Case 1:13-cv-01206-LPS Document 313 Filed 08/12/16 Page 1 of 98 PageID #: 6299
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`UCB, INC., UCB BIOPHARAMA SPRL,
`RESEARCH CORPORATION
`TECHNOLOGIES, INC. and
`HARRIS FRC CORPORATION,
`
`Plaintiffs,
`
`v.
`
`ACCORD HEATLHCARE, INC., et al.,
`
`Defendants.
`
`UNSEALED ON
`AUGUST 15, 20 16
`
`Civil Action No. 13-1206-LPS
`CONSOLIDATED
`
`Jack B. Blumenfeld, Maryellen Noreika, and Derek J. Fahnestock, MORRIS, NICHOLS,
`ARSHT & TUNNELL, LLP, Wilmington, DE
`
`George F. Pappas, Jeffrey B. Elikan, and Alexa Hansen, COVINGTON & BURLING LLP,
`Washington, DC
`
`Attorneys for Plaintiffs UCB Inc., Research Corporation Technologies Inc., Harris FRC
`Corporation, and UCB Biopharma SPRL
`
`John C. Phillips, Jr., David A. Bilson, and Megan C. Haney, PHILLIPS, GOLDMAN, &
`SPENCE, P.A., Wilmington, DE
`
`George C. Lombardi, Maureen L. Rurka, Samuel S. Park, John R. McNair, and Lesley M.
`Hamming WINSTON & STRAWN LLP, Chicago, IL.
`Charles B. Klein and Eimeric Reig-Plessis, WINSTON & STRAWN, Washington, DC.
`
`Attorneys for Defendants Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of
`New York LLC, Aurobindo Pharma Ltd., Aurobindo Pharma USA Inc., Breckenridge
`Pharmaceutical Inc., MSN Laboratories Pvt. Ltd., Sun Pharma Global FZE, Sun
`Pharmaceuticals Industries Ltd., Watson Laboratories Inc. - Florida, Watson Pharma Inc.,
`and Actavis, Inc.
`
`John W. Shaw, SHAW KELLER LLP, Wilmington, DE
`
`Karen Bromberg and Gurpreet S. Walia, COHEN & GRESSER LLP, New York, NY
`
`Attorneys for Defendants Accord Healthcare Inc. and Intas Pharmaceuticals Ltd.
`
`Breckenridge Pharm. v. Research Corp. Techs., IPR2016-01242
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`Case 1:13-cv-01206-LPS Document 313 Filed 08/12/16 Page 2 of 98 PageID #: 6300
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`Richard D. Kirk, Stephen B. Brauerman, and Vanessa R. Tiradentes, BAYARD, P.A.,
`Wilmington, DE
`
`Jeffer Ali & Sarah M. Stensland, CARLSON, CASPERS, VANDENBURGH, LINDQUIST &
`SCHUMAN, PA, Minneapolis, MN
`
`Attorneys for Defendant Alembic Pharmaceuticals Ltd.
`
`Kenneth L. Dorsney, MORRIS JAMES LLP, Wilmington, DE
`
`Richard T. Ruzich, Stephen R. Auten, and Ian Scott, TAFT STETTINIUS & HOLLISTER LLP,
`Chicago, IL
`
`Attorneys for Defendant Apotex Corp. and Apotex Inc.
`
`Adam W. Poff and Pilar G. Kraman, YOUNG, CONAWAY, STARGATT & TAYLOR LLP,
`Wilmington, DE
`
`Nicole W. Stafford, Eric C. Amell, and Aden M. Allen, WILSON SONSINI GOODRICH &
`ROSATI, Austin, TX
`David S. Steuer, WILSON SONSINI GOODRICH & ROSATI, Palo Alto, CA
`Y ongdan Li, WILSON SONSINI GOODRICH & ROSATI, Los Angeles, CA
`
`Attorneys for Defendants Mylan Pharmaceuticals Inc. and Mylan, Inc.
`
`Francis J. Murphy, Jr., MURPHY, SP AD ARO & LANDON, Wilmington, DE
`
`Michael J. Gaertner, David B. Abromowitz, and Timothy F. Petersen, LOCKE LORD LLP,
`Chicago, IL
`Andrea L. Wayda, LOCKE LORD LLP, New York, NY
`
`Attorney for Defendants Zydus Pharmaceuticals (USA) Inc. and Cadila Healthcare Ltd.
`
`OPINION
`
`August 12, 2016
`Wilmington, Delaware
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`Breckenridge Pharm. v. Research Corp. Techs., IPR2016-01242
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`Case 1:13-cv-01206-LPS Document 313 Filed 08/12/16 Page 3 of 98 PageID #: 6301
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`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.,
`
`Aurobindo 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. 1)
`
`The '551 patent generally relates to "anticonvulsant 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(cid:173)
`
`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).
`
`1
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`Case 1:13-cv-01206-LPS Document 313 Filed 08/12/16 Page 4 of 98 PageID #: 6302
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`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 oflaw 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 if 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 if 2)
`
`2
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`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 ii 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 ii 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 ii 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 ii 6)
`
`7.
`
`Defendant Alembic Pharmaceuticals Ltd. is a corporation organized and existing
`
`under the laws oflndia, having a principal place of business at Alembic Road, Vadodara-390
`
`003, Gujarat, India. (SUF ii 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 ii 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 ii 9)
`
`3
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`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 - 50003 8, Telagana, India. (SUF if 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 if 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 if 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 if 13) On August 1, 2016, the Court granted the parties'
`
`stipulation to substitute MSN Laboratories Ptv. Ltd. for Vennoot. (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 if 14)
`
`15.
`
`Defendant Sun Pharmaceutical Industries, Ltd., is a corporation organized and
`
`existing under the laws oflndia, having a principal place of business at SUN HOUSE, CTS No.
`
`201 Bil, Western Express Highway, Goregaon (E), Mumbai 400063, India. (SUF if 15)
`
`16.
`
`Defendant Watson Laboratories, Inc. - Florida (n/k/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 if 16)
`
`4
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`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 ii 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 ii 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 ii 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
`
`1 T9. (SUF ii 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 ii 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, Canonsburg,
`
`Pennsylvania 15317. (SUF ii 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 ii 23)
`
`5
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`24.
`
`Defendant Cadila Healthcare Limited is a corporation organized and existing
`
`under the laws oflndia, having a principal place of business at Zydus Tower, Satellite Cross
`
`Roads, Ahmedabad, 380015, Gujarat, India. (SUF if 24) 1
`
`B.
`
`Testifying Witnesses2
`
`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) 3 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)
`
`1 The following parties are no longer part of the case: UCB Pharma GmbH, Alembic Limited,
`Hetero USA Inc., Hetero Labs Limited, Glenmark Generics Inc. USA, Glenmark Generics Ltd.,
`Ranbaxy Laboratories Ltd., Ranbaxy Pharmaceuticals Inc., Ranbaxy Inc., and Sandoz Inc.
`
`2 The Court here identifies each of the witnesses who testified live at trial. Both sides also called
`additional witnesses who testified via deposition.
`
`3 References to the trial transcript are in the form: "([Witness last name] Tr. at [page])."
`
`6
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`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. Kohn's research focused on functionalized amino acids. (See, e.g., JTX-7;
`
`JTX-9; JTX-10; JTX-11; JTX-40)4
`
`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 lnstitute'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) 5
`
`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. Vellturo has expertise in
`
`4 The Court found Dr. Kohn to be a particularly credible witness.
`
`5 The Court found Dr. Bazil to be a particularly credible witness.
`
`7
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`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 Mc Duff 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. McDuffwas called at trial by Defendants.
`
`32.
`
`Dr. Henrik Klitgaard is a vice president and research fellow in the Neurosciences
`
`Therapeutic Area at UCB. (Klitgaard 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 oflacosamide 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
`
`8
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`doing medicinal chemistry and learning how medicinal chemistry does drug discovery" -
`
`"including developing drug candidates." (Heathcock Tr. at 95-96)
`
`35.
`
`"[B)ecause 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(cid:173)
`
`threatening or life-limiting, impacting the patient's quality oflife. (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_ VIM667)
`
`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,
`
`9
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`paramethadione, phenythenylate, phenacemide, metharbital, benzchloropropionamide,
`
`aminoglutethimide, acetazolamide, phensuximide, primidone, methsuximide, ethotoin,
`
`methazolamide, ethosuximide, diazepam, carbamazepine, clonazepam, lorazepam, valproic acid,
`
`clorazepate, felbamate, gabapentin, and lamotrigine. (SUF if 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 if 25)
`
`42.
`
`The active ingredient ofVimpat® is a compound called lacosamide. (SUF if 26)
`
`43.
`
`On October 28, 2008, NDA Nos. 022-253, and 022-254 were approved by the
`
`FDA to authorize the commercial marketing ofVimpat® 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 if 28) Injection is indicated as a short-term replacement when oral
`
`administration is not feasible in these patients. (SUF if 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 if 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
`
`ir 29)
`
`46.
`
`Vimpat® first launched in the U.S. market in 2008. (SUF if 84)
`
`47.
`
`Lacosamide had been formerly identified by or referred to as SPM 927, ADD
`
`234037, or harkoseride. (SUF if 85)
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`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 "stereoisomers," are
`
`molecules that "have the same connectivity" - i.e., 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." (Heathcock Tr. at 83)
`
`51.
`
`Racemic compounds and enantiomers 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)
`
`Racemates 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
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`... 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
`
`anticonvulsant activity based on "EDso" values obtained in the "maximal electroshock seizure"
`
`("MES") animal test. (Kohn Tr. at 382; Heathcock Tr. at 127; see also JTX-l at 21:30-22:27)
`
`EDso 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
`
`"TD so" 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
`
`TDso, "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
`
`(TDso/EDso)" is the "protective index'' ("PI"). (JTX-1at3:19-25; Kohn Tr. at 382) The larger
`
`the PI, the safer the drug. (Heathcock Tr. at 382)
`
`56.
`
`The '551 patent reports data on anticonvulsant activity in terms ofEDso, TDso,
`
`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:
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`58.
`
`In an FAA, R, R1, and R3 are variables, 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)6
`
`H.
`
`Aromatic, Heteroaromatic, and Nonaromatic 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 heteroatom.
`
`A heteroatom is any atom other than carbon. In heteroaromatic groups, the heteroatom 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-enantiomer ofN-benzyl-2-acetamido-3-methoxypropionamide.
`
`('551 patent at 38:37-40)
`
`63.
`
`Lacosamide has the following structure:
`
`6 Although all F AAs share the structure depicted and described here, the variables are not always
`labelled R, R1, and R3. Where different nomenclature is used, this Opinion will note it.
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`Lacosamide has a methoxymethyl group at R3. 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) 7 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 565-66, 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, lacosamide remains the
`
`only FAA that has been 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.
`
`7 Sixteen of the 24 AEDs that had been approved as of 1996 shared one of four common
`chemical cores. (Roush Tr. at 570; see also JTX-92 at PLS_ VIM 105-06, 113, 120, 123-26;
`PTX-66 at PLS VIM 2096-97, 2099-100, 2104-07, 2109, 2111-15; JTX-91 at DEF 8352)
`-
`-
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`at 1044-46; PTX-4 at 443) Thus, discovery of new drugs was driven by pharmacological data.
`
`(Heathcock 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 anticonvulsant 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 Vimpat®
`
`69.
`
`In the early 1980s, Dr. Kohn theorized that FAAs may demonstrate
`
`anticonvulsant 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"))
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`71.
`
`Beginning in 1985, Dr. Kohn published a series of papers reporting the results of
`
`his work with F AAs. 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 FAA
`
`compound to the filing of the '551 Patent, there was no pharmacological data published on any
`
`compound with a methoxymethyl group - which is a nonaromatic group - at R3. (Heathcock Tr.
`
`at 159-60, 167)