seizure” (“MES”) animal test. (Kohn Tr. at 382; Heathcock Tr. at 127; see also JTX-1 at 21:30-22:27) ED50 represents “the dose at which half of the [animals that were tested] did not have [a] convulsion” in response to an electric shock. (Heathcock Tr. at 127) “[T]he lower the number, the more potent the compound is.” (Id.; see also Kohn Tr. at 382-83,461) 54. The MES test was also used to measure neurotoxicity, which is reported as “TD50” values, representing “the dose at which half of the animals experience ... toxicity” as shown by “loss of balance.” (Heathcock Tr. at 128; see also, e.g., JTX-1 at 22:5-13, 26-27) For TD60, “a larger number” — indicating less toxicity — is desirable. (See Heathcock Tr. at 128) 55. “[T]he ratio between the median toxic dose and the median effective dose (TD50 /EDbo)” is the “protective index” (“PI”). (JTX-1 at 3:19-25; Kohn Tr. at 382) The larger the PI, the safer the drug. (Heath-cock Tr. at 382) 56. The ’551 patent reports data on anti-convulsant activity in terms of ED60, TD60, and PI values. (See ’551 patent at 21-24) The ’551 patent does not describe any human testing. (Pleasure Tr. at 287) G. Functionalized Amino Acids 57. The compounds described in the ’551 patent belong to a class of compounds called “functionalized amino acids” (“FAAs”). (Kohn Tr. at 372; Heathcock Tr. at 90-91) FAAs have the general structure depicted below: 58. In an FAA, R, R1; and R3 are vana-bles, meaning different elements or compounds of elements can be placed at each of these three sites, and each variation for any of these three sites yields a different FAA compound. (See Heathcock Tr. at 90-91; Kohn Tr. at 372-73) H. Aromatic, Heteroaromatic, and No-naromatic Groups 59. Aromatic groups are two-dimensional and have an electron configuration that confers stability to the unit. Aromatic groups are organized into a ring. (Kohn Tr. at 400-01) 60. Heteroaromatic groups are aromatic groups that contain at least one heteroa-tom. A heteroatom is any atom other than carbon. In heteroaromatic groups, the het-eroatom is most often oxygen, nitrogen, or sulfur. (Id. at 411) 61. Non-aromatic groups are compounds that have a three-dimensional structure and no unique stability provided by the electron structure. (Kohn Tr. at 400-01) Non-aromatic groups are not organized into a ring. (Id.) I. Lacosamide’s Structure 62. Claim 9 of the ’551 patent depends from claim 8 and claims the FAA compound lacosamide, which is the R-enan-tiomer of N-benzyl-2-acetamido-3-methox-ypropionamide. (’551 patent at 38:37-40) 63. Lacosamide has the following structure: Lacosamide has a methoxymethyl group at R8'. Methoxymethyl is a carbon-based, non-aromatic group. (Roush Tr. at 603) J. Drug Development in 1996 64. As of March 1996, a common approach to identify a lead AED was to start with FDA-approved drugs or compounds having proven clinical efficacy. (Roush Tr. at 565) A POSA would also look in the literature to find promising compounds that were either in clinical trials or were viewed as well-advanced preclinical candidates. (Roush Tr. at 566-66, 574) Looking at FDA-approved drugs or promising drugs in clinical or preclinical development yielded hundreds of potential start points. (Roush Tr. at 564-69, 572-74; see also JTX-91; JTX-92; PTX-320) 65. As of March 1996, no FAA compound had been approved as an AED by the FDA, nor had any FAA been identified as undergoing clinical evaluation or as a well-advanced preclinical candidate. (Roush Tr. at 570, 575-76) Twenty years later, laco-samide remains the only FAA that has béen approved for the treatment of epilepsy. (Kohn Tr. at 373) 66. Drug discovery is, and was as of March 1996, unpredictable. The myriad chemical and biological factors at play made it difficult to predict the effects of a particular compound in the body. (See Heathcock Tr. at 187-88; Roush Tr. at 567-68, 611-12; Pleasure Tr. at 1044-46; PTX-4 at 443) Thus, discovery of new drugs was driven by pharmacological data. (Heath-cock Tr. at 165-166; Roush Tr. at 566-67; see also Kohn Tr. at 521) 67. A POSA would consider a number of factors when seeking to develop a new AED. Among the most important are anti-convulsant activity (Heathcock Tr. at 165-66; Roush Tr. at 566-67), neurotoxicity (Kohn Tr. at 383; Heathcock Tr. at 127-28), and liver toxicity (Heathcock Tr. at 177). 68. Medicinal chemists also use structure-activity relationships (“SARs”) to design new drugs. (Heathcock Tr. at 103) This involves starting with a structure and “making changes and observing whether that change .., improves the potency or whatever biological property you are using as your endpoint, or if it doesn’t improve it. And then you continue to make changes of the sort that improve it.” (Heathcock Tr. at 103, 134) SARs allow chemists to determine “what areas of a molecule seem promising to continue to change.” (Roush Tr. at 586-87) K. Dr. Kohn’s Research Leading to Vim-pat® 69. In the early 1980s, Dr. Kohn theorized that FAAs may demonstrate anticon-vulsant activity. (Kohn Tr. at 375-77) This was a new theory that was outside the mainstream of AED discovery. (See id. at 373; Heathcock Tr. at 103-04,135 (describing Dr. Kohn’s FAAs as “novel”); JTX-9 at DEF_571; JTX-10 at DEF_645) 70. When Dr. Kohn started his research, he had no evidence that any FAA would exhibit anticonvulsant activity, low or no neurological toxicity, a high margin of safety, or minimal adverse effects during long-term chronic administration. (See Kohn Tr. at 375-77, 388-89) For many years, Dr. Kohn was working virtually alone in the field. (See Heathcock Tr. at 171 (describing prior art as “originat[ing] from Dr. Kohn’s laboratory”)) 71. Beginning in 1985, Dr. Kohn published a series of papers reporting the results of his work with FAAs. This prior art is discussed in the next section. (See infra Findings of Fact (“FF”) 85) 72. During the more than ten years from Dr. Kohn’s first publication of an F A A compound to the filing of the ’551 Patent, there was no pharmacological data published on any compound with a methoxyme-thyl group — which is a nonaromatic group — at R3. (Heathcock Tr. at 159-60, 167) 73. Based on the results of his 1987 paper, Dr. Kohn and his students focused on compounds with aromatic, particularly heteroaromatic, groups at R3. (Kohn Tr. at 402, 409-10) 74. Eventually, Dr. Kohn tested about 130 FAAs, approximately 50 of which had heteroaromatic groups at R3. (See JTX-7 at DEFJ566; DTX-2019 at DEF_194-96, DEF_244; JTX-11 at DEF_269-270; JTX-80 at DEF_710; JTX-56 at DEF_278-79; DTX-2012 (“’729 patent”), Tbl.l; JTX-67 at DEF_719; JTX-65 at DEF_723) Fourteen of the 16 FAAs with ED60s under 20 mg/kg had heteroaromatic groups at Rs. (See DTX-2019 at DEF_194; JTX-11 at DEF-269; JTX-80 at DEFJ710; JTX-56 at DEF_278-79; JTX-65 at DEF_723) Thus, about 30% of the compounds with heteroa-romatic groups at R3 had excellent anti-convulsant activity, compared to approximately only 3% of compounds with non-heteroaromatic groups at R3. 75. One of the most promising of the heteroaromatic compounds Dr. Kohn developed contained a furan group at R3. (Kohn Tr. at 436-47) 76. In the mid-1980s, Plaintiff RCT attempted to interest pharmaceutical companies in FAAs; only Eli Lilly & Co. (“Lilly”) took a license. (Id. at 407-08) 77. Under its license, Lilly evaluated the compound with furan at R3. (Id. at 435-37) Even though this compound exhibited excellent efficacy and relatively low neuro-toxicity, it was found to produce serious liver toxicity. (Id. at 437-39; JTX-11 at DEF_270; see also PTX-215 at KOHN-VIM44737) In late 1991, after five years, Lilly terminated its license and collaboration with Dr. Kohn. (PTX-215 at KOHN-VIM44737 (“You will note that the compound caused substantial hepatocellular necrosis, which was the basis for our termination of development.”); JTX-23; Kohn Tr. at 408, 437-39) 78. After Lilly terminated its license, Dr. Kohn largely focused his research on het-eroaromatic compounds. (Kohn Tr. 439-41) But by late 1993, Dr. Kohn was forced to reevaluate. (Id. at 441-42) He tested a set of 12 FAAs having different structures— with carbon-based, non-heteroaromatic groups at Rs. (Kohn Tr. at 441-44; see also JTX-40 at KOHN-VIM33271) Of those 12 compounds, ten showed only modest or marginal activity, one showed what Dr. Kohn termed “nice” activity, and one, (R.S) N-benzyl-2-acetamido-3-methoxypro-pionamide (“RS-BAMP”), showed promise. (Kohn Tr. at 445-46) 79. Dr. Kohn provided his findings on FAAs to RCT, which was “in charge to try to find a licensee” for Dr. Kohn’s patents. (See id. at 407) In November 1993, Dr. Kohn had biological test results of the racemic mixture with methoxymethyl (i.e., what the LeGall Thesis, described below, disclosed as compound 107e), which he sent to RCT and characterized as “impressive phase one results.” (DTX-2092 at RCT-VIM 68156; Kohn Tr. at 531-32) Dr. Kohn further indicated that “this data is for the racemate so I suspect that the D-isomer [ie., lacosamide] will have the highest ED50 value reported to date.” (DTX-2092 at RCT-VIM 68156; Kirkpatrick Tr. at 323-25; Kohn Tr. at 531-32) 80. Dr. Kohn was “ecstatic” when he received the biological data for the R-enan-tiomer (also known as the “D isomer”), lacosamide, “around the end of ’94” from the NIH. (Kohn Tr. at 448-49, 533; JTX-50) In October 1994, Dr. Kohn sent RCT what he called “neat test results” for laco-samide. (JTX-051; Kohn Tr. at 534; Kirkpatrick Tr. at 323) Dr. Kohn also wrote that “[a]ll of the pieces are in place for RCT to move forward taking actions that will lead to licensing within the next 6 to 9 months.” (JTX-051; Kohn Tr. at 534) “[S]hortly after that,” RCT “had a license agreement with [Plaintiff] Hands.” (Kohn Tr. at 534) 81. In June 1995, Harris “tentatively selected the methoxymethyl (d) as [its] lead candidate for further evaluation.” (DTX-2075; Harris Tr. at 331) That compound, ADD Number 234037 is lacosam-ide. (DTX-2075; Harris Tr. at 332; Kohn Tr. at 450) 82. In 1996, the mode of action for anti-convulsant activity of FAAs was unknown. (Roush Tr. at 567-69; Kohn Tr. at 451) Mode of action was an important factor in determining whether to investigate a particular class of compounds. (See JTX-142) Without knowing the mode of action, a POSA could not have predicted how structural modifications to a compound would affect its pharmacological properties. (See Roush Tr. at 567-68) 83. As of March 1996, there was limited data regarding the structure-activity relationships of FAAs, which concerned only the compounds’ anticonvulsant activity and neurotoxicity. (See id. at 575-76) There was no data available on other potential side effects of FAAs, such as liver toxicity. (Heathcock Tr. at 129, 178; Roush Tr. at 561-62) L. Prior Art 84. None of the prior art documents relied on by Defendants described laco-samide or provided any pharmacological data on either lacosamide or any FAA having a methoxymethyl group at R3 (which lacosamide has). (See Heathcock Tr. at 167, 177-78; see also JTX-9; JTX-10; JTX-11; JTX-80; JTX-56; JTX-65; JTX-67 (Kohn publications, none of which discusses LeGall Thesis compound 107e or any compound having a methoxymethyl at R3)) i. Dr. Kohn’s Prior Art Publications 85. In 1985, Dr. Kohn published the anticonvulsant activity of his first FAA compound, “the alanine compound,” or “AAB.” (Kohn Tr. at 387-88; JTX-57 at Tbl.4 (compound 6d); see also Heathcock Tr. at 98-99) According to Dr. Kohn, AAB demonstrated the “proof of concept” for FAAs. (Kohn Tr. at 389) AAB contains a methyl (CH3) at the a-carbon substituent R3 (Heathcock Tr. at 100), a benzyl at R, and a methyl substitution at Rj (Kohn Tr. at 457-58; see also Heathcock 100:9-11; DDX-105). 86. In 1987, Dr. Kohn and one of his graduate students, Judith Conley, reported on the anticonvulsant activity of 16 structural analogues of the “parent compound,” AAB. (JTX-7 at Abstract; Heathcock Tr. at 100) 87. Dr. Kohn reported that each of the groups at the different positions of his FAAs affected the properties of the molecule. (See JTX-7 at DEF_567 (“The specific activities of these compounds in the MES, sc Met, and toxicity tests can be independently modulated by alteration of the substitution pattern at the a-carbon atom, the N-acyl, and the N-amido moieties.”); Roush Tr. at 578, 619) 88. The 1987 paper also contained data relating to FAAs having a non-aromatic group at the R3 position. (See JTX-7 at DEF-563 (describing non-aromatic compounds); Roush Tr. at 579 (same); JTX-7 at DEF-566 (describing aromatic compound); Kohn Tr. at 401 (same)) The use of the aromatic group at R3 greatly improved the anticonvulsant activity. (See Roush Tr. at 579 (“[T]he important take-home message from the R3 analysis ... is that compounds that have an aromatic residue see a large jump in activity.”)) 89. The 1987 paper used unsubstituted benzyl at R and unsubstituted methyl at Rj as a reference point. (See JTX-7 at Tbls.2, 3; Heathcock Tr. at 100; Kohn Tr. at 467-68) The paper considered five possible modifications of the benzyl at R. (JTX-7 at Tbl.2) One of these modifications showed activity comparable to the base case (which had unsubstituted benzyl at R). (Id.; see also Kohn Tr. at 468) Each of the three modifications made at the Rj position decreased anticonvulsant activity when compared to the placement of unsubstituted methyl at Rt. (See JTX-7 at Tbl.3) 90. In 1988, Dr. Kohn reported data on the “enantiomers and racemates” of certain FAAs — particularly AAB (containing methyl at R3, benzyl at R, and methyl at Rx) and APB (containing phenyl at R3, rather than methyl, but otherwise the same as AAB). (JTX-10; Kohn Tr. at 473, 475) In two articles, Kohn published that the R enantiomers of AAB and APB were about 10 times more potent than the S enantiomers. (JTX-10 at DEF-646-47; JTX-9 at DEF-573; Kohn Tr. at 476, 481) Indeed, “[f]or both compounds, the anti-convulsant activity is due to the D|7R]-stereoisomer, and the L|7S]-stereoisomer is virtually inactive as an anticonvulsant.” (JTX-10 at abstract; Heathcock Tr. at 108) As Dr. Kohn concluded, “the anticonvul-sant activity observed resided primarily in the D-stereoisomers and represents the greatest pharmacological stereochemical differentiation reported to date among an-tiepileptic agents.” (JTX-9 at DEF-273) 91. The relative potency of the R enan-tiomer was demonstrated again in a paper published by Dr. Kohn in 1990. (JTX-11 at DEF-272; Heathcock Tr. at 109) 92. In the 1990 paper, in which Dr. Kohn applied the teachings of his 1987 paper, Dr. Kohn kept “Rj constant and R constant” as methyl and benzyl, respectively. (See Kohn Tr. at 485-86; JTX-11 at 919 Tbl.l) He reported that the most potent compound was 2g, which had 2-furanyl at R3, benzyl at R, and methyl at R^ (Kohn Tr. at 486; DDX-726) Compound 2g “was found to be significantly more potent than APB, and at the time in 1990 when this paper was published this was the most potent compound in the FAA family.” (Heathcock Tr. at 109) 93. Dr. Kohn’s 1990 paper also considered the effect of replacing an unsubstituted benzyl at R with a fluoro-substituted benzyl. (JTX-11 at DEF-272) The 1990 paper found that such a substitution yields a “far superior” protective index and a comparable anti-convulsant effect. (See id.; Kohn Tr. at 489) The substitution was made in an FAA with an unsubstituted methyl at Rj and an aromatic 2-furanyl structure at R3. (See JTX-11 at DEF-269-70) 94. Kohn 1991 summarizes the previous work with FAAs, explaining that that “you get potent protection if you have a benzyl on one end and a methyl on the other.” (Kohn Tr. at 493) All 26 compounds reported in Kohn 1991 had unsubstituted benzyl at R and unsubstituted methyl at R1; with different compounds at the Rs group attached to the a-carbon. (JTX-80 at DEFJ709, Tbl.l) 95. In Kohn 1991, compound 31 — in which Rs was methoxyamino (NHOCHg)— possessed' “the best activity to date” for any FAA. racemate. (Kohn Tr. at 494; Heatheock Tr. at 111; JTX-80 at Tbl.l) Another compound in Kohn 1991, compound 3n, in which R3 is methoxymethy-lamino (NCHsOCH3), was reported to have “essentially equivalent properties” to its “simpler variant,” methoxyamino compound 31. (Heatheock Tr. at 162-63; JTX-80 at Tbl.l) 96. Compound 31 contains a nonaromatic methoxyamino group at R3. (Heatheock Tr. at 136) Prior to March 1996, Lilly knew about compound 31 and tested it. (Kohn Tr. at 434; PTX-197 at KOHN-VIM1405) But Lilly never expressed any interest in compound 31. (Kohn Tr. at 435) Lilly instead focused all of its development efforts on a structurally different FAA compound with a heteroaromatic furan group at Rs. (See Kohn Tr. at 435-36) 97. Moreover, the EDeo data for compound 31 was published in 1991, five years before the priority date of the ’551 patent. (Heatheock Tr. at 126-27; Kohn Tr. at 434-35; JTX-80) Yet compound 31 was never pursued nor even suggested as a lead compound by anyone (until this litigation). (See Heatheock Tr. at 186-87) 98. Compound 31 possesses chemical properties that a POSA would have wished to avoid. (Roush Tr. at 604-05) Specifically, the compound contains: an N-0 bond. (See id.; Heatheock Tr. at 137-38; JTX-80) Medicinal chemists try to avoid developing compounds containing this bond because- it is- not sufficiently stable for use in drugs. (See Heatheock Tr. at 137-38; Roush Tr. at 604-05) 99. Dr. Kohn continued to explore heter-oaromatic groups, publishing data for many other compounds with heteroaromatic groups at R3 and demonstrating excellent -anticonvulsant activity. He reported nine -FAAs with heteroaromatic groups with ED60s below 20 mg/kg: Pyrimidine 8.1 JTX-65 at DEF 723 Furan 10.3 DTX-2019 atDEF 194 Oxazole 10.4 JTX-56 at DEF 278 Pyridine 10.8 JTX-65 at DEF 723 Thiazole 12.1 JTX-56 atDEF 278 Pyrazine 14.8 JTX-65 at DEF 723 Pyrrole 16.1 DTX-2019 at DEF1194 Pyrazole 16.5 JTX-56 at DEF 278 5-CH3-Furan 19.2 JTX-11 atDEF 269 100. All of the prior art compounds with nonaromatic, carbon-based groups at R8 had significantly lower anticonvulsant activity and would not have been of any interest. (Roush Tr. at 598) 101. In 1993, Dr. Kohn published the results of an experiment that reinforced the importance of an aromatic group at R3. (JTX-56; Roush Tr. at 591-92) He showed that when the heteroaromatic furan ring was chemically converted into the nonaro-matic tetrahydrofuran (“THF”) ring, two THF isomers were produced, which were five and nine times less active than the compound with a furan ring at R3. (JTX-56 at DEFJ279, Tbl.2) A POSA would take away from these data that an aromatic group is the key for good anticonvulsant activity. (Roush Tr. at 591) 102. In Kohn 1993, the “starting point” again was benzyl at R and methyl at Rj. (Kohn Tr. at 497-98) Kohn 1993 first investigated modifications of the 2-furanyl group at R3 with other heteroaromatic groups. (JTX-56 at Tbl.l; Kohn Tr. at 498) Kohn 1993 did not find any heteroaro-matic substitutions with improved activity relative to the 2-furanyl. (JTX-56 at Tbl.l) 103. In Bardel 1994, Dr. Kohn once again provided support for his hypothesis “that placement of a substituted heteroa-tom two atoms removed from the [a-carbon] site provided enhanced protection against MES-induced seizures.” (JTX-65 at 4568; Kohn Tr. at 505) ii. The LeGall Thesis 104. In 1987, Philippe LeGall, a graduate student of Professor Kohn’s at the University of Houston, completed work on his master’s thesis. (DTX-2019) The LeGall Thesis is a 178-page student thesis that did not undergo formal peer review. (Roush Tr. at 587) However, for purposes of this litigation, the parties agree that the LeGall Thesis was publicly accessible more than one year before the earliest priority date for the ’551 patent and constitutes a “printed publication” within the meaning of 35 U.S.C. § 102(b). (SUF ¶ 87) 105. The LeGall Thesis disclosed 15 new FAA compounds and provided anticonvul-sant data for all but one of those compounds. (DTX-2019 at DEF_194-96, 223, 244-45) 106. The most active compounds in the LeGall Thesis had heteroaromatic groups at the R3 position. (Id. at DEF_254) Specifically, the two most potent compounds had a furan group (ED60 = 10.3 mg/kg) or a pyrrole group (ED60 = 16.1 mg/kg) at R3 . (Id. at DEF_94) 107. Compound 107e from the LeGall Thesis is a racemate known as (R,S)-N-Benzyl 2-Aeetamido-3-methoxypropionam-ide. (Roush Tr. at 624; DTX-2019 at DEF_223, 250) Compound 107e is similar to lacosamide except that it contains both the R and S enantiomers in a mixture, rather than just the R enantiomer. (Heath-cock Tr. at 104-06) 108. The LeGall Thesis contains no pharmacological data for compound 107e. (Heathcock Tr. at 178) Compound 107e is the only one of LeGall’s 15 new compounds for which his Thesis provides no data at all. (Roush Tr. at 585, 599-601) 109. In particular, the LeGall Thesis discloses no efficacy or toxicity data for compound 107e, and no liver toxicity data for any compound. (Heathcock Tr. at 167, 178; Pleasure Tr. at 303-04; Roush Tr. at 603) 110. Compound 107e was one of a series of “polar analogue” compounds disclosed in the LeGall Thesis. (Roush Tr. at 583) These compounds all had nonaromatic, carbon-based groups at R3, instead of het-eroaromatic groups. (Roush Tr. at 583-86) As a group, the polar analogues showed little or no potency. (See DTX-2019 at DEF_244-45; Roush Tr. at 599-600, 744-45; Kohn Tr. at 422-24) In particular, the ED60 results were all greater than 100 and mostly greater than 300, as compared to (for instance) the far more potent results reported for furan and pyrole groups, which were 10 and 16, respectively. The potency results for the “polar analogue” compounds of the LeGall Thesis are shown in the table below: Compound Ri MES ED50 (mg/kg) cyano (107 a) CN >300 amido (107b) C(Q)NH2 >300 ethyl ester (107c) C(0)0CH2CH3 >300 hydroxymethyl (107d) CH2OH >100, <300 methoxymethyl (107e) CH2OCH3 not tested (See DTX-2019 at DEF_244-45) 111. LeGall recognized that heteroaro-matic compounds showed the most promise. In the conclusion of his thesis, he emphasized the “highly active” “five-mem-bered ring heteroaromatic” compounds; he did not mention the nonaromatic compound 107e. (DTX-2019 at DEF_254-55; Heathcock Tr. at 184-185; Roush Tr. at 583-85, 601) Dr. Heathcock described the heteroaromatic furan compound disclosed in the LeGall Thesis as Dr. Kohn’s “first big breakthrough.” based on its high potency. (Heathcock Tr. at 179-80) 112. Despite the fact that he did not have data for compound 107e, LeGall hypothesized that structural similarities between compound 107e and another compound, 86b, suggested that compound 107e “may have good anticonvulsant activity.” (DTX-2019 at DEF_245) 113. Compound 86b contained OCH2CH3 at R and had an ED60 value of 62.0 mg/kg. (DTX-2019 at DEF_196) While a more potent compound than the “polar analogue” compounds for which data was reported (see table above), by March 1996 a POSA would have found the potency of 86b to be uninteresting. (Heathcock Tr. at 186; Roush Tr. at 602-04) 114. “[A]ll fifteen molecules that Mr. LeGall synthesized had a benzyl group at R and a methyl group at R1;” making these “common structural elements]” in LeGall’s work. (Roush Tr. at 676-80) Le-Gall “didn’t consider any other options,” “only compounds with unsubstituted ben-zyls” at R and methyls at Rx. (Id. at 677-78) 115. The LeGall Thesis was not before the PTO when it examined the application that became the ’551 patent. (See Heath-cock Tr. at 76-77; JT-4; JTX-2) 116. For nine years after the LeGall Thesis, compound 107e was never mentioned in any article, patent, or other reference. (Heathcock Tr. at 159-61) iii. U.S. Patent No. 5,378,729 (the “’729 patent”) 117. The ’729 patent, entitled “Amino Acid Derivative Anticonvulsant” was filed on June 4, 1991 and issued on January 3, 1995 to inventors Dr. Kohn and Dr. Darrell Watson. (’729 Patent (DTX-2012) at cover) The ’729 patent discloses a broad genus of millions or billions of compounds of the generic formula: (Id. at 61:40-62:34; Roush Tr. at 749) 118. The ’729 patent includes many compounds and groups referred to as “preferred,” including a dozen sets of “preferred compounds” or “preferred embodiments,” and many preferred groups for each position of each compound or embodiment. (’729 patent at 5-10) 119. The first “[preferred compounds” of the ’729 patent define R as a benzyl group, which can be unsubstituted or substituted (up to 3 groups on the phenyl ring are described as “preferred” R groups of these preferred compounds). (’729 patent at 6:31-45; Roush Tr. at 746-48) A POSA reading the ’729 patent would understand this to mean that it is preferred that the benzyl group be either substituted or unsubstituted. (Roush Tr. at 746-47) Other classes of “preferred compounds” in the ’729 patent list the R groups as “aryl, aryl lower alkyl, heterocyclic or heterocyclic alkyl which is unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group” and the Rx groups as “hydrogen or lower alkyl which is unsubstituted or substituted with at least one electron withdrawing group or one electron donating group.” (’729 patent at 8:50-64, 9:20-22) 120. The ’729 patent also lists preferences for groups located at R3. The parameters for the preferred R3 groups encompass millions of possible groups. (See, e.g.,’729 patent at 6:14-31; Roush Tr. at 748-49) While lacosamide falls within the scope of the preferences of the ’729 patent (Heathcock Tr. at 125), neither methoxy-methyl nor any alkoxy alyl is explicitly listed as a preferred R3 group (’729 patent at 6:13-43, 8:65-9:2, 9:22-28). 121. The ’729 patent nowhere mentions lacosamide. (See generally ’729 Patent; Heathcock Tr. at 160) 122. The ’729 patent identifies scores of FAAs and provides pharmacological data for 54 FAAs in Table 1. None of these compounds is lacosamide, 107e, or any compound with a methoxymethyl group at R3. (Heathcock Tr. at 160, 197; Roush Tr. at 594-95, 741-42) 123. All 54 compounds for which data is provided have methyl at Rj. (Heathcock Tr. at 117; ’729 patent at Tbl.l) Forty-nine of these compounds have an unsubstituted benzyl at R; the other five have fluoro-substituted benzyls at R. (’729 patent at Tbl. 1) The pharmacological results for the compounds vary greatly. (See id.) 124. The ED60s of compounds in Table 1 with unsubstituted benzyl at R and unsubstituted methyl at Rx range from 3.3 mgdig to inactive. (Id.) Ten of the compounds with these substitutions showed no activity, while many others exhibited only weak activity. (Id.) 125. Of the 10 compounds with the best ED50 values, eight had heteroaromatic groups at Rs; the other two had nitrogen-based groups. (Heathcock Tr. at 198; Roush Tr. at 742-43; ’729 patent at Tbl.l (10 compounds with heteroaromatic groups at R3 shown as entries 9,10, 13, 18, 30, 32, 37, 45, 48, and 51)) The four compounds in Table 1 that had nonaromatic, carbon-based groups at R3 (the RS-, R-, and S-alanine compounds, and an allyl compound) had moderate to weak anticonvul-sant activity, with EDeos of 77, 55, 548, and 33.6 mg/kg, respectively. (Roush Tr. at 741-42; ’729 patent at Tbl.l) Thus, the data in the ’729 Patent would not have created an expectation in a POSA that nonaromatic, carbon-based groups at R3 would be promising. (Roush Tr. at 742-43) 126. The two compounds in the 729 patent with the best protective indices (PI) had fluoro-substituted benzyl groups at R. (Heathcock Tr. at 200; Roush Tr. at 593-94, 616-17) These compounds exhibited “basically no change in activity .,. but a strikingly large improvement in the neuro-toxicity data” relative to the compounds with unsubstituted benzyl at R. (Roush Tr. at 617) This suggested that substituted benzyl groups at R might confer desirable properties. (See JTX-7 at DEF_566, Tbl.4 (la vs. lm)) M. U.S. Patent No. 5,654,301 (the “’301 patent”) 127. The ’301 patent is a continuation-in-part of the ’729 patent and is entitled “Amino Acid Derivative Anticonvulsant.” (DTX-2016 (“’301 patent”) at DEF_337) The ’301 patent was filed on January 12, 1993. The ’301 patent is not prior art, but it is the reference patent for Defendants’ obviousness-type double patenting claim. 128. UCB listed the ’301 patent in the FDA’s “Orange Book” in association with ■NDA Nos. 022-253, 022-254 for Vimpat®. (DTX-2347 at DEF_9936) 129. Claim 39 of the ’301 patent is an FAA that covers many millions, if not billions, of compounds of the formula: (Roush Tr. at 631; ’301 patent at 93:3-23) 130. Claim 39 defines the R group as “aryl, aryl lower alkyl, heterocyclic, heter-ocyclic lower alkyl, cycloalkyl, or lower cycloalkyl lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group.” (’301 patent at 93:3-23) This broad definition permits R to be any of millions of possible groups. (See Heath-cock Tr. at 201-02) 131. Claim 39 defines the Rt group as “hydrogen or lower alkyl ... unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group.” (’301 patent at 93:3-23) The ’301 patent defines “lower alkyl” as “containing from 1 to 6 carbon atoms and may be straight chain or branched.” (Id. at 3:37-39) This definition of “lower alkyl” covers 32 different groups, which can be substituted at various positions with one or more electron donating or electron withdrawing groups. (Roush Tr. at 633-34) The number of possible Rx groups within claim 39 is thus very large. (Id. at 634) 132. Claim 39 requires one of R2 and R3 to be “hydrogen and the other is lower alkyl which is substituted with an electron donating group or a[n] electron withdrawing group.” (’301 patent at 93:3-23) Thus, the Rs of claim 39 can be any one of the large number of groups discussed above for R: — consisting of thousands, if not millions, of possible groups. (Roush Tr. at 634-35) 133. The ’301 patent lists categories of [t]he most preferred electron donating and electron withdrawing substi-tuent[s:] ... halo, nitro, alkanoyl, for-myl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamide, cyano, sul-fonyl, sulfoxide, heterocyclic, guani-dine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower al-kyl, amino, lower alkylamino, di(low-eralkyl)amino, amine lower alkyl mer-capto, mercaptoalkyl, alkylthio; and alkyldithio. (’301 patent at 5:14-22) Many of these “substituents” are themselves generic categories, creating a very large group of possible preferred electron-donating and electron-withdrawing groups. (Roush Tr. at 632-33) These groups apply to any of the R, Rx, or R3 positions on the FAA molecule. (’301 patent at 93:3-23) 134. Claim 39 permits the repeating unit “n” — for the core C-CNH structure — to be one to four. (Id.) 135. Claim 39 does not specify a particular stereochemistry, so it encompasses R enantiomers, S enantiomers, and racemic mixtures of both. (Roush Tr. at 635-36) 136. Lacosamide is one species of the millions of compounds in the genus claimed by claim 39. (Roush Tr. at 636) The ’301 patent, however, does not mention lacosamide. (See ’301 Patent at Tbls. 1-4) 137. Claim 44 depends from claim 39 and defines the Rs group as methoxymethyl (’301 patent at 94:12-13; Roush Tr. at 636); thus, it covers compounds of the formula: 138. The R and Rj groups of claim 44 are the same broad genera as those defined for claim 39. (’301 patent at 93:3-23, 94:12-13) Like claim 39, claim 44 permits the value of “n” to be between one and four and the stereochemistry to be R, S, or a mixture thereof. (’301 patent at 94:12-13; Roush Tr. at 635-36) Claim 44 covers a genus of millions of compounds. (Roush Tr. at 637-38; see also Heathcock Tr. at 200-02) 139. The PTAB has found that the genus covered by claim 44 of the ’301 patent encompasses “thousands of compounds,” observing that “a skilled artisan still has to pick from unsubstituted and substituted R (and Rx), and if substituted, which substitution.” (JTX-88 at DEF_7503) 140. Claim 45 can depend from “any one of claims 39-44” and limits n to one. (’301 patent at 94:14-15) Thus, claim 45 covers a genus of compounds of the formula: 141. This genus covers “millions and millions if not billions” of compounds. (Roush Tr. at 637) Lacosamide is one species of this genus. (Heathcock Tr. at 201; Roush Tr. at 638) 142. Even when claim 45 is limited to depending from claim 44, which defines the R3 group as methoxymethyl, genus claim 45 still encompasses millions of possibilities due to the millions of possible choices for R and Rx. (Roush Tr. at 637-38) 143. Claim 46 of the ’301 patent should read as follows: “An anti-convulsant composition comprising an anti-convulsant effective amount of a compound from any one of claim[s] 39-44 and a pharmaceutical carrier therefor.” (SUF ¶ 89) 144. Claim 47 of the ’301 patent claims “[a] method of treating CNS disorders in an animal comprising administering to said animal an anti-convulsant effective amount of a compound of any one of claims 39-44.” (’301 patent at 94:19-21) 145. Claims 46 and 47 of the ’301 patent each cover millions of compounds. Both claims incorporate the large genera of possible R, R1; and R3 groups from claim 39. (See Heathcock Tr. at 206-07) Even if claims 46 and 47 are limited to the genus of claim 45 as it depends from claim 44, they would still each encompass millions of compounds, due to the millions of possible choices for the R and Rt groups. (See Roush Tr. at 637-38) 146. The ’301 patent provides tables of pharmacological data for FAA compounds. (’301 patent at Tbls.1-4) None of these tables discloses pharmacological data for lacosamide, 107e, or any compound with a methoxymethyl at R8. (See id.) Table 1 of the ’301 patent is the same as Table 1 of the ’729 patent. Table 1 demonstrates that not all of the compounds covered by the ’301 patent have good anticonvulsant activity. Indeed, some of the compounds listed have no activity at the highest tested dose. (Roush Tr. at 740) Similarly, Tables 3 and 4 of the ’301 patent include examples of 22 other compounds. (’301 patent at Tbls.3-4) Fifteen of these compounds had no anticonvulsant activity at the highest tested dose. (See id.) 147. The ’301 patent does not mention liver toxicity. (See generally ’301 Patent) 148. The PTO Examiner who examined the application leading to the ’551 patent had the ’301 patent before her. (See Heath-cock Tr. at 148) Yet the Examiner never issued a double patenting rejection in her two reviews of the ’551 patent. (See generally JTX-2, JTX-4) N. Others’ Exploration into FAAs 149. Dr. Kohn was not the only researcher to investigate FAAs. Drs. Parusz-ewski and Hinko also published on the subject. (JTX-53; JTX-54; JTX-87) While their articles are not prior art, they were published very shortly after the priority date, so they “show[] what other people had been thinking about” as of the priority date. (Heathcock Tr. at 163; see also Roush Tr. at 699) 150. Dr. Paruszewski was aware of Dr. Kohn’s work. (Roush Tr. at 613; JTX-53 at DEF_7495 (citing Kohn)) None of Parusz-ewski’s compounds had a methoxymethyl group at Rs. (Heathcock Tr. at 168-69; Roush Tr. at 613) While Paruszewski used groups at the R and Rj positions that were not benzyl and methyl, 18 out of 30 of Paruszewski’s compounds had unsubstituted benzyl (PDX-88; Roush Tr. at 703-04) and 19 out of 30 had a methyl at Rx. However, only six of his 30 compounds used the benzyl/methyl combination. (Roush Tr. at 617-18; JTX-53 at DEF_7493, Tbl.l; JTX-54 at KOHN_VIM33299, TbLl) 151. One change Paruszewski made was to remove the carbonyl (C=0) to which the Rx group is attached. (Roush Tr. at 620-21; PTX-80 at PLS-VIM20940-41) He included this modification in a prior art patent application published on May 2, 1995. (PTX-80 at PLS-VIM20938) The modification increased anticonvulsant activity (ED50 = 31.17 mg/kg) compared to Dr. Kohn’s otherwise analogous alanine compound (EDB0 = 76.54mg/kg). (Roush Tr. at 620-21) 152. Dr. Hinko was also aware of Dr. Kohn’s work. (JTX-87 at DEF_7475 (citing Kohn’s papers); Roush Tr. at 618) Hinko did not use a methoxymethyl group at the R3 position; nor did he use a methyl group at Rj. (Roush Tr. at 614; JTX-87 at DEF_7476, Fig. 1(1)) The compounds made by Hinko had a structure based on a piperidine ring, in which “the R3 is all tied back if you will, connected back into formally the remnants of where the R! group has been in Dr. Kohn’s structures.” (Roush Tr. at 614, 622; JTX-87 at DEF_7476, Fig. 1(D) 153. Hinko also made many modifications to the R group, including “fluorines, tri-fluoro-methyls at different positions, methyls, nitros, [and] chlorines.” (Roush Tr. at 618-23; JTX-87 at DEF_7480, Tbl.l) Hinko also “put additional substituents on the carbon connecting the phenyl group to the nitrogen. ... So these are not phenyl-methyl [i.e., benzyl], these ... are phenyl-ethyl substituents” at the R position. (Roush Tr. at 619; JTX-87 at DEF-7480, Tbl.l) Only two out of Hinko’s 21 compounds used unsubstituted benzyl. (Roush Tr. at 618-19) 0. The ’551 Patent-in-Suit 154. The patent-in-suit is United States Patent No. RE 38,551. (SUF ¶ 30) The ’551 patent was filed on January 28, 2002 as a reissue of U.S. patent No. 5,773,475. (Id.) The ’551 patent claims priority to provisional patent application No. 60/013,522, which was filed on March 15, 1996. The ’551 patent issued on July 6, 2004 and will expire no later than March 17, 2022. 155. RCT is the current owner of the ’551 patent. Harris is the exclusive licensee of the ’551 patent. UCB BioPhar-ma SPRL is the exclusive sublicensee of the ’551 patent for use in humans. (SUF ¶ 31) 156. In the FDA’s “Orange Book,” the ’551 patent is listed in the entries for Vimpat®, as is the ’301 patent. (SUF ¶ 32) 157. It is undisputed that the ’551 patent was the first public description of lacosam-ide and that lacosamide was not described in any prior art, including the ’301 patent. (Heathcock Tr. at 167, 177; Roush Tr. at 561) The ’551 patent provides methods of synthesizing lacosamide. (’551 patent at 11:22-13:14) It also provides physical and spectroscopic data on lacosamide. (Id. at 12:17-32,13:6-14) 158. The ’551 patent also contains the first publication of any pharmacological data for lacosamide. (Id. at Tbl.l (listing ED60 and TDfi0 data for lacosamide in mice and rats)) The ’551 patent compares the physical and pharmacological properties of lacosamide against a number of other compounds to demonstrate lacosamide’s superior properties. (’551 patent at Tbls.1,6) 159. Claim 9 of the ’551 patent covers one compound, lacosamide. Claim 9, which depends from claims 1 and 8, discloses: I. A compound in the R configuration having the formula: wherein Ar is phenyl which is unsubstituted or substituted with at least one halo group; Q is lower alkoxy, and Q1 is methyl. 8. The compound according to claim 1 which is (R)-N Benzyl 2-Acetamido-3-methoxypropionamide. 9. The compound according to claim 8 which contains at least 90% (w/w) R stereoisomer. 160. Claims 10 through 13 disclose: 10. A therapeutic composition comprising an anticonvulsant effective amount of a compound according to any one of claims 1-9 and a pharmaceutical carrier therefor. 11. A method of treating central nervous system disorders in an animal comprising administering to said animal in need thereof an anticonvulsant effective amount of a compound according to any one of claims 1-9. 12. The method according to claim 11 wherein the animal is a mammal. 13. The method according to claim 12 wherein the mammal is a human. 161. After the ’551 patent issued, RCT told the PTO that the ’301 patent covered lacosamide. In an application to extend the term of the ’301 patent, RCT represented that “claims 39-45” of the patent “claim the active ingredient ... lacosamide.” (DTX-2095 at DEF_4996) That document also represented that claim 46 of the ’301 patent “cover[s] a therapeutic composition” of lacosamide and that “[c]laim 47[ ] cover[s] a method of treating central nervous system disorders” with lacosamide. (DTK-2095 at DEF_4997-98) 162. The PTO accepted RCT’s representations, concluding that “U.S. Patent No. 5,654,301, which claims the human drug product Vimpat® (lacosamide) Tablet and a method of using” it, “is eligible for patent term extension.” (DTX-2218 at DEFJ5206) The PTO noted, however, that RCT “also ha[d] applied for patent term extension of U.S. Patent No. RE38561” based on Vimpat®’s approval, and that “the certificate of extension is issued to the patent having the earliest date of issuance unless applicant elects a different patent.” (Id.) RCT elected to extend the ’551 patent — the later-expiring patent. (See id. at DEF_5209) P. Differences Between the ’301 and ’551 Patents 163. The differences between claims 44 and 45 of the ’301 patent, on the one hand, and claim 9 of the ’551 patent, on the other, are that claim 9 fills in the variables of the claim 44/45 equation, so as to narrow the genus of