Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW T. JOHN WARD, District Judge. I. INTRODUCTION This is a consolidation of four patent infringement suits brought by Plaintiff Allergan, Inc.’s (“Allergan”) pursuant to the Hatch-Waxman Act. See Drug Price Competition and Patent Term Restoration Act, which is commonly referred to as the Hatch-Waxman Act, in 1984. Pub. L. No. 98-417, 98 Stat. 1585. Defendants Sandoz, Inc. (“Sandoz”); Alcon Laboratories, Inc., Alcon Research, Ltd., Alcon, Inc., and Falcon Pharmaceuticals, Ltd. (“Alcon”); Apotex, Inc. and Apotex Corp. (“Apotex”); and Watson Laboratories, Inc. (“Watson”) (collectively “Defendants”) are each seeking approval from the Food and Drug Administration (“FDA”) to market generic copies of Allergan’s Combigan® product, used for the treatment of glaucoma and ocular hypertension. In this consolidated action, Allergan alleges that Defendants’ proposed generic pharmaceutical products infringe the asserted claims of United States Patent Nos. 7,030,149 (“the '149 patent”); 7,320,976 (“the '976 patent”); 7,323,463 (“the '463 patent”); and 7,642,258 (“the '258 patent”) (collectively, the “patents-in-suit”). The Court held a four-day bench trial in the case on August 2, 2011 through August 5, 2011. Pursuant to Fed.R.Civ.P. 52, and after having considered the entire record in this case and the applicable law, the Court concludes that: (1) each of the Defendants infringe claim 4 of the '149 Patent, claim 1 of the '976 patent, claims 1-6 of the '463 Patent, and claims 1-9 of the '258 Patent; and (2) the patents-in-suit are not invalid. These findings of fact and conclusion of law are set forth in further detail below. The Court’s findings of fact are based on the admissible evidence. Any finding of fact that is actually a conclusion of law should be treated as such. Any conclusion of law that is actually a finding of fact should be treated as such. II. FINDINGS OF FACT A. The Parties 1. Allergan, Inc. is a Delaware corporation with its principal place of business at 2525 Dupont Drive, Irvine, California 92612. 2. Sandoz Inc. is a Colorado corporation with its principal place of business at 506 Carnegie Center, Suite 400, Princeton, New Jersey 08540. 3. Alcon Laboratories, Inc. is a Delaware corporation, with a place of business in Texas. 4. Alcon Research, Ltd. is a Delaware corporation, with a place of business in Texas. 5. Alcon, Inc. no longer exists, based on a merger with Novartis AG. 6. Falcon Pharmaceuticals, Ltd. is a Texas corporation, with a place of business in Texas. 7. Apotex, Inc. is a Canadian corporation with a place of business at 150 Signet Drive, Toronto, Ontario, Canada M9L 1T9. 8. Apotex Corp. is a Delaware corporation with its principal place of business at 2400 North Commerce Parkway, Suite 400, Weston, Florida, 33326. 9. Watson Laboratories, Inc. is a Nevada corporation with a place of business at 400 Interpace Parkway, Parsippany, NJ 07054. B. Glaucoma and Ocular Hypertension 10. Glaucoma is an incurable disease of the eye that causes gradual damage to the optic nerve resulting in vision loss that, ultimately, can lead to blindness. (D.I. 238, Trial Tr. Day 1(AM) at 51:24-52:2; 52:21-53:7 (Whitcup).) About 2 million people in the United States are diagnosed with glaucoma every year. (Id. at 52:7-10 (Whitcup).) 11. While incurable, glaucoma can be managed by pharmaceutical and surgical treatment options that slow the progression of the disease. (D.I. 242, Trial Tr. Day 3(AM) at- 71:4-9 (Noeeker).) One such treatment option is to use medication to lower the intraocular pressure (“IOP”) in the eye. (Id. at 72:20-73:7 (Noeeker).) Scientists and medical professionals believe that the elevated IOP found in glaucoma patients contributes to the gradual retinal deterioration and loss of vision that are characteristics of the disease. (D.I. 238, Trial Tr. Day 1(AM) at 53:15-21; 54:10-21 (Whitcup); D.I. 242, Trial Tr. Day 3(AM) at 66:3-15 (Noeeker).) Intraocular pressure is measured in millimeters of mercury (“mm Hg”). (D.I. 242, Trial Tr. Day 3(AM) at 66:3-8 (Noeeker).) For each millimeter of mercury IOP is lowered, patients are 10% less likely to suffer visual field loss. (Id. at 67:14-18 (Noecker).) 12. Patients suffering from ocular hypertension (“OHT”) also have elevated IOP and, although not diagnosed with glaucoma, must be observed closely for its onset. (D.I. 242, Trial Tr. Day 3(AM) at 66:21-67:25 (Noeeker).) These patients can utilize the same pharmaceutical and surgical options used by glaucoma patients to attempt to reduce IOP. (Id. at 71:4-9 (Noeeker).) C. Treatment of Glaucoma and Ocular Hypertension with Brimonidine and Timolol 13. One treatment method for patients with glaucoma or ocular hypertension is the use of eye drops. This form of treatment is the most convenient and acceptable to patients. (D.I. 242, Trial Tr. Day 3(AM) at 71:4-9; 81:20-84:25 (Noeeker).) 14. There are at least 20 different glaucoma drugs on the market today that can be used in such treatments. (D.I. 238, Trial Tr. Day 1(AM) at 54:22-55:5 (Whitcup).) Those that are commonly used in clinical practice fall into several different classes of medication, and have different mechanisms of action. (D.I. 240, Trial Tr. Day 2(AM) at 50:10-18; (Tanna); D.I. 242, Trial Tr. Day 3(AM) at 72:6-78:8 (Noecker).) Most relevant here are two classes of medication, alpha2 adrenergic agonists and so-called “beta blockers.” 15. Brimonidine tartrate 0.2% was marketed by Allergan as Alphagan®, and was first developed by Allergan as a new glaucoma medication in the late 1980s and early 1990s. (D.I. 239, Trial Tr. Day 1(PM) at 75:8-10 (Batoosingh).) Brimonidine is an alphas adrenergic agonist that lowers IOP in glaucoma patients by reducing fluid production in the eye while also increasing outflow of that fluid from the eye. (D.I. 238, Trial Tr. Day 1(AM) at 59:22-60:7 (Whitcup); D.I. 239, Trial Tr. Day 1(PM) at 74:14-75:7 (Batoosingh).) The FDA approved Alphagan® in 1996. (D.I. 239, Trial Tr. Day 1(PM) at 75:8-10 (Batoosingh).) 16. Unlike many glaucoma medications, which are dosed twice a day (once in the morning and once in the evening, i.e., “BI”) or once a day (once in the morning or evening, i.e., “QD”), the FDA only approved Alphagan® for dosing three times a day (i.e., “TID”) due to a lowered efficacy of the drug with less frequent dosing. (PTX-75 at AGN-COMBI0478532; D.I. 238, Trial Tr. Day 1(AM) at 60:11-24 (Whiteup); D.I. 239, Trial Tr. Day 1(PM) at 75:11-89-19 (Batoosingh).) As explained further below, BID dosing with Alphagan® 0.2% results in an approximately 3.25 to 3.5 mm Hg higher IOP in the afternoon than TID. (D.I. 239, Trial Tr. Day 1(PM) at 79:24-80:4 (Batoosingh); DTX-137 at DEFS(B/T) 000346; PTX-134 at AGN_COMBI0676465; D.I. 241, Trial Tr. Day 2(PM) at 4:24-5:19.) This difference is both numerically significant and clinically relevant. (D.I. 239, Trial Tr. Day 1(PM) at 80:5-8 (Batoosingh); D.I. 241, Trial Tr. Day 2(PM) at 5:10-19 (Tanna).) This was referred to at trial as the “afternoon trough.” (D.I. 239, Trial Tr. Day 1(PM) at 77:13-17; 78:3-7 (Batoosingh).) 17. Although this third recommended dose, along with a substantial incidence of allergy, was a significant drawback of brimonidine, it still achieved commercial success as a therapy for glaucoma patients. (D.I. 239, Trial Tr. Day 1(PM) at 90:16-91:10 (Batoosingh).) Allergan attempted to secure FDA approval for Alphagan® as a BID drug but was unable to do so. (Id. at 75:14-20 (Batoosingh).) 18. Upon Alphagan®’s introduction to the market, it was apparent that brimonidine 0.2% had significant and problematic side-effects that limited its utility. (D.I. 239, Trial Tr. Day 1(PM) at 90:6-91:10 (Batoosingh).) Brimonidine 0.2% was found to cause a high rate of ocular allergy, which led patients to discontinue using the drug. (Id.) Once a patient develops an allergy to brimonidine, brimonidine is no longer available as a treatment option for that patient. (D.I. 242, Trial Tr. Day 3(AM) at 74:11-16 (Noecker).) Additionally, brimonidine was also known to cause systemic side effects, including somnolence and dry mouth. (D.I. 239, Trial Tr. Day 1(PM) at 90:6-91:10 (Batoosingh).) The high incidence of these various side effects in patients treated with brimonidine monotherapy is reported throughout the literature. (See, e.g., PTX-180 at AGN_COMBI0677278; PTX-77 at AGN-COMBI0481545.) 19. These side effects of Alphagan® were so significant that, as soon as Alphagan® was approved, Allergan began looking for a way to ameliorate them. After Alphagan®’s approval, Allergan began working on developing a better product, ultimately developing two products with lower concentrations of brimonidine that reduced many of problems that had been seen with Alphagan®. (D.I. 239, Trial Tr. Day 1(PM) at 91:11-23 (Batoosingh).) These products were known as Alphagan® P 0.15% and 0.1%. 20. As with Alphagan®, Allergan attempted to secure FDA approval for BID dosing for Alphagan® P. (D.I. 239, Trial Tr. Day 1(PM) at 92:15-20 (Batoosingh).) This effort was unsuccessful, and both Alphagan® P 0.15%, and Alphagan® P 0.1%, were approved only for TID dosing. (PTX-75; D.I. 239, Trial Tr. Day 1(PM) at 91:24-92:14 (Batoosingh).) Allergan received approval for Alphagan® P 0.15% and Alphagan® P 0.1% in 2001 and 2006, respectively. (PTX-75; D.I. 239, Trial Tr. Day 1(PM) at 92:21-22 (Batoosingh); D.I. 242, Trial Tr. Day 3(AM) at 12:14-18 (Le-Cause).) Alphagan® P 0.15% was approved on March 16, 2001, over a year before the filing date of the patents-in-suit. (D.I. 243, Trial Tr. Day 3(PM) at 79:17-25 (Noecker).) Clinical studies on Alphagan® P 0.15% showed that it was significantly less likely to cause allergic reactions and certain systemic side-effects than was original Alphagan®. (D.I. 242, Trial Tr. Day 3(AM) at 138:1-13 (Noecker).) 21. Timolol, a beta-blocker, was developed by Merck in the 1970s. The FDA first approved it as a treatment for glaucoma in 1978. (D.I. 241, Trial Tr. Day 2(PM) at 58:22-25 (Tanna).) Timolol is typically prescribed either once or twice daily. (D.I. 240, Trial Tr. Day 2(AM) at 95:14-15 (Tanna).) Timolol lowers IOP by suppressing aqueous humor production. (D.I. 242, Trial Tr. Day 3(AM) at 81:11-19 (Noecker).) 22. Although timolol is an established and commonly used drug, it is known to have serious and potentially life-threatening side effects, including pulmonary and cardiovascular side-effects. (D.I. 243, Trial Tr. Day 3(PM) at 125:25-127:11; 129:5-18 (Laskar).) Timolol is known to slow both heart and respiratory rates, and to lower blood pressure. (DTX-135 at 1960 (stating that the systemic absorption of beta-blockers like timolol “can produce significant side effects such as bradycardia, arrhythmias, bronchoconstriction, or bronchospasm as a result of interaction with the beta! and betag receptors in the heart, lungs, and blood vessels. The use of non-selective beta-blocker therapy is contraindicated in patients with actual or suspected cardiovascular or pulmonary dysfunction as beta-blockers can produce further arrhythmias or bronchospasm.”); DTX 123 at 1:64-67; DTX 157 at 45-46; D.I. 243, Trial Tr. Day 3(PM) at 125:25-127:11 (Laskar).) 23. Because of these side effects, treatment with timolol is contraindicated in a number of patients. (D.I. 242, Trial Tr. Day 3(AM) at 74:17-75:20 (Noecker).) For example, the label of the Alphagan® products contains the following warning about using brimonidine with a beta-blocker like timolol: However, since alpha-agonists, as a class, may reduce pulse and blood pressure, caution in using concomitant drugs such as beta-blockers (ophthalmic and systemic), antihypertensives and/or cardiac glycosides is advised. (DTX-129 at DEFS(B/T) 000233.) D. Glaucoma Treatment with Multiple Medications: Fixed and Unfixed Combinations 24. Although there are many individual medications available, for many patients, one glaucoma medication is not enough to treat their disease effectively. (D.I. 238, Trial Tr. Day 1(AM) at 54:22-55:17 (Whitcup).) For patients whose glaucoma cannot be effectively controlled with a single drug, the most common form of treatment is the serial or concomitant administration of two or more different medications, provided in two or more separate bottles, at least several minutes apart to prevent one of the drops from washing the other out. (D.I. 238, Trial Tr. Day 1(AM) at 55:1-56:2; 56:14-57:16 (Whitcup).) 25. This type of treatment is referred to by various terms, including adjunctive, concomitant, or serial therapy, and the combination of the products is considered “unfixed” because the amount the patient gets of each drug at any particular time is dependent on the treatment regimen prescribed by the doctor and on whether the patient properly administers the drugs. (D.I. 239, Trial Tr. Day 1(PM) at 64:10-66:3 (Batoosingh).) By contrast, a “fixed combination” combines two glaucoma drugs in the same bottle. (D.I. 240, Trial Tr. Day 2(AM) at 17:21-18:3 (Tanna).) It is “fixed” because the patient gets the same amount of each drug each time a drop of the combination is delivered to the eye. (D.I. 239, Trial Tr. Day 1(PM) at 64:10-24 (Batoosingh).) 26. There are advantages to using unfixed combinations over fixed combinations. For example, if a patient needs a smaller dose of one medication, a physician can prescribe a smaller dose of that medication without modifying the dose of the other. Unfixed combinations thus give physicians wide flexibility in treatment options. (D.I. 239, Trial Tr. Day 1(PM) at 64:10-20 (Batoosingh); D.I. 240, Trial Tr. Day 2(AM) at 132:14-133:3 (Tanna); D.I. 242, Trial Tr. Day 3(AM) at 79:7-18 (Noecker).) 27. Serial or concomitant administration of two drugs is different than administering them in a fixed combination. (D.I. 238, Trial Tr. Day 1(AM) at 56:14-57:19 (Whitcup).) When two ophthalmic products are used together in a concomitant regimen, they do not interact in a patient’s eye. The human eye maintains only a small volume of liquid, approximately 10 microliters, on its outer surface. Eye-drops (about 35-40 microliters) are absorbed or drain away quickly through the eye’s drainage ducts. (Id.; D.I. 242, Trial Tr. Day 3(AM) at 64:24-65:3 (Noecker) (“And then the biggest problem is the window of delivery. It’s there, you blink a bunch, and the eye is gone. So you have about a minute to get this right and get it into the eye. So if you’re a little slow out of the gate, it’s gone.”).) Thus, under recommended dosing, which requires administration of drugs in an adjunctive regimen at least five minutes apart, the second administered drug given as part of an adjunctive regimen would not interact with the first administered drug. (D.I. 238, Trial Tr. Day 1(AM) at 57:13-16 (Whitcup).) 28. Because serial therapy with an unfixed combination can necessitate application of five or more separate doses throughout the day, compliance can be difficult. (D.I. 239, Trial Tr. Day 1(PM) at 64:25-66:6 (Batoosingh).) Most patients, particularly the elderly (who are most susceptible to developing glaucoma), fail to comply with such demanding dosing regimens. (D.I. 240, Trial Tr. Day 2(AM) at 15:2-16:3 (Tanna).) As a consequence, their disease is not adequately treated and may progress more rapidly than it would with proper treatment. 29. Although, in theory, the problem of patient compliance could be addressed by the use of fixed combinations, historically, they have been difficult to develop. As of 2001, there was only one marketed, FDA-approved fixed combination, Cosopt®. (D.I. 238, Trial Tr. Day 1(AM) at 68:6-12 (Whitcup).) Alcon’s Betoptic® Pilo fixed combination product was approved in 1997 but was never marketed. (PTX-129 at AGN_COMBI06762992; D.I. 238, Trial Tr. Day 1(AM) at 68:13-25 (Whitcup).) As Dr. Whitcup described, development of a fixed combination is the “most difficult” task in ophthalmological drug development. (D.I. 238, Trial Tr. Day 1(AM) at 65:19-23 (Whitcup).) 30. The FDA has repeatedly expressed skepticism about fixed combination products and has set a high bar for approval. In the early 2000s, the FDA referred to the clinical results it had seen with fixed combination products as “very disappointing,” and the applications for several different combination ophthalmic products at that time remained pending and unapproved. (PTX-129 at AGNCOM-BI0672993 (quoting the FDA’s Dr. Wiley Chambers as saying that the results for combination products “ha[ve] been very disappointing to a number of people including myself’); PTX-53 at AGN_COM-BI0437800 (“Dr. Chambers did say he thinks the results with the combination drops have been ‘terribly disappointing.’ ”); D.I. 238, Trial Tr. Day 1(AM) at 89:18-91:11 (Whitcup).) Despite the fact that there are at least 20 different glaucoma drugs on the market, almost all of which are used in one unfixed combination or another, there are only two fixed combination glaucoma products currently approved and sold for glaucoma treatment in the United States — Cosopt® and the product at issue in this litigation, Combigan®. (D.I. 238, Trial Tr. Day 1(AM) at 54:22-55:5; 68:6-12 (Whitcup).) E. The Patents-in-Suit 31. The patents-in-suit are U.S. Patent Nos. 7,030,149 (“the '149 patent”); 7,320,-976 (“the '976 patent”); 7,323,463 (“the '463 patent”); and 7,642,258 (“the '258 patent”). The effective filing date for each of the patents-in-suit is April 19, 2002. (See JTX 1, JTX 2, JTX 3, and JTX 4 at p. 1.) 32. The named inventors of the patents-in-suit are Chin-Ming Chang, Gary J. Beck, Cynthia C. Pratt, and Amy L. Batoosingh. (JTX 1, JTX 2, JTX 3, and JTX 4 at p. 1.) 33. The four patents-in-suit generally relate to a fixed combination composition of 0.2% brimonidine and 0.5% timolol, a method of treating glaucoma or ocular hypertension by administering the aforementioned composition twice daily, or an article of manufacture comprising packaging material indicating that twice daily administration of the composition is useful for treating glaucoma or ocular hypertension. (See JTX 1-4.) Like the brimonidine tartrate and timolol maleate single agent products (Alphagan® and Timoptic®), the combination product of the patents-in-suit is applied topically to the eye. (See e.g., JTX 1 at Abstract.) 34. The patents-in-suit also describe suitable preservatives for the combination product. (See id. at col. 2, II. 29 et seq.) The patents-in-suit list BAK as the first such preservative. The patents-in-suit acknowledge that “typically such preservatives are employed at a level of from 0.004% to 0.02%”. (Id.) The patents-in-suit further state that the preservative, preferably BAK, “may be employed at a level of from 0.001% to less than 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% by weight.” (Id.) 35. The '149 patent issued on April 18, 2006, and is titled “Combination of Brimonidine and Timolol for Topical Ophthalmic Use.” The application for the '149 patent was filed on April 19, 2002. (JTX 1 at p. 1.) The '149 patent has four claims to methods of treating glaucoma or ocular hypertension with a 0.2% brimonidine tartrate/0.5% timolol formulation administered twice a day. Claims 1-3, as construed by the Court, require that combination treatment to be as effective as serial administration with 0.2% brimonidine 3 times a day and 0.5% timolol twice a day. The Court granted summary judgment of non-infringement to Defendants of claims 1 through 3 before trial. Claim 4 of the '149 patent covers the improvement in the prior three times a day brimonidine therapy “without loss of efficacy” whereby the brimonidine is combined with timolol in twice daily dosing. (JTX-1.) As construed by the Court in its Markman order, “without loss of efficacy” means “without decrease in lowering intraocular pressure (IOP).” (D.I. 151 at 20-21.) 36. The '976 patent issued on January 22, 2008, and is titled “Combination of Brimonidine and Timolol for Topical Ophthalmic Use.” The application for the '976 patent was filed on October 14, 2003, and is a continuation of the application for the '149 patent. (JTX 2 at p. 1.) The '976 patent has one claim to a method of treating glaucoma or ocular hypertension with a therapeutically effective amount of a formulation containing 0.2% brimonidine tartrate and 0.5% timolol administered twice a day. (JTX-2.) 37. The '463 patent issued on January 29, 2008, and is titled “Combination of Brimonidine and Timolol for Topical Ophthalmic Use.” The application for the '463 patent was filed on February 3, 2003, and is a division of the application for the '149 patent. (JTX 3 at p. 1.) The '463 patent has six claims to compositions containing 0.2% brimonidine tartrate and 0.5% timolol and articles of manufacture containing these compositions along with packaging material indicating use twice a day for glaucoma treatment. (JTX-3.) 38. The '258 patent issued on January 5, 2010, and is titled “Combination of Brimonidine and Timolol for Topical Ophthalmic Use.” The application for the '258 Patent was filed on August 24, 2007, and is a continuation-in-part of the application for the '976 patent. (JTX 4 at p. 1.) The '258 patent also has nine claims to certain compositions containing 0.2% brimonidine tartrate and 0.5% timolol and articles of manufacture that include those compositions. (JTX-4.) 39. The claims of the patents-in-suit all have an effective filing date of April 19, 2002. 40. -The '149, '976, and '463 patents provide two examples, one relating to the formulation of the combination product and the second to a clinical study using the combination product. 41. Example I of the patents-in-suit describes what is stated to be a representative pharmaceutical composition of the invention. As set out in the corresponding Table, the composition includes mono and dibasic sodium phosphate as buffers, sodium hydroxide and hydrochloric acid to adjust pH, if necessary, and BAK as the preservative. 42. The '149, '976, and '463 patents share a common specification, and the '258 patent is a continuation-in-part of the '149 patent. The specification of the '258 patent is the same as the specifications of the '149, '976, and '463 patents, but adds two additional Examples. (See Trial Tr. Day 2(PM) at 45:24-46:3; 46:12-14 (Laskar).) The new Example II in the '258 patent is the same as the composition described in Example I, but specifies that “0.5% timolol free base is used instead of timolol maleate” and states that “[t]he composition is effective as described in Example I, but is more stable.” Example III is also the same as the composition described in Example I, but specifies that “0.5% timolol free base is used instead of timolol maleate and 0.18% brimonidine free base is used instead of brimonidine tartrate” and states that “[t]he composition is effective as described in Example I, but is more stable.” Allergan has asserted all claims of all four patents-in-suit against the Defendants. (See infra at fn 3.) 43. The patents-in-suit discuss the pri- or art concomitant (serial) administration of brimonidine and timolol. (See, e.g., JTX 1 at col. 1:7-12; see also Trial Tr. Day 2(AM) at 14:7-25 (Tanna).) Specifically, the patents-in-suit discuss the prior art serial administration of Alphagan® (brimonidine 0.2%) TID and Timoptic® (0.5% timolol maleate) BID. (See, e.g., JTX 1 at col. 2, 11. 58-64; see also Trial Tr. Day 1(AM) at 142:9-13 (Beck).) Ms. Amy Batoosingh, one of the inventors, stated that an advantage of a fixed combination is that patient compliance is increased because only one drop is needed in place of multiple drops of the individual active agents; in fact, she stated this is a “huge advantage.” (Trial Tr. Day 1(AM) at 64:25-66:6 (Batoosingh).) F. Nature of the Action 44. This civil case is brought before the United States District Court for the Eastern District of Texas. This action arises under the Patent Laws of the United States, 35 U.S.C. §§ 1 et seq., 45. Congress passed the Drug Price Competition and Patent Term Restoration Act, which is commonly referred to as the Hatch-Waxman Act, in 1984. Pub. L. No. 98-417, 98 Stat. 1585. The Hatch-Wax-man Act (the “Act”) amended the Federal Food, Drug, and Cosmetic Act, Pub. L. No. 52-675, 52 Stat. 1040 (1938) (codified as amended at 21 U.S.C. §§ 301 et seq. (1994)) (the “FDCA”), as well as the patent laws. See Bristol-Myers Squibb Co. v. Royce Lab., Inc., 69 F.3d 1130, 1131-32 (Fed.Cir.1995). 46. As the statute’s name suggests, “Congress sought to strike a balance between incentives, on the one hand, for innovation, and on the other, for quickly getting lower-cost generic drugs to market.” Teva Pharm. Indus. Ltd. v. Crawford, 410 F.3d 51, 54 (D.C.Cir.2005). “The Hatch-Waxman Amendments help to expedite the marketing of generic drugs.” Teva Pharm., USA, Inc. v. Leavitt, 548 F.3d 103, 104 (D.C.Cir.2008). 47. The Act allows generics to obtain FDA approval by submitting bioequivalence studies as opposed to clinical evidence of safety or efficacy, which would be costlier and more time consuming. Crawford, 410 F.3d at 54 (citing 21 U.S.C. § 355(j)). Under the FDCA, as amended by the Act, a pharmaceutical manufacturer submits an ANDA when seeking expedited FDA approval of a generic version of a drug previously approved by the FDA (a “listed drug”). See 21 U.S.C. § 355(j). An ANDA can be filed if the generic drug manufacturer’s active ingredient is the “bioequivalent” of the listed drug. See 21 U.S.C. § 355(j)(2)(A)(iv). When submitting an ANDA, a manufacturer must certify one of four statements concerning the applicable listed drug. If an ANDA is certified under Paragraph IV, the applicant must notify the patent’s owner of the certification. See 21 U.S.C. § 355(j)(2)(B). 48. The Act created an incentive for generic drug companies to challenge patents believed to be unnecessary or invalid by granting the generic drug company, if its challenge is successful, 180 days of exclusive marketing rights of the generic version of the drug. Leavitt, 548 F.3d at 104 (citing 21 U.S.C. §§ 355(j)(2)(A)(vii), 355(j)(5)(B)(iv)). 49. Allergan is the holder of approved New Drug Application (“NDA”) No. 21-398 for Combigan® 0.2% brimonidine/0.5% timolol ophthalmic solution. It is undisputed that Allergan owns all rights, title, and interest in and to the patents-in-suit. (D.I. 207 at 18.) It is also undisputed that each of the four patents-in-suit is listed in the FDA Orange Book for Combigan®. (D.I. 207 at 18.) 50. The Patent Act provides that “(i)t shall be an act of infringement to submit ... an application under section 505(j) of the Federal Food, Drug, and Cosmetic Act or described in section 505(b)(2) of such Act for a drug claimed in a patent or the use of which is claimed in a patent.” 35 U.S.C. § 271(e)(2)(A). “Under § 271(e)(2)(A), a court must determine whether, if the drug were approved based upon the ANDA, the manufacture, use, or sale of that drug would infringe the patent in the conventional sense.” Glaxo, Inc. v. Novopharm, Ltd., 110 F.3d 1562, 1569 (Fed.Cir.1997). 51. “If the court determines that the patent is not invalid and that infringement would occur, and that therefore the ANDA applicant’s Paragraph IV certification is incorrect, the patent owner is entitled to an order that FDA approval of the ANDA containing the Paragraph IV certification not be effective until the patent expires.” Royce Lab., 69 F.3d at 1135 (emphasis omitted). G. The Accused Products 1.Sandoz’s ANDA 91-087 52. On or about February 23, 2009, Allergan received a Paragraph IV letter from Sandoz regarding the '149 and '976 patents. The letter indicated that Sandoz had submitted ANDA No. 91-087 for the purpose of obtaining approval to commercially manufacture, use, offer for sale, or sell a generic version of Combigan® prior to the expiration of the '149 and '976. 53. On April 7, 2009, Allergan filed a Complaint for infringement of the '149 and '976 patents against Sandoz, alleging that the filing of ANDA No. 91-087 constituted an act of infringement of the '149 and '976 patents. (Civil Action No. 2:09-cv-97). 54. On October 20, 2009, Allergan received a second Paragraph IV letter from Sandoz regarding the '463 Patent. 55. On November 9, 2009, Allergan filed an Amended Complaint against San-doz to additionally assert the '463 patent. 56. On or about February 16, 2010, Allergan received a third Paragraph IV letter from Sandoz regarding the '258 patent. 57. On March 19, 2010, Allergan filed a Second Amended Complaint' against San-doz to additionally assert the '258 patent. 2. Alcon’s ANDA No. 91-574 58. On or about September 29, 2009, Allergan received a Paragraph IV letter from Alcon regarding the '149, '976, and '463 patents. The letter indicated that Alcon had submitted ANDA No. 91-574 for the purpose of obtaining approval to commercially manufacture, use, offer for sale, or sell a generic version of Combigan® prior to the expiration of the '149, '976, and '463 patents. 59. On November 6, 2009, Allergan filed a Complaint for infringement of the '149, '976, and '463 patents against Alcon, alleging that the filing of ANDA No. 91-574 constituted an act of infringement of the '149, '976, and '463 patents. (Civil Action No. 2:09-cv-348). 60. On or about April 2, 2010, Allergan received a second Paragraph IV letter from Alcon regarding the '258 patent. 61. On April 28, 2010, Allergan filed an Amended Complaint against Alcon to additionally assert the '258 patent. 3. Apotex’s ANDA No. 91-442 62. On or about May 4, 2010, Allergan received a Paragraph IV letter from Apotex regarding the '149, '976, '463, and '258 patents. The letter indicated that Apotex had submitted ANDA No. 91-442 for the purpose of obtaining approval to commercially manufacture, use, offer for sale, or sell a generic version of Combigan® prior to the expiration of the '149, '976, '463, and '258 patents. 63. On June 15, 2010, Allergan filed a Complaint for infringement of the '149, '976, '463, and '258 patents against Apotex, alleging that the filing of ANDA No. 91-442 constituted an act of infringement of the '149, '976, '463, and '258 patents. (Civil Action No. 2:09-cv-348). 4. Watson’s ANDA No. 201949 64. On or about July 30, 2010, Allergan received a Paragraph IV letter from Watson dated July 26, 2010. The letter indicated that Watson had submitted ANDA No. 201949 for the purpose of obtaining approval to commercially manufacture, use, offer for sale, or sell a generic version of Combigan® prior to the expiration of the '149, '976, '463, and '258 patents. 65. On September 2, 2010, Allergan filed a Complaint for infringement of the '149, '976, '463, and '258 patents against Watson, alleging that the filing of ANDA No. 201949 constituted an act of infringement of the '149, '976, '463, and '258 patents. (Civil Action No. 2:09-ev-00344). H. Procedural Posture 1.The Sandoz Action: Civil Action No. 2:09-cv-97 66. On April 7, 2009, Allergan filed suit against Sandoz for infringement of the '149 and '976 patents. 67. On October 15, 2009, Allergan moved to consolidate Allergan, Inc. v. Sandoz Inc., C.A. No. 2:09-cv-97 (TJW) with Allergan, Inc. v. Hi-Tech Pharmacol Co., Inc., C.A. No. 2:09-cv-182 (TJW), for pretrial and trial purposes. Neither Sandoz nor Hi-Tech opposed this motion. 68. On October 22, 2009, the Court ordered the cases consolidated. 2. The Alcon Action: Civil Action No. 2:09-cv-348 69. On November 6, 2009, Allergan filed suit against Alcon for infringement of the '149, '976, and '463 patents. 70. On January 13, 2010, Allergan moved to consolidate Allergan, Inc. v. Hi-Tech Pharmacol Co., Inc., C.A. No. 2:09-cv-182 (TJW) with Allergan, Inc. v. Alcon Laboratories, Inc., et al, C.A. No. 2:09-cv-348 (TJW), for pretrial and trial purposes. Neither Sandoz, HiTech nor Alcon opposed this motion. 71. On January 19, 2010, the Court ordered the cases consolidated. 3. The Apotex Action: Civil Action No. 2:10-cv-0200 72. On June 15, 2010, Allergan filed suit against Apotex for infringement of the '149, '976, '463, and '258 patents. 73. On September 2, 2010, Allergan moved to consolidate Allergan, Inc. v. Apotex Corp. and Apotex, Inc., C.A. No. 2:10-CV-200 with Allergan, Inc. v. Sandoz Inc., C.A. No. 2:09-cv-97 (TJW) for pretrial and trial purposes. 74. On September 9, 2010, the Court ordered the cases consolidated. 4. The Watson Action: Civil Action No. 2:10-cv-00344 75. On September 2, 2010, Allergan filed suit against Watson for infringement of the '149, '976, '463, and '258 patents. 76. On March 1, 2011, Allergan and Watson jointly moved to consolidate Allergan, Inc. v. Watson Laboratories, Inc., C.A. No. 2:10-cv-00344 (TJW) with Allergan, Inc. v. Sandoz Inc., C.A. No. 2:09-cv-97 (TJW) for pretrial and trial purposes. 77. On March 2, 2011, the Court ordered the cases consolidated. 5. The Court’s Claim Construction, Summary Judgment, and Parties’ Stipulation 78. The Court held a Markman hearing in this consolidated matter on January 28, 2011. Following the hearing, the court issued an order construing the disputed claim terms of the patents-in-suit. 79. The Court granted Defendants’ Motion for Partial Summary Judgment of Noninfringement with respect to claims 1-3 of the '149 patent. (See D.I. 218.) 80. Defendants have stipulated that each of their proposed products described in their respective ANDAs (ANDA No. 91-087 for Sandoz; ANDA No. 91-574 for Alcon; ANDA No. 91-442 for Apotex; ANDA No. 201949 for Watson) meet all of the limitations of claim 4 of the '149 patent, claim 1 of the '976 patent, claims 1-6 of the '463 patent, and claims 1-9 of the '258 patent. (D.I. 234.) I. Parties’ Contentions 81. Allergan contends that Sandoz, Alcon, Apotex, and Watson are each infringing each of the claims of each of the Patents-in-Suit under 35 U.S.C. § 271 either literally or under the doctrine of equivalents, by Sandoz’s, Alcon, Apotex and Watson’s filing of ANDA Nos. 91-087, 91-574, 91-442, and 201949, respectively, seeking to market generic copies of Allergan’s COMBIGAN® product that practice the inventions of the patents-in-suit. (D.I. 233 at 12-16.) Allergan also contends that the asserted claims of patents-in-suit are valid. (Id.) 82. Defendants contend that the patents-in-suit are invalid for anticipation in view of U.S. Patent No. 5,502,052 to De-Santis (“DeSantis”) and obviousness over DeSantis when viewed by a person of ordinary skill in the art. (Id.) Defendants also contend that claims 1-3 of the '149 patent are invalid under 35 U.S.C. § 112, first paragraph, for lacking written description and for failing to satisfy the enablement requirement. (Id.) J. U.S. Patent No. 5,502,052 (“DeSantis”) 83. U.S. Patent No. 5,502,052 to De-Santis (“DeSantis”) (DTX 123), issued on March 26, 1996, which is more than one year before the April 19, 2002 priority date of the patents-in-suit. 84. DeSantis describes combinations of an alpha^adrenergic agonist and a beta-blocker for controlling the IOP in patients with glaucoma or ocular hypertension. (DTX 123 at col. 1, 11. 12-24 and col. 3, 11. 3-6; see also Tr. Trial Tr. Day 2(AM) at 20: 7-17 (Tanna); 29:9-30:3 (Tanna); Trial Tr. Day 2(PM) at 68:2-6; 94:2-10 (Laskar); Trial Tr. Day 3(PM) at 53:3-6 and 11-14 (Noeeker).) 85. DeSantis describes the alphagagonists that can be used in the combination products in broad terms, stating: The alpha-2 agonists which can be employed in the compositions of the present invention include all pharmaceutically acceptable compounds which have alpha-2 agonist activity and are effective in controlling intraocular pressure. (Id. at col. 3, ll. 17-21; see also Trial Tr. Day 3(AM) at 24:15-22 (Tanna).) 86. DeSantis identifies a number of alpha2-agonists that may be used in the claimed combination, including “all pharmaceutically acceptable compounds which have alpha2-agonist activity and are effective in controlling intraocular pressure,” (DTX 123 at col. 3, ll. 18-21; see also Trial Tr. Day 2(AM) at 24:15-22 (Tanna)), which includes “clonidine derivatives or ‘clonidine-like’ drugs,” further described as follows: In addition to the 2-(arylimino) imidazolidines identified above, other groups or classes of alpha-2 agonists which may be utilized in the present invention include 2-(arylimino) oxazolidines; 2-(arylme-thylene) imidazolidines; 2-(arylimino) pyrrolidines; arylalkylaminoguanidines, such as aryl-imidazoquinazolines and pheny-lacetylguanidines; and 2-(phenyl-imino) diazocyclopentenes. All of these groups of drugs may be referred to as being clonidine derivatives or “clonidinelike” drugs. A comprehensive discussion of the properties of clonidine and clonidine-like compounds is presented in a publication by Timmermans et al. titled “Structure-Activity Relationships in Clonidine-Like Imidazolidines and Related Compounds” (pages 1-97, published in 1980 by Gustav Fischer Verlag, of Stuttgart and New York). The entire contents of that publication are hereby incorporated in the present specification by reference. As indicated by Timmermans et al., the molecular structure of clonidine consists of three parts: an aromatic (i.e., aryl) portion, a bridge, and an imidazolidine moiety. Timmermans et al. disclose many compounds which have been produced by modifying one or two of these three parts, but which retain one of the three parts intact. For purposes of the present specification, all such compounds are defined as being “clonidine derivatives.” (Id. at col. 4, ll. 34-57.) 87.Timmermans (DTX 124), which was published in 1980 and cited above, discloses “UK-14,304-18 (tartrate),” which is brimonidine tartrate. (See Timmermans at 28-9; see also Trial Tr. Day 2(AM) 20:21-22:6 (Tanna) and 41:25-43:23; Trial Tr. Day 2(PM) at 70:2-7; 70:11-25; 71:1-14; 71:21-72:1 (Laskar).) Allergan’s expert, Dr. Robert Noecker, confirmed that Timmermans discloses brimonidine and its tartrate salt. (Trial Tr. Day 3(PM) at 53:19-54:9 and 64:8-65:1 (Noecker).) 88. By April 2001, brimonidine was a known alpha2-agonist that had been shown useful for lowering IOP at a concentration of 0.2%. (See Serle 1993 (DTX 193); see also Trial Tr. Day 2(AM) at 22:12-24:14 (Tanna); Trial Tr. Day 2(PM) at 73:18-25; 74:9-10 (Laskar); Trial Tr. Day 1(AM) at 146:18-19(Beck); Trial Tr. Day 1(PM) at 74:14-75:10 (Batoosingh).) 89. By April 2001, a person of ordinary skill in the art would have considered brimonidine to be one of the best alpha2-agonist for treating glaucoma or ocular hypertension. (See Trial Tr. Day 1(PM) at 105:23-106:6 (Batoosingh); see also Trial Tr. Day 2(AM) at 22:12-24:14 (Tanna); Trial Tr. Day 1(AM) at 146:18-19 (Beck).) 90. DeSantis gives the preferred amount of alpha2-agonist in the combinations as an amount of about 0.02 to 2.0 percent by weight (“wt. %”). (See DTX 123 at col. 4, 11. 58-61; see also Trial Tr. Day 2(AM) at 25:8-26:9 (Tanna); Trial Tr. Day 2(PM) at 79:21-24 (Laskar).) 91. DeSantis also states that the “preferred beta-blockers include timolol,.... ” (Id. at col. 5, 1. 34; see also Trial Tr. Day 2(AM) at 26:10-27:5 (Tanna); Trial Tr. Day 2(PM) at 81:17-82:4 (Laskar).) 92. The preferred amount of the beta-blocker in the combinations is stated to be an amount of about 0.01 to 3.0 wt. %. (See id. at col. 5, ll. 37-40; see also Trial Tr. Day 2(AM) at 28:11-29:3 (Tanna); Trial Tr. Day 2(PM) at 82:8-12 (Laskar).) 93. As discussed by Defendants’ expert, Dr. Tanna, DeSantis also discloses beta-blockers that may be utilized in the disclosed invention include all pharmaceutically acceptable compounds that are capable of reducing the production of aqueous humor when applied topically. (DTX 123 at col. 4, ll. 62-65; see Trial Tr. Day 2(AM) at 27:24-28:10 (Tanna).) 94. Timolol is listed in the title of De-Santis. (DTX 123 at p. 1; see also Tr. Trial Tr. Day 2(AM) at 26:10-27:5 (Tanna); Trial Tr. Day 2(AM) at 81:23-25 (Laskar).) 95. Timolol is the only claimed beta-blocker in DeSantis. (DTX 123 at col. 6, ll. 42-48; see also Trial Tr. Day 2(AM) at 26:10-27:5 (Tanna); Trial Tr. Day 2(PM) at 82:1-4 (Laskar).) 96. DeSantis discusses “formulatory ingredients” such as “benzalkonium chloride” that “will typically be employed in an amount of from about 0.001% to 1.0% by weight (wt.%).” (Id. at col. 5, 1. 41-col. 6, 1. 1; see also Trial Tr. Day 2(AM) at 31:17-32:14 (Tanna); Trial Tr. Day 2(PM) at 87:11-15 (Laskar).) 97. DeSantis states BAK is an example of a suitable antimicrobial preservative that can be used with the disclosed anti-glaucoma single composition: In addition to the above described principal active ingredients, the anti-glaucoma compositions of the present invention may further comprise various formulation ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, ON-AMER M and other agents equally well known to those skilled in the art. (DTX 123 at col. 5, ll. 41-18; see also Trial Tr. Day 2(AM) at 31:17-32:14 (Tanna); Trial Tr. Day 2(PM) at 87:11-15 (Laskar).) 98. DeSantis states that the compositions typically include the preservative in an amount of from about 0.001 % to about 1.0% by weight. (See DTX 123 at col. 6, ll. 1-6; see also Trial Tr. Day 2(AM) at 31:17-32:14 (Tanna); Trial Tr. Day 2(PM) at 87:11-15 (Laskar).) K. The Development of Combigan® 99. After nine years of formulation development and clinical trials, Allergan brought Combigan®, a fixed combination glaucoma medication comprising 0.2% brimonidine and 0.5% timolol, to the market. (D.I. 238, Trial Tr. Day 1(AM) at 135:8-24; PTX-24.) The development of the product is described below. 1. Formulation Challenges in Developing Combigan® 100. Drug formulation is a challenging and unpredictable endeavor, and the formulation of ophthalmic drugs is even more complex than normal drug formulation. (D.I. 238, Trial Tr. Day 1(AM) at 133:4-23, 134:5-24 (Beck); D.I. 242, Trial Tr. Day 3(AM) at 64:9-65:3 (Noecker).) This is because ophthalmic drugs are generally formulated as aqueous solutions, stability is more of a challenge than it would be for drugs formulated as tablets or other dosage forms. Also, the surface area of the eye is very small, and the residence time for an eye drop is very short. (Id.) With the small surface area and the short residence time, it is a challenge to design an aqueous drug that can quickly pass through the hydrophobic corneal membrane to reach the site of action in the eye. (Id.) Many of these difficulties were acknowledged by Defendants’ formulation expert, Dr. Laskar. (See, e.g., D.I. 241, Trial Tr. Day 2(PM) at 53:21-55:25 (Laskar) (discussing the importance of the selection of buffering systems, tonicity agents, viscosity agents, pH, and preservative for an ophthalmic formulation).) 101. Formulating a fixed combination ophthalmic drug adds yet another layer of complexity on top of the considerations already described. As described in an article appearing in Review of Ophthalmology: For many reasons, not every possible pair of glaucoma drugs can be combined in one bottle; many stars must be aligned for such a combination to be feasible. For instance, both drugs must be soluble at the same pH or one of the drugs could end up in clump of powder at the bottom of the bottle. More importantly, the two drugs to be combined must have comparable dosing frequency and timing. (PTX-122; see also D.I. 238, Trial Tr., Day 1(AM) at 137:4-138:23 (Beck).) 102. At trial, the difficulties involved in fixed combination ophthalmological formulations were conceded by Defendants’ formulation expert, Dr. Laskar. (See, e.g., D.I. 241, Trial Tr. Day 2(PM) at 34:12-35:3 (Laskar)) (discussing “significant formulation challenges that he faced in developing combination product due to the fact that ‘the active ingredients were incompatible’ ”); D.I. 243, Trial Tr. Day 3(PM) at 124:3-125:1 (Laskar) (discussing potential reactivity between active ingredients); id. at 123:2-6, 11-17; 126:3-6 (acknowledging that “[y]ou can’t predict how that — what’s going to happen when you put two salts together in an aqueous solution until you actually do so”). 103. Formulating brimonidine tartrate and timolol maleate into a fixed combination presented many challenges to Allergan’s formulators. A fixed combination formulation of these two compounds required combining two different active ingredients that had two different salts, and that had previously been formulated at two different pH values, with two different buffer systems, and with two different concentrations of preservative. As discussed more fully below, each of these differences presented its own set of challenges. 104. First, the use of two different active ingredients posed challenges to the formulators because these ingredients “have two different physical chemical characteristics, so each of these two separate active ingredients will demand a different formulation, and somehow we have to accommodate the demands of both actives in a single formulation.” (D.I. 238, Trial Tr. Day 1(AM) at 137:2-12 (Beck).) The formulators did not know how the two would behave together in a single formulation. (Id. at 144:2-6.) 105. Further, Defendants’ expert, Dr. Laskar, acknowledged that reactivity can occur between brimonidine and timolol because the secondary amines in brimonidine can act as nucleophiles that attack the electron-poor carbon-nitrogen double bonds present in timolol. (D.I. 243, Trial Tr. Day 3(PM) at 124:3-125:1 (Laskar).) 106. Second, the use of active ingredients with two different salts presented additional challenges. As Mr. Beck explained, “[i]f the salt forms dissociate from the active ingredients, which they often do in solution and pH dependent, they too can have reactivities with the active ingredients, for example.” (D.I. 238, Trial Tr. Day 1(AM) at 137:16-25 (Beck),) Dr. Laskar also agreed that “there is no reliable way of predicting the influence of a particular salt species on the behavior of the parent compound in dosage forms.” (D.I. 243, Trial Tr. Day 3(PM) at 123:2-6,11-17; 126:3-6 (Laskar); DTX-274.) 107. Third, the pH differences between previous formulations of brimonidine tartrate and timolol maleate presented an additional challenge to the inventors. Brimonidine tartrate had previously been formulated at a pH in the range of 6.3 to 6.5 in Allergan’s Alphagan® product, and timolol maleate had been formulated at a pH of 7.0 in Timoptic®. (JTX-9I at AGN_COMBI0000683; PTX-74 at AGN-COMBI0478511; D.I. 238, Trial Tr. Day 1(AM) at 139:5-8 (Beck).) Because pH is measured on a logarithmic scale, this difference of up to 0.7 pH units is significant. (D.I. 238, Trial Tr. Day 1(AM) at 139:2-21 (Beck)); (D.I. 241, Trial Tr. Day 2(PM) at 139:16-140:14 (Laskar).) 108. The importance of pH to an ophthalmic formulation was a fact agreed to by numerous witnesses — both Allergan’s and Defendants’ — at trial. Mr. Beck explained that pH is important because it affects solubility, stability, and bioavailability. (D.I. 238, Trial Tr. Day 1(AM) at 139:22-140:5) (Beck.) Dr. Laskar explained that the pH of an ophthalmic formulation is important to the “stability, comfort, and bioavailability.” (D.I. 241, Trial Tr. Day 2(PM) at 59:13-18 (Laskar); id. at 54:13-55:13 (“Q: As to pH adjusting agents, is that a specific concern with regard to ophthalmic products or drugs? A: Absolutely.”).) Dr. Tanna also agreed that “pH can have a significant effect on an active ingredient.” (D.I. 241, Trial Tr. Day 2(PM) at 14:7-10 (Tanna).) 109. Fourth, brimonidine and timolol had previously been formulated with different buffer systems, presenting yet another challenge to the inventors. Alphagan® had been formulated with a citric acid buffer system, and Timoptic® used a phosphate buffer system. (JTX-9I at AGN_COMBI0000683; PTX-74 at AGN-COMBI0478511; D.I. 241, Trial Tr. Day 2(PM) at 134:12-135:2 (Laskar)). The buffer system affects the isotonicity of a formulation, and adjusting the buffers to achieve the appropriate isotonicity is not a routine matter. (Chang Deposition Tr. at 107:19-24; D.I. 241, Trial Tr. Day 2(PM) at 136:2-7,13-17 (Laskar).) 110. Finally, brimonidine and timolol had previously been formulated with two different concentrations of the BAK preservative. Alphagan® contained 50 ppm BAK, but Timoptic® contained 100 ppm, twice the concentration in Alphagan®. (JTX-9I at AGN-COMBI0000683; PTX-74 at AGN_COMBI0478511.) When asked whether he would agree that “the formulators of Timoptic used the .01% BAK, because they believed that that was necessary for that formulation,” Dr. Laskar acknowledged that he “would agree that they had some reason to do so.” (D.I. 241, Trial Tr. Day 2(PM) at 135:20-136:1 (Laskar)). 111. In light of all these challenges, the path to the final formulation that resulted in the Combigan® product was anything but straightforward. In addition to the brimonidine tartrate and timolol maleate that are included in the final formulation, Allergan investigated several other active ingredients for use in the combination, including levobunolol as an alternate beta blocker. (D.I. 238, Trial Tr. Day 1(AM) at 146:7-21 (Beck).)' 112. Once brimonidine and timolol were selected as the active ingredients, the inventors also tried a number of different vehicles for the formulation, many of which ultimately turned out to be failures. 113. Early in the formulation process, Allergan was investigating at least two possible vehicles for its formulation. One was formulated in Synergel, a viscous polymeric substance, as the delivery vehicle. (PTX-26; D.I. 238, Trial Tr. Day 1(AM) at 148:22-150:21 (Beck).) The other contained Purite®, a mild preservative with few detrimental effects on the eye, and the preservative that was used with Alphagan® P. (PTX-26; D.I. 238, Trial Tr. Day 1(AM) at 147:3-148:2) (Beck); (PTX-75 at AGN_COMBI0478533.) Although Allergan had estimated its probability of success with both of these formulations as “good,” both ended up failing, demonstrating the unpredictability of the art. (PTX-26; D.I. 238, Trial Tr. Day 1(AM) at 147:3-150:21 (Beck).) 114. Allergan inventor Mr. Beck explained that he was attempting to use the Synergel vehicle to improve the residence time on the eye in an attempt to increase the penetration across the cornea. (D.I. 238, Trial Tr. Day 1(AM) at 149:1-150:13 (Beck).) In practice, however, the Synergel formulation proved too viscous because it did not allow for sterile filtration. (Id. at 150:24-152:12; PTX-24 at AGN-COMBI0145291-293.) 115. Like the Synergel formulation, the inventors also had problems with the Purite® formulation. The inventors were attempting to use the Purite® preservative as a replacement for the commonly-used benzalkonium chloride (“BAK”) preservative, which is known to be toxic to the eye. (D.I. 238, Trial Tr. Day 1(AM) at 147:16-148:5 (Beck); PTX-24 at AGN_COM-BI0145296.) But they discovered that the Purite® degraded the timolol too quickly to make a stable formulation and were forced to abandon the attempt. (D.I. 238, Trial Tr. Day 1(PM) at 3:25-7:15 (Beck); PTX-35; PTX-128.) 116. The Allergan formulators also tried a carboxymethylcellulose (“CMC”) vehicle for the formulation because it was thought to increase the comfort of an eye drop, but found that it was not compatible with the benzalkonium chloride (“BAK”) preservative. Because CMC has a negative charge and BAK has a positive charge, they can form a complex that makes sterile filtering difficult. (D.I. 238, Trial Tr. Day 1(AM) at 153:6-20 (Beck); D.I. 239, Trial Tr. Day 1(PM) at 8:11-25 (Beck); PTX-159.) 117. Even after settling on an appropriate vehicle and preservative for the brimonidine and timolol formulation, the inventors faced further hurdles with the formulation. In the course of stability studies on the formulation, Allergan found novel degradants — which can be caused by breaking down of the active ingredients, impurities, or complexation of the active ingredient with something else in the formulation — that they did not expect to see. (D.I. 239, Trial Tr. Day 1(PM) at 9:1-10:6 (Beck).) Mr. Beck explained that “the monotherapy formulations did not have these degradants. These were new degradants as a result of the combination of the two active ingredients in the formulation.” (Id. at 10:7-17.) 118. As a result of the unexpected degradants, Allergan was required to conduct toxicology studies to determine whether the degradants would compromise the safety of the formulation. (Id. at 10:18-12:12 (“We didn’t know whether or not these degradants could compromise safety in the products. So we were obligated to conduct studies to ensure that they were safe. And this would be before we would go into human clinical studies.”); PTX-126.) 119. After force-degrading the formulation for seven months to obtain sufficient quantities of the degradants to perform a study, Allergan ran a one-month toxicology study in rabbits to evaluate the safety of the degradants, and submitted that study to the FDA. (D.I. 239, Trial Tr. Day 1(PM) at 12:13-13:25 (Beck); JTX-9H.) Although Allergan ultimately determined that the degradants did not compromise the safety of the products, there was no way of knowing the potential safety ramifications of the degradants without running the study. (D.I. 239, Trial Tr. Day 1(PM) at 13:14-25 (Beck).) 120. Furthermore, because of the difficulties involved in combining two active ingredients that had been formulated at different pH values, the inventors did several studies to select the appropriate pH for the formulation. (D.I. 239, Trial Tr. Day 1(PM) at 15:18-18:17 (Beck); PTX-38 at AGN-COMBI0171458; PTX-89.) They could not simply choose either the pH of Alphagan® (6.3) or Timoptic® (7.0), but rather had to run the experiments to determine the appropriate pH for the combination. (D.I. 239, Trial Tr. Day 1(PM) at 15:24-16-5) (Beck) (“Q: Why didn’t you just pick the pH that was the closest to the pH of the eye? A: We couldn’t do that. Again, pH has a significant impact of stability of a product and aqueous environment. And it has an impact on the molecule’s ability to penetrate the cornea.”); see also D.I. 241, Trial Tr. Day 2(PM) at 54:23-55:23 (Laskar) (discussing the critical nature of pH to an ophthalmic formulation); D.I. 241, Trial Tr. Day 2(PM) at 14:7-10 (Tanna) (“Q. So you would agree with me, Dr. Tanna, that a pH can have a significant effect on an active ingredient? A. Yes, it can.”). The inventors eventually settled on a final target pH of 6.9 for the formulation. (PTX-100; JTX-9 at AGN_COMBI0055391.) 121. The different preservative concentrations of Alphagan® (50 ppm BAK) and Timoptic® (100 ppm BAK) also required the inventors to perform a number of different tests to determine the optimum pH for the combination formulation. Because BAK is known to be toxic to cells, Allergan’s inventors generally “want to formulate the product at the lowest [concentration] of BAK that [they] can.” (D.I. 239, Trial Tr. Day 1(PM) at 19:19-20:2 (Beck).) However, because BAK is also able to increase the uptake of an active ingredient, the inventors were concerned that reducing the BAK concentration would negatively impact the uptake of timolol into the eye, adversely affecting its efficacy. (Id. at 21:19-24:7.) Therefore, in addition to performing several titration to failure studies to determine how much BAK was needed to properly preserve the formulation, they also performed tests to ensure that a reduced concentration of BAK would not have a negative impact on the uptake of the active ingredients. (Id. at 19:11-24:7; PTX-101; PTX-61.) 122. Ultimately, the Allergan formulators spent nearly a year developing the formulation of Combigan®. (D.I. 238, Trial Tr. Day 1(AM) at 135:8-24 (Beck); D.I. 239, Trial Tr. Day 1(PM) at 24:4-7 (Beck).) Far from Defendants’ characterizations as a “routine” exercise, this process was complex, difficult, and unpredictable. This is consistent with the unpredictable arts. See Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed.Cir.2008) (“To the extent an art is unpredictable, as the chemical arts often are, KSR’s focus on these ‘identified, predictable solutions’ may present a difficult hurdle because potential solutions are less likely to be genuinely predictable.”). 123.Defendants argue that this evidence of formulation challenges is a red herring and nothing more than general formulation practices employed by a person of ordinary skill in the art as of 2002. The Court disagrees and finds that this is nothing more than unsupported attorney argument. To be sure, Dr. Tanna admitted that he did not consider any formulation difficulties faced by the inventors in his obviousness analysis and does not consider himself to have expertise in the area of formulation. (D.I. 240, Trial Tr. Day 2(AM) at 120:3-7 (Tanna) (“Q: So I take it you did not take into consideration any formulation difficulties the formulators in this case may have faced when rendering your obviousness opinion? A: Correct. I — I did not.”); D.I. 240, Trial Tr. Day 2(AM) at 119:14-120:2 (Tanna).) Likewise, Dr. Laskar admitted at trial he did not take into account any information about the actual formulation work done by the inventors. (D.I. 241, Trial Tr. Day 2(PM) at 144:12-18; 145:17-20 (Laskar).) Moreover, Dr. Laskar agreed that formulation difficulties are an important part of obviousness considerations, and admitted to applying for his own combination patent where there were formulation challenges overcome in making the combination. (D.I. 241, Trial Tr. Day 2(PM) at 160:10-19 (Laskar).) The Court finds it disingenuous to blindly assert that formulations challenges only apply to some patents and not others, especially when Defendants’ experts did not even consider the formulation challenges overcome by Allergan. 124. The final formulation of Combigan® developed by Mr. Beck and his team is as follows: (JTX-9 at AGN_COMBI0055391.) 125. Because the final formula is disclosed and claimed in the patents-in-suit, the patent inherently discloses all of the drug formulation challenges presented at trial even though the specifications of the patent may not specifically discuss these formulation challenges. That is, the claims are not directed to a general abstract combination of two drugs, but instead are directed to a specific formulation that was determined only after overcoming the inherent formulation challenges. Thus, Defendants assertion that the patents-in-suit do not set forth any difficulties in development of the fixed combination product is a self-serving view of what the patents-in-suit disclose. Again, both Dr. Tanna and Dr. Laskar admitted that they did not consider or take into account any information about the actual formulation work done by the inventors. (D.I. 240, Trial Tr. Day 2(AM) at 120:3-7 (Tanna); D.I. 241, Trial Tr. Day 2(PM) at 144:12-18; 145:17-20 (Laskar).) Moreover, Dr. Laskar agreed that formulation difficulties are an important part of obviousness considerations, and admitted to applying for his own combination patent where there were formulation challenges overcome in making the combination. (D.I. 241, Trial Tr. Day 2(PM) at 160:10-19 (Laskar).) 2. Clinical Challenges in Developing Combigan®: Reducing Brimonidine Therapy from Three to Two Times a Day Without Loss of Efficacy 126. In addition to the significant formulation challenges that the inventors of the four patents-in-suit faced, there was also a unique clinical challenge in the development of Combigan®. According to Ms. Amy Batoosingh, the clinical lead for the project and an inventor on the patents-in-suit, reducing the dose of brimonidine from three times a day to twice a day without losing efficacy was the key clinical challenge on the product: Q. From the clinical perspective that you brought to the project, what were the challenges in developing a brimon