Janssen Products, L.P. v. Lupin Ltd. (109 F. Supp. 3d 650, 2014)

United States District Court for the District of New Jersey 2014-08-14

Citations

Full opinion text

OPINION

WALLS, Senior District Judge.

By complaints, Plaintiff patent-holders and drug-makers have sued Defendant generic drug manufacturers for alleged infringements of patents on a chemical compound used in the manufacture of Plaintiff’s product, Prezista. The patents, for this opinion, are U.S. Patent No. 7,700,645 B2 (the “'645 Patent”), U.S. Patent No. 7, 126,015 B2 (the “'015 Patent”), and U.S. Patent No. 7,772,411 B2 (the “'411 Patent”).

Prezista is an ethanolate form of the chemical compound named darunavir. The '015 Patent claims processes for manufacturing a chemical structure or moiety, bis-THF, that is part of the darunavir molecule. The '411 Patent is directed to a process for manufacturing darunavir in Prezista and Defendant Mylan’s generic version. The '645 Patent claims the ethanolate form that Plaintiff Janssen developed and sells as Prezista.

Earlier summary judgment motion practice by the parties caused the Court to determine that:

1) Janssen’s motion for summary judgment of infringement of the '411 Patent against Mylan was granted.

2) Janssen’s motion for summary judgment on the validity of the '645 Patent was denied.

3) Janssen’s motion for summary judgment of infringement of the '015 and '408 Patents was granted in part and denied in part: the Court found that Lupin infringed certain claims of the '015 Patent, including asserted claim 1.

4) Teva’s motion for summary judgment of non-infringement of the '645 Patent was denied.

5) Mylan’s motion for summary judgment of non-infringement of the '645 Patent was denied.

6) Lupin’s and Teva’s motion for summary judgment of non-infringement of the '015 and '408 Patents was denied.

Before trial, Teva and Janssen resolved their dispute, and the '408 Patent is no longer at issue.

A bench trial has been held on the remaining matters: the validity of the patents — as to Lupin, claim 4 of the '645 Patent and claim 1 of the '015 Patent, and as to Mylan, claim 13 of the '411 Patent.

This Opinion will be based and concentrated on what the Court has found to be material and supportive facts necessary to answer the primary question: Did either Defendant prove invalidity of a patent-in-suit by clear and convincing evidence?

To find the answer(s), the Court has reviewed the relevant evidence adduced at trial, aided by recollection, notes, trial transcripts, and the parties’ proposed findings of fact. The Court has evaluated the credibility of all witnesses, lay and expert, testing not only what the person said, but how it was said and what was not said, against these criteria: Was this more likely so or not? Did what was said make sense in the totality of the circumstances? Was this, after all, clearly convincing to the fact finder?

To its chagrin, the Court has determined that expert witnesses, though not all, called by the defense were more interested in obfuscation than in helping the Court as a fact finder “seek the truth.” Too often-— and too repeatedly — the Court had to importune and finally direct certain defense witnesses to directly answer questions posed. The trial transcripts will identify these persons as Dr. Trevor Laird and Dr. Michael Zaworotko. See, e.g., Laird Tr. 1450:20-1451:5, 1486:23-1487:10, 1488:5-22; Zaworotko Tr. 1650:16-19, 1684:5-24, 1712:18-19. Ironically, such representatives of science were more interested in evasion than intellectual candor. As to their testimony, the Court as fact finder invokes falsus in uno, falsus in omnibus. Each did the cause of his particular Defendant no good.

In challenging the patents’validity, Defendants face a heavy burden. By statute, issued patents are “presumed valid,” 35 U.S.C. § 282 (2012), and Defendants must overcome that presumption by clear and convincing evidence. ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc., 694 F.3d 1312, 1327 (Fed.Cir.2012). “Clear and convincing evidence is such evidence that produces ‘an abiding conviction that the truth of [the] factual contentions are highly probable.’ ” Id. (quoting Colorado v. New Mexico, 467 U.S. 310, 316, 104 S.Ct. 2433, 81 L.Ed.2d 247 (1984)).

The Court finds that neither Defendant met its obligation to overcome the presumption of validity of the patents-in-suit by clear and convincing evidence.

I. Findings of Fact

To the extent any finding of fact reflects a legal conclusion, it shall be to that extent deemed a conclusion of law, and vice versa.

A. Background

i. The patents at issue

On October 24, 2006, the Patent and Trademark Office (“PTO”) issued the '015 Patent, entitled “Method for the Preparation of Hexahydro-furo-[2,3-b]furan-3-ol.” Pre-Trial Order at 12, ¶ 34. Lupin does not contest — for the purposes of this litigation only — that the '015 Patent has a priority date of September 10, 2001, nor that Janssen R & D Ireland holds title to the '01‘5 Patent. Id. at 12, ¶¶ 35, 36. Janssen is asserting claim 1 of the '015 Patent against Lupin. Id. at 12, ¶ 37.

On August 10, 2010, the PTO issued the '411 Patent, entitled “Process for the Preparation of (3R,3aS,6aR)-hexahydrofu-ro[2,3-b]furan-3-yl(lS,2R)-3-[[ (4-amino-phenyl) sulfonyl](isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate.” Id. at 13, ¶ 44. Mylan does not contest — for the purposes of this litigation only — that the '411 Patent has a priority date of Decernber 23, 2003, nor that Janssen R & D Ireland holds title to the '411 Patent. Id. at 13, ¶ 45, 46. Janssen is asserting claim 13 of the '411 Patent against Mylan. Id. at 13, ¶ 47.

On April 20, 2010, the PTO issued the '645 Patent, entitled “Pseudopolymorphic Forms of a HIV Protease Inhibitor.” Id. at 11, ¶ 29. Lupin does not contest — for the purposes of this litigation only — that the '645 Patent has a priority date of May 16, 2002, nor that Janssen R & D Ireland holds title to the '645 Patent. Id. at 11, ¶¶ 30, 31. Janssen is asserting claim 4 of the '645 Patent against Lupin. Id. at 11, ¶ 32. •

ii.Prezista (darunavir)

Janssen Products, L.P. is the holder of approved New Drug Application (“NDA”) No. 21-976 for Prezista (darunavir). Janssen manufactures, markets and sells Prezista, a human immunodeficiency virus (HIV-1) protease inhibitor. Id. at 9, ¶¶ 14, 15. The FDA has approved Prezista for the treatment of HIV-1 infection in adult patients and in pediatric patients 3 years of age and older. Id. at 9, 16. The active pharmaceutical ingredient in Prezista is darunavir in an ethanolate form. Id. at 9, ¶ 17. Prezista tablets are currently sold in the United States in 75 mg, 150 mg, 400 mg, 600 mg, and 800 mg dosage strengths. Id. at 9, ¶ 18. The '645 Patent is listed in an FDA publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations (known as the “Orange Book”) with respect to Prezista. Id. at 9, ¶ 20.

iii.The ANDAs

On June 23, 2010, Mylan filed ANDA No. 202136 with the FDA, seeking approval to sell darunavir tablets, 75 mg, 150 mg, 300 mg, 400 mg, and 600 mg, described in the ANDA. Id. at 9,1121.

On June 23, 2010, Lupin filed ANDA No. 202073 with the FDA seeking approval to sell darunavir tablets, 400 mg and 600 mg, described in the ANDA. On June 3, 2011, Lupin amended its ANDA No. 202073 to incorporate additional strengths of 75 mg, 150 mg, and 300 mg. Id. at 10, ¶¶ 23-24.

iv.Claim construction

In its Markman opinion, the Court construed “solvate” in the asserted claims of the '645 Patent to mean “a crystal form that contains stoichiometric or non-stoichiometric amounts of solvent.” ECF No. 477 at 5; Pre-Trial Order at 13, ¶ 48. The Court also construed the term “compound of formula (6)” in the asserted claims of the '411 Patent as “darunavir,” or the graphic depiction of darunavir. Markman Op. at 11; Pre-Trial Order at 13-14, ¶ 49.

B. The '015 Patent

i. The invention and the claim at issue

The invention of the '015 Patent “relates to a method for the preparation of [bis-THF] .... ” Defendants’ Trial Exhibit (“DTX”) 7 ('015 Patent) at col. 1:12-14. The specification states that bis-THF “is an important pharmacological moiety present in the structure of retroviral protease inhibitors ...” id. at col. 1:18-24, and identifies and incorporates by reference the European versions of G.D. Searle & Co.’s (“Searle”) darunavir patent, id. at col. 1:18-24. It recommends bis-THF as having “particular interest” for use in darunavir. Id. at col. 28:24-31; col. 28:37-40.

The specification also indicates that the “main object of the ... ['015] invention is to provide an improved method for producing [bis-THF] when compared to the art-known methods and their drawbacks.” Id. at col. 2:25-28. “[A]nother object” of the '015 Patent is “to provide a method for the synthesis of [bis-THF] which is suitable for industrial scaling-up.” Id. at col. 2:28-30.

Claim 1 of the '015 Patent, which is being asserted against Lupin, recites:

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.

Id. at col. 38:44-39:40.

ii. Development of the '015 Patent invention

Tibotee, later acquired by Johnson & Johnson in 2002, Stoffels Tr. 98:18-21; 99:1-4, began considering compounds containing bis-THF for- possible use as protease inhibitors, and immediately recognized the difficulty of synthesizing bis-THF. Reider Tr.2004:17-23. The bis-THF molecule has a double-ring structure, with three “chiral centers,” also known as “stereocenters” or “optical centers.” DTX 7 ('015 Patent) at col. 9:21-28. The three chiral centers made bis-THF an “incredibly complex” molecule that presented a “formidable challenge” to synthesize. Reider Tr.2004:17-23; see also id.' 2008:23-2009:3; Ganem Tr. 1159:11-15. Tibotee initially explored whether it could avoid the problem by replacing bis-THF with a different chemical group that would have similar benefits but would be easier to synthesize. Wigerinck Tr. 186:19-188:5; see generally Plaintiffs Trial Exhibit (“PTX”) 346 (Laboratory Notebook 37); PTX 351 (Tibotee Feb. 2001 Powerpoint) at PREZ04980686. Tibotee made and tested many compounds containing alternatives to bis-THF but none of the compounds had activity comparable to the compounds with bis-THF. Wigerinck Tr. 190:17-191:10, 200:12-20; PTX 351 (Tibotec Feb. 2001 Powerpoint) at PREZ04980686. After concluding that bis-THF was a “special and crucial” component for the design of protease inhibitors, Tibotee began developing a process for making bis-THF that could be used for synthesis on an industrial scale. Wigerinck Tr. 191:11-17.

Tibotee began working- on this scalable synthesis for bis-THF in May 1999. Id. at 238:22-239:9. The work done over the next two years, including attempting more than twenty methods for making bis-THF before selecting the route claimed in the '015 Patent, is summarized in a progress report that Tibotee prepared in October 2000. Id. .at 257:7-258:14; PTX 404 (Tibotec Progress Report). Initially, Tibotee tried the synthesis that was favored in the prior art, i.e., starting with a compound known as dihydrofuran, essentially the “left ring” of bis-THF’s double ring, and proceeding from there to build the right-hand ring. Wigerinck Tr. 239:24-241:12, 258:15-259:10. This strategy was described, inter alia, in the earliest prior art synthesis of bis-THF, the Pezechk 1986 Article (PTX 391), and in multiple references by Dr. Arun Ghosh, one of the pioneers to use bis-THF as part of an HIV protease inhibitor, including Scheme 2 of the Ghosh 1996 Article (PTX 389). See Wigerinck Tr. 239:24-241:12, 243:2-7. At trial, the experts from both sides agreed that starting with bis-THFs left-hand ring was a logical strategy. See Reider Tr. 2009:21-2010:16 (“the literature taught that this is a great place to start”); Ganem Tr. 1204:2-5 (agreeing that this is a “reasonably straightforward way[ ] of thinking about how to make a two-ring bicyclic structure”).

However, when Tibotec used this strategy, it encountered a problem with a step in the synthesis described in the Pezechk 1986 Article and the Ghosh 1996 Article. Both methods used ozonolysis, a reaction step using ozone, with which Tibotec and the prior art had not had a problem on a laboratory scale. Wigerinck Tr. 243:15-244:4; Ganem Tr. 1207:19-24. But Tibotec found that when it attempted the ozonolysis step on a larger scale, the reaction would generate smoke, even after stopped, which suggested that the reaction could not be controlled and had the potential to explode. Wigerinck Tr. 243:15-245:13.

In the end, none of the routes that Tibotec explored starting with bis-THF’s left-hand ring proved satisfactory. See PTX 404 (Tibotec Progress Report) at PREZ05110825-26.

Tibotec also explored several routes that started with bis-THF’s right-hand ring and then built the molecule’s left ring. Unlike dihydrofuran, the right hand ring was not commercially available, “so that made the route more complex.” Wigerinck Tr. 259:20-260:11; see PTX 404 (Tibotec Progress Report) at PREZ0511082732. None of these efforts succeeded. Id.

Finally, Tibotec explored the use of starting materials that had neither of bis-THF’s rings and thus entailed creating both rings. Wigerinck Tr. 260:14-25; PTX 404 (Tibotec Progress Report) at PREZ05110833-42. The scientists at Tibotec, including Dr. Wigerinck, “did not expect [this concept] to work.” Wigerinck Tr. 260:14-25. Creating both rings from scratch was the approach that Dr. Ghosh had used in his initial synthesis of bis-THF for Merck in the early 1990s — an approach that Merck had rejected as unduly complicated: Dr. Ghosh believed “nobody in [his] right mind would launch a project based upon this literature of bis-tetrahydrofuran, when they see the synthesis [is] so complex.” Tr. 2457:24-2458:2. Tibotec failed in its efforts to reproduce the process that Dr. Ghosh had used, Wigerinck Tr. 241:24-242:8, but developed different routes which also involved creating both rings from scratch.

The route that Tibotec ultimately adopted and claimed in the '015 Patent was described in the October 2000 Progress Report as Route 4.1. PTX 404 (Tibotec Progress Report) at PREZ0511083339; Ganem Tr. 1211:2-8. This route starts with an “open chain molecule,” Reider Tr. 2011:14-17, with chirality built in. The starting material is a “protected glyceraldehyde” known as glyceraldehyde acetonide, and Tibotec referred to this route internally as the “glyceraldehyde acetonide” or “protected glyceraldehyde” route. PTX 404 (Tibotec Progress Report) at PREZ05110833; Wigerinck Tr. 260:14-261:4. The protected glyceraldehyde is referred to in the '015 Patent as compound (1). See DTX 7 ('015 Patent) at col. 2:50-65.

Tibotec recognized that the protected glyceraldehyde route was problematic in several respects. Glyceraldehyde acetonide was not commercially available; “you can’t buy it.” Wigerinck Tr. 202:20-203:17. It was also unstable and could not be stored for long periods of time. Id.; Ganem Tr. 1211:9-1212:2. In addition, glyceraldehyde acetonide “has the chirality in it from the very beginning at the center,” which complicates the synthesis. Reider Tr. 2012:8-24.

Despite the complexity of the protected glyceraldehyde route, Tibotec came to recognize that it was “the best route from both an economic and a technical viewpoint.” PTX 396 (E-mail from M. Lubben dated May 22, 2001) at PREZ0500.1242-43; Wigerinck Tr. 261:24-262:25. Tibotec selected this route for its commercial process and uses it to this day. Reider Tr. 2025:1-15. The “protected glyceraldehyde route” is described and claimed in the '015 Patent, and it is the subject of claim. 1 of the '015 Patent.

Lupin uses the claim 1 method to make bis-THF for use as a component of its ANDA products. This Court has granted summary judgment that Lupin’s importation or sale of darunavir containing bis-THF made by that method would infringe claim 1 of the '015 Patent. Summ. J. Op. at 49-59 (ECF No. 769).

C. The '411 Patent

i. The invention and the claim at issue

The '411 Patent has a priority date of December 23, 2003, the latest of the three patents at issue in this litigation. PreTrial Order at 13; DTX 13 ('411 Patent) (cover). The '411 Patent discloses the full “suite” of Tibotec’s darunavir patents, “bringing] all the pieces together” and enabling production of the darunavir molecule as a pharmaceutically acceptable drug capable of being manufactured on an industrial scale. Reider Tr. 1990:22-1991:19, 2035:5-12.

Asserted claim 13 of the '411 Patent depends from claim 2, which in turn depends from claim 1. The claim requires a five-step process for synthesizing darunavir. Independent claim 1 recites a four-step synthesis of the right-hand sulfonamide component of the darunavir molecule (referred to in the patent as the “compound of formula (5)”). The third step is “(Hi) reducing the nitro moiety of the resultant compound of step (ii),” and the separate fourth step is “(iv) deprotecting the resultant compound of step (Hi).” DTX 13 ('411 Patent) at col. 23:45-48. The fifth and final step involves coupling the compound of formula (5) to a bis-THF derivative to form darunavir. Id. at col. 23:48-51; Reider Tr. 2035:20-2036:5; Laird Tr. 1460:23-1461:8.

Claim 2, which depends from claim 1, adds a requirement for a “tert-butoxycarbonyl,” or “boc” protecting group to be used in the chemical intermediates of claim l. DTX 13 ('411 Patent) at col. 23:52-25:3; Reider Tr. 2051:5-25. The boc protecting group is one of many possible protecting groups, DTX 13 ('411 Patent) at col. 6:27-67, and before the '411 Patent, had never been used in the synthesis of darunavir, Reider Tr. 2051:7-12.

Claim 13, which depends from claim 2, identifies a specific coupling agent, BNPC, for use in the final step of the process in which the bis-THF moiety is coupled with the sulfonamide moiety to form darunavir. Id. at 2054:4-9; DTX 13 ('411 Patent) at col. 26:10-13.

ii. Development of the '411 Patent invention

The invention of the '411 Patent is a method for making darunavir by making the sulfonamide, or “right-hand side” of the darunavir molecule, and then coupling the sulfonamide with the left-hand bis-THF to form the completed darunavir molecule. Reider Tr. 1991:15-19. The inventors of the '411 Patent did not set out to create a new manufacturing process for darunavir. Wigerinck Tr. 176:19-177:8. Rather, they expected to use the process developed by Searle that Searle had granted Tibotec a license to use under Searle’s '775 Patent, which discloses a commercially suitable method of manufacturing darunavir. Id.; Stoffels Tr. 90:23-91:8. Searle had successfully manufactured approximately 100 kilograms of a starting material suitable to make the right-hand sulfonamide component of darunavir. They transferred that material to Tibotec where the Tibotec inventors initially worked with it. Wigerinck Tr. 281:5-282:2. This starting material had a “dibenzyl” protecting group. Id.

Tibotec recognized that Searle’s dibenzyl-protected starting material provided an “attractive” and “short synthesis route” for making darunavir. Id. at 281:5-282:2. Specifically, the Searle dibenzyl route allowed two chemical transformations — the “reduction” and “deprotection” transformations — to be consolidated into a single step, thus saving time and expense. Id. at 282:22-283:6. However, Tibotec “unexpectedly” experienced “big, big problems” with the Searle dibenzyl route. Id. at 282:3-16. The route had a tendency to “poison” the palladium catalyst used in the hydrogenation step used for deprotecting, or removing, the dibenzyl protecting group. Id. at 282:3-18, 284:9-285:17. Catalyst poisoning refers to the tendency of certain contaminants to bind to the catalyst instead of the desired chemical compound. Reider Tr. 2046:1-16. This slows down the reaction, leading to high levels of impurities and the need for excessive amounts of the palladium catalyst, a precious metal “more expensive than gold.” Wigerinck Tr. 283:23-284:8, 285:10-17; PTX 374 (ChemShop Project Report) at PREZ04997815.

In addition to catalyst poisoning, Tibotec experienced safety issues with the Searle dibenzyl route, specifically serious exothermic reactions that suddenly released heat and had the potential to cause a “runaway” reaction and explosions. Wigerinck Tr. 283:7-20.

The Searle '775 Patent also taught the use of a different protecting group, the benzyloxy carbonate, or CBZ, protecting group. Reider Tr. 2039:17-21. Tibotec considered using CBZ instead of dibenzyl, but did not pursue this option because the two protecting groups were removed “in an identical way” and Tibotec “would be facing the same difficulties” as it had with the dibenzyl-protected process. Wigerinck Tr. 287:14-19.

Eventually Tibotec concluded that it could solve the problems it had identified only by giving up the major advantage of the Searle route, which was performing reduction and deprotection simultaneously in one step. Tibotec separated these into two separate steps, which increased cost and lengthened the time of production. Id. at 282:22-283:6. Tibotec accomplished the separation of the deprotection and reduction steps by replacing the dibenzyl protected starting material with a “boc” protected starting material. Id. at 285:18-286:2. Unlike the dibenzyl group, the boc protecting group did not require a catalyzed hydrogenation reaction for deprotection, and as a result, Tibotec could better control the reaction that had previously led to an exotherm and poisoned catalyst. Id.

In addition to building the sulfonamide, the '411 Patent covers the final process step in which bis-THF is attached to the rest of the darunavir molecule' — the “coupling” step. Tibotec also sought to improve this step. As discussed, bis-THF is separately manufactured by the process claimed in the '015 Patent. DTX 13 ('411 Patent) at col. 15:4-6. Then it is coupled to the sulfonamide, or right-hand side of the molecule, which is called the compound of formula (5) in the '411 Patent. Id. at col. 15:6-10; 16:26-48. This coupling step requires a coupling agent, which activates the bis-THF so that the coupling reaction can take place. Reider Tr. 2035:24-2036:12. Tibotec first tried disuceinimidyl carbonate (“DSC”) as a coupling agent, but was dissatisfied and searched for years for a better option; it even hired an independent laboratory, Carbogen, to study alternatives to DSC. Wigerinck Tr. 295:5-21; PTX 434 (Carbogen Process Research Report) at PREZ5073327. Carbogen concluded that “commercially available alternative coupling agents with promising reactivity were not uncovered.” PTX 434 (Carbogen Process Research Report) at PREZ5073327.

Tibotec continued to experiment, and two years later, discovered the bis-(4-nitrophenyl) carbonate, or BNPC, coupling agent recited in claim 13 of the '411 Patent. PTX 433 (Chem-Pharm Team Meeting Minutes) at PREZ05041021. Tibotec claimed the BNPC coupling agent in the '411 Patent. DTX 13 ('411 Patent) at col. 26:10-13.

Before trial, the Court granted summary judgment to Janssen that Mylan infringes claim 13 of the '411 Patent. Summ. J. Op. at 5-8.

D. The '645 Patent

i. The invention and the claim at issue

The invention of the '645 Patent is the ethanolate form of fhe drug that Janssen developed and sells as Prezista. Asserted claim 4 is a dependent claim that depends from claim 3. Claim 3 recites “[a] composition comprising an ethanolate solvate of the compound [darunavir], in which the ratio of compound to ethanol is about 1:1, and an inert carrier.” PTX 1 ('645 Patent) at col. 30:35^40. Claim 4 recites “[t]he composition of claim 3 wherein the inert carrier is a pharmaceutically acceptable carrier.” Id. at col. 30:41-42.

ii. Development of the '645 Patent invention

When Tibotec initially synthesized darunavir, the compound was in the form of a “sticky oil,” which Tibotec could not use for development or testing. Wigerinck Tr. 303:16-22; 304:19-305:1. Tibotec set out to transform the “sticky oil” formulation of darunavir into a solid powder form. Id. at 299:24-300:5, 303:16-22. Initially, Tibotec tried making salt forms of darunavir, as salts are common for pharmaceuticals (approximately half of all marketed pharmaceuticals are salts) since they typically •have good solubility, which allows them to dissolve in the body. Id. at 300:18-301:8; Myerson Tr. 638:18-639:6; Gould Tr. 1291:4-6, 1291:23-24. Tibotec created and tested multiple salt forms, and while the salt forms of darunavir could have been used and delivered inside a capsule, Tibotec determined that they were not optimal. Wigerinck Tr. 301:9-16, 335:9-11; Reider Tr. 2080:19-2081:5.

Tibotec also made prodrugs of darunavir, Wigerinck Tr. 300:18-21, 301:17-202:15, but rejected that formulation because it was “quite complex to make.” Id. at 303:11-15.

After rejecting both salts and prodrug formulations of darunavir, Tibotec sought a different formulation, and to assist in this effort it hired ChemShop, a laboratory which had expertise in making solid forms of pharmaceutical substances. Id. at 284:15-17, 303:16-24, 306:14-24. Chem-Shop found that making a solid powder form of darunavir was “unexpectedly difficult,” id. at 303:16-24, and did not succeed in crystallizing darunavir from any solvent, id. at 306:14-24. After ChemShop’s failure, Dr. Wigerinck brought the project back in-house at Tibotec where the Tibotec chemists repeated the crystallization experiments that ChemShop had performed, but again failed. Id. at 303:24-304:4. After that, over the course of several weeks, Dr. Wigerinck had each of Tibotec’s 20 chemists perform two crystallization experiments a day, one in the morning and one in the afternoon, so that in total Tibotec was performing “more than 40 experiments a day, just to try to convert the sticky oil to a white powder.” Id. at 304:5-11. In these experiments, Tibotec used many different solvents, including ethanol, and a variety of other conditions. Id. at 307:12-18, 311:9-16. Tibotec failed to obtain a crystalline powder form of darunavir from ethanol. Id. at 311:9-13.

When these efforts failed, Dr. Wigerinck instructed his scientists to employ a “scratching” technique to try to “obtain a first crystal” of darunavir. Id. at 304:5-18, 307:22-25. The technique is “long-known” in the art for trying to create a crystalline form of a compound. Zaworotko Tr. 1614:9-13. In these experiments, Tibotec continued to vary the solvents, anti-solvents, temperatures (“25 degrees, 60 degrees, 80 degrees”), purification methods, and even the rates of scratching. Wigerinck Tr. 319:1-322:12. Eventually, using isopropanol as a solvent, Tibotec discovered conditions that would make a powder— a relatively pure crystalline form of darunavir. Id. at 323:21-325:1; PTX 344 (Vergouwen Laboratory Notebook) at PREZ0007450; DTX 2088 (Translation of PTX 344); Wigerinck Tr. 532:10-533:19, 536:7-16.

This crystalline material that Tibotec had made turned out to be a solvate — a crystal in which the solvent is part of the crystal. Myerson Tr. 570:23-571:3. This was not what Tibotec had hoped for, as solvates are “not that easy to handle” and “are not ideal because they can have limited stability” Wigerinck Tr. 178:11 -13, 299:21 -23, 332:14-15, 494:19-21.

The solvate from isopropanol was also problematic- because there were unacceptable amounts of isopropanol sticking to the powder. Id. at 325:15-326:5. Using an isopropanol solvate can present a “toxicity issue” and the amount of isopropanol in the resulting solvate was “above what a person [should] ingest.” Myerson Tr. 589:4-13. To solve this problem, Tibotec tried recrystallizing the isopropanol solvate in an ethanol/water mixture, but the results were still unsatisfactory. Tibotec then repeated the dissolution and re-crystallization steps a second time on the resulting powder, this time using pure ethanol as a solvent. Wigerinck Tr. 324:22-328:1; PTX 377 (Tibotec Research Information Report) at PREZ05002056. This entire process took Tibotec six weeks. Wigerinck Tr. 326:6-328:1.

Using this three-step crystallization procedure, Tibotec was able to make an ethanolate where the ratio of darunavir to ethanol in its ethanolate was about 1:1. PTX 377 (Tibotec Research Information Report) at PREZ05002056; Wigerinck Tr. 332:7-18, 327:1-328:1. The three-step process is described in the specification of the '645 Patent as Example 1. DTX 1 ('645 Patent) at col. 15:49-67; Myerson Tr. 588:4-590:9; Zaworotko Tr. 1713:22-1714:3.

After creating an ethanolate of darunavir, Tibotec continued to search for a solid form of darunavir that would not be a solvate. Wigerinck Tr. 332:7-333:16. Tibotec commissioned a study by a third-party contractor to “obtain [darunavir] in a non solvated form,” but its efforts were unsuccessful.' PTX 356 (Solvías Polymorphism Study Report) at PREZ0497447-8; Wigerinck Tr. 333:3-16, 334:25-335:11. Tibotec was never able to find a better formulation than darunavir ethanolate. Wigerinck Tr. 335:9-11.

Before trial, Lupin entered into a so-ordered stipulation stating that it does not dispute infringement of the asserted claims of the '645 Patent (including claim 4) and that “a judgment of infringement ■will be entered against Lupin” as to “any of the Asserted Claims [that] are not invalid....” ECF No. 375.

II. Conclusions of Law

A. Legal Standards for Obviousness, Enablement and Written Description Under the patent statute, a “patent is presumed to be valid, 35 U.S.C. § 282 (1994), and this presumption can only be overcome by clear and convincing evidence to the contrary.” Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1374 (Fed.Cir.2001).

“[O]bviousness is ultimately a question of law....” Boston Scientific Scimed, Inc. v. Cordis Corp., 554 F.3d 982, 990 (Fed.Cir.2009); 35 U.S.C. § 103. That “legal question” is “based on underlying factual determinations,” Unigene Labs., Inc. v. Apotex, 655 F.3d 1352, 1360 (Fed.Cir.2011), which include: “1) the scope and content of the prior art; 2) the level of ordinary skill in the art; 3) the differences between the claimed invention and the pri- or art; and 4) evidence of secondary factors, also known as objective indicia of nonobviousness.” Id. (listing what are called the “Graham factors” from Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966)). “Obviousness requires more than a mere showing that the prior art includes separate references covering each separate limitation in a claim under examination.” Id. (citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007)). “Rather, obviousness requires the additional showing that a person of ordinary skill at the time of the invention would have selected and combined those prior art elements in the normal course of research and development to yield the claimed invention.” Id. Obviousness is judged from the perspective of a hypothetical person of ordinary skill in the art, who is “a person of ordinary creativity, not an automaton.” KSR, 550 U.S. at 421, 127 S.Ct. 1727.

In addition, an “obviousness determination requires that a skilled artisan would have perceived a reasonable expectation of success in making the invention in light of the prior art.” In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1069 (Fed.Cir.2012) (citation omitted). Courts must be aware of the “danger of hindsight bias” in an obviousness analysis. Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1320 (Fed.Cir.2004); see also KSR, 550 U.S. at 421, 127 S.Ct. 1727; Graham, 383 U.S. at 36, 86 S.Ct. 684; In re NTP, Inc., 654 F.3d 1279, 1299 (Fed.Cir.2011).

Challenges to validity based on inadequate written description and enablement require resolution of facts. See Trading Techs. Int’l, Inc. v. Open E Cry, LLC, 728 F.3d 1309, 1318 (Fed.Cir.2013); Wyeth & Cordis Corp. v. Abbott Labs., 720 F.3d 1380, 1384 (Fed.Cir.2013). The written description requirement is satisfied if the patent specification “clearly allowfs] a person of ordinary skill in the art to recognize that [the inventor] invented what is claimed.” Crown Packaging Tech., Inc. v. Ball Metal Beverage Container Corp., 635 F.3d 1373, 1380 (Fed.Cir.2011). The enablement requirement “is met when at the time of filing the application one skilled in the art, having read the specification, could practice the invention without ‘undue experimentation.’ ” Cephalon, Inc. v. Watson Pharms., Inc., 707 F.3d 1330, 1336 (Fed.Cir.2013) (citation omitted). To satisfy the enablement requirement a patent does not need to describe what was known in the art. Epistar Corp. v. ITC, 566 F.3d 1321, 1336-37 (Fed.Cir.2009).

B. The '015 Patent

i. Obviousness

1. Level of Ordinary Skill in the Art

Janssen and Lupin offered separate definitions for a person having ordinary skill in the art. Dr. Paul Reider, on behalf of Janssen, said that a person of ordinary skill in the art would have had a master’s degree in chemistry and several years of laboratory experience. Reider Tr. 2003:4-7. Dr. Bruce Ganem, on behalf of Lupin, opined that a person of ordinary skill in the art would have a Ph.D. in chemistry and work experience in the pharmaceutical industry specifically directed to synthetic chemistry. Ganem Tr. 1001:10-16, 1003:15-1004:12. The Court finds that either of these definitions is satisfactory and that regardless of which is chosen, the analysis herein would be the same. Dr. Reider and Dr. Ganem each stated that their opinions on validity did not depend on the definition of the level of ordinary skill in the art and would be the same under either side’s definition. Reider Tr. 2003:17-20; Ganem Tr. 1006:11-14. The Court adopts Dr. Reider’s broader definition of a person of ordinary skill in the art which the trial evidence has shown to be pragmatically realistic.

2. Scope and Content of the Prior Art

Under Graham, the Court must define the scope and content of the prior art as of September 10, 2001, the priority date of the '015 Patent.- Pre-Trial Order ¶ 35. A reference qualifies as prior art for an obviousness determination under 35 U.S.C. § 103 only when it is analogous to the claimed invention. Innovention Toys, LLC v. MGA Entm’t, Inc., 637 F.3d 1314, 1321 (Fed.Cir.2011). “Two separate tests define the scope of analogous prior art: (1) whether the art is from the same field of endeavor, regardless of the problem addressed and, (2) if the reference is not within the field of the inventor’s endeavor, whether the reference still is reasonably pertinent to the particular problem with which the inventor is involved.” In re Bigio, 381 F.3d 1320, 1325 (Fed.Cir.2004). “A reference is reasonably pertinent if, even though it may be in a different field from that of the inventor’s endeavor, it is one which, because of the matter with which it deals, logically would have commended itself to an inventor’s attention in considering the problem.” In re Clay, 966 F.2d 656, 659 (Fed.Cir.1992).

Janssen identifies seven prior art references that describe methods of making bis-THF:

The Pezechk 1986 Article (PTX 391): This article describes a method for synthesizing bis-THF that starts with dihydrofuran, an achiral cyclic compound virtually identical to the lefthand ring in bis-THF’s double-ring structure. PTX 391 at PREZ05017244-45.

The Ghosh 1994 Article (DTX 91): This article “touts bis-THF” for use as a component for analogs of a protease inhibitor known as saquinavir. Ganem Tr. 1217:15-18, 1196:4-8; DTX 91 at PREZ05005264. The method described, developed by Merck, starts with diethyl malate, a linear, open chain (nom-ring) structure with a chiral center. DTX 91 at PREZ05005263; Ganem Tr. 1159:16-22.

The Ghosh 1995 Article (PTX 222): In this 1995 article, Dr. Ghosh adopted the approach that Pezechk advocated earlier and synthesized bis-THF by starting with dihydrofuran and constructing only a second ring. PTX 222 at 507; Ganem Tr. 1117:11-16.

The Ghosh 1996 Article (PTX 389): This article describes two methods for making bis-THF. Scheme 1 is the diethyl malate route previously disclosed in the Ghosh 1994 Article. PTX 389 at PREZ04989981; Ganem Tr. 1159:16-22. Scheme 2 starts with dihydrofuran and is similar to the route described in the Ghosh 1995 Article. PTX 389 at PREZ04989981.

U.S. Patent No. 7,470,506 (PTX 35): The '506 Patent was filed in 1998. Dr. Erickson is the first named inventor and Dr. Ghosh is one of three co-inventors. Like the Pezechk 1996 Article and various articles by Dr. Ghosh, the '506 Patent teaches a synthesis that starts with dihydrofuran. PTX 35 at Fig. 2.

The Ghosh 1999 Article (PTX 392): This 1999 article also uses dihydrofuran as a starting point, with certain improvements in the method described in Dr. Ghosh’s earlier articles: PTX 392 at PREZ05142935.

The Uchiyama 2001 Article (DTX 790): The route described in this article also starts with dihydrofuran. DTX 790 at 4654-55.

Based on these references, Janssen argues that the prior art taught that a method using bis-THF’s left-hand ring as a starting point was desirable, see PTX 222 (Ghosh 1995 Article) at 506 (describing the method as “convenient,” “efficient,” and “operationally simple”), and that nothing in any prior art reference suggested that this method had any drawbacks or disadvantages. Janssen asserts that the method of claim 1 of the '015 Patent is not identified anywhere in the bis-THF prior art, and that to find prior art that describes these steps of the '015 Patent’s method (involving a protected glyceraldehyde, nitromethane, and the use of a Michael addition reaction and a Nef reaction — reactions used in the claimed method of the '015 Patent), Lupin had to go outside the relevant art and turn to references that do not relate to protease inhibitors in general or to bis-THF in particular.

Lupin argues, however, that a person of ordinary skill in the art would have been motivated to devise an improved synthesis of bis-THF in view of the known drawbacks of prior art syntheses, and that a person of ordinary skill in the art would have been motivated to apply retrosynthetic analysis in order to find an improved synthesis route. Retrosynthetic analysis is a technique originally developed by Nobel laureate Dr. Elias Corey. Ganem Tr. 1011:10-13; see generally DTX 1400 (Corey 1967); DTX 1399 (Corey 1975). The technique involves developing a synthetic scheme by working backwards from a target molecule and in an iterative manner breaking strategic bonds in order to identify a simpler compound. The goal of the technique is to get to a starting material that is commercially available or could be easily prepared from the literatqre along with a set of well-known or otherwise established reactions that then may be used in the forward direction to synthesize the target molecule. Ganem Tr. 1009:4-12, 1013:22-1014:5; Reider Tr. 2138:24-2139:15; DTX 1399 (Corey 1975) at 6117; DTX 1400 (Corey 1967) at 19-21. According to Lupin, a person of ordinary skill in the art applying retrosynthetic analysis would have been led to prior art identifying key starting materials, intermediates and the Michael addition reaction using nitromethane suitable in devising a bis-THF.synthetic scheme. In particular, Lu-pin identifies four references that it argues should be considered prior art, summarized below:

The Patrocinio 1994 and Costa 1997 Articles (DTX 792A and DTX 793A): These articles are two publications from the same laboratory that describe the same study, with Costa providing additional detail. Reider Tr. 2022:2-13. These references identify a protected glyceraldehyde (a synthetically useful chiral building block easily obtained fyom inexpensive D(+)-mannitol) and the use of a Michael addition reaction using nitromethane as a reagent for the transformation of compound (1) to compound (3). Ganem Tr. 1087:2-1088:12.

The Seebach 1979 and Rosini 1988 Articles (DTX 794A and DTX 795A): These articles, specifically referred to in the Patrocinio 1994 and Costa 1997 Articles, describe chemistry performed on a class of compounds known as nitroalkanes. They disclose the Nef reaction (“the transformation of a nitroalkene derivative into a carbonyl derivative,” Kesteleyn Tr. 984:4-10), one of the reactions used in the claimed method of the '015 Patent. Ganem Tr. 1065:23-1067:19.

The Patrocinio 1994, Costa 1997, Seebach 1979, and Rosini 1988 Articles do not mention protease inhibitors in general or bis-THF in particular. Reider Tr. 2022:14-17, 2023:19-22; Ganem Tr. 1191:5-8. The ideas in those references were well known in the art between 1994 and 2001 when the relevant bis-THF art was being developed, but no one in the art turned to their teachings for the synthesis of bis-THF. Ganem Tr. 1070:7-21,1072:6-12, 1118:25-1119:21. When asked by this Court why no one looked to the Patrocinio 1994, Costa 1997, Seebach 1979, and Rosini 1988 Articles in designing routes for synthesizing bis-THF if it was obvious to do so, Dr. Ganem only stated: “It’s possible that they didn’t search for it. I don’t know.” Ganem Tr. 1070:14-18. The Court finds that this testimony demonstrates that it is only with hindsight that one of ordinary skill in the art would have come across these four references.

These four references are not analogous prior art because they would not logically have commended themselves to a person skilled in the art. This Court is not convinced that the retrosynthetic analysis described by Dr. Ganem “unambiguously” leads to these four references, and subsequently to the starting point of the claim 1 synthesis. Ganem Tr. 1186:16-22. Retro-synthetic analysis is a “stimulating tool for creativity” that allows a chemist to consider a wide array of possible synthetic routes. Reider Tr. 2019:21-2020:11. As credibly explained by Dr. Reider, referencing the work by the pioneer of retrosynthetic analysis Dr. Corey, retrosynthetic analysis does not lead unambiguously anywhere, but rather suggests exploration and analysis of a large number of possible routes for creating molecules. Id. Dr. Ganem agreed on cross-examination that “retrosynthetic analysis doesn’t point to one unequivocal choice.” Ganem Tr. 1182:25-1183:3.

Dr. Ganem’s retrosynthetic analysis also improperly relies on hindsight. Real-world evidence demonstrates that retro-synthetic analysis would lead persons of skill in the art to choose dihydrofuran, not a protected glyceraldehyde, as the starting point for synthesizing bis-THF. As Dr. Ganem conceded, the authors of Uchiyama 2001 applied retrosynthetic analysis in developing their synthesis of bis-THF. Id. at 1188:17-1189:22. Their application of retrosynthetic analysis resulted in the selection of dihydrofuran as a starting point. Id.; DTX 790 (Uchiyama 2001 Article) at 4654. Similarly, Tibotec utilized a form of retrosynthetic analysis by studying various ways of breaking the bonds of bis-THF to arrive at different synthetic routes, and that analysis led to the dihydrofuran method taught in the prior art. Reider Tr. 2010:21-2011:17; PTX 404 (Tibotec Progress Report).

In sum, retrosynthetic analysis provides no reason to search out or come across the Patrocinio 1994, Costa 1997, Seebach 1979, or Rosini 1988 Articles. They are random references that have nothing to do with bis-THF, darunavir, protease inhibitors or HIV/AIDS drugs. As Dr. Ganem conceded, these references were available before Ghosh’s work, but neither Dr. Ghosh — who had studied with Dr. Corey, the pioneer of retrosynthetic analysis, at Harvard — nor anyone else in the art used those references in a method for making bis-THF. Ganem Tr. 1070:10-18, 1118:25-1119:18. The only explanation for pulling these references out of the vast sea of chemistry literature is the knowledge — obtained from working backwards from the '015 Patent— that they can be tacked together to recreate the process that Tibotec created. As a result, the scope and content of the prior art is limited to the seven references that- Janssen identifies.

3. Differences between the Asserted Claims and the Prior Art

This Court finds that the process described in claim 1 for making bis-THF is unlike the processes for making bis-THF described in the prior art. The process of claim 1 starts with a protected glyceraldehyde (referred to in the '015 Patent as compound (1)), which does not contain either of bis-THF’s rings. That compound is then transformed using nitromethane to a compound referred to as compound (3). Compound (3) is further transformed, in part by the use of a Nef reaction, to a compound referred to as compound (6). In the final step of the claimed process, compound (6) is transformed via an intramolecular eyclization reaction to form the second ring of bis-THF. The result is compound (7), or bis-THF. See Reider Tr. 2018:6-2019:2. The claim 1 process is “counterintuitive” and “dramatically” different from the prior art methods. Reider Tr. 2013:24-2014:1, 2025:1-5. This Court finds that claim 1 would not have been obvious to a person of ordinary skill in the art.

Using a protected glyceraldehyde (compound (1) of the '015 Patent) as the starting point for synthesizing bis-THF was “counterintuitive” and not obvious. Reider Tr. 2013:22-2014:21. Unlike the routes described in the prior art that start with a molecule containing bis-THF’s lefthand ring, the claim 1 process starts with a compound that contains neither of the bis-THF rings, which means that both of the bis-THF rings have to be created, instead of only one. See Reider Tr. 2009:21-2010:16; Ganem Tr. 1117:17-24. There were also other drawbacks to starting with a protected glyceraldehyde — it is “not commercially available in scale. It’s not stable, and it has chirality in it from the very beginning at the center.” Reider Tr. 2012:13-24. For these reasons, a person of ordinary skill in the art would not have chosen a protected glyceraldehyde as the starting point for making bis-THF. Reid-er Tr. 2019:10-13. There would have been no reason, other than hindsight, for a person of ordinary skill to pick the Patrocinio and Costa references from the large library of chemical literature and to select a protected glyceraldehyde as a starting point for making bis-THF.

To resay, Dr. Ganem’s retrosynthetic analysis is not persuasive. Real-world evidence, rather than conjecture in court testimony, demonstrates that restrosynthetic analysis would lead persons of ordinary skill in the art to choose dihydrofuran, not a protected glyceraldehyde, as the starting point for synthesizing bis-THF. As Dr. Ganem conceded, the authors of the Uchiyama 2001 Article applied retrosynthetic analysis in developing their synthesis of bis-THF, Ganem Tr. 1188:17-1189:22, and their application resulted in the selection of dihydrofuran as a starting point. Id.; DTX 790 (Uchiyama 2001 Article) at 4654. Similarly, in designing its program to synthesize bis-THF, Tibotec utilized a form of retrosynthetic analysis — that is, studying various ways of breaking the bonds of bis-THF to arrive at different synthetic routes. Again, that analysis led to the dihydrofuran method taught in the prior art, and Tibotec worked with that method before developing the method claimed in the '015 Patent. Reider Tr. 2010:21-2011:17; PTX 404 (Tibotec Progress Report).

Lupin attempts to turn the scope of the claim into an issue in its obviousness case by pointing out that claim 1 is not limited to an industrial scale synthesis. The '015 Patent’s value is that it allows the manufacture of bis-THF on an industrial scale, but the full scope of the claim is very different from anything in the prior art, no matter how it is analyzed. The prior art taught starting with dihydrofuran and then making bis-THF’s other ring and it discouraged making both rings from scratch. The prior art taught starting with a commercially available, stable compound that was achiral. This is true whether on a laboratory scale or an industrial scale. And the prior art provided no motivation to change the known methods, whether for laboratory scale or industrial scale synthesis. Dr. Ganem admitted that “nothing in the prior art stated that there was any problem with the Ghosh synthesis based on ozonolysis,” at “any scale.” Ganem Tr. 1207:19-24. It follows that one of skill in the art would have seen no reason to modify the Ghosh dihydrofuran route, whether for laboratory or industrial use.

4. Secondary Considerations

The last of the Graham factors directs the Court’s attention to secondary considerations, or “objective indicia of nonobviousness.” Graham, 383 U.S. at 17-18, 86 S.Ct. 684. “Objective indicia of nonobviousness play a critical role in the obviousness analysis.” Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed.Cir.2013). “Objective indicia ‘can be the most probative evidence of nonobviousness in the record, and enables the court to avert the trap of hindsight.’ ” Id. (citation omitted).

a. Failure of others

Janssen first asserts that the failure of others in finding an improved synthesis route for bis-THF, particularly one that could be used on an industrial scale, goes to the nonobviousness of the '015 Patent. Janssen states that Dr. Ghosh, a chemist of “greater than ordinary skill,” Ganem Tr. 1201:20-22, was unable to create a commercially viable synthesis. Dr. Ghosh described his initial method, which he worked on while at Merck and which is discussed in the Ghosh 1994 Article (DTX 91), as “not a very good step.” Ghosh Tr. 2457:21-22. He said that “nobody in [his] right mind would launch a project based upon this literature ... when they see the synthesis [is] so complex.” Id. at 2457:24-2458:2.

Janssen states that over the next seven years, Dr. Ghosh and others attempted to develop improved processes for making bis-THF. Dr. Ghosh’s work is described in the Ghosh 1995 Article (PTX 222), the Ghosh 1996 Article (PTX 389), the '506 Patent (PTX 35), and the Ghosh 1999 Article (PTX 392). In 2001, Dr. Uchiyama also tried to improve the synthesis. DTX 790 (Uchiyama 2001 Article). Tibotec determined that the method described in these references was useful only on a laboratory scale, DTX 7 ('015 Patent) at col. 2:22-24, and that the batting average for these prior art attempts to improve the synthesis was “pretty pathetic.” Ganem Tr. 1197:23-1198:2, 1201:7-10, 1217:18-21. Janssen claims that the Tibotec inventors succeeded where others had failed by developing a novel method of manufacturing bis-THF that is suitable for synthesis on both a laboratory and on an industrial scale. Reider Tr. 2009:4-8; Wigerinck Tr. 266:10-12.

Lupin responds that none of the prior art syntheses of bis-THF reflect a “failure of others,” but rather reflect a successful effort on the part of the researchers to synthesize bis-THF, albeit on a small scale. Ganem Tr. 1104:5-11.

This Court finds that the “failure of others” to create a commercially available synthesis of bis-THF weighs against a finding of obviousness as to claim 1 of the '015 Patent. It is clear to the Court that in the time period between 1994, when Ghosh published the synthesis route he had worked on at Merck, and 2001 when Tibotec discovered the patented process, there indeed was a failure of others to synthesize bis-THF on a commercial scale. See generally PTX 222 (Ghosh 1995 Article); PTX 389 (Ghosh 1996 Article); PTX 35 ('506 Patent); PTX 392 (Ghosh 1999 Article). The Court finds Lupin’s disingenuous argument about these prior art references, which were obviously working toward a synthesis that could actually be used in commercial production and subsequently in a pharmaceutical product, rather than only on a laboratory scale, utterly unpersuasive.

b. Commercial success

Next, Janssen argues that the commercial success of Prezista is a secondary factor that weighs against a finding of obviousness. Janssen asserts that bis-THF is a key component of the darunavir molecule in Prezista, Wigerinck Tr. 191:11-17; Reider Tr. 2025:8-13, and that since its introduction, Prezista has been a huge success, with approximately one million prescriptions annually. Stoffels Tr. 104:12-16,105:18-20,108:13-17,112:1-11. Worldwide sales of Prezista in 2013 were more than $1.6 billion and U.S. sales were more than $800 million. Leffler Tr. 2288:21-24, 2311:9-15; Stoffels Tr. 112:12-14. Prezista is “the number-one selling protease inhibitor.” Leffler Tr. 2311:22-2312:3. Sales figures and market data are strong evidence of commercial success. See Tec Air, Inc. v. Denso Mfg. Mich., Inc., 192 F.3d 1353, 1360-61 (Fed.Cir.1999).

Lupin responds by arguing that Janssen’s general allegations of commercial success lack a specific nexus to the process steps required by claim 1 of the '015 Patent. See In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed.Cir.2011) (“Where the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention.”). Lupin asserts that when it comes to why doctors prescribe Prezista, the particular process by which darunavir is made, including the process used to make bis-THF, has never been shown to be clinically relevant. Zingman Tr. at 861:16-25. In support, Lupin asserts that Janssen has never marketed that Prezista includes a bis-THF group, Falcon Tr. 2494:15-17, and also makes clear that bis-THF alone has weak pharmacologic activity and that it has not been approved by the FDA for any clinical use. Wigerinck Tr. 463:3-20; Reider Tr. 2210:10-12.

This Court is unpersuaded by Lupin’s argument of lack of nexus and finds that the secondary consideration of commercial success weighs against a finding of obviousness. Prezista could never have been launched as a commercial product — let alone become the success it has become— without a method for making bis-THF suitable for manufacture in industrial scale quantities. Leffler Tr. 2322:16-20. Bis-THF is a critical component of darunavir, accounting for 90 percent of the cost of manufacture. Wigerinck Tr. 279:20-25. Janssen uses the process of claim 1 of the '015 Patent to manufacture the bis-THF in Prezista. Reider Tr. 2025:8-15. This Court finds that there is a nexus between Prezista’s commercial success and the claim 1 invention. See Tec Air, 192 F.3d at 1360-61 (finding a nexus between a product’s commercial success and a patent on a method used to manufacture a component of the product); Akzo N.V. v. Int’l Trade Comm’n, 808 F.2d 1471, 1481 (Fed.Cir.1986) (finding commercial success where a product made by a patented method was commercially successful).

The Court finds no merit in Lupin’s lack of nexus argument that doctors do not make prescription decisions based on the method of manufacturing bis-THF, Zing-man Tr. 890:3-6, or its argument that Janssen does not promote the presence of bis-THF in darunavir in its marketing materials, Falcon Tr. 2494:15-17. Assuming that these contentions are trué, they do not detract from the causal nexus between the method of making bis-THF and Prezista’s commercial success. The success of darunavir, and Prezista, is attributable to multiple factors, with the manufacturing processes as critical steps in the chain of success. Stoffels Tr. 136:18-20 (“[W]e never would have had the drug if we didn’t develop the drug and had invested over a billion dollars in this molecule.”).

Because there is a nexus between claim 1 of the '015 Patent and the commercial success of Prezista, which was demonstrated at trial to be quite significant, this secondary consideration weighs against a finding of obviousness.

c. Praise and industry acceptance

Praise and industry acceptance provide additional evidence of nonobviousness. See Power-One, Inc. v. Artesyn Techs., Inc., 599 F.3d 1343, 1352 (Fed.Cir.2010) (praise); Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1574 (Fed.Cir.1996) (industry acceptance). Prezista has received widespread praise: the guidelines for treating AIDS patients that are promulgated by the U.S. Department of Health and Human Services list Prezista as one of only two “preferred” protease-inhibitor based regimens for treating HIV/AIDS. PTX 592 (Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents) at F-4. This is the “highest possible recommendation” in the guidelines. Zingman Tr. 908:7-909:3. Prezista’s acceptance among physicians is reflected by it being the leading protease inhibitor for treating AIDS. Leffler Tr. 2312:2-3. As with commercial success, none of this would have been possible without the method of making bis-THF that the '015 Patent describes and claims.

Lupin expresses the exact same lack of nexus arguments as it did with regard to commercial success. For the same reasons, the Court finds a causal nexus between claim 1 of the '015 Patent and the praise and industry acceptance of Prezista. The Court finds the showing Janssen made as to praise and industry acceptance persuasive such that these secondary factors also weigh against a finding of obviousness.

d. Copying

Finally, Janssen asserts that Lupin and Teva both copied the '015 invention and argues that such copying is another objective indicium of non-obviousness. Reider Tr. 2027:16-2028:20. Lupin and Teva both admitted using the method of claim 1 of the '015 Patent to manufacture bis-THF for their respective ANDA products. Summ. J. Op. at 54.

Lupin counters that in the context of Hatch-Waxman cases, the Federal Circuit has deemed evidence of copying by generic manufacturers to be “not probative of nonobviousness because a showing of bioequivalence is required for FDA approval.” Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1377 (Fed.Cir.2013); see also Mitsubishi Chem. Corp. v. Barr Labs., Inc., 718 F.Supp.2d 382, 443-44 (S.D.N.Y.2010) (“[C]opying bears little weight on its own as an objective indicator of non-obviousness in the context of generic drugs. The burdensome NDA [New Drug Application] procedures provide generic drug manufacturers with an incentive to copy an already approved drug, so that they can avail themselves of the less burdensome ANDA procedure of the Hatch-Waxman Act.”). Lupin is correct, and as such the Court will not consider this secondary consideration of nonobviousness.

5. Conclusion: The '015 Patent was not obvious

This Court finds that claim 1 of the '015 Patent would not have been obvious to one of ordinary skill in the art under 35 U.S.C. § 103. Lupin has fallen well short of its mandate to provide evidence to support “ ‘an abiding conviction’ ” that any of its factual contentions are “ ‘highly probable.’” ActiveVideo, 694 F.3d at 1327 (quoting Colorado v. New Mexico, 467 U.S. at 316, 104 S.Ct. 2433). Rather, Lupin’s case amounts only to a hindsight reconstruction of the invention.

In asserting that a retrosynthetic analysis would have “unambiguously” led a person of ordinary skill in the art to the starting point used in claim 1 of the '015 Patent, Dr. Ganem was improperly relying on hindsight. Dr. Ganem analogized his analysis to using a roadmap to find his way to his goal, Ganem Tr. Í009:19-1010:5-that is improper use of hindsight. When used to prove that an invention is obvious, working backwards presents a clear risk of hindsight. This Court is not aware of any case in which a court relied on retrosynthetic analysis as part of an obviousness analysis.

Secondary considerations provide additional evidence pf nonobviousness. Here the objective considerations all confirm the nonobviousness of the '015 invention: failure by others, see DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1328 (Fed.Cir.2009); commercial success, Tec Air, 192 F.3d at 1360-61; praise and industry acceptan