Case 2:10-cv-05954-WHW-CLW Document ~@~ Filed 09/Z3/14 Page 1 of 65 PagelD: ~18929
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`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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`Plaintiffs Janssen Products, L.P. and Janssen R&D Ireland (collectively, "Janssen" or
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`"Janssen Plaintiffs") move for summary judgment of infringement of U.S. Patent No. 7,772,411
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`B2 (the "’411 Patent"). Defendants Mylan Pharmaceuticals, Inc. and Mylan Inc. (collectively,
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`"Mylan") oppose. Janssen also moves for summary judgment on the validity of U.S. Patent No.
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`7,700,645 B2 (the "’645 Patent"). Lupin Limited and Lupin Pharmaceuticals, Inc. (collectively,
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`"Lupin"), Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries, Ltd. (collectively,
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`"Teva") and Mylan (all collectively, "Defendants") oppose, and Defendants Teva and Mylan also
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`move for summary judgment of non-infringement of the claims of the ’645 Patent, which Janssen
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`opposes. Janssen further moves for summary judgment of infringement of U.S. Patent Nos.
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`7,126,015 B2 (the "’015 Patent") and 7,595,408 B2 (the "’408 Patent"). Defendants oppose, and
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`Defendants Lupin and Teva also move for summary judgment of non-infringement of the claims
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`of the ’015 Patent and the ’408 Patent, which Janssen opposes. The motions have been decided
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`from the written submissions of the parties under Federal Rule of Civil Procedure 78. Janssen’s
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`Lupin Ex. 1023 (Page 1 of 65)
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`motion for summary judgment of infringement of the ’411 Patent is granted. Janssen’s motion for
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`summary judgment on the validity of the ’645 Patent is denied. Janssen’s motion for summary
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`judgment of infringement of the ’015 and ’408 Patents is granted in part and denied in part. Teva’s
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`motion for summary judgment of non-infringement of the ’645 Patent is denied. Mylan’s motion
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`for summary judgment of non-infringement of the ’645 Patent is denied. Lupin and Teva’s motion
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`for summary judgment of non-infringement of the ’015 and ’408 Patents is denied.
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`FACTUAL AND PROCEDURAL BACKGROUND
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`This consolidated action arises out of Defendants having filed Abbreviated New Drug
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`Applications ("ANDAs") with the Food and Drug Administration (the "FDA") seeking approval
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`to sell generic versions of Janssen’s highly successful HIV drug PREZISTA® (also known by its
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`compound name, darunavir) 75 mg, 150 mg, 300 mg, 400 mg, and 600 mg products. Markman
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`Op. at 1-2 (ECF No. 477). Janssen sued the various Defendants after receiving notice that they had
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`submitted these ANDAs to the FDA.
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`The ’411 Patent is directed to a process for manufacturing the compound (3R,3aS,6aR)-
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`hexahydrofuro[2,3-b]furan-3-yl(1 S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino-l-benzyl-
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`2-hydroxypropyl-carbamate, also known as darunavir, the drug in both PREZISTA® and Mylan’s
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`generic version of PREZISTA®. Mylan’s Opp’n to Janssen’s Mot. for Summ. J. on ’411 Patent at
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`3-4 (ECF No. 588). The ’645 Patent claims the ethanolate form of the drug that Janssen developed
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`and sells as PREZISTA®. Janssen’s Br. in Support of Summ. J. on ’645 Patent at 2 (ECF No.
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`528). Both the ’015 Patent and the ’408 Patent claim processes for manufacturing bis-THF, a
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`chemical structure or moiety that is part of the darunavir molecule. Janssen’s Br. in Support of
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`Summ. J. on ’015, ’408 Patents at 2 (ECF No. 535).
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`Lupin Ex. 1023 (Page 2 of 65)
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`On September 15, 2011, this Court consolidated the patent infringement actions brought
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`by the Janssen Plaintiffs for the purposes of pretrial proceedings and trial. ECF No. 71. The Court
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`held its Markman claim construction hearing on October 1, 2013, and on October 9, 2013, issued
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`its Markman opinion construing the claim terms and phrases needing construction as identified by
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`the parties. ECF No. 477. On November 22, 2013, Janssen filed three separate motions for
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`summary judgment: one for infringement of the claims of the ’411 Patent, ECF No. 524, one for
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`the validity of the ’645 Patent, ECF No. 528, and one for the infringement of the ’015 Patent and
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`the ’408 Patent, ECF No. 535. That same day, Defendants Teva and Mylan filed separate motions
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`for summary judgment of non-infringement of the ’645 Patent, ECF Nos. 525,540, and Defendants
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`Lupin and Teva j ointly filed a motion for summary judgment of non-infringement of the claims of
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`the ’015 Patent and the ’408 Patent, ECF No. 533. Oppositions to all of those motions were filed
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`on December 23, 2013, ECF Nos. 579, 588, 595, 600, 608, 609, and replies were filed on January
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`15, 2014, ECF Nos. 655, 656, 657, 659, 662, 664.
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`STANDARD OF REVIEW
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`The same summary judgment standard applies to motions involving patent claims as
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`applies to motions involving other types of claims. See, e.g., Becton Dickinson & Co. v. C.R. Bard,
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`Inc., 922 F.2d 792, 795-96 (Fed. Cir. 1990); Aria Group ]nt’l, Inc. v. L.A. Gear Calif., Inc., 853
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`F.2d 1557, 1560-61 (Fed. Cir. 1988), abrogated on other grounds by Egyptian Goddess, Inc. v.
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`Swisa, Inc., 543 F.3d 665 (Fed. Cir. 2008).
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`Summary judgment is appropriate where "the movant shows that there is no genuine
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`dispute as to any material fact and the movant is entitled to judgment as a matter of law." Fed. R.
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`Civ. P. 56(a). A factual dispute between the parties must be both genuine and material to defeat a
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`motion for summary judgment. Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 247-48 (1986). A
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`Lupin Ex. 1023 (Page 3 of 65)
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`disputed fact is material where it would affect the outcome of the suit under the relevant substantive
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`law. Scott v. Harris, 550 U.S. 372, 380 (2007). A dispute as to a material fact is genuine where a
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`rational trier of fact could return a verdict for the non-movant. Id. The movant bears the initial
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`burden of demonstrating the absence of a genuine issue of material fact for trial. Beard v. Banks’,
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`548 U.S. 521,529 (2006). If the movant carries this burden, the non-movant "must do more than
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`simply show that there is some metaphysical doubt as to the material facts." Scott, 550 U.S. at 380
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`(citing Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574, 586-87 (1986)). At this
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`stage, "the judge’s function is not himself to weigh the evidence and determine the truth of the
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`matter." Anderson, 477 U.S. at 249. Each party must support its position by "citing to particular
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`parts of materials in the record.., or showing that the materials cited do not establish the absence
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`or presence of a genuine dispute, or that an adverse party cannot produce admissible evidence to
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`support the fact." Fed. R. Civ. P. 56(c)(1).
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`The determination of patent infringement is a two-step process: "first, the scope of the
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`claims are determined as a matter of law, and second, the properly construed claims are compared
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`to the allegedly infringing device to determine, as a matter of fact, whether all of the limitations of
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`at least one claim are present, either literally or by a substantial equivalent, in the accused device."
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`Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1323 (Fed. Cir. 2002); accord, e.g., CCS
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`Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1365 (Fed. Cir. 2002). "[S]ummary judgment of
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`non-infringement can only be granted if, after viewing the alleged facts in the light most favorable
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`to the non-movant, there is no genuine issue whether the accused device is encompassed by the
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`claims." PitneyBowes, Inc. v. Hewlett-PackardCo., 182 F.3d 1298, 1304 (Fed. Cir. 1999).
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`Lupin Ex. 1023 (Page 4 of 65)
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`DISCUSSION
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`I.
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`The ’411 Patent: Janssen’s Motion for Summary Judgment of Infringement
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`The ’411 Patent provides "a new process for the synthesis of compound of forumula (6)
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`[i.e., darunavir]." Janssen’s Br. in Support of Suture. J. on ’411 Patent at 2 (ECF No. 524). More
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`specifically, the ’411 Patent "provides a convenient process for the production of compound of
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`formula (6) and intermediates.., thereof at industrial scale." Id. The ’411 Patent is made up of
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`eighteen claims, and Janssen accuses Mylan of infringing claims 1, 2, 4, 6-10, 13, 15 and 18. Claim
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`1, which is the only independent claim, reads:
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`1.
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`A process for preparing compound of formula (6), [graphic depiction of
`darunavir]
`Or an addition salt, thereof; comprising:
`(i) introducing an isobutylamino group in compound of formula (1),
`[graphic depiction of formula 1 ]
`wherein
`PG represents an amino-protecting group;
`R(sub 1) is hydrogen or C(sub 1-6)alkyl;
`introducing a p-nitrophenylsulfonyl group in the resultant compound
`step(i):
`reducing the nitro moiety of the resultant compound of step (ii);
`(iii)
`(iv) deprotecting the resulting compound of step (iii); and
`coupling the resultant compound of step (iv) with a (3R,3aS,6aR)-
`(v)
`hexahydrofuro[2,3-b] furan-3-yl derivative.
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`(ii)
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`Decl. of Eugene M. Gelernter ("Gelernter Decl.") Ex. 1 at col. 23:10-51 (’411 Patent). The other
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`asserted claims are dependent claims that depend from claim 1, directly or indirectly. Janssen’s
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`Br. in Support of Summ. J. on ’411 Patent at 4 (ECF No. 524). As a result, they "incorporate by
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`reference all the limitations" of claim 1 and "specify... further limitation[s] of the subject matter
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`claimed." 35 U.S.C. § 112(d), (e).
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`Janssen and Mylan disagreed about how the term "compound of formula (6)" was to be
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`construed. At the Markman hearing, Janssen proposed a construction of "compound of formula
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`(6)" as meaning darunavir, while Mylan argued that "compound of formula (6)" should be
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`Lupin Ex. 1023 (Page 5 of 65)
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`construed to mean a "crystalline form of darunavir." This Court agreed with Janssen and adopted
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`its proposed construction of "compound of formula (6)" as meaning darunavir. Markman Op. at
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`11 (ECF No. 477). Based on that claim construction, Janssen now moves for summary judgment
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`of infringement of the ’411 Patent against Mylan. Janssen’ s summary j udgment motion is granted.
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`a. Janssen’s Arguments in Support of Summary Judgment
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`Janssen claims that applying the claim construction that this Court has
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`adopted--"compound of formula (6)" as meaning darunavir--it is undisputed that the process
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`Mylan uses to manufacture darunavir meets every limitation of each of the asserted claims of the
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`’411 Patent. Janssen’s Br. in Support of Summ. J. on ’411 Patent at 10 (ECF No. 524). Janssen
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`argues that Mylan has no infringement defense under this Court’s claim construction, and the only
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`infringement defense that Mylan ever raised in this case, both in its non-infringement contentions
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`and in its expert’s report, was an assertion that its process for making darunavir would not infringe
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`if the term "compound of formula (6)" in claim 1 was construed to mean "crystalline form of
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`darunavir" because Mylan’s generic product is amorphous darunavir, rather than crystalline. Id. at
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`11. Accordingly, Janssen argues that Mylan’ s assertion that its ANDA Products "contain darunavir
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`(amorphous)" has "no bearing on infringement because the claims, as construed by the Court, are
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`directed to a process for making darunavir, not a process for making darunavir in a crystalline
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`form." Id.
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`b. Mylan’s Arguments in Opposition to Summary Judgment
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`Mylan opposes Janssen’s motion by arguing that genuine issues of material fact exist for
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`trial as to any infringement of the ’411 Patent. Mylan states that Janssen’s arguments in support of
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`its motion for summary judgment "ignore well-established estoppel and disclaimer doctrines that
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`are triggered by, and which the Court should consider in connection with, an infringement
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`Lupin Ex. 1023 (Page 6 of 65)
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`analysis." Mylan’s Opp’n to Summ. J. on ’411 Patent at 1 (ECF No. 608). Mylan contends that to
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`this end, there is a dispute over whether Mylan’s products are amorphous or crystalline in form,
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`and if the Court determines that they are amorphous in form, Mylan cannot infringe the asserted
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`claims of the ’411 Patent, even given this Court’s construction of the term "compound of formula
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`(6)." Id. at 1-2. Mylan supports this argument by asserting that during prosecution of the ’411
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`Patent, "Janssen amended then-pending claims to unequivocally disclaim claim scope directed to
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`methods of preparing amorphous darunavir," and that as a result, "Janssen is estopped at least from
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`arguing that any amorphous product, including Mylan Pharms’ ANDA Products, infringe the
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`asserted claims of the ’411 patent, either literally or under the doctrine of equivalents." Id. at 2.
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`c. Janssen’s Motion for Summary Judgment is Granted
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`This Court agrees with Janssen that Mylan has no defense to infringement of the asserted
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`claims of the ’411 Patent under this Court’s claim construction. "The court’s construction of the
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`claims often decides the question of infringement .... " Networld, LLC v. Centraal Corp., 242
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`F.3d 1347, 1350 (Fed. Cir. 2001). This Court’s construction of the claim term "compound of
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`formula (6)" as meaning darunavir, and not a crystalline form of darunavir, has that effect here,
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`where Mylan’s non-infringement contentions and expert testimony depended wholly on this Court
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`adopting its proposed claim construction. All of Mylan’s non-infringement arguments in
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`opposition to Janssen’s motion are based on the proposition that Janssen has "disclaim[ed] claim
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`scope directed to methods of preparing amorphous darunavir." Mylan’s Opp’n to Summ. J. on
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`’411 Patent at 2 (ECF No. 608); see id. 9, 11. This Court heard those arguments from Mylan during
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`claim construction, and dealt with them explicitly in its claim construction opinion. See Markman
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`Op. at 9-14 (ECF No. 477). The Court rejected those arguments and adopted Janssen’s proposed
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`construction. See id. As such, there is no factual issue to preclude summary judgment for Janssen
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`Lupin Ex. 1023 (Page 7 of 65)
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`on Mylan’ s infringement of the ’411 Patent. Even if this Court were to determine, as Mylan wishes,
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`that its ANDA products contain amorphous darunavir, that determination would have no effect on
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`Mylan’s infringement of the ’411 Patent, which this Court held claims a process for producing
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`"compound of formula (6)" and not a crystalline form of that compound. Because it is undisputed
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`that Mylan meets every limitation of each of the asserted claims of the ’411 Patent when producing
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`darunavir for use in its ANDA products, Janssen’s motion for summary judgment is granted. To
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`the extent Mylan argues that Janssen is barred from relying on the doctrine of equivalents as a
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`theory of infringement, such arguments are irrelevant to this motion. Janssen moves for summary
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`judgment only on a literal infringement theory, and summary judgment of literal infringement is
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`granted by this Court. The doctrine of equivalents is inapposite.
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`II.
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`The ’645 Patent
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`The ’645 Patent is made up of eight claims, and Janssen accuses Defendants of infringing
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`all eight. Janssen’s Br. in Support of Summ. J. on ’645 Patent at 2 (ECF No. 528). Claim 1 is a
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`representative claim, and it recites "[a]n ethanolate solvate of the compound [known as darunavir],
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`in which the ratio of compound to ethanol is about 1:1." Decl. of Irena Royzman in Support of
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`Janssen’s Mot. for Summ. J. on the Validity of the ’645 Patent ("Royzman Decl.") Ex. 1 at col.
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`29:62-67 (’645 Patent). The remaining claims recite:
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`(2) A solvate having the formula: [graphic depiction of darunavir].
`(3) A composition comprising an ethanolate solvate of the compound [known as
`darunavir], in which the ratio of compound to ethanol is about 1:1, and an inert
`carrier.
`(4) The composition of claim 3 wherein the inert carrier is a pharmaceutically
`acceptable carrier.
`(5) The composition of claim 4 wherein the pharmaceutically acceptable carrier is
`a solid inert carrier.
`(6) A composition comprising a solvate having the formula: [graphic depiction of
`darunavir] and an inert cartier.
`(7) The composition of claim 6 wherein the inert carrier is a pharmaceutically
`acceptable earner [sic].
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`Lupin Ex. 1023 (Page 8 of 65)
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`(8) The composition of claim 7 wherein the pharmaceutically acceptable carrier is
`a solid inert carrier.
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`Id. at col. 30:1-65.
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`In its Markman opinion, this Court construed "solvate" to mean "a crystal form that
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`contains either stoichiometric or non-stoichiometric amounts of solvent." Markman Op. at 5 (ECF
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`No. 477). An ethanolate solvate is a solvate in which the solvent is ethanol. Janssen’s Br. in
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`Support of Summ. J. on ’645 Patent at 2 (ECF No. 528).
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`a. Janssen’s Motion for Summary Judgment on Validity of the ’645 Patent
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`Janssen now moves for summary judgment as to the validity of the ’645 Patent. Defendants
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`have asserted that the ’645 Patent is invalid as obvious. In addition, Mylan and Lupin (but not
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`Teva) have asserted that claims 1-2 (but not claims 3-8) are anticipated, and that claims 3-8 (but
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`not claims 1-2) fail to meet the written description and enablement requirements. Id. at 8. Because
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`Defendants have raised a genuine issue of material fact as to the obviousness of the ’645 Patent as
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`of the applicable priority date, Janssen’s motion is denied. Because Janssen’s motion is denied on
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`those grounds, this Court need not, and will not, address the anticipation, written description and
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`enablement arguments raised by Mylan and Lupin.
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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). That "legal question" is "based on underlying
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`factual determinations," Unigene Labs., Inc. v. Apotex, 655 F.3d 1352, 1360 (Fed. Cir. 2011),
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`Lupin Ex. 1023 (Page 9 of 65)
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`which include: "1) the scope and content of the prior art; 2) the level of ordinary skill in the art;1
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`3) the differences between the claimed invention and the prior art; and 4) evidence of secondary
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`factors, also known as objective indicia of nonobviousness." Id. "Obviousness requires more than
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`a mere showing that the prior art includes separate references covering each separate limitation in
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`a claim under examination." Id. (citing KSR Int’l Co. v. Teleflexlnc., 550 U.S. 398, 418 (2007)).
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`"Rather, obviousness requires the additional showing that a person of ordinary skill at the time of
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`the invention would have selected and combined those prior art elements in the normal course of
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`research and development to yield the claimed invention." Id.
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`In addition, an "obviousness determination requires that a skilled artisan would have
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`perceived a reasonable expectation of success in making the invention in light of the prior art." In
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`re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3 d 1063, 1069
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`(Fed. Cir. 2012) (citation omitted). Courts must be aware of the "danger of hindsight bias" in an
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`obviousness analysis. Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1320 (Fed. Cir.
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`2004); see also KSR, 550 U.S. at 421; Graham v. John Deere Co., 383 U.S. 1, 36 (1966); In re
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`NTP, Inc., 654 F.3d 1279, 1299 (Fed. Cir. 2011).
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`1 Here, the parties do not dispute the characteristics of a person of ordinary skill in the art with
`respect to the patent-in-suit. That person of ordinary skill in the art would have had a "high level
`of education (e.g. a Ph.D. in chemistry or a related discipline), several years of training or
`experience in his or her pertinent field, and an appreciation for the various factors that relate to
`drug development, including an understanding of crystallization methods, crystallization
`screening, and characterization of crystalline solids." Royzman Decl. Ex. 7 ¶ 69 (Zaworotko
`Opening Report). In the alternative, "one of ordinary skill in the art could have a slightly lower
`education level (’the equivalent of a senior graduate student with a Bachelor’s or Master’s degree
`in chemistry or a related discipline’) along with other qualifications discussed above." Janssen’s
`Br. in Support of Summ. J. on ’645 Patent at 16 (ECF No. 528) (quoting Royzman Decl. Ex. 7
`¶ 69).
`
`10
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`Lupin Ex. 1023 (Page 10 of 65)
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`(i)
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`Janssen’s Arguments in Support of Summary Judgment
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`Janssen argues that Defendants’ obviousness argument is completely based on hindsight,
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`and that the asserted claims in the ’645 Patent require an ethanolate of damnavir where the ratio
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`of compound to ethanol is about 1 : 1--an invention that Janssen claims was not known in the prior
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`art. Janssen’s Br. in Support of Suture. J. on ’645 Patent at 16 (ECF No. 528). Janssen argues that
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`there were many prior art references on potential protease inhibitors, and that those references
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`included U.S. Patent No. 6,248,775 (the "’775 Patent") and Amn K. Ghosh et al., Potent
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`Protease ]nhibitors Incorporating High-Affinity P2-Ligands and (R)-Hydroxyethylamino
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`Sulfonamide Isotere, 8 Bioorganic & Medicinal Chemistry Letters 687-90 (1998) (the "Ghosh
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`1998 Article"), both of which the ’645 Patent incorporated by reference, and neither of which
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`disclosed a solvate or ethanolate of damnavir. Janssen’s ’645 Statement of Facts ¶ 20 (ECF No.
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`528-1). Instead, Janssen claims that the "prior art taught that there was no way to predict whether
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`a given compound will form a solvate." Janssen’s Br. in Support of Suture. J. on ’645 Patent at 17
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`(ECF No. 528). To illustrate, Janssen cites to prior art for the ’645 Patent, specifically Teva’s U. S.
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`Patent No. 6,861,426 (the "’426 Patent"), which states:
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`Solid-state chemistry of a crystal cannot predict[] whether an organic solvent can
`incorporate into the crystal. The manner in which s[o]lvation of a crystal may occur
`is also unpredictable. There are no rules [that] exist that allow prediction of
`whether a compound will exist as solvated forms of an organic solvent.
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`Janssen also argues that the ’645 Patent was not obvious because there was no reason to
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`select darunavir as a lead compound. "A lead compound.., is ’a compound in the prior art that
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`would be most promising to modify in order to improve upon.., its activity .... " Otsuka Pharm.
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`Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012) (quoting Takeda Chem. Indus., Ltd. v.
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`Alphapharm P~y., Ltd., 492 F.3 d 1350, 1358 (Fed. Cir. 2007)). An obviousness analysis for a patent
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`11
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`Lupin Ex. 1023 (Page 11 of 65)
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`on a new chemical compound must address "whether a chemist of ordinary skill would have
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`selected the asserted prior art compounds as lead compounds, or starting points, for further
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`development efforts." Otsuka, 678 F.3d at 1291.
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`Janssen argues that at the time of the applicable priory date,2 "all aspects of the HIV life
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`cycle were under investigation as potential targets for therapeutics," Janssen’s ’645 Statement of
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`Facts ’[l 21 (ECF No. 528-1); Royzman Decl. Ex. 4 at 85:3-6 (Marshall Dep.), researchers were
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`investigating many potential treatments (entry inhibitors, viral co-receptor antagonists, viral fusion
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`inhibitors, reverse transcriptase inhibitors, and protease inhibitors), Janssen’s Br. in Support of
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`Summ. J. on ’645 Patent at 19 (ECF No. 528), and that "[m]any groups of researchers were
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`working on potential protease inhibitors and there was vast literature on the subj ect," id. According
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`to Janssen, Defendants and their experts engage in hindsight reconstruction of the invention by
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`using the patent-in-suit as a guide and focusing on two references (the ’775 Patent and the Ghosh
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`1998 Article)that the ’645 Patent identifies as disclosing darunavir, Royzman Decl. Ex. 1 at col.
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`1:49-55 (’ 645 Patent). Janssen asserts that without hindsight, "a person of ordinary skill would not
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`have focused on the ’775 Patent and the Ghosh 1998 Article, and those references would not have
`
`given such a person reason to focus on darunavir, rather than other compounds, as a ’starting
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`point[ ], for further development efforts.’" Janssen’s Br. in Support of Summ. J. on ’645 Patent at
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`20 (ECF No. 528) (quoting Otsuka, 678 F.3d at 1291).
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`Finally, Janssen argues that there would have been no reason to try to create an ethanolate
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`of darunavir, and no "reasonable expectation of success" in doing so. Id. at 23 (quoting Otsuka,
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`678 F.3d at 1292). Janssen asserts that the ’775 Patent and the Ghosh 1998 Article do not provide
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`any reason to try to create a solvate or ethanolate of darunavir, where the Ghosh 1998 Article "does
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`2 All parties agree that May 16, 2002 is the relevant date for assessing the validity of the ’645
`Patent. See Janssen’s Br. in Support of Summ. J. on ’645 Patent at 4 (ECF No. 528).
`
`12
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`Lupin Ex. 1023 (Page 12 of 65)
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`

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`Case 2:10-cv-05954-WHW-CLW Document ~@~ Filed 09/Z3/14 Page 13 of 65 PagelD: ~18987
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`not describe any formulation for any compound," and the ’775 Patent "has an extensive discussion
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`of possible solid and non-solid formulations for the disclosed compounds, without mentioning
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`solvates or ethanolates." Id. Janssen states that without hindsight, "there would have been no
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`reason to view a solvate or ethanolate of darunavir as desirable in any way," especially given the
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`literature--including articles written by Defendants’ proposed expert Dr. Zaworotko--
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`discouraging the use of solvate forms because of their lower stability. Id. at 24. And Janssen states
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`that even if Defendants could show that a person of ordinary skill had reason to try to create a
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`solvate or ethanolate of darunavir, they still could not show by clear and convincing evidence that
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`such a person would have had a "reasonable expectation of success" in doing so due to the
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`"unpredictability of the chemical arts" and the notorious unpredictability of solvate formation. Id.
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`at 24-25.
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`(ii) Lupin and Mylan’s Arguments in Opposition to Summary Judgment
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`Lupin and Mylan, on the other hand, argue that summary judgment is inappropriate
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`because, at the very least, they raise genuine issues of material fact as to whether the ’645 Patent
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`was obvious as a matter of law.
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`Lupin and Mylan first argue that Janssen ignores the prior art disclosure of darunavir and
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`applies an improper lead compound analysis. According to Lupin and Mylan, once a drug is in
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`clinical trials--as darunavir was by May 2002--it is necessarily a "lead" compound. See, e.g.,
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`Richardson-Vicks Inc. v. Upjohn Co., 122 F.3d 1476, 1484 (Fed. Cir. 1997) (explaining how FDA
`
`actions, e.g. approval of a drug after clinical trials, would have motivated a skilled person). Lupin
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`and Mylan also assert that Janssen improperly argues that there were other compounds disclosed
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`in the Ghosh 1998 Article and the ’775 Patent that showed similar or better potency to darunavir
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`because the Federal Circuit has never mandated proof of a single lead compound. See, e.g., Altana
`
`13
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`

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`Case 2:10-cv-05954-WHW-CLW Document 9@9 Filed 09/23/14 Page 14 of 65 PagelD: ~8988
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`Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009) (finding it "rigid" to
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`require that prior art "must point to only a single lead compound for further development efforts"
`
`for obviousness); Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369, 1376
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`(Fed. Cir. 2013) (holding that preference for other options in primary reference was irrelevant).
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`Lupin and Mylan contend that whether the Ghosh 1998 Article or the ’775 Patent provided
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`motivation is not an issue to be properly resolved on summary judgment because there is varying
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`expert testimony as to why one would consider darunavir among the compounds commonly set
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`forth in the ’775 Patent and the Ghosh 1998 Article.
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`Second, Lupin and Mylan argue that Janssen ignores the ample motivation in the prior art
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`to prepare a solvated form of darunavir. They state that by May 2002 darunavir was in clinical
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`trials, and as a result was well within the "compound &interest" stage for form screening, and that
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`the FDA and ICH Harmonized Tripartite ("ICH") Guidelines mandated crystal form testing in
`
`connection with drug product development--which would have provided ample motivation to a
`
`skilled person to conduct crystal form studies on darunavir. Lupin and Mylan’s Opp’n to Janssen’s
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`Mot. for Summ. J. on ’645 Patent at 18 (ECF No. 609). Given that oral dosing (e.g. tablets,
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`capsules) is the most common and preferred dosing approach--which typically involves drugs
`
`prepared as solids with a stable pharmaceutical composition--Lupin and Mylan argue that such a
`
`preference would naturally apply to darunavir and that FDA guidelines and other literature
`
`specifically recognized the need to conduct crystallization screens to meet the goal of stable
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`formulation. See id. at 19. Lupin and Mylan argue that such motivation would not change simply
`
`because other options (in this case the esters, salts and non-solid formulations disclosed in the ’775
`
`Patent) are available.
`
`14
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`

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`Case 2:10-cv-05954-WHW-CLW Document ~@~ Filed 09/Z3/14 Page 15 of 65 PagelD: ~18989
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`In response to Janssen’s argument that "solvate formation is notoriously unpredictable,"
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`Lupin and Mylan argue that there was a reasonable expectation that a routine crystallization screen
`
`would have produced the 1 : 1 solvate. Lupin and Mylan state that Janssen’ s argument "improperly
`
`equates a reasonable expectation of success with the ability to predict a priori all empirical
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`properties of a crystal, the latter of which requires synthesis and testing." Id. at 20. Lupin and
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`Mylan also assert that several statements from references, patent prosecution histories and case
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`law quoted by Janssen as to the unpredictability of solvate formation post-date the filing at issue
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`here and therefore fail to establish the state of the art of solvate formation in 2002. Id. at 21. They
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`also state that the prior art "provided guidance through disclosure of numerous ethanol solvates of
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`compounds, and more specifically, APIs in the same class as, and with a similar chemical structure
`
`to, darunavir. Id. at 22. It follows that, according to Lupin and Mylan, it would have been clear to
`
`a skilled person that "preformulation of darunavir required routine crystallization screening of API
`
`candidates; that there was a reasonable expectation that hydrates or solvates of darunavir would
`
`form; and that ethanolate solvates of compounds (including in the same class as darunavir, and
`
`also prepared from ethanol) were known, with some considered preferred embodiments." Id. at
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`22-23. Lupin and Mylan also contend that Janssen’s argument that a routine crystallization screen
`
`would be complex and contain "an infinite number of combinations of conditions" is contradicted
`
`by relevant regulatory guidelines and literature. See id. at 25. They cite to the prior art paper
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`Stephen Byrn et al., Pharmaceutical SoBds: A Strategic Approach to Regulatory Considerations,
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`12 Pharmaceutical Res. 945 (1995) which explains that the "first step in the polymorphs decision
`
`tree is to crystallize the substance from a number of different solvents" including "those used in
`
`the final crystallization steps and those used during formulation and processing and may also
`
`15
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`Lupin Ex. 1023 (Page 15 of 65)
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`

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`Case 2:10-cv-05954-WHW-CLW Document ~@~ Filed 09/2;3/14 Page 16 of 65 PagelD: ~18940
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`include water, methan