In re '318 Patent Infringement Litigation

• Decision Date: 26 September 2008
• Docket Number: Civ. No. 05-356-SLR.
• Citation: 578 F.Supp.2d 711
• Parties: In re '318 PATENT INFRINGEMENT LITIGATION.
• Court: U.S. District Court — District of Delaware

578 F.Supp.2d 711

In re '318 PATENT INFRINGEMENT LITIGATION.

Civ. No. 05-356-SLR.

United States District Court, D. Delaware.

September 26, 2008.

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Steven J. Balick, Esquire, John G. Day, Esquire, and Tiffany Geyer Lydon, Esquire of Ashby & Geddes, Wilmington, DE, of Counsel, George F. Pappas, Esquire, Roderick R. McKelvie, Esquire, Christopher N. Sipes, Esquire and Kurt G. Calia, Esquire of Covington & Burling LLP, Washington, D.C., Patricia Clarke Lukens, Esquire of Johnson & Johnson, New Brunswick, NJ, for Plaintiffs.

Edward V. Filardi, Esquire of Skadden, Arps, Slate, Meagher & Flom LLP, New York, NY, for Plaintiff Synaptech, Inc.

Frederick L. Cottrell, III, Esquire and Anne Shea Gaza, Esquire of Richards, Layton & Finger, P.A., Wilmington, DE, of Counsel, Alan H. Bernstein, Esquire, James J. Kuzuch, Esquire, Mona Gupta, Esquire, and William C. Youngblood, Esquire of Caesar, Rivise, Bernstein, Cohen & Pokotilow, Ltd., Philadelphia, PA, for Defendant Alphapharm Pty Ltd.

John C. Phillips, Jr., Esquire and Brian E. Farnan, Esquire of Phillips, Goldman & Spence, P.A., Wilmington, DE, of Counsel, George C. Lombardi, Esquire, Taras A. Gracey, Esquire, Lynn M. Ulrick, Esquire, Mustafa A. Hersi, Esquire and David T. Bower, Esquire of Winston & Strawn LLP, Chicago, IL, for Defendant Barr Laboratories, Inc.

**AMENDED OPINION

SUE L. ROBINSON, District Judge.

I. INTRODUCTION

Plaintiffs Janssen Pharmaceutica N.V. and Janssen, L.P. (collectively, "Janssen" or "plaintiffs") are the exclusive licensees of U.S. Patent No. * *4,663,318 ("the * * '318 patent"), claiming the treatment of Alzheimer's disease with galanthamine.¹ Janssen is the holder of approved new drug application ("NDA") No. 21-169 for galanthamine hydrobromide tablets, sold under the tradename Razadyne®² in three dosage forms. In 2005, several generic drug manufacturers filed with the Food and Drug Administration ("FDA") abbreviated new drug applications ("ANDA's") containing paragraph IV certifications for generic galanthamine hydrobromide. See 21 U.S.C. § 355(j)(2)(A)(vii)(IV). Janssen sued each for patent infringement pursuant to 35 U.S.C. § 271(e)(2)(A).³ The actions were consolidated.⁴ (D.I.29) Janssen's suit triggered the 30-month stay on the FDA's approval of generic galanthamine hydrobromide.⁵ See 21 U.S.C § 355(j)(5)(B)(iii). Defendants conceded infringement of claims 1 and 4 of the '318 patent. (D.I.49) The consolidated action proceeded on three invalidity issues raised by defendants: anticipation, obviousness, and enablement. A bench trial was held between May 21, 2007 and May 25, 2007 on these issues, which were fully briefed post-trial. The court has jurisdiction pursuant to 28 U.S.C. §§ 1331, 1338(a) and 1400(b). Having considered the documentary evidence and testimony, the court makes the following findings of fact and conclusions of law pursuant to Fed.R.Civ.P. 52(a).

II. FINDINGS OF FACT AND CONCLUSIONS OF LAW

A. Background

1. Alzheimer's disease

1. In 1906, Dr. Alois Alzheimer discovered Alzheimer's disease ("AD") in a fifty-one year old female patient who had "developed memory loss and paranoia." (D.I. 384 at 95:7-17) Dr. Alzheimer performed an autopsy and observed neurofibrillary tangles and plaques, which today are the "classic ... pathological hallmarks" of AD. (Id.)

2. For many years, the term "Alzheimer's disease" referred to a person with "pre senile" onset of dementia, or a person developing the condition at between 60 to 65 years of age. (Id. at 95:22-25) In contrast, senile dementia "refer[red] to a person who developed memory loss and dementia and appeared to have the equivalent of [AD]" with an onset age of over 60 or 65 years of age. (Id. at 96:14-24) By the mid-1980s, AD generally referred to "the entire spectrum of the disorder" including both pre-senile and senile dementia. (Id. at 96:6-8, 97:1-3)

3. In 1984, AD was recognized as a progressive dementia that begins with an onset of memory problems. (PTX-752 at 4924-25) As AD progresses, initial memory problems develop into more serious memory problems and begin to affect other higher brain functions, such as judgment, reasoning, language ability, perception, and recognition. (D.I. 384 at 100:4-101:4) The behavioral and functional abilities of AD patients are also affected. (Id.)

4. The course of AD varies broadly with-each patient. For some patients, the disease can progress rapidly, within one or two years, while in others the disease can progress over a 20-year period. (Id.)

2. The prior art

a. Cholinergic deficit hypothesis and the focus on AChe inhibitors

5. Very little was known about the possible causes of AD until the 1970s when researchers associated decreases in acetylcholine ("ACh")⁶ levels in the brain with the disease. (D.I. 384 at 118:16-24) Specifically, researchers learned that ACh plays an important role in memory. (Id. at 117:24-25) Research groups determined that the chemical marker for ACh was markedly decreased in AD patients and that the extent of this decrease correlated with the number of plaques and tangles in the brain, as well as with the degree of intellectual impairment. (DTX-167 at 8268; DTX-139 at 789; D.I. 384 at 122:2-11, 124:14-126:8) This development was inspired, in part, by Dr. David Drachman's 1974 article entitled "Human Memory and the Cholinergic System." (D.I. 384 at 110:7-25, 118:4-11, 122:12-18; DTX-495)

6. In the years following, several competing hypotheses existed for treating AD. (D.I. 386 at 1121:6-1122:10) Included within these hypotheses was the "cholinergic deficit hypothesis," also referred to as the "cholinergic hypothesis." (Id.) The cholinergic hypothesis relates to the idea that a reduction in ACh or a deficiency in the cholinergic cells (the group of brain cells that use ACh as a chemical messenger) contributes to AD. (D.I. 384 at 126:24-128:7) Put another way, ACh reduction contributes to the clinical symptoms of AD. (Id.; DTX-167 at 1459)

7. By the mid-1980s, the "primary emphasis in the treatment of [AD was] on enhancing cholinergic function." (PTX-752 at 4924 (1984)) Dr. Allen Levey, Chairman of the Department of Neurology and Director of the Alzheimer's Disease Research Center at Emory University, testified for defendants that the focus in the art at that time was on enhancing cholinergic activity. (D.I. 384 at 167:11-19) Dr. Levey further explained that this was due to the "solid scientific support" the cholinergic hypothesis had received. (Id.) For example, a loss of cholinergic neurons was observed in the brains of AD patients autopsied after death. (PTX-663 at 1184-85)

8. Scientists developed different treatment approaches based on the cholinergic hypothesis that focused on correcting the ACh deficit: (1) pre-synaptic, (2) intrasynaptic, and (3) post-synaptic. These approaches took many forms, including ACh precursors (a pre-synaptic approach) and muscarinic agonists⁷ (a post-synaptic approach). (D.I. 384 at 128:13-130:18)

9. Dr. Raymond Bartus, a leading researcher on memory loss, published an article in Science magazine in 1982 entitled "The Cholinergic Hypothesis of Geriatric Memory Dysfunction" (hereinafter, "Bartus"). (PTX-653) Under the heading "Directions for Future Research," Bartus stated:

A question that is beginning to emerge is why different cholinomimetics [⁸] seem to produce different results on memory in geriatric subjects. The absence of clear positive effects of choline and lecithin on geriatric patients is also perplexing. Among the many possible explanations, one that is consistent with all available data[,] is that the more directly one stimulates the muscarinic receptor, the more robust and consistent are the effects on memory performance in aged subjects[.]

(Id. at 1784) The direct-acting muscarinic agonists suggested by Bartus are a postsynaptic approach.

10. In 1986, D.F. Swaab and E. Fliers, of the Netherlands Institute for Brain Research, published a book chapter⁹ entitled "Clinical Strategies in the Treatment of Alzheimer's Disease" (hereinafter, "Swaab and Fliers"). (PTX-714) With respect to the cholinergic system, Swaab and Fliers noted that, "although `some clinical improvement can occasionally be seen' (Barbeau, 1978), a satisfactory treatment of the cognitive impairment of [AD] by means of pharmacological substitution for deficits in the cholinergic system seems, at present, not to be feasible." (Id. at 419)

11. Dr. Levey testified that by 1986, the pre- and post-synaptic approaches had proved largely unsuccessful in treating AD. (D.I. 384 at 129:19-130:10) Consequently, Dr. Levey testified that one of the prominent approaches for finding a treatment for AD was the intra-synaptic approach. (Id. at 130:19-23) The intra-synaptic approach used drugs to block acetylcholinesterase ("AChe") activity. (Id.) AChe breaks down ACh in the brain, causing a deficiency of ACh in AD patients. (DTX-167 at 8268; DTX-139; D.I. 384 at 105:8-21) Cholinesterase inhibitors ("CIs") are a class of drugs which are able to inactivate AChe. (D.I. 384 at 107:13-21) By inactivating AChe, CIs raise the level of ACh by preventing it from being broken down as quickly. (Id.) Scientists used CIs in an attempt to increase ACh function and thereby improve cognitive function in AD patients. (Id. at 130:16-18; PTX-763 at 12332)

12. A tertiary amine is a compound that can cross the blood-brain barrier. (D.I. 384 at 178:5-25) As of 1986, two reversible tertiary amines, physostigmine and tetrahydroaminoacridine ("THA"),¹⁰ had been studied as potential treatments for AD. (D.I. 384 at 230:6-15; PX-698 at 749) Physostigmine and THA were known as reversible tertiary CIs, meaning they could enter the brain, inhibit AChe, and increase the levels of ACh in the brains of AD patients. (D.I. 384 at 178:5-179:2; D.I. 385 at 382:9-383:15) The benefits in the memory and cognitive function of AD patients attributable to...