UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
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`JANSSEN PRODUCTS, L.P., et al.,
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`Plaintiffs,
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`OPINION
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`V.
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`Civ. No. 2:10-cv-05954 (WHW)
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`FILED UNDER SEAL
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`LUP1N LIMITED, et al.,
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`Defendants.
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`Walls~ Senior District Judge
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`By complaints, Plaintiff patent-holders and drug-makers have sued Defendant generic drug
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`manufacturers for alleged infringements of patents on a chemical compound used in the
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`manufacture of PlaintifFs product, Prezista. The patents, for this opinion, are U.S. Patent No.
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`7,700,645 B2 (the "’645 Patent"), U.S. Patent No. 7,126,015 B2 (the "’015 Patent"), and U.S.
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`Patent No. 7,772,411 B2 (the "’411 Patent").
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`Prezista is an ethanolate form of the chemical compound named darunavir. The ’015 Patent
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`claims processes for manufacturing a chemical structure or moiety, bis-THF, that is part of the
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`darunavir molecule. The ’411 Patent is directed to a process for manufacturing darunavir in
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`Prezista and Defendant Mylan’s generic version. The ’645 Patent claims the ethanolate form that
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`Plaintiff Janssen developed and sells as Prezista.
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`Earlier summary judgment motion practice by the parties caused the Court to determine
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`that:
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`1) Janssen’ s motion for summary judgment of infringement of the ’411 Patent against
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`Mylan was granted.
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`2) Janssen’s motion for summary judgment on the validity of the ’645 Patent was
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`denied.
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`3) Janssen’ s motion for summary judgment of infringement of the ’015 and ’408 Patents
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`was granted in part and denied in part: the Court found that Lupin infringed certain
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`claims of the ’015 Patent, including asserted claim 1.
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`4) Teva’s motion for summary judgment of non-infringement of the ’645 Patent was
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`denied.
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`5) Mylan’s motion for summary judgment of non-infringement of the ’645 Patent was
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`denied.
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`6) Lupin’ s and Teva’ s motion for summary j udgment of non-infringement of the ’015
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`and ’408 Patents was denied.
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`Before trial, Teva and Janssen resolved their dispute, and the ’408 Patent is no longer at
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`issue.
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`A bench trial has been held on the remaining matters: the validity of the patents--as to
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`Lupin, claim 4 of the ’645 Patent and claim 1 of the ’015 Patent, and as to Mylan, claim 13 of the
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`’411 Patent.
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`This Opinion will be based and concentrated on what the Court has found to be material
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`and supportive facts necessary to answer the primary question: Did either Defendant prove
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`invalidity of a patent-in-suit by clear and convincing evidence?
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`To find the answer(s), the Court has reviewed the relevant evidence adduced at trial, aided
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`by recollection, notes, trial transcripts, and the parties’ proposed findings of fact. The Court has
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`evaluated the credibility of all witnesses, lay and expert, testing not only what the person said, but
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`how it was said and what was not said, against these criteria: Was this more likely so or not? Did
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`what was said make sense in the totality of the circumstances? Was this, after all, clearly
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`convincing to the fact finder?
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`To its chagrin, the Court has determined that expert witnesses, though not all, called by the
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`defense were more interested in obfuscation than in helping the Court as a fact finder "seek the
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`truth." Too often--and too repeatedly--the Court had to importune and finally direct certain
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`defense witnesses to directly answer questions posed. The trial transcripts will identify these
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`persons as Dr. Trevor Laird and Dr. Michael Zaworotko. See, e.g., Laird Tr. 1450:20-1451:5,
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`1486:23-1487:10, 1488:5-22; Zaworotko Tr. 1650:16-19, 1684:5-24, 1712:18-19. Ironically, such
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`representatives of science were more interested in evasion than intellectual candor. As to their
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`testimony, the Court as fact finder invokesfalsus in uno, falsus in omnibus. Each did the cause of
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`his particular Defendant no good.
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`In challenging the patents’ validity, Defendants face a heavy burden. By statute, issued
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`patents are "presumed valid," 35 U.S.C. § 282 (2012), and Defendants must overcome that
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`presumption by clear and convincing evidence. ActiveVideo Networks, Inc. v. Verizon Commc ’ns,
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`Inc., 694 F.3d 1312, 1327 (Fed. Cir. 2012). "Clear and convincing evidence is such evidence that
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`produces ’an abiding conviction that the truth of [the] factual contentions are highly probable.’"
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`Id. (quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)).
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`The Court finds that neither Defendant met its obligation to overcome the presumption of
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`validity of the patents-in-suit by clear and convincing evidence.
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`I. Findings of Fact
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`To the extent any finding of fact reflects a legal conclusion, it shall be to that extent deemed
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`a conclusion of law, and vice versa.
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`A, Background
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`i. The patents at issue
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`On October 24, 2006, the Patent and Trademark Office ("PTO") issued the ’015 Patent,
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`entitled "Method for the Preparation ofHexahydro-furo-[2,3-b]furan-3-ol." Pre-Trial Order at 12,
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`1 34. Lupin does not contest--for the purposes of this litigation only--that the ’015 Patent has a
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`priority date of September 10, 2001, nor that Janssen R&D Ireland holds title to the ’015 Patent.
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`Id. at 12, 11 35, 36. Janssen is asserting claim 1 of the ’015 Patent against Lupin. Id. at 12, 1 37.
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`On August 10, 2010, the PTO issued the ’411 Patent, entitled "Process for the Preparation
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`of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)
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`amino]-l-benzyl-2-hydroxypropylcarbamate." Id. at 13, 1 44. Mylan does not contest--for the
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`purposes of this litigation only--that the ’411 Patent has a priority date of December 23, 2003, nor
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`that Janssen R&D Ireland holds title to the ’411 Patent. Id. at 13, 11 45, 46. Janssen is asserting
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`claim 13 of the ’411 Patent against Mylan. Id. at 13, 1 47.
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`On April 20, 2010, the PTO issued the ’645 Patent, entitled "Pseudopolymorphic Forms of
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`a HIV Protease Inhibitor." Id. at 11, 1 29. Lupin does not contest--for the purposes of this litigation
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`only--that the ’645 Patent has a priority date of May 16, 2002, nor that Janssen R&D Ireland holds
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`title to the ’645 Patent. Id. at 11, 11 30, 31. Janssen is asserting claim 4 of the ’645 Patent against
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`Lupin. Id. at 11, 1 32.
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`ii. Prezista (darunavir)
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`Janssen Products, L.P. is the holder of approved New Drug Application ("NDA") No. 21-
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`976 for Prezista (darunavir). Janssen manufactures, markets and sells Prezista, a human
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`immunodeficiency virus (HIV-1) protease inhibitor. Id. at 9, 11 14, 15. The FDA has approved
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`Prezista for the treatment of HIV-1 infection in adult patients and in pediatric patients 3 years of
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`age and older. Id. at 9, 1 16. The active pharmaceutical ingredient in Prezista is darunavir in an
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`ethanolate form. Id. at 9, 1 17. Prezista tablets are currently sold in the United States in 75 mg, 150
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`mg, 400 mg, 600 mg, and 800 mg dosage strengths. Id. at 9, 1 18. The ’645 Patent is listed in an
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`FDA publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations
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`(known as the "Orange Book") with respect to Prezista. Id. at 9, 1 20.
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`iii. The ANDAs
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`On June 23, 2010, Mylan filed ANDA No. 202136 with the FDA, seeking approval to sell
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`darunavir tablets, 75 mg, 150 mg, 300 mg, 400 mg, and 600 mg, described in the ANDA. Id. at 9,
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`121.
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`On June 23, 2010, Lupin filed ANDA No. 202073 with the FDA seeking approval to sell
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`darunavir tablets, 400 mg and 600 mg, described in the ANDA. On June 3,2011, Lupin amended
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`its ANDA No. 202073 to incorporate additional strengths of 75 mg, 150 mg, and 300 mg. Id. at
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`10, 11 23-24.
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`iv. Claim construction
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`In its Markman opinion, the Court construed "solvate" in the asserted claims of the ’645
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`Patent to mean "a crystal form that contains stoichiometric or non-stoichiometric amounts of
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`solvent." ECF No. 477 at 5; Pre-Trial Order at 13, 1 48. The Court also construed the term
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`"compound of formula (6)" in the asserted claims of the ’411 Patent as "darunavir," or the graphic
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`depiction of darunavir. Markman Op. at 11; Pre-Trial Order at 13-14, 1 49.
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`B. The ’015 Patent
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`i. The invention and the claim at issue
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`The invention of the ’015 Patent "relates to a method for the preparation of
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`[bis-THF] .... " Defendants’ Trial Exhibit ("DTX") 7 (’015 Patent) at col. 1:12-14. The
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`specification states that bis-THF "is an important pharmacological moiety present in the structure
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`of retroviral protease inhibitors .... " id. at col. 1:18-24, and identifies and incorporates by
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`reference the European versions of G.D. Searle & Co.’s ("Searle") darunavir patent,1 id. at col.
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`1:18-24. It recommends bis-THF as having "particular interest" for use in darunavir. Id. at col.
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`28:24-31; col. 28:37-40.
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`The specification also indicates that the "main object of the . . . [’015] invention is to
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`provide an improved method for producing [bis-THF] when compared to the art-known methods
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`and their drawbacks." Id. at col. 2:25-28. "[A]nother object" of the ’015 Patent is "to provide a
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`method for the synthesis of [bis-THF] which is suitable for industrial scaling-up." Id. at col. 2:28-
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`30.
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`Claim 1 of the ’015 Patent, which is being asserted against Lupin, recites:
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`A method for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7)
`starting from an intermediate of formula (1)... transforming said intermediate of
`formula (1) into a nitromethane derivative of formula (3) . . subsequently
`transforming said nitromethane derivative into a tetrahydrofuran derivative of
`formula (6) . . . and then transforming the intermediate of formula (6) into
`hexahydro-furo[2,3-b]furan-3-ol of formula (7) by way of an intermolecular
`cyclisation reaction.
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`Id. at col. 38:44-39:40.
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`ii. Development of the ’015 Patent invention
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`Tibotec, later acquired by Johnson & Johnson in 2002, Stoffels Tr. 98:18-21; 99:1-4, began
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`considering compounds containing bis-THF for possible use as protease inhibitors, and
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`immediately recognized the difficulty of synthesizing bis-THF. Reider Tr. 2004:17-23. The bis-
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`1 After discovering that certain compounds of interest were of a family of compounds covered by
`patents owned by Searle, Tibotec approached Searle and obtained a license to use the compounds
`that Searle had discovered, including darunavir, in further research and development efforts.
`Stoffels Tr. 89:22-25, 90:20-91:8.
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`THF molecule has a double-ring structure, with three "chiral centers," also known as
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`"stereocenters" or "optical centers." DTX 7 (’015 Patent) at col. 9:21-28. The three chiral centers
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`made bis-THF an "incredibly complex" molecule that presented a "formidable challenge" to
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`synthesize. Reider Tr. 2004:17-23; see also id. 2008:23-2009:3; Ganem Tr. 1159:11-15. Tibotec
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`initially explored whether it could avoid the problem by replacing bis-THF with a different
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`chemical group that would have similar benefits but would be easier to synthesize. Wigerinck Tr.
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`186:19-188:5; see generally Plaintiff’ s Trial Exhibit ("PTX") 346 (Laboratory Notebook 37); PTX
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`351 (Tibotec Feb. 2001 Powerpoint) at PREZ04980686. Tibotec made and tested many
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`compounds containing alternatives to bis-THF but none of the compounds had activity comparable
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`to the compounds with bis-THF. Wigerinck Tr. 190:17-191:10, 200:12-20; PTX 351 (Tibotec Feb.
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`2001 Powerpoint) at PREZ04980686. After concluding that bis-THF was a "special and crucial"
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`component for the design of protease inhibitors, Tibotec began developing a process for making
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`bis-THF that could be used for synthesis on an industrial scale. Wigerinck Tr. 191:11-17.
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`Tibotec began working on this scalable synthesis for bis-THF in May 1999. Id. at 238:22-
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`239:9. The work done over the next two years, including attempting more than twenty methods
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`for making bis-THF before selecting the route claimed in the ’015 Patent, is summarized in a
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`progress report that Tibotec prepared in October 2000. Id. at 257:7-258:14; PTX 404 (Tibotec
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`Progress Report). Initially, Tibotec tried the synthesis that was favored in the prior art, i.e., starting
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`with a compound known as dihydrofuran, essentially the "left ring" of bis-THF’s double ring, and
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`proceeding from there to build the right-hand ring. Wigerinck Tr. 239:24-241:12, 258:15-259:10.
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`This strategy was described, inter alia, in the earliest prior art synthesis of bis-THF, the Pezechk
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`1986 Article (PTX 391), and in multiple references by Dr. Arun Ghosh, one of the pioneers to use
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`bis-THF as part of an HIV protease inhibitor, including Scheme 2 of the Ghosh 1996 Article (PTX
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`389). See Wigerinck Tr. 239:24-241:12, 243:2-7. At trial, the experts from both sides agreed that
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`starting with bis-THF’ s left-hand ring was a logical strategy. See Reider Tr. 2009:21-2010:16 ("the
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`literature taught that this is a great place to start"); Ganem Tr. 1204:2-5 (agreeing that this is a
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`"reasonably straightforward way[ ] of thinking about how to make a two-ring bicyclic structure").
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`However, when Tibotec used this strategy, it encountered a problem with a step in the
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`synthesis described in the Pezechk 1986 Article and the Ghosh 1996 Article. Both methods used
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`ozonolysis, a reaction step using ozone, with which Tibotec and the prior art had not had a problem
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`on a laboratory scale. Wigerinck Tr. 243:15-244:4; Ganem Tr. 1207:19-24. But Tibotec found that
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`when it attempted the ozonolysis step on a larger scale, the reaction would generate smoke, even
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`after stopped, which suggested that the reaction could not be controlled and had the potential to
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`explode. Wigerinck Tr. 243:15-245:13.
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`In the end, none of the routes that Tibotec explored starting with bis-THF’s left-hand ring
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`proved satisfactory. See PTX 404 (Tibotec Progress Report) at PREZ05110825-26.
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`Tibotec also explored several routes that started with bis-THF’s right-hand ring and then
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`built the molecule’s left ring. Unlike dihydrofuran, the right hand ring was not commercially
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`available, "so that made the route more complex." Wigerinck Tr. 259:20-260:11; see PTX 404
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`(Tibotec Progress Report) at PREZ05110827-32. None of these efforts succeeded. Id.
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`Finally, Tibotec explored the use of starting materials that had neither of bis-THF’s rings
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`and thus entailed creating both rings. Wigerinck Tr. 260:14-25; PTX 404 (Tibotec Progress
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`Report) at PREZ05110833-42. The scientists at Tibotec, including Dr. Wigerinck, "did not expect
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`[this concept] to work." Wigerinck Tr. 260:14-25. Creating both rings from scratch was the
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`approach that Dr. Ghosh had used in his initial synthesis ofbis-THF for Merck in the early 1990s-
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`an approach that Merck had rejected as unduly complicated: Dr. Ghosh believed "nobody in [his]
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`right mind would launch a project based upon this literature of bis-tetrahydrofuran, when they see
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`the synthesis [is] so complex." Tr. 2457:24-2458:2. Tibotec failed in its efforts to reproduce the
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`process that Dr. Ghosh had used, Wigerinck Tr. 241:24-242:8, but developed different routes
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`which also involved creating both rings from scratch.
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`The route that Tibotec ultimately adopted and claimed in the ’015 Patent was described in
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`the October 2000 Progress Report as Route 4.1. PTX 404 (Tibotec Progress Report) at
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`PREZ05110833-39; Ganem Tr. 1211:2-8. This route starts with an "open chain molecule," Reider
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`Tr. 2011:14-17, with chirality built in. The starting material is a "protected glyceraldehyde" known
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`as glyceraldehyde acetonide, and Tibotec referred to this route internally as the "glyceraldehyde
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`acetonide" or "protected glyceraldehyde" route. PTX 404 (Tibotec Progress Report) at
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`PREZ05110833; Wigerinck Tr. 260:14-261:4. The protected glyceraldehyde is referred to in the
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`’015 Patent as compound (1). See DTX 7 (’015 Patent) at col. 2:50-65.
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`Tibotec recognized that the protected glyceraldehyde route was problematic in several
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`respects. Glyceraldehyde acetonide was not commercially available; "you can’t buy it." Wigerinck
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`Tr. 202:20-203:17. It was also unstable and could not be stored for long periods of time. Id.; Ganem
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`Tr. 1211:9-1212:2. In addition, glyceraldehyde acetonide "has the chirality in it from the very
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`beginning at the center," which complicates the synthesis. Reider Tr. 2012:8-24.
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`Despite the complexity of the protected glyceraldehyde route, Tibotec came to recognize
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`that it was "the best route from both an economic and a technical viewpoint." PTX 396 (E-mail
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`from M. Lubben dated May 22, 2001) at PREZ05001242-43; Wigerinck Tr. 261:24-262:25.
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`Tibotec selected this route for its commercial process and uses it to this day. Reider Tr. 2025:1-
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`15. The "protected glyceraldehyde route" is described and claimed in the ’015 Patent, and it is the
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`subject of claim 1 of the ’015 Patent.
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`Lupin uses the claim 1 method to make bis-THF for use as a component of its ANDA
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`products. This Court has granted summary judgment that Lupin’s importation or sale of darunavir
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`containing bis-THF made by that method would infringe claim 1 of the ’015 Patent. Summ. J. Op.
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`at 49-59 (ECF No. 769).
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`C. The ’411 Patent
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`i. The invention and the claim at issue
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`The ’411 Patent has a priority date of December 23, 2003, the latest of the three patents at
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`issue in this litigation. Pre-Trial Order at 13; DTX 13 (’411 Patent) (cover). The ’411 Patent
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`discloses the full "suite" of Tibotec’s darunavir patents, "bring[ing] all the pieces together" and
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`enabling production of the darunavir molecule as a pharmaceutically acceptable drug capable of
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`being manufactured on an industrial scale. Reider Tr. 1990:22-1991 : 19, 2035:5-12.
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`Asserted claim 13 of the ’411 Patent depends from claim 2, which in turn depends from
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`claim 1. The claim requires a five-step process for synthesizing darunavir. Independent claim 1
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`recites a four-step synthesis of the right-hand sulfonamide component of the darunavir molecule
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`(referred to in the patent as the "compound of formula (5)"). The third step is "(iii) reducing the
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`nitro moiety of the resultant compound of step (ii)," and the separate fourth step is "(iv)
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`deprotecting the resultant compound of step (iii)." DTX 13 (’411 Patent) at col. 23:45-48. The fifth
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`and final step involves coupling the compound of formula (5) to a bis-THF derivative to form
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`darunavir. Id. at col. 23:48-51; Reider Tr. 2035:20-2036:5; Laird Tr. 1460:23-1461:8.
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`Claim 2, which depends from claim 1, adds a requirement for a "tert-butoxycarbonyl," or
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`"boc" protecting group to be used in the chemical intermediates of claim 1.2 DTX 13 (’411 Patent)
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`2 A protecting group protects part of the molecule from unwanted reactions while other parts of
`the molecule are being worked on. Reider Tr. 2038:20-2039:10.
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`at col. 23:52-25:3; Reider Tr. 2051:5-25. The boc protecting group is one of many possible
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`protecting groups, DTX 13 (’411 Patent) at col. 6:27-67, and before the ’411 Patent, had never
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`been used in the synthesis of darunavir, Reider Tr. 2051:7-12.
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`Claim 13, which depends from claim 2, identifies a specific coupling agent, BNPC, for use
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`in the final step of the process in which the bis-THF moiety is coupled with the sulfonamide moiety
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`to form darunavir. Id. at 2054:4-9; DTX 13 (’411 Patent) at col. 26:10-13.
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`ii. Development of the ’411 Patent invention
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`The invention of the ’411 Patent is a method for making darunavir by making the
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`sulfonamide, or "right-hand side" of the darunavir molecule, and then coupling the sulfonamide
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`with the left-hand bis-THF to form the completed darunavir molecule. Reider Tr. 1991:15-19. The
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`inventors of the ’411 Patent did not set out to create a new manufacturing process for darunavir.
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`Wigerinck Tr. 176:19-177:8. Rather, they expected to use the process developed by Searle that
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`Searle had granted Tibotec a license to use under Searle’s ’775 Patent, which discloses a
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`commercially suitable method of manufacturing darunavir. Id.; Stoffels Tr. 90:23-91:8. Searle had
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`successfully manufactured approximately 100 kilograms of a starting material suitable to make the
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`right-hand sulfonamide component of darunavir. They transferred that material to Tibotec where
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`the Tibotec inventors initially worked with it. Wigerinck Tr. 281:5-282:2. This starting material
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`had a "dibenzyl" protecting group. Id.
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`Tibotec recognized that Searle’s dibenzyl-protected starting material provided an
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`"attractive" and "short synthesis route" for making darunavir. Id. at 281:5-282:2. Specifically, the
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`Searle dibenzyl route allowed two chemical transformations--the "reduction" and "deprotection"
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`transformations--to be consolidated into a single step, thus saving time and expense. Id. at 282:22-
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`283:6. However, Tibotec "unexpectedly" experienced "big, big problems" with the Searle dibenzyl
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`route. Id. at 282:3-16. The route had a tendency to "poison" the palladium catalyst used in the
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`hydrogenation step used for deprotecting, or removing, the dibenzyl protecting group. Id. at 282:3-
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`18, 284:9-285:17. Catalyst poisoning refers to the tendency of certain contaminants to bind to the
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`catalyst instead of the desired chemical compound. Reider Tr. 2046:1-16. This slows down the
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`reaction, leading to high levels of impurities and the need for excessive amounts of the palladium
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`catalyst, a precious metal "more expensive than gold." Wigerinck Tr. 283:23-284:8, 285:10-17;
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`PTX 374 (ChemShop Proj ect Report) at PREZ04997815.
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`In addition to catalyst poisoning, Tibotec experienced safety issues with the Searle dibenzyl
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`route, specifically serious exothermic reactions that suddenly released heat and had the potential
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`to cause a "runaway" reaction and explosions. Wigerinck Tr. 283:7-20.
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`The Searle ’775 Patent also taught the use of a different protecting group, the benzyloxy
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`carbonate, or CBZ, protecting group. Reider Tr. 2039:17-21. Tibotec considered using CBZ
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`instead of dibenzyl, but did not pursue this option because the two protecting groups were removed
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`"in an identical way" and Tibotec "would be facing the same difficulties" as it had with the
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`dibenzyl-protected process. Wigerinck Tr. 287:14-19.
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`Eventually Tibotec concluded that it could solve the problems it had identified only by
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`giving up the major advantage of the Searle route, which was performing reduction and
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`deprotection simultaneously in one step. Tibotec separated these into two separate steps, which
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`increased cost and lengthened the time of production. Id. at 282:22-283:6. Tibotec accomplished
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`the separation of the deprotection and reduction steps by replacing the dibenzyl protected starting
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`material with a "boc" protected starting material. Id. at 285:18-286:2. Unlike the dibenzyl group,
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`the boc protecting group did not require a catalyzed hydrogenation reaction for deprotection, and
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`as a result, Tibotec could better control the reaction that had previously led to an exotherm and
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`poisoned catalyst. Id.
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`In addition to building the sulfonamide, the ’411 Patent covers the final process step in
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`which bis-THF is attached to the rest of the darunavir molecule--the "coupling" step. Tibotec also
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`sought to improve this step. As discussed, bis-THF is separately manufactured by the process
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`claimed in the ’015 Patent. DTX 13 (’411 Patent) at col. 15:4-6. Then it is coupled to the
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`sulfonamide, or right-hand side of the molecule, which is called the compound of formula (5) in
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`the ’411 Patent. Id. at col. 15:6-10; 16:26-48. This coupling step requires a coupling agent, which
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`activates the bis-THF so that the coupling reaction can take place. Reider Tr. 2035:24-2036:12.
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`Tibotec first tried disuccinimidyl carbonate ("DSC") as a coupling agent, but was dissatisfied and
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`searched for years for a better option; it even hired an independent laboratory, Carbogen, to study
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`alternatives to DSC. Wigerinck Tr. 295:5-21; PTX 434 (Carbogen Process Research Report) at
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`PREZ5073327. Carbogen concluded that "commercially available alternative coupling agents with
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`promising reactivity were not uncovered." PTX 434 (Carbogen Process Research Report) at
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`PREZ5073327.
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`Tibotec continued to experiment, and two years later, discovered the bis-(4-nitrophenyl)
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`carbonate, or BNPC, coupling agent recited in claim 13 of the ’411 Patent. PTX 433 (Chem-Pharm
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`Team Meeting Minutes) at PREZ05041021. Tibotec claimed the BNPC coupling agent in the ’411
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`Patent. DTX 13 (’411 Patent) at col. 26:10-13.
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`Before trial, the Court granted summary judgment to Janssen that Mylan infringes claim
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`13 of the ’411 Patent. Summ. J. Op. at 5-8.
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`FOR PUBLICATION
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`PagelD: 55146
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`D, The ’645 Patent
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`i. The invention and the claim at issue
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`The invention of the ’645 Patent is the ethanolate form of the drug that Janssen developed
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`and sells as Prezista. Asserted claim 4 is a dependent claim that depends from claim 3. Claim 3
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`recites "[a] composition comprising an ethanolate solvate of the compound [darunavir], in which
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`the ratio of compound to ethanol is about 1:1, and an inert carrier." PTX 1 (’645 Patent) at col.
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`30:35-40. Claim 4 recites "[t]he composition of claim 3 wherein the inert carrier is a
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`pharmaceutically acceptable cartier." Id. at col. 30:41-42.
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`ii. Development of the ’645 Patent invention
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`When Tibotec initially synthesized darunavir, the compound was in the form of a "sticky
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`oil," which Tibotec could not use for development or testing. Wigetinck Tr. 303:16-22; 304:19-
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`305:1. Tibotec set out to transform the "sticky oil" formulation of darunavir into a solid powder
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`form. Id. at 299:24-300:5, 303:16-22. Initially, Tibotec tried making salt forms of darunavir, as
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`salts are common for pharmaceuticals (approximately half of all marketed pharmaceuticals are
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`salts) since they typically have good solubility, which allows them to dissolve in the body. Id. at
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`300:18-301:8; Myerson Tr. 638:18-639:6; Gould Tr. 1291:4-6, 1291:23-24. Tibotec created and
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`tested multiple salt forms, and while the salt forms of darunavir could have been used and delivered
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`inside a capsule, Tibotec determined that they were not optimal. Wigetinck Tr. 301:9-16, 335:9-
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`11; Reider Tr. 2080:19-2081:5.
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`Tibotec also made prodrugs of darunavir, Wigetinck Tr. 300:18-21, 301:17-202:15, but
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`rej ected that formulation because it was "quite complex to make." Id. at 303:11-15.
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`After rej ecting both salts and prodrug formulations of darunavir, Tibotec sought a different
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`formulation, and to assist in this effort it hired ChemShop, a laboratory which had expertise in
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`FOR PUBLICATION
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`PagelD: 55147
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`making solid forms of pharmaceutical substances. Id. at 284:15-17, 303:16-24, 306:14-24.
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`ChemShop found that making a solid powder form of darunavir was "unexpectedly difficult," id.
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`at 303:16-24, and did not succeed in crystallizing darunavir from any solvent, id. at 306:14-24.
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`After ChemShop’s failure, Dr. Wigerinck brought the project back in-house at Tibotec where the
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`Tibotec chemists repeated the crystallization experiments that ChemShop had performed, but
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`again failed. Id. at 303:24-304:4. After that, over the course of several weeks, Dr. Wigerinck had
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`each of Tibotec’s 20 chemists perform two crystallization experiments a day, one in the morning
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`and one in the afternoon, so that in total Tibotec was performing "more than 40 experiments a day,
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`just to try to convert the sticky oil to a white powder." Id. at 304:5-11. In these experiments,
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`Tibotec used many different solvents, including ethanol, and a variety of other conditions. Id. at
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`307:12-18, 311:9-16. Tibotec failed to obtain a crystalline powder form of darunavir from ethanol.
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`Id. at 311:9-13.
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`When these efforts failed, Dr. Wigerinck instructed his scientists to employ a "scratching"
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`technique to try to "obtain a first crystal" of darunavir. Id. at 304:5-18, 307:22-25. The technique
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`is "long-known" in the art for trying to create a crystalline form of a compound. Zaworotko Tr.
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`1614:9-13. In these experiments, Tibotec continued to vary the solvents, anti-solvents,
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`temperatures ("25 degrees, 60 degrees, 80 degrees"), purification methods, and even the rates of
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`scratching. Wigerinck Tr. 319:1-322:12. Eventually, using isopropanol as a solvent, Tibotec
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`discovered conditions that would make a powder--a relatively pure crystalline form of darunavir.
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`Id. at 323:21-325:1; PTX 344 (Vergouwen Laboratory Notebook) at PREZ0007450; DTX 2088
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`(Translation of PTX 344); Wigerinck Tr. 532:10-533:19, 536:7-16.
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`This crystalline material that Tibotec had made turned out to be a solvate--a crystal in
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`which the solvent is part of the crystal. Myerson Tr. 570:23-571:3. This was not what Tibotec had
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`hoped for, as solvates are "not that easy to handle" and "are not ideal because they can have limited
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`stability." Wigerinck Tr. 178:11-13,299:21-23,332:14-15,494:19-21.
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`The solvate from isopropanol was also problematic because there were unacceptable
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`amounts of isopropanol sticking to the powder. Id. at 325:15-326:5. Using an isopropanol solvate
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`can present a "toxicity issue" and the amount of isopropanol in the resulting solvate was "above
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`what a person [should] ingest." Myerson Tr. 589:4-13. To solve this problem, Tibotec tried
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`recrystallizing the isopropanol solvate in an ethanol/water mixture, but the results were still
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`unsatisfactory. Tibotec then repeated the dissolution and re-crystallization steps a second time on
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`the resulting powder, this time using pure ethanol as a solvent. Wigerinck Tr. 324:22-328:1; PTX
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`377 (Tibotec Research Information Report) at PREZ05002056. This entire process took Tibotec
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`six weeks. Wigerinck Tr. 326:6-328:1.
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`Using this three-step crystallization procedure, Tibotec was able to make an ethanolate
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`where the ratio of darunavir to ethanol in its ethanolate was about 1 : 1. PTX 377 (Tibotec Research
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`Information Report) at PREZ05002056; Wigerinck Tr. 332:7-18, 327:1-328:1. The three-step
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`process is described in the specification of the ’645 Patent as Example 1. DTX 1 (’645 Patent) at
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`col. 15:49-67; Myerson Tr. 588:4-590:9; Zaworotko Tr. 1713:22-1714:3.
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`After creating an ethanolate of darunavir, Tibotec continued to search for a solid form of
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`darunavir that would not be a solvate. Wigerinck Tr. 332:7-333:16. Tibotec commissioned a study
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`by a third-party contractor to "obtain [darunavir] in a non solvated form," but its efforts were
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`unsuccessful. PTX 356 (Solvias Polymorphism Study Report) at PREZ0497447-8; Wigerinck Tr.
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`333:3-16, 334:25-335:11. Tibotec was never able to find a better formulation than darunavir
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`ethanolate. Wigerinck Tr. 335:9-11.
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`PagelD: 55149
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`Before trial, Lupin entered into a so-ordered stipulation stating that it does not dispute
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`infringement of the asserted claims of the ’645 Patent (including claim 4) and that "a judgment of
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`infringement will be entered against Lupin" as to "any of the Asserted Claims [that] are not
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`invalid .... " ECF No. 375.
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`II. Conclusions of Law
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`A, Legal Standards for Obviousness, Enablement and Written Description
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`Under the patent statute, a "patent is presumed to be valid, 35 U.S.C. § 282 (1994), and
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`this presumption can only be overcome by clear and convincing evidence to the contrary." Bristol-
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`Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1374 (Fed. Cir. 2001).
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`"[O]bviousness is ultimately a question of law .... " Boston Scientific Scimed, Inc. v.
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`Cordis Corp., 554 F.3d 982, 990 (Fed. Cir. 2009); 35 U.S.C. § 103. That "legal question" is "based
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`on underlying factual determinations," Unigene Labs., Inc. v. Apotex, 655 F.3d 1352, 1360 (Fed.
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`Cir. 2011), which include: "1) the scope and content of the prior art; 2