Full opinion text
Opinion and Order BARBARA S. JONES, District Judge. TABLE OF CONTENTS INTRODUCTION ..............................................................303 I. The Parties .............................................................304 A. Teva ................................................................304 B. Sandoz ..............................................................304 C. Mylan...............................................................304 II. The Patents-in-Suit.....................................................304 A. Overview .........................■...................................304 B. Copaxone® — Teva NDA ..............................................306 C. Sandoz’s and Momenta’s ANDA .......................................307 D. Mylan and Ñateo ANDA ..............................................307 III. Procedural History and Claim Construction ...............................308 A. July 2011 Inequitable Conduct Trial ...................................309 i. Teva’s Witnesses ..............................................309 ii. Defendants’ Witnesses .........................................310 B. September 2011 Infringement and Invalidity Trial ......................310 i. Teva’s Witnesses ..............................................310 ii. Mylan’s Witnesses.............................................311 iii. Sandoz’s Witnesses ............................................312 iv.Witnesses Testifying by Deposition .............................312 IV.The Patents-in-Suit and the Patent Claims at Issue .......................313 A. Molecular Weight Claim Limitations ..................................313 i. Average Molecular Weight Limitations .........................313 ii. Molar Fraction Limitations ....................................313 iii. Predetermined Molecular Weight Profile Limitations ............314 B. Process Limitations ..................................................314 C. Treatment of Multiple Sclerosis .......................................315 D. Pharmaceutical Composition .........................................315 V. Copolymer-1 and Multiple Sclerosis ......................................315 A. Multiple Sclerosis: The Disease .......................................315 B. The Weismann Scientists’ Discovery of Copolymer-1 ....................316 C. Teva’s Agreement with Weizmann .....................................318 D. Discovery of the Process for Achieving Low Molecular Weight Copolymer-1.......................................................321 VI. Background on Polypeptide Chemistry, Synthesis, Analytical Testing........321 A. Polypeptide Chemistry ...............................................321 B. Synthesis of Copolymer-1.............................................322 C. Size Exclusion Chromatography ......................................323 D. Level of Ordinary Skill in the Art .....................................328 DISCUSSION..................................................................329 I. Infringement ...........................................................329 A. General Principles ...................................................329 B. Findings of Fact as to Mylan .........................................330 i. Mylan’s ANDA Product ........................................330 ii. Amino Acid Composition................. 331 iii. Molecular Weight .............................................331 iv. Mylan’s Manufacturing Process ................................333 v. ANDA Process ............... 334 vi. Mylan’s ANDA Product Label ..................................335 C. Conclusions of Law as to Mylan’s Product .............................335 i. Mylan’s Proposed Product Infringes Each o f the Asserted Claims because Mylan’s Product is Copolymer-1 ...............335 ii. The Reason for Mylan’s Molar Ratio is Irrelevant to the Infringement Analysis .......................................343 iii. The Doctrine of Equivalents....................................345 iv. Mylan’s Product Meets the Molecular Weight Limitations ........347 1) Average Molecular Weight Limitations.......................347 2) Copolymer-1 Molar Fraction Limitations.....................348 3) TFA Copolymer-1 Molar Fraction Limitations................348 v. Mylan’s Process Meets the Process Limitations ..................348 vi. Mylan Meets the Treatment Limitations ........................349 vii. Mylan Infringes All Asserted Claims ............................349 D. Findings of Fact as to Sandoz.........................................349 i. Sandoz’s ANDA Product and its Active Ingredient................349 1) Amino Acid Composition ....................................350 2) Molecular Weight...........................................350 ii. Sandoz’s Manufacturing Process ...............................352 iii. Sandoz’s ANDA Product Label .................................356 E. Conclusions of Law as to Sandoz’s Product ............................356 i. Sandoz’s Proposed Product Infringes Each of the Asserted Claims because Sandoz’s Product is Copolymer-1...............356 ii. Sandoz’s Product Meets the Molecular Weight Limitations .....358 1) Average Molecular Weight Limitations.......................358 2) Sandoz’s Proposed Post-Trial Claim Construction.............359 3) Copolymer-1 Molar Fraction Limitations ......................360 4) TFA Copolymer-1 Molar Fraction Limitations................360 iii. Sandoz’s Process Meets the Process Limitations .................361 iv. Sandoz’s Viscometer Process Meets the Test Reaction Limitations ................................ 361 v. Sandoz Meets the Treatment Limitations........................362 vi. Sandoz Infringes All of the Asserted Claims .....................363 II. INVALIDITY DEFENSES ...............................................363 A. Best Mode............................................................363 i. General Principles.............................................363 ii. The Use of Phenol to Pre-treat HBr/Acetic Acid .................364 iii. The Level of Bromotyro sine Impurity ..........................367 iv. The Patents’ Lack of Disclosure Regarding Phenol Is Not a Best Mode Violation.........................................368 v. The Patents’ Lack of Disclosure Regarding a “Low Bromotyrosine” Content of Copolymer-1 Is Not a Best Mode Violation .......................:.....................369 B. Inequitable Conduct............................. 369 i. General Principles................... 370 ii. The Decision to File the '037 Application ........................370 iii. The Relevant Contents of the'037 Application ...................371 iv. The April 1994 Data Table......................................372 v. The April 1994 Data Table Is Consistent with Example 2..........374 vi. Example 2 Is Representative of Teva’s Toxicity Data as a Whole ......................................................375 vii. The Patent Office Was Aware That Not All High Molecular Weight Copolymer-1 Batches Were Toxic .....................377 viii. Dr. Pinchasi’s Views on the RBL Degranulation Test ............377 ix. Professor Arnon Believed the RBL Degranulation Test To Be a Reliable Screening Test for Toxicity.........................378 x. The RBL Degranulation Test Described in the Patent Is a Well-Accepted Test in the Scientific Community...............379 xi. The Patent Office Knew About the Reproducibility of the RBL Degranulation Test.....................................380 xii. The April 1994 Data Table and the RBL Degranulation Information Were Not Material ..............................380 xiii. Defendants Failed to Establish that Dr. Pinchasi Intended to Deceive the PTO ........’....................................381 C. Lack of Enablement..................................................382 i. General Principles .. ¡..........................................382 ii. A Person of Ordinary Skill .....................................383 iii. Self-Standards ................................................383 iv. Universal Calibration ..........................................390 v. Teva’s Experimentation with Copolymer-1 ......................391 vi. Self-Standards ..................... 392 vii. Universal Calibration ..........................................395 viii. In re Wands Factors ............................j..............397 ix.The Patents-in-Suit Provided Sufficient Direction or Guidance ...................................................398 D. INDEFINITENESS ..................................................400 i. General Principles.............................................400 ii. None of the Asserted Claims Are Indefinite ......................400 E. OBVIOUSNESS .....................................................401 i. General Principles........ 401 ii. The Scope and Content of the Prior Art .........................402 1) The '550 Patent ....................... 402 2) EP'620 Patent Application..................................403 3) The Teitelbaum 1971 Article and 1974 Abstract ................403 4) Prior Art Regarding the Use of HBr/acetic Acid To Achieve Desired Molecular Weight.........................404 iii. Secondary Considerations of Non-obviousness ...................406 iv. The Prior Art Does Not Teach Copolymer-1 Compositions with the Claimed Average Molecular Weight Characteristics ..............................................407 v. There Is No “Overlap” in Average Molecular Weight Ranges or Molar Fraction Limitations ...............................408 vi. The Defendants Have Not Demonstrated Evidence of Any Reason or Motive to Alter the Molecular Weight of Copolymer-1 ................................................411 vii. The Claimed Ranges Do Not “Abut” the Prior Art ...............411 viii. The Prior Art “Taught Away” from Molecular Weights in the Claimed Ranges .............................................412 ix. The Claimed Weight Characteristics of the Patents-in-Suit Are Not Obvious.............................................413 x. The Claimed Process for Making Copolymerl in HBr/Acetic Acid Is Not Obvious .........................................413 xi. Secondary Considerations of Non-obviousness ...................416 1) Commercial Success.........................................416 2) Long-felt, Unmet Need......................................417 3) Failure of Others ...........................................417 4) Unexpected Results .........................................418 5) Copying....................................................419 CONCLUSION .................................................................419 INTRODUCTION This case involves the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified at 21 U.S.C. §§ 355, 360cc (2003); 35 U.S.C. §§ 156 (2002), 271 (2003)) (the “Hatch-Waxman Act”). Plaintiff Teva Pharmaceuticals USA, Inc. holds a patent on a glatiramer acetate product which it markets as Copaxone®, a medicine for treating multiple sclerosis (“MS”). The Defendants have filed abbreviated new drug applications (“ANDAs”) with the FDA seeking to market a generic alterative to Copaxone® prior to the expiration of Teva’s patents. The Plaintiffs, Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc., and Yeda Research and Development Co. Ltd. (collectively, “Teva”) allege infringement. The Defendants, Sandoz Inc., Sandoz International GmbH, Novartis AG, and Momenta Pharmaceuticals, Inc. (“Momenta”) (collectively, the “Sandoz” Defendants), Mylan Pharmaceuticals Inc., Mylan Inc., and Natco Pharma Ltd. (collectively, the “Mylan” Defendants) (collectively, with the Sandoz Defendants, “Defendants”) claim Teva’s patents are invalid and unenforceable, among other defenses. Specifically, Teva filed separate suits, first against the Sandoz Defendants, and second against the Mylan Defendants. The Court consolidated the cases on October 22, 2010. (Dkt. 200 in 08 Civ. 7611.) Teva alleges Sandoz infringes four U.S. patents — No. 7,199,098, No. 6,939,539, No. 6,054,430, and No. 6,620,847 — under 35 U.S.C. §§ 271(a), 271(b), 271(c), and 271(e)(2). Sandoz counterclaims and seeks a declaratory judgment of non-infringement, unenforceability, and invalidity of nine U.S. patents: No. 7,199,098, No. 6,939,539, No. 6,054,430, No. 6,620,847, No. 5,981,589, No. 6,342,476, No. 6,362,161, No. 5,800,808, and No. 6,048,898. With respect to Mylan, Teva alleges Mylan infringes seven U.S. patents under 35 U.S.C. § 271(e)(2): No. 7,199,098, No. 6,939,539, No. 6,054,430, No. 6,620,847, No. 5,981,589, No. 6,342,476, and No. 6,362,161. Mylan, in turn, counterclaims and seeks a declaratory judgment of non-infringement, unenforceability, and invalidity of the same nine U.S. patents as Sandoz. I. The Parties A.Teva Teva Pharmaceuticals USA, Inc. (“Teva USA”) is a Delaware corporation with its principal place of business in North Wales, Pennsylvania. (Joint Pretrial Order Stipulations (“JPO”) ¶ 55.) Teva Pharmaceutical Industries Ltd. (“Teva Ltd.”) is an Israeli company with its principal place of business in Israel. (JPO ¶ 56.) Teva Neuroscience, Inc. is a Delaware corporation with its principal place of business in Kansas City, Missouri. (JPO ¶ 57.) Yeda Research and Development Co. Ltd. markets and commercializes new developments from the laboratories of the Weizmann Institute of Science (“Weizmann”). (JPO ¶ 58.) Its principal place of business is in Israel. (JPO ¶ 58.) B. Sandoz Sandoz Inc. is a Colorado corporation with its principal place of business in Princeton, New Jersey. (JPO ¶ 62.) San-doz Inc. does business in the State of New York, including in the Southern District of New York. (First Am. Compl. ¶ 6.) Momenta is a Delaware corporation with its principal place of business in Cambridge, Massachusetts. (JPO ¶ 9.) Momenta does business in the State of New York, including in the Southern District of New York. (First Am. Compl. ¶ 9.) C. Mylan Mylan Pharmaceuticals Inc. is a West Virginia corporation’ with its principal place of business in Morgantown, West Virginia. (JPO ¶ 59.) Mylan Pharmaceuticals does business in the State of New York, including in the Southern District of New York. (Mylan Answer ¶ 8.) Mylan Inc. is a Pennsylvania corporation with its principal place of business in Canonsburg, Pennsylvania. (JPO ¶ 60.) Mylan Inc. does business in the State of New York, including in the Southern District of New York. (Mylan Answer ¶ 9.) Natco Pharma Ltd. (“Natco”) is an Indian company with its principal place of business in India. (JPO ¶ 61.) Natco does business in the State of New York, including in the Southern District of New York. (Natco Answer ¶ 10.) II. The Patents-in-Suit A. Overview The patents-in-suit are U.S. Patent Nos. 5,981,589 (“'589 Patent”), 6,054,430 (“'430 Patent”), 6,342,476 (“'476 Patent”), 6,362,-161 (“'161 Patent”), 6,620,847 (“'847 Patent”), 6,939,539 (“'539 Patent”) and 7,199,-098 (“'098 Patent”) (collectively, the “Orange Book Patents”) and U.S. Patent Nos. 5,800,808 (“'808 Patent”) and 6,048,-898 (“'898 Patent”) (collectively with the Orange Book Patents, the “patents-in-suit”). (JPO ¶ 64.) Each of the patents-in-suit is entitled “Copolymer-1 improvements in compositions of copolymers.” (JPO ¶ 67.) The four inventors named on the patents-in-suit are Eliezer Konfino, Michael Sela, Ruth Arnon, and Dvora Teitelbaum. (Plaintiffs’ Trial Exhibits (“PTX”) 1-9.) Eliezer Konfino worked for Teva and retired from the company in December 1991. Michael Sela, Ruth Ar-non, and Dvora Teitelbaum worked at Weizmann. (JPO ¶ 66.) The patents-in-suit each claim priority to (i) U.S. Patent Application No. 08/248,037, filed May 24, 1994 (“'037 application”), abandoned, and (ii) Patent Application No. 08/344,248, filed November 23, 1994 (“'248 application”), also abandoned. (JPO ¶¶ 79-80.) The substantive portion of the patent specification is identical for each of the patents-in-suit. Accordingly, for ease of reference, unless noted otherwise, all citations to the specification are to the '808 patent specification. The patents-in-suit are directed to improved compositions of copolymer-1. (PTX 1 at 1:1-2.) The patents explain that the improved compositions consist of a lower molecular weight form of copolymer-1 that may be used for the treatment of multiple sclerosis. (PTX 1 at 1: 43-53.) The patent specification defines the molecular weight characteristics of the lower molecular weight copolymer-1 in several ways. The patent specification explains, for example, that the lower molecular weight copolymer-1 can be substantially free of species over 40 kilodaltons (“kDa”), and it describes a preferred composition that has “less than 5% of species” having a molecular weight over 40 kDa. The patents also describe a more preferred composition having “less than 2.5% of species” having a molecular weight over 40 kDa. (PTX 1 at 1:64-2:4.) In addition, the patents describe the claimed lower molecular weight copolymer-1 as “having over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa.” (PTX 1 at 2:5-7.) A “molar fraction” in this context refers to the proportion of molecules (as measured by the number of “moles” of molecules) between 2 kDa and 20 kDa, as compared to the total number (or “moles”) of all of the molecules in the sample. Finally, the lower molecular weight co-polymer-1 is defined in the patents-in-suit by its average molecular weight. The patent specification provides various ranges for the average molecular weight values for the lower molecular weight copolymer1. Those ranges are reflected in the asserted claims, which are discussed in further detail below. The patents also describe a synthetic process for making the claimed copolymer-1. (PTX 1 at 4:28-6:3.) The patent specification describes two ways of producing a lower molecular weight copolymer-1. (PTX 1 at 2:14-41, 2:51-3:18, 4:28-6:3.) First, in Example 1, the patents describe making copolymer-1 and then “fractionating” — or dividing into smaller portions — the resulting copolymer-1 to isolate a low molecular weight fraction. (PTX 1 at 2:57-3:2.) In addition, the patents provide examples describing processes for making copolymer-1 of varying molecular weights. (PTX 1 at 4:28-6:3.) Second, the patents describe the use of a particular reagent in the synthetic process — hydrobromic acid in the form of hydrogen bromide (“HBr”) in acetic acid — to cleave an intermediate product called protected copolymer-1 polypeptides into smaller polypeptides. The patents-in-suit teach that the time and temperature of the HBr/acetic acid treatment step can be varied to control the amount of cleavage that occurs, and hence, the molecular weight of the resulting copolymer-1. (PTX 1 at 4:59-6:3.) The patent specification describes the use of a calibrated size exclusion chromatography (“SEC”) column, Superóse 12, to measure the molecular weight distribution and average molecular weight of copolymer-1 samples. (PTX 1 at 3:6-13.) Example 2, entitled “Toxicity Analysis,” appears in the specification of each of the patents-in-suit and describes two different toxicity tests for copolymer-1: the in vivo mouse test and the in vitro rat basophilic leukemia (“RBL”) degranulation test. (PTX 1 at 3:21-4:27.) Referring to the in vivo mouse test, Example 2 states that “[tjhree batches of copolymer-1 having an average molecular weight of 7.3 and 8.4 kDa (less than 2.5% copolymer-1 species over 40 kDa) and 22 kDa (more than 5% copolymer-1 species over 40 kDa) were subjected to the toxicity test” in which five mice in each experimental group were injected with the test solution. (PTX 1 at 3:23-40.) It goes on to state that “[if], at the end of 48 hours, all the animals were alive and no adverse signs had been observed, then the batch was designated ‘non-toxic’ ” and if “one or more of the mice had died or had shown adverse signs, then the batch was designated ‘toxic’.” (PTX 1 at 3:36-40.) In regard to the in vivo test, Example 2 concludes that “the batches with the average molecular weight of 7.3 and 8.4 kDa were both designated ‘non-toxic’, whereas in the batch with the average molecular weight of 22 kDa, 3 out of 5 mice had died at the end of 48 hours, and it was consequently designated ‘toxic.’” (PTX 1 at 3:41-45.) With respect to the RBL degranulation test, Example 2 explains that the purpose of this test was to “screen out those batches of copolymer-1 which invoke substantial degranulation and thus might elicit undesirable local and/or systemic side effects.” (PTX 1 at 3:63-67.) Example 2 reports that “[flour batches of copolymer-1, with average molecular weight between 6,250-14,500, were analyzed for both % of the species with molecular weight over 40 kDa and for degranulation of RBL’s.” (PTX 1 at 4:11-15.) Example 2 sets forth the results of the RBL degranulation test in the following table: Average % of species % Serotonin M.W. with M.W. Release (Daltons) over 40 KDa 6,250 <2.5 12.4 7,300 <2.5 21.0 13,000 >5 66.9 14,500 >5 67.8 (PTX 1 at 4:15-24.) In regard to the RBL test data, Example 2 concludes, “[a]s can be seen, when the % of high molecular weight species is low (<2.5), the % release of serotonin indicative of toxicity is low, and vice versa.” (PTX 1 at 4:25-27.) The patent specification also describes pharmaceutical compositions comprising the lower molecular weight copolymer-1, as well as the treatment of multiple sclerosis using lower molecular weight copolymer-1. (PTX 1 at 1:51-53.) B. Copaxone® — Teva NDA Teva USA is the holder of New Drug Application (“NDA”) No. 20-622, for glatiramer acetate, which was approved by the United States Food and Drag Administration (“FDA”) on December 20, 1996; (JPO ¶¶ 82, 83.) The Teva entities market and sell glatiramer acetate under the trade-name Copaxone® in the United States. (JPO ¶ 84.) Glatiramer acetate is a form of copolymer-1. (Sept. Tr. (Grant) 220:13-221:2; Sept. Tr. (Owens) 630:11-631:8; PTX 206 at SDZ00000031; PTX 320 at MYL0000236.) Copaxone® was first offered for sale in the United States on April 2, 1997. (Sept. Tr. (Congleton) 45:14-21.) It is approved for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (“RRMS”), including patients who have experienced a first clinical episode and have magnetic resonance imaging features consistent with multiple sclerosis. (JPO ¶ 85.) Each of the patents-in-suit is assigned to and owned by Yeda. (JPO ¶ 68.) Teva Ltd. is the exclusive licensee of each of the patents-in-suit. (JPO ¶ 69.) The Teva entities caused the Orange Book Patents to be listed in the FDA’s publication, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (“the Orange Book”). (JPO ¶ 65.) C. Sandoz’s and Momenta’s ANDA Momenta entered into a collaboration and license agreement with Sandoz AG on June 13, 2007, regarding, among other things, the development of a generic Copaxone® product. (PTX 957 (Brugger Dep.) at 105:12-106:08; PTX 175.) Sandoz Inc. submitted an ANDA, No. 90-218, on December 27, 2007, seeking approval from the FDA to manufacture and sell a generic Copaxone® product before the expiration of the Orange Book Patents. (JPO ¶¶ 92, 93.) [Redacted] Sandoz Inc. submitted a major amendment to its ANDA. (Sept. Tr. (Grant) 221:8-164; PTX 351.) [Redacted] Sandoc Inc. submitted a “Briefing Book” to the PDA, in advance of [Redacted] meeting between Sandoz Inc. and the FDA regarding Sandoz’s ANDA (“Briefing Book”). (Sept. Tr. (Gokel) 419:19-420:5; PTX 913.) The Briefing Book, among other things, described changes that Sandoz Inc. planned to make to its manufacturing process. (PTX 913.) Sandoz amended its ANDA [Redacted] (Haberg Reply Decl. Ex. A.) Pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), Sandoz Inc. filed a certification with the FDA, alleging that the claims of the Orange Book Patents are invalid, unenforceable, and/or would not be infringed by the manufacture, use, importation, sale or offer for sale of Sandoz’s ANDA proposed glatiramer acetate product (“Paragraph IV Certification”). (JPO ¶ 94.) Sandoz Inc. sent a letter (“the Notice Letter”), dated July 10, 2008, to Teva USA, Teva Ltd., Teva Neuroscience, and Yeda, notifying them that Sandoz Inc. filed an ANDA for glatiramer acetate and was providing information to Teva pursuant to 21 U.S.C. § 355(j)(2)(B)(i)-(ii). (JPO ¶ 95.) On August 28, 2008, Teva sued Sandoz Inc. and Momenta for infringement of the Orange Book Patents. Teva Pharmaceuticals USA Inc. v. Sandoz Inc., No. 08 Civ. 7611(BSJ)(AJP) (S.D.N.Y.). (JPO ¶ 97.) Sandoz Inc. and Momenta counterclaimed for, among other things, a declaratory judgment of non-infringement, invalidity, and unenforceability of all nine patents-in-suit. (Dkt. 14 at ¶¶ 89-116 in No. 08 Civ. 7611; Dkt. 16 at ¶¶ 89-116 in No. 08 Civ. 7611.) D. Mylan and Ñateo ANDA Mylan Inc. and Natco signed an agreement, dated June 7, 2008, relating to the development and marketing of a glatiramer acetate product in the United States. (JPO ¶ 87; PTX 245.) On June 29, 2009, Mylan Pharmaceuticals submitted an ANDA, No. 91-646, seeking approval to manufacture and sell Mylan’s proposed glatiramer acetate product before the expiration of the Orange Book Patents. (JPO ¶¶ 86, 88). [Redacted] On April 19, 2011, the Mylan entities submitted a major amendment to the ANDA.. (DTX 1411.) The major amendment did not make any changes to the manufacturing process. ' Pursuant to 21 U.S.C. § 355(j)(2)(A)(vii)(IV), Mylan Pharmaceuticals filed a certification with the FDA, alleging that the claims of the Orange Book Patents are invalid, unenforceable, and/or would not be infringed by the manufacture, use, importation, sale or offer for salé of Mylan’s proposed glatiramer acetate product (“Paragraph IV Certification”). (JPO ¶ 89.) Mylan Pharmaceuticals sent a notice letter, dated September 16, 2009, to Teva USA, Teva Ltd., Teva Neuroscience, and Yeda, notifying them that Mylan filed an ANDA for glatiramer acetate and was providing information to Teva pursuant to 21 U.S.C. § 355(j)(2)(B)(ii). (JPO ¶ 90.) On October 16, 2009, Teva and Yeda sued the Mylan entities and Natco for infringement of the Orange Book Patents. Teva Pharmaceuticals USA, Inc. v. Mylan Pharmaceuticals, Inc., No. 09 Civ. 8824(BSJ)(AJP) (S.D.N.Y.). (JPO ¶ 91.) The Mylan Defendants counterclaimed for, among other things, a declaratory judgment of non-infringement and invalidity of all nine patents-in-suit. (Dkt. 8 at ¶¶ 82-117 in 09 Civ. 8824; Dkt. 34 at ¶¶ 187-224 in 09 Civ. 8824.) III. Procedural History and Claim Construction Teva and Sandoz submitted claim construction briefing in late 2009, and a claim construction hearing was held on January 20, 2010. (Dkts) 68-72, 76-82, 89r93, 96-97, 102, 104-05, 114-19 in 08 Civ. 7611.) Sandoz moved for summary judgment on the basis of indefiniteness on December 23, 2009. (Dkts. 120-22 in 08 Civ. 7611.) On September 7, 2010, 749 F.Supp.2d 130 (S.D.N.Y.2010), the Court denied Sandoz’s motion for summary judgment. (Dkt. 181 in 08 Civ. 7611.) Sandoz subsequently submitted supplemental claim construction briefing regarding the term “average molecular weight.” (Dkts. 192-93, 204-06 in 08 Civ. 7611.) Teva and Mylan submitted claim construction briefing from April to July 2010. (Dkts. 38-39, 41, 43-45, 57-65 in 09 Civ. 8824.) Mylan moved for summary judgment on the basis of indefiniteness on November 15, 2010. (Dkt. 96-98 in 09 Civ. 8824.) On August 24, 2011, the Court issued a Memorandum and Order denying Mylan’s motion for summary judgment and construing the disputed claim terms as follows: • “Copolymer-1” is construed to mean “a mixture of polypeptides composed of alanine, glutamic acid, lysine, and tyrosine in a molar ratio of approximately 6:2:5:1, respectively, non-uniform with respect to molecular weight and sequence, which is synthesized by polymerization of suitably protected amino acid carboxyanhydrides.” (Claim Consti’uction Order (“CCO”) at 12.) • “Average molecular weight” is construed to mean “peak molecular weight detected using an appropriately calibrated suitable gel filtration column.” (Id. at 40.) • “Copolymer-1 having a molecular weight” is construed to mean “copolymer-1 having a peak molecular weight detected using an appropriately calibrated suitable gel filtration column.” (Id. at 40, n. 10.) • “Polypeptides composed of glutamic acid, lysine, alanine and tyrosine” is construed to mean “more than one polypeptide, each consisting essentially of glutamic acid, lysine, alanine and tyrosine residues.” (Id. at 14-15.) • “Copolymers of alanine, glutamic acid, lysine and tyrosine” is construed to mean “more than one polymer molecule, each consisting essentially of glutamic acid, lysine, alanine and tyrosine residues.” (Id. at 15.) • “Copolymer-1 fraction” is construed to mean “a portion of a copolymer-1 mixture having a narrower molecular weight distribution than the starting protected copolymer-1 mixture.” (Id. at 16.) • “Toxicity” is construed to mean “the degree to which a substance exhibits negative effects in mouse mortality or RBL degranulation test.” (Id. at 44.) • “Predetermined” is construed to mean “determined beforehand.” (Id. at 47.) • “Predetermined by a test reaction” is construed to mean “determined beforehand by a reaction carried out to determine results of varying reaction conditions.” (Id. at 50.) (Dkt. 273 in 08 Civ. 7611; Dkt. 194 in 09 Civ. 8824.) A. July 2011 Inequitable Conduct Trial After denying Teva’s motion for a summary judgment finding of no inequitable conduct (Dkt. 232 in 08 Civ. 7611; Dkt. 141 in 09 Civ. 8824), the Court held a bench trial regarding Defendants’ inequitable conduct defense in July 2011. The Court heard live testimony from the following witnesses: i. Teva’s Witnesses Dr. Irit Pinchasi Dr. Irit Pinchasi is a former Vice President for Innovative R & D at Teva. (July Tr. (Pinchasi) 13:13-17.) Dr. Pinchasi testified regarding the research and development of Teva’s Copaxone® product; the inventions described in the patents-in-suit; the technology related to those inventions; and Teva’s initial patent application filed in May 1994. Professor Ruth Arnon Professor Ruth Arnon is a named inventor on the patents-in-suit. (PTX 1.) She is currently Professor Emeritus at Weizmann and President of the Israel Academy of Sciences and Humanities. (July Tr. (Arnon) 303:14-17.) She was formerly the Chair of the Department of Chemical Immunology, Dean of the Faculty of Biology, and Vice President of Weizmann. (July Trial Tr. (Arnon) 307:16-21.) Professor Arnon testified regarding the discovery and development of copolymer1; the inventions of the patents-in-suit; the technology related to those inventions; and the initial patent application filed in May 1994. Dr. Barbara Baird Dr. Barbara Baird is the Horace White Professor and Chair of the Department of Chemistry and Chemical Biology at Cornell University. (July Tr. (Baird) 569:7-11; PTX 768.) Dr. Baird is an expert in the RBL degranulation test, and has been using this test for over thirty years. (July Tr, (Baird) 572:7, 573:6-14, 576:10-12, 585:22-586:1.) At trial, Dr. Baird testified regarding the RBL degranulation test and its use by Weizmann and Teva, including in the patents-in-suit. ii. Defendants’ Witnesses Dr. Ian Kimber Dr. Ian Kimber is Chair of the Department of Toxicology at the University of Manchester. His research has covered immunology and toxicology, with a particular focus on the regulation of immune responses and allergic disease. (July Tr. (Kimber) 368:17-20.) At trial, he testified regarding the toxicity testing described in the patents-in-suit. Eugene Rzucidlo Eugene Rzucidlo is an attorney at the law firm Hershkovitz & Associates who practices before the United States Patent and Trademark Office (“PTO”). He was previously a patent examiner at the PTO and a' member of the Board of Patent Appeals. (July Tr. (Rzucidlo) 498:24-499:8.) He has practiced before the PTO continuously since 1985. (July Tr. (Rzucidlo) 499:16-500:11.) At trial, Rzucidlo testified regarding the process of patent prosecution and the prosecution histories of the patents-in-suit. B. September 2011 Infringement and Invalidity Trial Starting on September 7, 2011, the Court held a bench trial regarding Plaintiffs’ infringement claims and Defendants’ remaining non-infringement and invalidity defenses. The Court heard testimony from Sandoz on its non-infringement, obviousness; lack of enablement, and indefiniteness defenses. The Court heard testimony from Mylan on its non-infringement, best mode, and obviousness defenses. During the trial, Mylan notified Plaintiffs and the Court that it was no longer asserting that the patents are invalid based on anticipation or public use. (Sept. Tr. 1349:9-1351:24.) At the September trial, the Court heard live testimony from the following witnesses: i. Teva’s Witnesses Jon Congleton Jon Congleton is the Senior Vice President and General Manager of Teva Neuroscience. (Sept. Tr. (Congleton) 39:19-22.) He has been with Teva Neuroscience for over fifteen years. (Sept. Tr. (Congleton) 41:12-13.) Prior to becoming Senior Vice President, Congleton served as both product director and director of marketing for Copaxone®. (Sept. Tr. (Congleton) 42:1-13.) At trial, Congleton testified regarding the nature of Teva’s business, sales and marketing of Copaxone®, and the history and state of the market for multiple sclerosis treatments. Dr. Robert Lisak Dr. Robert Lisak has been the Chairman of the Department of Neurology and Professor of Immunology and Microbiology at Wayne State University for the past twenty-five years. He is also Chief of Neurology at Harper University Hospital. (Sept. Tr. (Lisak) 78:6-79:7, 84:6-11; PTX 419.) He is an expert in multiple sclerosis and its treatment. (Sept. Tr. (Lisak) 87:24-88:6.) Dr. Lisak testified regarding multiple sclerosis and its treatment; the long-felt need for a drug like Copaxone®; the failure of others to develop safe and effective multiple sclerosis treatments; and Defendants’ infringement of claim limitations related to treating multiple sclerosis. Dr. Gregory Grant Dr. Gregory Grant is a Professor of Biochemistry in Medicine and Developmental Biology at the School of Medicine at Washington University School of Medicine. (Sept. Tr. (Grant) 178:9-13; PTX 760.) He is also Director of the Protein and Nucleic Acid Chemistry Laboratories of Washington University. (Sept. Tr. (Grant) 178.T4-17; PTX 760.) He is an expert in the characterization of proteins and polypeptides using size exclusion chromatography. (Sept. Tr. (Grant) 188:11-17.) Dr. Grant testified regarding the background of the chemistry and molecular weight measurement technique described in the patents-in-suit and Defendants’ infringement with regard to the claim limitations relating to molecular weight. He also provided rebuttal testimony regarding the issues of non-obviousness, definiteness, and enablement. Dr. George Gokel Dr. George Gokel is a Distinguished Professor of Science and Associate Director of the Center for Nanoscience at the University of Missouri in St. Louis. (Sept. Tr. (Gokel) 334:3-8; PTX 774.) He is an expert in chemistry, including synthetic and peptide chemistry. (Sept. Tr. (Gokel) 340:4-10.) Dr. Gokel testified regarding the chemistry described in the patents-in-suit; Defendants’ infringement with regard to the claim limitations relating to copolymer-1 and the process for making copolymer-1; and provided an overall infringement opinion. He also provided rebuttal testimony regarding the issues of non-obviousness and best mode. Dr. Nicole Sampson Dr. Nicole Sampson is a Professor of Chemistry at Stony Brook University. (Sept. Tr. (Sampson) 536:6-10; PTX 436.) She is an expert in peptide and polymer chemistry. (Sept. Tr. (Sampson) 542:20-25.) Dr. Sampson testified regarding Defendants’ infringement with regard to the co-polymer-1 claim limitations under the doctrine of equivalents and provided rebuttal testimony on the issue of non-obviousness, ii. Mylan’s Witnesses Dr. Walter Owens Dr. Walter Owens is the Vice President of Global Research and Development at Mylan Inc. (Sept. Tr. (Owens) 594:8-17.) He testified regarding the development of Mylan’s generic Copaxone® product, including Mylan’s use of universal calibration and the testing of its proposed product on the experimental autoimmune encephalomyelitis model. Dr. Stephen Kent Dr. Stephen Kent is a professor of chemistry, biochemistry, and molecular biology at the University of Chicago, where he has worked for the last ten years. He is an expert in the chemical synthesis and analysis of peptides and proteins. (Sept. Tr. (Kent) 651:10-16.) At trial, he testified regarding, among other things, Mylan’s best mode defense and provided rebuttal testimony regarding Mylan’s infringement with regard to the copolymer-1 claim limitations. Dr. Allen Zeiger At the time of his retirement in 1998, Dr. Allen Zeiger was a professor of biochemistry and molecular biology at Jefferson Medical College at Thomas Jefferson University in Philadelphia. (Sept. Tr. (Zeiger) 785:2-12; DTX 1966; DTX 4030.) As a professor, he taught gel filtration chromatography (i.e., SEC) to graduate level students for 35 years. (Sept. Tr. (Zeiger) 870:23-871:3.) Dr. Zeiger is an expert in the fields of biochemistry, immunochemistry, synthetic peptide chemistry, peptide polymer chemistry, and in the characterization of the properties of peptide polymers. (Sept. Tr. (Zeiger) 798:4-6, 799:7-8, 798:7-13, 799:7-8, 798:14-17, 799:7-8, 798:18-20, 799:7-8, 798:21-23, 799:10-23, 870:23-871:3.) At trial, he testified regarding, among other things, Mylan’s obviousness defense. Dr. Susan Rice Dr. Susan Rice has her own consulting firm, Susan A. Rice and Associates, Inc. (Sept. Tr. (Rice) 995:23-996:10.) She testified regarding toxicity data disclosed in the patents-in-suit, and whether the data demonstrate that the claimed copolymer-1 has unexpected results over the prior art. Dr. Ari Green Dr. Ari Green received his M.D. in 2001 from the University of California San Francisco, where he is now an Assistant Professor of Neurology and the Assistant Director of the Multiple Sclerosis Center. (Sept. Tr. (Green) 1354:16-23; PTX 1964.) He provided testimony regarding secondary considerations of non-obviousness. iii. Sandoz’s Witnesses Dr. John Bishop Dr. John Bishop is Senior Vice President, Pharmaceutical Sciences, at Momenta. (Sept. Tr. (Bishop) 1062:25-1063:5.) He testified regarding, among other things, the development of Momenta’s generic Copaxone® product. Dr. Trevor Laird Dr. Trevor Laird is currently Owner and Senior Consultant for Scientific Update, a consultancy in the area of organic process chemistry. At trial, Dr. Laird testified regarding, among other things, Sandoz’s obviousness defense and provided rebuttal testimony on Sandoz’s infringement with regard to the “test reaction” claim limitations. Dr. Carl Scandella Since 1992, Dr. Carl Scandella has provided consulting services in the areas of biomolecule purification and analysis, process development, and manufacture of clinical lots, including the use of SEC. (Sept. Tr. (Scandella) 1169:15-18; DTX 3564.) During the course of his career, he has used a wide variety of analytical techniques for molecular weight measurement, including SEC, ultracentrifugation, MAL-DI-TOF mass spectrometry, and light scattering, among others. (Sept. Tr. (Scandella) 1186:17-1187:12.) Dr. Scandella is an expert on SEC and the characterization of molecular weight. (Sept. Tr. (Scandella) 1191:9-15.) At trial, he testified regarding the Defendants’ lack of enablement and indefiniteness defenses. Dr. Randolph Wall Dr. Randolph Wall is a Distinguished Professor in the Department of Microbiology, Immunology and Molecular Genetics at the UCLA School of Medicine and is the Associate Director of the UCLA Broad Stem Cell Center. (Sept. Tr. (Wall) 1747:15-18.) He has been a professor at UCLA since 1972. (Sept. Tr. (Wall) 1747:19-20.) Dr. Wall is an expert in SEC. (Sept. Tr. (Wall) 1756:16-20; 1761:18.) At trial, he was a rebuttal witness for Sandoz regarding its lack of enablement and indefiniteness defenses. iv. Witnesses Testifying by Deposition The parties submitted designated deposition testimony from several witnesses including the following: Weizmann employees Professor Ruth Arnon and Dr. Michael Sela; current or former Teva employees Dr. Irit Pinchasi, Eliezer Konfino, Dr. Alexander Gad, and Dr. Haim Varkony; Mylan employees Dr. Stephen Wayne Taitón and Dr. Ross Wallingford; Natco employees Dr. Bhujanga Rao, Dr. Duddhi Linga Rao, and Dr. Satyanarayana Kota; current or former Momenta employees Dr. Corinne Bauer, Dr. Steve Brugger, Dr. Ganesh Venkataraman, and Dr. Mani Iyer; Sandoz employees Dr. Anup Ray and Shrinvasa Rao; and Defendants’ expert witnesses Dr. Jerard Hurwitz (Mylan) and Dr. Frantisek Svec (Sandoz). None of these witnesses testified at the September trial. IV. The Patents-in-Suit and the Patent Claims at Issue Prior to the September trial, Plaintiffs voluntarily limited the number of asserted claims to narrow the issues for trial. The asserted claims of the patents-in-suit are claim 1 of the '808 patent; claim 1 of the '589 patent; claims 1, 2, and 3 of the '898 patent; claims 1, 2, and 3 of the '430 patent; claim 1 of the '476 patent; claim 1 of the '161 patent; claims 1 and 6 of the '847 patent; claims 1, 8, 9, 10, 12, 23, 30, and 31 of the '539 patent; and claims 1 and 8 of the '098 patent. Plaintiffs assert claim 3 of the '430 patent and claim 3 of the '898 patent against Mylan only. The asserted claims claim, among other things, copolymer-1 with lower molecular weight characteristics, methods of making lower molecular weight copolymer-1, pharmaceutical compositions comprising lower molecular weight copolymer-1, as well as methods of treating multiple sclerosis using the claimed lower molecular weight copolymer-1. The asserted claims contain limitations relating generally to one or more of the molecular weight attributes of the claimed copolymer-1, the process for making the claimed copolymer-1, and the use of the claimed copolymer-1 for treating multiple sclerosis. A. Molecular Weight Claim Limitations All but three of the 22 asserted claims of the patents-in-suit include numerical limitations directed to molecular weight attributes of either the copolymer-1 end product and/or an intermediate product called .trifluoroacetyl (“TFA”) copolymer-1. The molecular weight limitations' can be categorized as “average molecular weight” and “molar fraction” limitations. (PTX 1-2; PTX 4-9.) In addition, three of the asserted claims are directed to a “predetermined molecular weight profile” and have no numerical limitations. (PTX 3.) i. Average Molecular Weight Limitations Claim 1 of the '808 patent, claim 1 of the '589 patent, claims 1 and 6 of the '847 patent and claims 1, 8, 9,10,12, 23, 30, and 31 of thé '539 patent are directed to copolymer-1 having an “average molecular weight” falling within a particular numeric range. (PTX 1; PTX 2; PTX 7; PTX 8.) For example, claim 1 of the '539 patent provides: A copolymer-1 composition comprising a mixture of polypeptides composed of glutamic acid, lysine, alanine and tyrosine, wherein the mixture has an average molecular weight of about 4 to about 9 kilodaltons, wherein the mixture of polypeptides is non-uniform with respect to molecular weight and sequence, and wherein the composition is suitable for treating multiple sclerosis. (PTX 8 at 5:18-24 (emphasis added).) The asserted claims containing “average molecular weight” limitations require copolymer-1 having an average molecular weight of “about 5 to 9 kilodaltons” (claim 1 of the '808 patent and claim 1 of the '589 patent), “about 4 to about 9 kilodaltons” (claims 1 and 6 of the '847 patent and claims 1, 8, 9, 12, 23, 30, and 31 of the '539 patent), and “6.25 to 8.4 kilodaltons” (claim 10 of the '539 patent). (PTX 1; PTX 2; PTX 7; PTX 8.) ii. Molar Fraction Limitations Several of the asserted claims include limitations relating to the molecular weight distribution of a sample of copolymer-1 or the intermediate TFA copolymer-1. These “molar fraction” limitations are expressed as a certain percentage of the copolymer-1 polypeptides (or TFA copolymer-1 molecules) having molecular weights falling within a molecular weight range or above a particular molecular weight value. (PTX 4; PTX 5; PTX 6; PTX 8; PTX 9.) Claim 1 of the '430 patent exemplifies the copolymer-1 molar fraction and TFA copolymer-1 molar fraction limitations: Copolymer-1 having over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa, prepared by a process comprising the steps of: reacting protected copolymer-1 with hydrobromic acid to form trifluoroacetyl copolymer-1 having over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa, wherein said reaction takes place for a time and at a temperature predetermined by test reaction, and treating said trifluoroacetyl copolymer-1 having over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa with aqueous piperidine solution to form copolymer-1 having over 75% of its molar fraction within the molecular weight range from about 2kDa to about 20kDa. (PTX 4 at 5:21-6:8 (emphasis added).) The copolymer-1 “molar fraction” limitations include “over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa” (claims 1, 2, and 3 of the '430 patent); “less than 2.5% ... over 40 kilodaltons” (claims 8 and 30 of the '539 patent); “less than 5% ... over 40 kilodaltons; and ... over 75% ... within a molecular weight range of about 2 kilodaltons to about 20 kilodaltons” (claim 1 of the '476 patent; claim 1 of the '161 patent; claim 1 of the '098 patent); and “less than 2.5% ... above 40 kDa” (claims 9, 10, and 31 of the '539 patent and claim 8 of the'098 patent). (PTX 4; PTX 5; PTX 6; PTX8; PTX9.) All of the TFA copolymer-1 molar fraction limitations require “trifluoroacetyl co-polymer-1 having over 75% of its molar fraction within the molecular weight range from about 2 kDa to about 20 kDa” (claims 1, 2, and 3 of the '430 patent; claim 1 of the '476 patent; claim 1 of the '161 patent). (PTX 4; PTX 5; PTX 6.) iii. Predetermined Molecular Weight Profile Limitations Claims 1, 2 and 3 of the '898 patent do not include any-numerical molecular weight limitations. Instead, they require that the copolymer-1 have a “predetermined molecular weight profile.” (PTX 3.) For example, claim 1 of the '898 patent provides: A method of manufacturing copolymer1 of a predetermined molecular weight profile, comprising the steps of: selecting a predetermined molecular weight profile, reacting protected eopolymer-1 with hydrobromic acid to form trifluoroacetyl copolymer-1 having the predetermined molecular weight profile, wherein said reaction takes place for a time and at a temperature predetermined by test reaction, and treating said trifiuoroacetyl copolymer-1 having the predetermined molecular weight profile with aqueous piperidine solution to form copolymer-1 having the predetermined molecular weight profile. (PTX 3 at 5:35-6:11 (emphasis added).) B. Process Limitations Twelve of the asserted claims are directed either to a method of manufacturing copolymer-1 having the desired molecular weight characteristics or to copolymer-1 that is made by a particular process. Although the details of each claim may vary, claim 1 of the '589 patent is illustrative of the claims directed to a process for making the claimed copolymer-1: Copolymer-1 having a molecular weight of about 5 to 9 kilodaltons, made by a process comprising the steps of: reacting protected copolymer-1 with hydrobromic acid to form trifluoroacetyl copolymer-1, treating said trifluoroacetyl copolymer-1 with aqueous piperidine solution to form copolymer-1, and purifying said copolymer-1, to result in co-polymer-1 having- a molecular weight of about 5 to 9 kilodaltons. (PTX 2 at 6:4-13 (emphasis added).) The asserted process for making and product-by-process claims are claim 1 of the '808 patent; claim 1 of the '589 patent; claims 1, 2, and 3 of the '898 patent; claims 1, 2, and 3 of the '430 patent; claim 1 of the '476 patent; claim 1 of the '161 patent; and claims 1 and 6 of the '847 patent. Claims 1, 2, and 3 of the '898 patent; claims 1, 2, and 3 of the '430 patent; claim 1 of the '476 patent and claim 1 of the '161 patent also require that the hydrogen bromide (“HBr”) treatment step “take[] place for a time and at a temperature predetermined by test reaction.” (PTX 3; PTX 4; PTX 5; PTX 6.) C. Treatment of Multiple Sclerosis Ten of the asserted claims include limitations relating to the treatment of multiple sclerosis. Claim 1 of the '476 patent and claims 23, 30, and 31 of the '539 patent are directed to methods for treating multiple sclerosis. Claim 1 of the '161 is directed to “[a] composition for the treatment of multiple sclerosis.” Claims 1, 8, 9, and 10 of the '539 patent recite “wherein the composition is suitable for treating multiple sclerosis.” Claim 12 of the '539 patent recites “a dose therapeutically effective to treat multiple sclerosis of a copolymer-1 composition.” (PTX 5; PTX 6; PTX 8.) D. Pharmaceutical Composition Four of the asserted claims include limitations relating to the use of the lower molecular weight copolymer-1 as a pharmaceutical composition. Claims 12, 23, 30, and 31 of the '539 patent are directed to the use of lower molecular weight' copolyttier-1 as a pharmaceutical composition. (PTX 8.) For example, claim 12 of the '539 provides: A pharmaceutical composition comprising: a dose therapeutically effective to treat multiple sclerosis of a copolymer-1 composition, wherein the copolymer-1 composition comprises a mixture of polypeptides composed of glutamic acid, lysine, alanine and tyrosine, wherein the mixture has an average molecular weight of about 4 to about 9 kilodaltons, wherein the mixture of polypeptides is non-uniform with respect to molecular weight and sequence; and a pharmaceutically acceptable excipient. (PTX 8 at 5:54r-63.) V. Copolymer-1 and Multiple Sclerosis A. Multiple Sclerosis: The Disease Multiple sclerosis is an inflammatory disease of the central nervous system first recognized in the 1860s by the French neurologist Jean-Martin Charcout. (See Sept. ’ Tr. (Lisak) 88:8-89:18.) It is an unpredictable disease involving two of the most complex systems in the body — the immune system and the central nervous system. (Sept. Tr. (Lisak) 136:3-10.) In persons afflicted with multiple sclerosis, autoimmune cells attack myelin, a protective sheath wrapped around nerves found in the brain and the spinal cord. (Sept. Tr. (Lisak) 88:8-89:4.) This leads to the degeneration of myelin and, eventually, the degeneration or death of underlying nerve cells. (Sept. Tr. (Lisak) 90:4-92:11.) This degeneration process eventually prevents the central nervous system from functioning properly as the brain loses the ability to send or receive messages to and from various parts of the body and as other functions of the brain or spinal cord become impaired. (Sept. Tr. (Lisak) 90:4-92:11.) As multiple sclerosis progresses, the immune system’s attack on myelin causes multiple lesions or scars to form on the brain and the spinal cord. (Sept. Tr. (Lisak) 89:11-15.) The appearance of these multiple scars or scleroses accounts for the disease name “multiple sclerosis.” (Sept. Tr. (Lisak) 89:11-15.) The most common form of multiple sclerosis is RRMS. (Sept. Tr. (Lisak) 96:17-19.) Approximately 85% of all multiple sclerosis patients have this form of the disease. (Sept. Tr. (Lisak) 89:11-15.) Patients with RRMS experience periodic relapses or attacks which are accompanied by steadily worsening disability as the functioning of the nervous system becomes more impaired over time. (Sept. Tr. (Lisak) 95:16-96:25.) The symptoms of RRMS include blurred and double vision, loss of balance and coordination, tremors, fatigue, bladder and bowel dysfunction, paralysis, and even death in some patients. (Sept. Tr. (Lisak) 92:20-93:21.) Patients may exhibit different neurologic symptoms at various times and many patients become permanently disabled. (Sept. Tr. (Lisak) 92:20-93:21.) The initial onset of multiple sclerosis typically occurs early in life — between the ages of twenty and forty. (Sept. Tr. (Lisak) 94:10-18.) Dr. Lisak testified that the disease strikes patients in the “prime of life” — when they are beginning their careers, finishing school, or beginning to raise a family. (Sept. Tr. (Lisak) 94:10-18.) There is no way to predict when relapses associated with multiple sclerosis will occur and thus the disease acts like a “hanging sword,” threatening sufferers with future attacks of unknown length that may result in increased or complete disability. (Sept. Tr. (Lisak) 97:1-9.) Prior to the 1990s, there were no treatments available to prevent relapses or slow the progression of disability associated with the disease. (Sept. Tr. (Lisak) 102:2-9; Sept. Tr. (Green) 1391:21-1392:4.) The only option for a physician was to treat a patient’s symptoms and to try to shorten the duration of a relapse. (Sept. Tr. (Lisak) 102:2-9; Sept. Tr. (Green) 1391:21-1392:4.) B. The Weismann Scientists’ Discovery of Copolymer1 Professor Arnon, Professor Sela, and Dr. Teitelbaum are Ph.D. immunologists who worked together at Weizmann, a world-renowned research institute located in Israel.. (July Tr. (Pinchasi) 9:12-20; 16:11-17:5; July Tr. (Arnon) 302:23-303:13, 304:11-17; 304:18-305:14.) In about 1966, Professor Arnon and her colleagues became interested in studying an autoimmune disease called experimental autoimmune encephalomyelitis (“EAE”), which is an animal model for multiple sclerosis. (July Tr. (Arnon) 309:11-310:10.) It was already understood by that time that EAE was induced by a single protein called myelin basic protein (“MBP”), but nothing was known about the mechanism of the disease. (July Tr. (Arnon) 309:11-310:10.) Professor Arnon and her colleagues theorized that if they could produce a synthetic polymer that mimicked MBP, it could be used as a research tool to study the mechanism of EAE. (July Tr. (Arnon) 309:11-311:8.) Professor Arnon and her colleagues synthesized three synthetic polymers, which they called copolymer-1, copolymer-2, and copolymer-3. The copolymers differed in their amino acid composition, but were all targeted to have a molecular weight of 23,000 daltons, which was the molecular weight of MBP. (July Tr. (Arnon) 310:11— 311:8.) Professor Arnon and her colleagues tried without success for over a year to use the synthetic copolymers to induce EAE in animals. (July Tr. (Arnon) 310:11-23.) Eventually, it occurred to them that the synthetic copolymers' they made were not similar enough to MBP to induce EAE, but might be similar enough to MBP to compete with it and prevent its activity. (July Tr. (Arnon) 310:11-23.) The experiments they set up to test their hypothesis were successful. (July Tr. (Ar-non) 310:11-23.) Instead of inducing EAE, copolymer-1 proved to be effective in suppressing EAE. (July Tr. (Arnon) 310:24-311:13.) The other two copolymers were much less effective. (July Tr. (Ar-non) 311:9-13.) At the time Professor Arnon and her colleagues discovered that copolymer-1 was effective in suppressing EAE, there were practically no treatments available for multiple sclerosis. (July Tr. (Arnon) 311:14-23.) The only options for patients were immunosuppressive drugs, but these had very severe side effects and were not routinely used. (July Tr. (Arnon) 311:14— 23.) Professor Amon and her colleagues published their initial findings in 1971 in the European Journal of Immunology (“1971 Teitelbaum article”). (PTX 499.) The article described copolymer-1 as having a molecular weight of 23,000 daltons. (July Tr. (Arnon) 311:24-312:22; PTX 499 at 242.) In 1974, the PTO granted U.S. Patent No. 3,849,550 (“the '550 Patent”) to Yeda. (DTX 1219.) The patent named Professor Arnon, Professor Sela, Dr. Teitelbaum, and their co-workers as inventors, and disclosed and claimed the copolymers that they discovered could treat EAE. (DTX 1219.) The first placebo controlled clinical study of copolymer-1 for the treatment of multiple sclerosis was conducted by Professor Murray Bornstein of the Abert Einstein College of Medicine in New York (“Bornstein trial”). (July Tr. (Arnon) 316:6-15; July Tr. (Pinchasi) 22:4-24; Sept. Tr. (Lisak) 108:25-104:13.) Fifty patients were enrolled in the pilot trial, 25 of whom received copolymer-1. (Sept. Tr. (Lisak) 109:24-110:4; PTX 31 at 408.) Professor Arnon and her . colleagues at Weizmann participated in the basic design of the Bornstein trial and supplied Dr. Bornstein with copolymer-1 for use in the trial. (July Tr. (Arnon) 316:16-21.) The copolymer-1 they supplied was intended to have a molecular weight of 23,000 daltons in order to match the molecular weight of MBP. (July Tr. (Arnon) 316:22-317:11.) In fact, however, the batches ranged from 14,000 to 23,000 daltons. (July Tr. (Arnon) 317:12-15; Sept. Tr. (Lisak) 110:11-21; PTX 31 at 408.) , The results of the Bornstein trial were published in 1987 in the New England Journal of Medicine (“1987 Bornstein article”). (July Tr. (Arnon) 327:22-328:9; Sept. Tr. (Lisak) 108:25-109:13; PTX 31.) While the results ■ from the study were encouraging, they did not definitively establish whether the copolymer-1 composition studied was a safe and effective treatment for RRMS. (PTX 31 at 408; Sept. Tr. (Lisak) 108:25-111:22.) During the Bornstein trial, Dr. Born-stein notified Professor Arnon and her colleagues that some of the patients experienced local injection site reactions and that, on rare occasions, some patients experienced systemic side effects that included difficulty breathing, palpitations, severe flush, sweating, and severe anxiety. (July Tr. (Arnon) 317:16-320:6; July Tr. (Pinchasi) 23:17-24:23; PTX 28.) His report of these side effects was of grave concern to Professor Arnon. (July Tr. (Arnon) 320:7-16.) She knew copolymer-1 was to be given to patients on a daily basis and, as a result, that any side effects would be a severe issue. (July Tr. (Arnon) 320:7-16.) At that time, however, neither Professor Arnon nor her colleagues had any idea what was causing the side effects or how they could get rid of them. (July Tr. (Arnon) 320:7-16.) Based on Dr. Bornstein’s reports, Professor Arnon and her colleagues looked for screening assays that could be used to differentiate between batches that would cause side effects and those that would not. (July Tr. (Arnon) 320:17-2 5.) They eventually utilized the in vitro RBL degranulation test. (July Tr. (Arnon) 320:17-25; DTX 3114.) In the RBL degranulation test, RBL cells are preloaded with radio-labeled serotonin and then exposed to copolymer-1. (July Tr. (Arnon) 327:8-21; July Tr. (Baird) 587:3-589:20.) The amount of serotonin released, or degranulated, by the cells is then measured. (July Tr. (Arnon) 327:8-21; July Tr. (Pinchasi) 25:11-26:1; July Tr. (Baird) 587:3-589:20; DTX 3114.) The RBL test was and still is used as a model for allergic-type reactions, because the degranulation it exhibits in the presence of a stimulant mimics the immune response of human mast cells — a central cell in the allergic immune response system — in responding to allergens or other substances. (July Tr. (Arnon) 321:8-18, 322:21-323:4; July Tr. (Baird) 576:24-577:7, 578:16-582:16, 585:9-21; PTX 522.) The Weizmann scientists adopted the term “toxicity” to refer to the results of the RBL degranulation test. (July Tr. (Arnon) 327:8-21.) If 30% or more serotonin was released upon exposure to copolymer-1, the batch was designated “toxic” and