Full opinion text
OPINION STARK, District Judge: TABLE OF CONTENTS INTRODUCTION...............................................................594 FINDINGS OF FACT...........................................................595 I. BACKGROUND........................................................595 A Nature and Stage of the Proceedings..................................595 B. Key Players........................................................595 C. The Claimed Invention — Adapalene Gel, 0.3%..........................596 D.Priority Dates, Expiration, and Asserted Claims of the Patents-in-Suit.............................................................599 II.FINDINGS OF FACT RELEVANT TO OBVIOUSNESS...................602 A. State of the Art of Acne Treatment...................................602 B. The Use of Topical Treatments for Acne...............................602 C. Galderma Selects Differin® 0.1% as the Optimal Dose for Acne Treatment.......................................................603 1. Shroot Patents: '720 Patent (1988), '895 Patent (1992), and '440 Reissue Patent (1993)..........................................603 2. Versehoore (1991)...............................................604 3. Alirezai(1996)...................................................604 4. Allee and Versehoore (JAAD Supplement, 1997).....................605 a. Allee (1997) Indicates to One Of Ordinary Skill in the Art That Galderma Considered 0.1% Adapalene as the Optimal Concentration.............................................605 b. Versehoore (1997) Confirms to One of Ordinary Skill in the Art That Galderma Considered 0.1% Adapalene as the Optimal Concentration.....................................606 5. Czernielewski (2001).............................................607 6. Differin® 0.1% Gel Data Sheet (1996)..............................607 D. The Prior Art Taken as a Whole Does Not Motivate One of Ordinary Skill in the Art to Develop a 0.3% Adapalene Formulation..............607 E. None of the Art Cited by Tolmar Establishes the Obviousness of the Claimed Invention................................................608 1. The Shroot Patents..............................................608 a. The Broad Disclosure of the Shroot Patents Provides No Motivation or Suggestion to Select 0.3% Adapalene for the Treatment of Acne ........................................608 2. Versehoore (1997)...............................................609 3. Galderma’s IND and Other Internal FDA Documents................610 4. Photodamage and Actinic Keratosis Articles (2000)..................612 a. The Goldfarb References (2000)......................'.........612 b. Euvrard (2002)..............................................613 F. Objective Indicia of Nonobviousness...................................614 1. Unexpected Results of the Clinical Studies .........................614 2. Prior Art Taught Away from Increasing the Concentration of Retinoids ....................................................616 3. Differin® 0.3%, Gel Is a Commercial Success.......................616 a. Differin® 0.3%, Gel Is a Success in the Marketplace.............616 b. Differin® 0.3%, Gel’s Marketplace Success is Due to the Patented Features and Benefits.............................617 III. THE ASSERTED PATENTS ARE NOT INVALID FOR LACK OF WRITTEN DESCRIPTION...........................................617 A. It Was Well Known to Use Topical Retinoids as a Component of Combination Therapy to Treat Severe Forms of Acne Prior to 2002.....617 B. One of Ordinary Skill in the Art in 2002 Would Understand that the Inventors Actually Invented a 0.3% Adapalene Gel that Could Be Used to Treat Severe Acne ........................................619 IV. CLAIMS 2, 35 AND 36 OF THE '181 PATENT AND CLAIMS 3, 40 AND 41 OF THE '044 PATENT DO NOT INCLUDE NEW MATTER, HAVE A MARCH 12, 2002 PRIORITY DATE, AND ARE NOT ANTICIPATED BY WO 03/075908 .....................................619 V. THE '377, '181, '060, '588, AND '044 PATENTS WERE NOT INEQUITABLY PROCURED.........................................621 A. Galderma’s IND for Differin® 0.3% Adapalene Gel Does Not Rise to the Level of “But For” Materiality..................................621 1. Galderma’s Phase I studies in healthy subjects are not predictive of what will be seen in acne patients.............................621 2. Galderma’s Studies in Patients With Photodamaged Skin Are Not Predictive of What Will Be Seen in Acne Patients.................622 3. Galderma’s Phase I PK Study in Acne Patients Formed the Preliminary Basis for the Invention of the Patents-in-Suit.....623 B. Galderma’s Clinical Trials for Differin® 0.3% Adapalene Gel Do Not Rise to the Level of “But For” Materiality...........................623 1. Galderma’s U.S. Phase II Study Is Consistent with Representations Made to the PTO...............................623 a. Efficacy....................................................624 b. Onset of Action .......................... 624 c. Tolerability.................................................624 2. Galderma’s U.S. Phase III Study Is Consistent with Representations Made to the PTO.............................•.. 625 a. Efficacy....................................................625 b. Onset of Action .............................................626 c. Tolerability.................................................626 3. The Data from the European Phase III Study, While Consistent with the Statements in the Patents-in-Suit, Was Unreliable.....627 a. Efficacy....................................................627 b. Onset of Action .............................................627 c. Tolerability... .............................................628 C. Dr. Graeber Did Not Act With an Intent to Deceive.....................628 D. Dr. Czernielewski Did Not Act With an Intent to Deceive................629 VI. INVENTORSHIP UNDER 35 U.S.C. § 102(f) .............................629 VII. STANDING ...........................................................630 A The 1995 License Between CIRD Galderma (Galderma R & D) and Galderma S.A.....................................................630 B. 2004 Exclusive License Between Galderma R & D and Galderma S.A.....631 C. 1998 Exclusive License Between Galderma S.A. and Galderma Labs.....631 VIII.INFRINGEMENT BY TOLMAR’S ADAPALENE 0.3% GEL ANDA PRODUCT ..........................................................631 A. Tolmar’s ANDA....................................................631 B. The Composition of Tolmar’s Adapalene 0.3% Gel ANDA Product.........632 C. Tolmar’s Stipulations of Infringement.................................632 D. Infringement of Claim 27 of the '060 Patent............................632 1. Poloxamer 182 in Tolmar’s Proposed Product Is Equivalent to Poloxamer 124 in Claim 27 of the '060 Patent...................., 632 2. Prosecution History Estoppel Does Not Apply to Claim 27 of the '060 Patent...................................................634 DISCUSSION..................................................................636 I. OBVIOUSNESS........................................................636 A Tolmar’s Obviousness Challenge Relies on a Flawed Legal Framework......................................................637 B. Tolmar’s Prior A’t Does Not Establish a Motivation to Triple the Concentration of Adapalene from 0.1% to 0.3% .......................638 1. The Shroot Patents..............................................638 2. Differin® 0.1% Gel Data Sheet....................................639 3. Verschoore (1997)...............................................639 4. Goldfarb (2000).................................................639 5. Euvrard (2002) .................................................640 6. Czernielewski (2001).............................................640 C. The Prior Art Teaches Away from Increasing the Concentration of Adapalene Above 0.1% ............................................641 1. Verschoore (1991) and Alirezai (1996)..............................641 2. Allec (1997), Verschoore (1997), and Czernielewski (2001).............642 3. Tretinoin and Tazarotene ........................................642 D. Secondary Considerations of Non-Obviousness.........................642 1. Unexpected Results.............................................642 2. Commercial Success.............................................644 II. ANTICIPATION.......................................................644 III. INVENTORSHIP......................................................645 A. Nonjoinder........................................................645 B. Misjoinder..........................................................646 IV. WRITTEN DESCRIPTION.............................................646 V. INEQUITABLE CONDUCT ............................................647 A. Allegedly Withheld Prior Art.........................................648 B. Statements in Galderma’s IND.......................................648 1. No But-for Materiality...........................................649 2. No Affirmative Acts of Egregious Misconduct.......................649 3. No Intent to Deceive............................................650 C. “Rapid Onset” Language............................................650 D. “Statistically the Same” Language....................................650 1. No But-for Materiality...........................................651 2. No Affirmative Egregious Act of Misconduct .......................651 3. No Intent to Deceive............................................651 VI. INFRINGEMENT UNDER THE DOCTRINE OF EQUIVALENTS.........651 A. Poloxamer 124 and Poloxamer 182 ....................................652 B. Prosecution History Estoppel Is Not Proven...........................652 VII. STANDING ...........................................................652 A. Galderma S.A. Has Standing.........................................654 B. Galderma Labs Lacks Standing ......................................654 VIII. EXCEPTIONAL CASE.................................................655 CONCLUSION.................................................................655 INTRODUCTION Plaintiffs, Galderma Laboratories, L.P. (“Galderma Labs”), Galderma S.A., and Galderma Research and Development, S.N.C. (“Galderma R & D”) (collectively, “Galderma”), market a topical anti-acne medication containing 0.3% by weight adapalene under the trade name Differin® Gel, 0.3%. The Food and Drug Administration (“FDA”) Orange Book lists United States Patent Nos. 7,579,377 (“the '377 patent”); 7,737,181 (“the '181 patent”); 7,838,558 (“the '558 patent”); 7,834,060 (“the '060 patent”); and 7,868,044 (“the '044 patent”) in connection with Galderma’s Differin® Gel, 0.3% product. On September 14, 2009, Defendant, Tolmar, Inc. (“Tolmar”), filed an Abbreviated New Drug Application (“ANDA”) seeking approval to market a generic version of Galderma’s Differin® Gel, 0.3%. In January 2010, Galderma initiated this litigation against Tolmar in connection with the Paragraph IV certifications contained in Tolmar’s ANDA. The Court held a bench trial from March 5 through March 14, 2012. Tolmar disputed infringement with respect to certain claims of the patents-in-suit, contends the patents-in-suit are invalid under 35 U.S.C. §§ 102, 103, and 112, and also asserts inequitable conduct and lack of standing. The parties completed post-trial briefing on April 30, 2012. (D.I. 316; D.I. 317; D.I. 330; D.I. 331) Tolmar received tentative FDA approval to market its generic 0.3% adapalene product on March 14, 2012. On June 4, 2012, the Court enjoined Tolmar from launching its generic version of 0.3% adapalene until the Court issued its opinion resolving the disputed issues in this case. (D.I. 334) The 30-month stay expired on June 10, 2012. As explained below, the Court finds in favor of Plaintiffs on all issues with the limited exception of standing with respect to one of the Plaintiffs. FINDINGS OF FACT I.BACKGROUND A. Nature and Stage of the Proceedings 1. Galderma markets a topical anti-acne medication containing 0.3% by weight of adapalene under the trade name Differin® Gel, 0.3%. (PTX 301) 2. Tolmar has filed an ANDA seeking approval to market a generic version of Galderma’s Differin® Gel, 0.3%. Tolmar’s ANDA application with Paragraph IV certifications constituted an act of infringement under 35 U.S.C. § 271(e)(2). (See D.I. 1; D.I. 44) 3. Tolmar received tentative approval from the FDA on March 14, 2012 to market its generic 0.3% adapalene product. (See Tr. at 1976:20-22.) The thirty-month stay barring Tolmar from marketing its drug expired June 10, 2012. (See D.I. 287, Exh. 1, Uncontested Fact 48; 21 U.S.C. § 355(j)(5)(B)(iii); 21 C.F.R. § 314.107(b)(3)) B. Key Players 4. Dr. Michael Graeber is a named inventor on the Galderma patents-in-suit. (PTX 1-5) Dr. Graeber is currently employed by Galderma R & D. Dr. Graeber has a medical degree and clinical experience in treating patients with various dermatological conditions, including acne. (Tr. at 295:25-297:13) 5. Dr. Janusz Czernielewski is a named inventor on the Galderma patents-in-suit. (PTX 1-5) Dr. Czernielewski is currently employed by Galderma. Dr. Czernielewski has a medical degree with a specialty in dermatology, a Ph.D. in Immunology, and an MBA. He has clinical experience in treating patients with various dermatological conditions, including acne. (Tr. at 1768:22-1772:13) 6. Dr. Braham Shroot is a former employee of Galderma, the named inventor on the “Shroot patents,” and an author of several articles discussed during trial. (Tr. at 956:20-957:7) 7. Dr. Michael T. Goldfarb is a dermatologist at the University of Michigan and named author on the “Goldfarb photodamage” references discussed during trial. (Tr. at 1291:19-22) 8. Dr. Seth J. Orlow is an expert witness proffered by Galderma. Dr. Orlow is an attending physician in dermatology and pediatrics with a focus on treating children and adolescents; he is also Director of the Dermatology Service at the NYU Langone Medical Center. Dr. Orlow has an M.D. and a Ph.D. in Molecular Pharmacology from Albert Einstein College of Medicine. (PTX 106) Dr. Orlow has experience running dose response curves, specifically for retinoids. (Tr. at 1237:23-1238:14) 9. Dr. Diane Thiboutot is an expert witness proffered by Galderma. Dr. Thiboutot is a dermatologist and professor of dermatology at the Pennsylvania State University, Milton S. Hershey Medical Center. Dr. Thiboutot has first-hand experience with the clinical trials that led to the approval of Galderma’s 0.3% ádapalene product. (See Tr. at 1378:11-1386:25) 10. Dr. Kenneth A. Walters is an expert witness proffered by Galderma. Dr. Walters is the Director of Research and Development and Business Development at An-ex Analytical Services Ltd., a contract service provider, where he has managed over 200 projects developing and contributing to the development of dermatological and transdermal systems containing a variety of drugs. (Tr. at 83:21-87:24) 11. Dr. Ronald Thisted is an expert witness proffered by Galderma. Dr. Thisted is currently Chair of the Department of Health Studies at the University of Chicago, a department within the Pritzker School of Medicine and the Division of Biological Sciences at the University. Dr. Thisted received his Ph.D. in statistics from Stanford in 1977. (PTX 115) Dr. Thisted offered testimony concerning the statistical issues in the case. 12. Mr. John Jarosz is an expert witness proffered by Galderma. Mr. Jarosz is the managing principal of Analysis Group, Inc., an economic, financial, and strategy consulting firm, and Director of the firm’s Washington, D.C. office. (PTX 120) 13. Dr. Howard Maibach is an expert witness proffered by Tolmar. Dr. Maibach received his Doctorate of Medicine from Tulane University and has practiced in the field of dermatology since 1961. (Tr. at 930:12-931:9, 931:15-23) 14. Dr. Russell O. Potts is an expert witness proffered by Tolmar. Dr. Potts has worked extensively on research relating to skin barrier function and the development of topical drug delivery products for nearly the past 30 years. (Tr. at 223:6-21, 224:11-225:7, 227:18-229:2) 15. Dr. Marcello Pagano is an expert witness proffered by Tolmar. Dr. Pagano is a Professor of Statistical Computing at the Harvard School of Public Health, as well as a Senior Scientist at The Children’s Hospital in Boston. (Tr. at 620:6-25) 16. Dr. Thomas D. Vander Veen is an expert witness proffered by Tolmar. Dr. Vander Veen is a Director at Navigant Economics, a global economic consulting firm. (Tr. at 1648:8-13) C. The Claimed Invention — Adapalene Gel, 0.3% 17. 0.3% adapalene gel, marketed by Galderma as Differin® Gel, 0.3%, was approved in 2007, and is one of the most recent retinoid analog products on the market for the treatment of acne. (PTX 301 at GAL000056165) 18. Differin® Gel, 0.1% (containing 0.1% by weight adapalene) was approved by the FDA in 1996 for the treatment of acne. (PTX 255) 19. The use of Galderma’s Differin® Gel, 0.3% has been shown to reduce lesion counts and improve acne when compared to 0.1% adapalene, while at the same time maintaining comparable tolerability. (PTX 1-5 at Figures 1-3 and Examples 2-3; PTX 231 at 244-49; PTX 212 at 358 (“demonstrating equivalent tolerability”)) 20. The Galderma patents-in-suit claim priority from a French application, FR 02 03070, filed on March 12, 2002, and the patents contain similar specifications. (PTX 42) All of the asserted claims of the patents-in-suit are entitled to the March 12, 2002, priority date. 21. The patents’ specifications indicate that “it has now surprisingly been shown that, in addition to exhibiting better therapeutic efficacy compared to known compositions, the compositions according to the invention exhibits good tolerance, comparable to those of the known compositions with a lower concentration of active principle.” (E.g., PTX 3 at 2:24-29) 22. The specifications note that the “pharmaceutical composition containing 0.3% of adapalene exhibits a benefit/risk ratio which makes it particularly suitable for the treatment of dermatological maladies having an inflammatory or proliferative component, and in particular, common acne.” (E.g., PTX 3 at 6:52-57) 23. The patents-in-suit contain data from the Phase II clinical trials with adapalene. The results of these trials show that 0.3% adapalene was more effective than 0.1% adapalene while at the same time maintaining a comparable tolerability profile to 0.1% adapalene. (E.g., PTX 3' at Figures 1-3, Examples 2-3) 24. For example, the patents state: These observations lead to the following conclusions: the 0.3% adapalene gel acts more rapidly than the 0.1% adapalene gel; specifically, from the fourth week of treatment, a difference is noted between the effectiveness of the 0.1% adapalene gel and the 0.3% adapalene gel; the 0.3% adapalene gel produces a clearly greater therapeutic effect after 8 weeks of treatment. (E.g., PTX 3 at 5:30-36) 25. The patents also include the following table: (E.g., PTX 3 at 6:23^1) . 26. The patents state, “[f]rom this table, it is noted that the occurrence of undesirable side effects is statistically the same for the two gels with the different concentrations of active agent.” (PTX 3 at 6:43-45) 27. This sentence is correct as the differences between the adverse events reported in the table with the 0.3% adapalene gel and the 0.1% adapalene gel are not statistically significant. (Tr. at 1494:2-14; 1496:14-23) 28. The patents then state that “[t]he intensity of the undesirable side effects is average, which leads to the conclusion that the two gels are well-tolerated by the patients.” (E.g., PTX 3 at 6:45-47) 29. Galderma also conducted Phase III clinical trials in order to obtain market approval from the FDA to sell a 0.3% adapalene product. In conducting the trials, the FDA required Galderma to compare the efficacy of the 0.3% adapalene product to the 0.1% adapalene product, as well as to a control vehicle, in order to gain FDA approval. (PTX 307 at GAL000033735; Tr. at 1410:16-20; see also Tr. at 1411:25-1412:5 (Dr. Thiboutot testifying that “[t]he protocol and the statistical analysis package were agreed upon with the FDA prior to the initiation of [the U.S. Phase III] trial”)) 30. The results of these trials confirmed that 0.3% adapalene gel was more effective than both the vehicle control and the 0.1% adapalene product; the FDA approved the 0.3% adapalene product in June 2007. (PTX 301; PTX 307 at GAL000033743; Tr. at 1411:2-24; 1412:6-10) 31. The U.S. Phase III trial also highlighted the unexpected tolerability profile of adapalene 0.3% gel. (PTX 231 at 248; Tr. at 1260:3-15; 1425:18-1426:1; 1427:21-1428:1) This clinical trial also demonstrated that with both adapalene 0.3% and adapalene 0.1% gel, the severity of most of the patient-reported adverse events and physician-reported local tolerability assessments was low and their effects were transient. (PTX 231 at 245-46, 248; Tr. at 1426:12-1427:12; 1412:20-24; 1416:9-1417:16; 1418:13-1419:18; 1421:5-1425:11) 32. Additionally, of the 258 patients in the adapalene 0.3% group, only three withdrew due to an adverse event, compared to two patients out of 261 in the adapalene 0.1% group, and one out of 134 in the gel vehicle group. (PTX 231 at 246; Tr. at 1425:13-17) 33. The publication reporting the results from the Phase III study specifically states that “[b]oth concentrations of adapalene gel were safe and well tolerated in this study. The signs and symptoms of skin irritation were mostly mild to moderate in severity and transient in nature. Importantly, despite the increase in adapalene concentration, the incidence of severe skin irritation was low and comparable between the two treatment groups.” (PTX 231 at 248) 34. In a book chapter published in 2010, Tolmar’s expert, Dr. Maibach, concluded that this paper demonstrated statistical superiority of 0.3% adapalene over 0.1% adapalene “while demonstrating equivalent tolerability.” (PTX 212 at 358 (emphasis added); Tr. at 1128:4-17) 35. All of the claims asserted at trial recite the 0.3% adapalene gel for use in the treatment of acne, and some more specifically recite common acne. (PTX 2 at claims 2, 35, and 36; PTX 3 at claims 5, 24, and 27; PTX 4 at claims 4 and 5; PTX 5 at claims 3, 40, and 41) 36. Galderma’s Differin® Gel, 0.3% is a 0.3% by weight adapalene gel and is approved by the FDA for use in the treatment of acne. (PTX 301) 37. Galderma’s Differin® Gel, 0.3% is the commercial embodiment of the claims asserted in this litigation. (PTX 301; Tr. at 1265:13-16) Tolmar does not dispute that Galderma’s Differin® Gel, 0.3% is an embodiment of the claims asserted in this litigation. 38. The Galderma patents-in-suit asserted against Tolmar at trial (the '181 patent, the '044 patent, the '558 patent, and the '060 patent) are directed towards 0.3% adapalene compositions that are effective for the treatment of acne or common acne and/or methods of using 0.3% adapalene compositions for the treatment of acne or common acne. (PTX 2-5) The '060 patent and the '044 patent contain claims reciting methods of effectively treating common acne or acne, using pharmaceutical compositions containing 0.3% adapalene. The '181 patent and the '558 patent contain claims to effective pharmaceutical compositions containing 0.3% adapalene for the treatment of acne or common acne. D. Priority Dates, Expiration, and Asserted Claims of the Patents-in-Suit 39. U.S. Patent Application No. 10/937,612, from which the '377 patent issued, was filed in the United States Patent and Trademark Office (“PTO”) on September 10, 2004. (PTX 1; PTX 6) 40. The '377 patent, entitled “Administration of 6-[3-(l-adamantyl)-4-methoxy-phenyl]-2-naphthoic acid for the Treatment of Dermatological Disorders,” issued on August 25, 2009, naming Michael Graeber and Janusz Czemielewski as the inventors, and listing Galderma Research & Development, Biot (FR) as the assignee. (PTX 1; PTX 6.) 41. The '377 patent claims priority from Provisional Application No. 60/370,-223, filed on April 8, 2002, and French Application No. 02 03070, filed on March 12,2002. (PTX 1; PTX 6) 42. The '377 patent is a continuation of PCT Application No. PCT/EP03/03246, filed on March 12, 2003. (PTX 1; PTX 6) 43. The PTO issued a Certificate of Correction on November 4, 2010 for the '377 patent term adjustment. (PTX 1 at GAL000277171) 44. The '377 patent is currently owned by Galderma Research & Development, S.N.C. and expires on September 10, 2026. (PTX 19; PTX 55-59; D.I. 287, Exh. 1, Uncontested Fact 15) 45. U.S. Patent Application No. 11/494,693, from which the '181 patent issued, was filed in the PTO on July 28, 2006. (PTX 2; PTX 20) 46. The '181 patent, entitled “Pharmaceutical Compositions Comprising 0.3% By Weight of 6-[3-(l-adamantyl)-4-methoxy-phenyl]-2-naphthoic acid for the Treatment of Dermatological Disorders,” issued on June 15, 2010, naming Michael Graeber and Janusz Czemielewski as the inventors, and listing Galderma Research & Development, Biot (FR) as the assignee. (PTX 2; PTX 20) 47. The '181 patent claims priority from Provisional Application No. 60/370,-223, filed on April 8, 2002, and French Application No. 02 03070, filed on March 12,2002. (PTX 2; PTX 20) 48. The '181 patent is a continuation-in-part of U.S. Patent Application No. 10/937,612, filed on September 10, 2004 and issued as the '377 patent, which is a continuation of PCT Application No. PCT/ EP03/03246, filed on March 12, 2003. (PTX 2; PTX 20) 49. The '181 patent is terminally disclaimed to the '377 patent, U.S. Patent No. 7,642,288, and U.S. Patent Application Nos. 12/437,008 (which issued as the '060 patent) and 12/103,182 (which issued as the '558 patent). (PTX 2; PTX 20) 50. The '181 patent is currently owned by Galderma Research & Development, S.N.C. and expires on March 12, 2023. (PTX 19; PTX 32; PTX 55-59; D.I. 287, Exh. 1, Uncontested Fact 23) 51. Galderma asserted at trial that Tolmar infringes claims 35 and 36 of the '181 patent, and Tolmar has conceded infringement of those claims. (Tr. at 53:14-17) 52. U.S. Patent Application No. 12/437,008, from which the '060 patent issued, was filed in the PTO on May 7, 2009. (PTX 3; PTX 33) 53. The '060 patent, entitled “Administration of 6-[3-(l-adamantyl)^l-methoxy-phenyl]-2-naphthoic acid for the Treatment of Dermatological Disorders,” issued on November 16, 2010, naming Michael Graeber and Janusz Czemielewski as the inventors, and listing Galderma Research & Development, Biot (FR) as the assignee. (PTX 3; PTX 33) 54. The '060 patent claims priority from Provisional Application No. 60/370,-223, filed on April 8, 2002, and French Application No. 02 03070, filed on March 12, 2002. (PTX 3; PTX 33) 55. The '060 patent is a continuation of U.S. Patent Application No. 10/937,612, filed on September 10, 2004 and issued as the '377 patent, which is a continuation of PCT Application No. PCT/EP03/03246, filed on March 12, 2003. (PTX 3; PTX 33) 56. The '060 patent is terminally disclaimed to the '377 patent, U.S. Patent No. 7,642,288, and U.S. Patent Application No. 12/103,182 (which issued as the '558 patent). (PTX 3; PTX 33) 57. The '060 patent is currently owned by Galderma Research & Development, S.N.C. and expires on March 12, 2023. (PTX 19; PTX 32; PTX 55-59; D.I. 287, Exh. 1, Uncontested Fact 31) 58. Galderma asserted at trial that Tolmar infringes claims 24 and 27 of the '060 patent. Tolmar has conceded infringement of claim 24, but denies that it infringes claim 27. (Tr. at 53:14-17) However, Tolmar has stipulated that if claim 27 of the '060 patent is held valid and enforceable, and if Tolmar’s formulation is found equivalent to the claimed formulation, and finally if prosecution history estoppel does not apply, Tolmar will induce infringement of that claim. (Tr. at 72:13-73:2) 59. U.S. Patent Application No. 12/103,182, from which the '558 patent issued, was filed in the PTO on April 15, 2008. (PTX 4; PTX 37) 60. The '558 patent, entitled “Administration of 6-[3-(l-adamantyl)^l-methoxy-phenyl]-2-naphthoic acid for the Treatment of Dermatological Disorders,” issued on November 23, 2010, naming Michael Graeber and Janusz Czernielewski as the inventors, and listing Galderma Research & Development S.N.C., Valbonne (FR) as the assignee. (PTX 4; PTX 37) 61. The '558 patent claims priority from Provisional Application No. 60/370,-223, filed on April 8, 2002, and French Application No. 02 03070, filed on March 12, 2002. (PTX 4; PTX 37) 62. The '558 patent is a divisional of U.S. Patent Application No. 10/937,612, filed on September 10, 2004, and issued as the '377 patent, which is a continuation of PCT Application No. PCT/EP03/03246, filed on March 12, 2003. (PTX 4; PTX 37) 63. The '558 patent is terminally disclaimed to the '181 patent and U.S. Patent Application No. 11/494,69 (which issued as the '181 patent). (PTX 4; PTX 37) 64. The '558 patent is currently owned by Galderma Research & Development, S.N.C. and expires on March 12, 2023. (PTX 19; D.I. 287, Exh. 1, Uncontested Fact 35) 65. Galderma asserted at trial that Tolmar infringes claim 5 of the '558 patent, and Tolmar has conceded that it infringes this claim. (Tr. at 53:14-17) 66. U.S. Patent Application No. 12/772,861, from which the '044 patent issued, was filed in the PTO on May 3, 2010. (PTX 5; PTX 47) 67. The '044 patent, entitled “Method for the Treatment of Acne Using Compositions Comprising 0.3% By Weight of 6-[3-(l-adamantyl)-4-methoxyphenyl]-2-naphthoic acid,” issued on January 11, 2011, naming Michael Graeber and Janusz Czernielewski as the inventors, and listing Galderma Research & Development, Biot (FR) as the assignee. (PTX 5; PTX 47) 68. The '044 patent claims priority from Provisional Application No. 60/370,-223, filed on April 8, 2002, and French Application No. 02 03070, filed on March 12, 2002. (PTX 5; PTX 47) 69. The '044 patent is a divisional of U.S. Patent Application No. 11/494,693, filed on July 28, 2006 and issued as the '181 patent, which is a continuation-in-part of Application No. 10/937,612, filed on September 10, 2004 and issued as the '377 patent, which is a continuation of PCT Application No. PCT/EP03/03246, filed on March 12, 2003. (PTX 5; PTX 47) 70. The '044 patent is terminally disclaimed to the '377 patent and U.S. Patent No. 7,642,288 and U.S. Application Nos. 12/437,008 (which issued as the '060 patent), 12/591,343, and 12/902,972. (PTX 5; PTX 47) 71. The '044 patent is currently owned by Galderma Research & Development, S.N.C. and expires on March 12, 2023. (PTX 19; D.I. 287, Exh. 1, Uncontested Fact 47) 72. Galderma asserted at trial that Tolmar infringes claims 40 and 41 of the '044 patent, and Tolmar has conceded infringement of those claims. (Tr. at 53:14-17) II. FINDINGS OF FACT RELEVANT TO OBVIOUSNESS A. State of the Art of Acne Treatment 73. Acne is one of the most common skin diseases, affecting almost 80% of adolescents and young adults. (DTX 520 at S2; PTX 231 at 242) 74. In the field of dermatology it is recognized that, when treating a patient with acne, a pharmaceutical composition or treatment method must not only reduce the number of acne lesions and their severity, but must also be well-tolerated by the patient, in order to actually be useful or effective for the treatment of acne. (PTX 209 at SI; Tr. at 1376:25-1377:7; 1399:20-21) 75. This tolerability component of a treatment is particularly important because acne treatment is not temporary, but rather may last for years. (See Tr. at 1186:15-1187:14) Additionally, the patient population most affected by acne (adolescents and young adults) tends not to be very tolerant of cutaneous side effects caused by many topical products, such as erythema, dryness, peeling, scaling, and other cutaneous irritation. (See Tr. at 1187:6-17) 76. Poorly tolerated side effects often lead to non-compliance, and a pharmaceutical composition cannot be useful or effective for the treatment of acne if patients refuse to use it. (PTX 209 at SI; Tr. at 1376:25-1377:7) 77. All of the clinical experts in the case have indicated that tolerability and efficacy are intertwined. Dr. Orlow stated that if side effects cause a patient to cease treatment, it “defeats the whole purpose and renders a treatment not useful, because you can’t then treat the patient by not putting on the medicine.” (Tr. at 1203:14-18) Dr. Thiboutot stated that “something can’t be efficacious unless somebody is actually able to tolerate it and use it.” (Tr. at 1399:20-21) Defendant’s expert, Dr. Maibach, agreed that “the tolerability of a medication is an important consideration in patient compliance” and that “compliance is important in determining a drug’s efficacy.” (Tr. at 1082:13-18) 78. Good tolerability of a composition, e.g., its ability to minimize side effects, is therefore an important aspect of the medication that reasonable physicians consider when treating acne patients. (PTX 209 at SI) B. The Use of Topical Treatments for Acne 79. As of the 2002 effective filing dates of the patents at issue, a variety of topical and systemic drugs were available that affected the pathogenesis of acne and have been used to treat acne. (See, e.g., PTX 188 at 1-2; DTX 520 at S38; PTX 280 at TOL173189-90; Tr. at 1305:18-1310:9) 80. Topical retinoids were, and are, considered first line acne therapy. (DTX 520 at S5, S8, S38) 81. Topical retinoids target comedones, which are precursors to other types of acne lesions, and also target inflammation, which significantly decreases inflammatory acne lesion counts. (DTX 520 at S5-S9; Tr. at 1310:2-9; 1371:25-1372:10) At a molecular level, it is believed that retinoids work by binding to retinoic acid receptors. (PTX 228 at S22-S23; Tr. at 1395:25-1396:19) 82. Tretinoin (Retin-A®), all-trans retinoic acid, was the first retinoid introduced for topical use, in 1971. (See PTX 209 at S2) Tretinoin was initially formulated in a hydroalcoholic vehicle, but skin irritation was a common complaint from patients using that formulation. (Id.) 83. The extent of tretinoin-induced irritation was determined to be dose related, such that the higher the concentration of tretinoin in the vehicle, the more irritation the product caused. Some patients could not tolerate an optimal tretinoin concentration because of the irritation issues arising with higher doses of tretinoin. (See PTX 209 at SI (“Tretinoin-induced irritation, for example, is generally dose- and vehicle-related.”); Tr. at 1193:2-14) In other words, even if a physician wanted to use a stronger tretinoin concentration to increase the efficacy in a patient, that use could be limited by the intolerability of the preparation. (See Tr. at 1193:6-10) 84. With tretinoin, one of the ways irritation was reduced was by decreasing the concentration of active drug in the topical formulation. One of the initial formulations of Retin-A® was the cream, which was first approved by the FDA, in 1973, at a 0.1% concentration. (See Tr. at 1189:7-11.) In light of the irritation caused by the 0.1% tretinoin cream, a 0.05% tretinoin cream was later introduced, followed by a further reduction to 0.025% tretinoin cream, in 1988. (See Tr. at 1189:12-15) 85. Unlike tretinoin, which activates all three RAR receptors (PS, Xu, X<|>), tazarotene, another retinoid, was developed as a receptor-selective retinoid. (Tr. at 1395:19-1396:19 (indicating tazarotene was approved in 1997)) It was initially thought that this receptor selectivity would yield increased tolerability (similar to that observed with adapalene). (Id.) In clinical practice, however, this has not been the case. (Tr. at 1396:20-23) 86. As stated by Dr. Maibach in one of his publications, “tazarotene is thought to be the most irritating of the topical retinoids,” causing itching, burning, irritation, and erythema. (PTX 212 at 358) In one study, “half of the patients applying tazarotene for only 2 to 10 minutes daily reported local skin irritation.” (PTX 212 at 358) 87. As with tretinoin, increased concentrations of tazarotene were considered to be effective but also to lead to increased irritancy. (See PTX 209 at S3 (“A dose-response relationship was noted for both efficacy and tolerability [for tazarotene].”)) C. Galderma Selects Differin® 0.1% as the Optimal Dose for Acne Treatment 88. Before 2002, the 0.1% concentration of adapalene was considered the “optimal concentration for efficacy and safety.” (PTX 228 at S21 (figure 7); PTX 163 at S119, S121, S124) Prior to 2002, despite extensive work and publications regarding adapalene, there are no references describing testing of any dosage above 0.1% for the treatment of acne. (See Tr. at 1226:3-7; 1298:22-1299:14; see also Tr. at 873:11-23 (Dr. Potts admitting that nobody had tested anything above 0.1% adapalene in the treatment of acne as of 2001)) 1. Shroot Patents: '720 Patent (1988), '895 Patent (1992), and '440 Reissue Patent (1993) 89. The Shroot patents disclose a general chemical formulation that “could result in hundreds, if not thousands of different compounds” to treat a broad range of diseases, in different dosage forms, administered in many different ways to the body, across a broad range of concentrations. (See Tr. at 1276:22-1277:8; 883:6-887:20) From this large genus of potential treatments, Galderma selected 0.1% adapalene as the concentration of adapalene with which to begin development of a topical treatment for acne. Dr. Shroot testified that, at the time of the Shroot patents’ disclosure, the 0.1% dose was considered an optimal dose for adapalene formulations. (See Tr. at 1841:18-23) 2. Verschoore (1991) 90. In 1991, Galderma published its first study on use of adapalene in acne patients as Verschoore et al., Efficacy and Safety of CD 271 Alcoholic Gels in the Topical Treatment of Acne Vulgaris, 124 British J. of Derm. 368-71 (1991) (“Verschoore (1991)”). (PTX 244) 91. The Verschoore (1991) article reports the results of a Phase II clinical trial where 0.03% and 0.1% adapalene formulations, as well as 0.025% tretinoin, were tested on the faces of patients with acne. Improvements in acne and tolerability were evaluated. (See PTX 244 at TOL173195;Tr. at 1229:4-8) 92. The results of this study suggest that increasing the concentration of adapalene beyond 0.1% would result in significantly increased irritation. (See Tr. at 1230:15-20) 93. The 0.1% adapalene formulation is reported as generally causing increased irritation compared to the 0.03% adapalene formulation. (See PTX 244 at TOL173197) Table 2. Mean skin safety scores at week 1 in each treatment group (PTX 244 at TOL173197, Table 2) In reviewing Table 2, Dr. Orlow noted that “what you can see if we look at the two columns for the .03 percent adapalene and the 0.1 percent adapalene is that for a number of measures, there are notable increases in the local irritation score.” (Tr. at 1229:18-21.) 94. As Dr. Orlow testified, one of ordinary skill in the art would view this data comparing 0.03% adapalene to 0.1% adapalene as suggesting a “significant increase in tolerability measures” would result from a further tripling of the adapalene dose from 0.1% to 0.3%. (Tr. at 1230:15-20) 3. Alirezai (1996) 95. The trend of increased irritation between the 0.03% and 0.1% dosages disclosed in Verschoore (1991) was later confirmed in the same dosages in aqueous gels in a publication by Alirezai et al., entitled “Comparative Study of the Effectiveness and Tolerance of 0.1 and 0.03 Percent Adapalene Gels and of a 0.025 Percent Tretinoin Gel in the Treatment of Acne,” 123 Ann. Dermatol. Venereol. 165-170 (1996) (“Alirezai (1996)”). (PTX 162) This article was considered by the patent Examiner in connection with all of the patents-in-suit. (See PTX 1-5) 96.The Alirezai article discloses a Phase II dose-ranging study conducted on 0.03% adapalene gel, 0.1% adapalene gel, and 0.025% tretinoin. (DTX 207 at TOL175384; Tr. at 974:24-975:3, 982:2-10) The article concludes that the “study demonstrates the effectiveness of adapalene in the topical treatment of acne, with the presence of a dose effect between the concentrations of 0.03 and 0.1%.” (DTX 207 at TOL175388) 97. These data, like the data from the study described in Verschoore (1991), describe the results of a Phase II clinical trial with 0.03% adapalene, 0.1% adapalene, and 0.025% tretinoin gels. This study, conducted on the faces of acne patients, demonstrates that the tolerability of the 0.1% dosage was different than that of the 0.03% dosage. {See PTX 162 at 168— 69) 98. With regards to burning, severe burning was seen in no patients treated with the 0.03% adapalene, but was seen in 13% of patients treated with the 0.1% adapalene aqueous gel. {See id. at 168) Additionally, significantly higher levels of “average” burning and itching after application were observed with the 0.1% formulation as compared to the 0.03% formulation. (PTX 162 at 168; Tr. at 1096:8-1097:18) Statistically higher levels of average persistent burning occurred with the 0.1% formulation as opposed to the 0.03% formulation. {See PTX 162 at 169; Tr. at 1098:7-17) 4. Allec and Verschoore (JAAD Supplement, 1997) 99. In a June 1997 supplement to the Journal of the American Academy of Dermatology (Volume 36, Number 6, Part 2), multiple articles were published that discussed “Adapalene: A novel topical retinoid receptor agonist for acne.” (DTX 155 at TOL011449; see Tr. at 1211:2-6) Within this supplement were two articles: one written by Allec et al., which discloses how 0.1% adapalene was considered the “optimal concentration for efficacy and safety” and which was considered by the Examiner during the prosecution of the patents-in-suit {e.g., PTX 1-5), and one written by Verschoore et al., which describes cumulative irritation testing on the backs and forearms of healthy subjects, including the testing of a 0.3% adapalene concentration. Both articles were understood to have been associated with Galderma at the time of the publication. {See PTX 163 at S119; DTX 155) 100. As both Dr. Orlow and Dr. Maibach testified, at the time this supplement was published, it was understood by those of ordinary skill in the art that no other group anywhere in the world had more experience with adapalene than the group at Galderma. {See Tr. at 1156:11-14; Tr. at 1206:20-1207:4) a. Allec (1997) Indicates to One Of Ordinary Skill in the Art That Galderma Considered 0.1% Adapalene as the Optimal Concentration 101. The Allec article, Skin Distribution and Pharmaceutical Aspects of Adapalene Gel, 35(6), J. Am. Acad, of Dermatol. S119-S125 (1997), teaches away from increasing the concentration of adapalene to treat acne, because it indicates 0.1% is the optimal concentration for the topical treatment of acne. (PTX 163 at S119, ¡3121, S123; Tr. at 1205:28-1206:19) The Allec article was considered by the PTO during the prosecution history of the asserted patents. {See, e.g., PTX 1-5) 102. The Allec article states: Our objective was to develop a formulation optimized for the topical treatment of acne by enhancing the concentration of active ingredient at the site of action to diminish local and systemic side effects and taking into account patient compliance. We describe the results of in vivo models used to select the optimal concentration of adapalene for efficacy and safety, the skin distribution profile of the drug after topical application of adapalene 0.1% gel, the concept of targeted delivery to the pilosebaceous unit, and finally the composition of adapalene 0.1% gel. (PTX 163 at S119 (emphasis added)) 103. A person of ordinary skill in the art would have recognized these statements as a conclusion of the company that developed adapalene had determined, from all the data it had on hand, that 0.1% was the optimal concentration for acne treatment, balancing efficacy and safety. (Tr. at 1206:10-19) 104. The Allec article further included a section under the heading “Selection of The Optimal Concentration of Adapalene For Efficacy And Safety,” describing efficacy studies performed in the Rhino mouse model and irritation studies completed in the rabbit irritation model. (PTX 163 at S121-22) That section concluded: “Based on these in vivo results, 0.1% was considered as the optimal concentration of drug for adapalene gel. This choice was subsequently confirmed in clinical trials of safety and efficacy.” (PTX 163 at S123 (emphasis added)) 105. A person of ordinary skill in the art would understand this statement to reference clinical trials in humans. (See Tr. at 1209:6-8) 106. This statement also demonstrated to one skilled in the art that Galderma had carried out the dose-response curve and had determined that 0.1% was the optimal dose for the treatment of acne, particularly in light of the results of the clinical trials set forth in the Verschoore (1991) and Alirezai (1996) articles. {See Tr. at 1209:21-1210:5; 1211:2-20) One of ordinary skill would understand those Phase II studies, which discouraged increasing the adapalene dosage beyond 0.1%, to support the statements in the Allec article regarding how the 0.1% adapalene concentration yields the optimal “balance of efficacy and tolerability.” (Tr. at 1235:23-1236:22) b. Verschoore (1997) Confirms to One of Ordinary Skill in the Art That Galderma Considered 0.1% Adapalene as the Optimal Concentration 107. Ten pages from Allec in the same supplement is another article, entitled Verschoore, et al., Adapalene 0.1% Gel Has Low Skin Irritation Potential, 86(6) J. Am. Acad, of Dermatol. S104-109 (1997) (“Verschoore (1997)”). (DTX 155) This article discusses the results of Phase I clinical trials conducted by Galderma on either the backs or forearms of healthy volunteers. (See DTX 155 at TOL1144955) 108. The focus of the article is a discussion of the results of two Phase I studies (studies A and B), which compared adapalene 0.03%, adapalene 0.1%, and 0.025% tretinoin gel. (DTX 155 at TOL11449-54) There is one line of data on a chart in the article that indicates that 0.3% adapalene gel had been tested, as well as an apparent reference in the introduction of the article. (See DTX 155 at TOL011450, TOL01145253, at Table I (Row 4)) 109. Based predominantly on the results of studies A and B, the article concludes that “[a]dapalene aqueous gel 0.1% was well-tolerated when applied topically in standard cumulative irritation tests.” (DTX 155 at TOL011454) It also states that “[t]he lower degree of skin irritation in clinical use has been confirmed in trials in acne patients in whom equal or superior efficacy to a tretinoin gel was demonstrated” and cites to references 4 and 5. (Id.) These two references also specifically disclose studies of 0.1% adapalene gel. (See Tr. at 895:2-17 (Dr. Potts confirming references 4 and 5 do not discuss 0.3% adapalene)) 110. Accordingly, Verschoore (1997) demonstrates that Galderma decided to pursue and obtain clinical approval for 0.1% adapalene. Further, the mention of the 0.3% concentration in the article demonstrates to one skilled in the art that the 0.3% adapalene was tried and rejected as the dosage to pursue for further clinical testing. (See Tr. at 1227:21-1228:6; 1211:2-21) 5. Czernielewski (2001) 111. In 2001, Galderma published another paper by Czernielewski, et al., entitled “Adapalene Biochemistry and the Evolution of a New Topical Retinoid for Treatment of Acne,” 15 (Suppl. 3) J. Eur. Acad. Dermatol. Venerol. 5-12 (2001), a review article that summarized the findings of other adapalene 0.1% studies, including Alirezai (1996) and Verschoore (1997). (PTX 177) The Czernielewski article was considered by the patent examiner in all of the Galderma patents-in-suit. (See, e.g., PTX 1-5) 112. The Czernielewski article discloses that the “primary objective in the development of adapalene was to create a topical agent with retinoid therapeutic effects that is considerably less irritating than topical tretinoin.” (DTX 21, DTX 21A at GAL0022189) The article further states that “adapalene is a very well tolerated compound with markedly lower irritation potential as compared with tretinoin.” (DTX 21, DTK 21A at GAL00022189) 113. The Czernielewski article suggests that 0.1% adapalene is the optimal dose for the treatment of acne. It states: “Adapalene 0.1% became the standard concentration for subsequent adapalene formulations.” (PTX 177 at TOL171093) Notably, in making this statement, the Czernielewski article cites to the Phase II study in the Alirezai (1996) article (PTX 162) as reference 20. (See PTX 177 at TOL171093, TOL171095) 114. The Czernielewski article does not disclose any information about any doses higher than 0.1% adapalene. (See Tr. at 874:23-24) Dr. Potts conceded that the Czernielewski article does not speak to 0.3% adapalene at all. (See Tr. at 874:23-24) 6. Differin® 0.1% Gel Data Sheet (1996) 115. The Differin® Gel, 0.1 % product insert (“the Differin® 0.1% Gel Data Sheet”) contains a section entitled “Over-dosage,” which states: “OVERDOSAGE: DIFFERIN® Gel is intended for cutaneous use only. If the medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur.” (PTX 255 at TOL 171086) D. The Prior Art Taken as a Whole Does Not Motivate One of Ordinary Skill in the Art to Develop a 0.3% Adapalene Formulation 116. Based on prior experience with tretinoin and tazarotene, the person of ordinary skill in the art would have had a reasonable expectation that tripling the concentration of adapalene to 0.3% would increase the incidence and severity of side effects compared to the 0.1% concentration. (Tr. at 1256:7-1257:4) If one were to modify the 0.1% formulation to be a 0.3% formulation, one would have expected a clinically meaningful increase in the incidence and severity of irritation. (See Tr. at 1256:7-1257:4 (Dr. Orlow indicating “there was expectation on the part of one of ordinary skill in the art that tripling the concentration was going to cause a significant increase in tolerability issues”)) 117. In March 2002, general experience with topical acne medications tended to show that dose and irritation correlated. (PTX 209 at SI) The experience in the art, thus, taught away from increasing the concentration of adapalene to obtain a product with a still-favorable tolerability profile. 118. In allowing the asserted patents, the Examiner indicated: “the present claims require the effective use of 0.3% of adapalene, and applicant has shown through unexpected results that the particular dosage of 0.3% adapalene was more effective than 0.1% adapalene in treating acne lesions while minimizing side effects, and Shroot in view of Differin® Gel Data Sheet does not render obvious the use of 0.3% adapalene as disclosed.” (PTX 36 at 5-6) E. None of the Art Cited by Tolmar Establishes the Obviousness of the Claimed Invention 119. A person of ordinary skill in the field of the asserted patents is a person with an advanced degree (an M.D. or a Ph.D. in clinical pharmacology or a related field) and several years of experience either as a dermatologist treating skin diseases with topical medications, or as a clinical researcher designing clinical trials or evaluating results of clinical trials of topical formulations for the treatment of dermatological disorders. (See Tr. at 1180:4-12) 120. Tolmar contends that each of the asserted claims of the patents-in-suit would have been obvious to a person having ordinary skill in the art at the time of invention. Specifically, Tolmar contends that the asserted claims would have been obvious over the following combinations of references: • Differin® 0.1% Adapalene Gel/Data Sheet in combination with any of Verschoore (1997) and/or the Shroot patents • and/or Goldfarb (2000) and/or Euvrard (2002); • Verschoore (1997) alone or in combination with the Differin® 0.1% Adapalene Gel/Data Sheet; and • The Shroot patents alone or in combination with any of Verschoore (1997) and/or Czernielewski (2001) and/or Goldfarb (2000) and/or Euvrard (2002) or further in combination with the Differin® 0.1% Adapalene Gel/Data Sheet. 121. None of these references, alone or in combination, provide sufficient motivation or reasonable expectation of success for a person of ordinary skill in the art to develop a 0.3% adapalene formulation for the treatment of acne. 1. The Shroot Patents 122. U.S. Reissue Patent No. RE 34,-440 to Shroot (“the '440 reissue patent”) (DTX 152) is a reissue of the Shroot U.S. Patent No. 5,089,895 (“the '895 patent”) (PTX 156), which is a divisional of the Shroot U.S. Patent No. 4,940,696, which is a divisional of the Shroot U.S. Patent No. 4,717,720 (“the '720 patent”) (PTX 155), which issued on January 5, 1988 (collectively, “the Shroot patents”). As the Shroot patents are in the same patent families, their specifications are nearly identical. (Compare DTX 152, and PTX 155, with PTX 156) a. The Broad Disclosure of the Shroot Patents Provides No Motivation or Suggestion to Select 0.3% Adapalene for the Treatment of Acne 123. As stated by Dr. Orlow, the Shroot patents disclose a “prototypie structure, which, with the various R groups, varied, could result in hundreds, if not thousands of different compounds. That could be used to treat a broad range of conditions ... administered in many different ways to the body ... across a broad range of concentrations.” (Tr. at 1276:22-1277:8) There is nothing in the Shroot patents that directs one of ordinary skill in the art to a gel containing 0.3% adapalene for the treatment of acne. (See Tr. at 1277:20-1278:1) 124. Not only do the Shroot patents disclose a broad range of chemical compounds, but the Shroot patents further disclose broad dosage ranges of the potential active ingredients and in different types of formulations: The topical or ocular composition contains preferably between 0.0005 and 5 weight percent of the active compound based on the total weight of the composition .... The concentration of the compound^) of Formula I in the cosmetic compositions is between 0.0005 and 2 weight percent, preferably between 0.01 and 1 weight percent, based on the total weight of the composition. (DTX 152 at 6:3-6, 6:19-22) 125. Dr. Shroot described the “range of doses” tested in the rabbit irritation test of the patents was “a vast data set.” (Tr. at 1841:12-17) 126. The range of 0.0005% to 5% for topical compositions covers four orders of magnitude (or a 10,000-fold dosage range). (Tr. at 1277:13-19) The range of .0005% to 2% for cosmetic compositions covers a 4,000-fold range. (Id.; Tr. at 886:24-887:8) Even the “preferred” range of 0.01% to 1% is a hundred-fold dosage range. (Tr. at 887:9-20; 1277:13-19) 127. Several of the examples in the Shroot patents disclose adapalene topical formulations.' Example A and Example E disclose the low dose of 0.001% adapalene, and Example D discloses the highest disclosed dose of 0.1% adapalene. (E.g., PTX 155 at 16:43, 17:23, 17:29-31, 17:36) There is nothing in the Shroot patents that specifically suggests selecting 0.3% adapalene out of those broad ranges. (Tr. at 1277:23-1278:1) 128. Furthermore, the Shroot patents indicate the claimed compounds can be used in a wide range of applications, including “systemic treatment” of dermatological diseases (acne in addition to other keratinization disorders), dermatological diseases with inflammatory and/or immunoallergic components, atopy (cutaneous or respiratory), and ophthalmology. (See, e.g., PTX 155 at 1:8-22, 4:53-5:4) 129. The Shroot patents indicate the resultant compositions may be administered in a number of different ways, including enterally (tablets, gelules, lozenges, syrups, suspension, solutions, powders, granules, or emulsions), parenterally (solutions or suspensions for perfusion or injection), topically, or ocularly. (See, e.g., PTX 155 at 5:26-33) 130. The Shroot patents further indicate that there are a number of different composition types capable of topical administration, such as ointments, tinctures, creams, pomades, powders, impregnated pads, buffers, solutions, lotions, gels, sprays, and suspensions. (E.g., PTX 155 at 5:34-42) Dr. Potts indicated that this is a “large number” of different topical applications. (See Tr. at 886:3 — 17) • 2. Verschoore (1997) 131. The Verschoore (1997) article is entitled “Adapalene 0.1% gel as low skin-irritation potential,” and lists co-inventor Janusz Czernielewski as a co-author. (DTX 155) Verschoore (1997) was not cited to or considered by the U.S. Patent Office during prosecution of any of the patents-in-suit. 132. There is a table in Verschoore (1997) that reports some of the results of thirteen different Phase I studies undertaken by Galderma “in 339 healthy human volunteers to investigate the cutaneous safety of adapalene (Table I).” (DTX 155 at TOL11450) One of the thirteen studies involved testing 0.3% adapalene on the back of 25 healthy individuals compared to a vehicle. (Id. at TOL11452-53 at Table I (Row 4)) There is a single row in the table reporting some data from this study that appears to be referenced in the introduction of the article. (See id. at TOL11450) This line of data shows that 0.3% adapalene performed well in the occlusion test on the back of healthy individuals. 133. The Phase I irritation test described in Verschoore (1997) was a screening test done on uncompromised healthy skin on the back as a prelude — not a substitute — to clinical testing on the face or on patients with disease. (See DTX 155 at TOL011454 (describing skin irritation model as “pharmacologic model” for skin penetration or biologic activity); Tr. at 1099:25-1100:8; 1794:7-1795:23; 1225:21-24 (Dr. Orlow indicating that success in Phase I does not necessarily predict success in subsequent clinical testing)) It was conducted using the repeat insult patch test (RIPT), which applies the tested products under occlusion on the backs of healthy individuals and not on facial skin afflicted with acne. (See DTX 155 at TOL011452) 134. Thus, the purpose of the Phase I studies reported in the Verschoore (1997) article was to establish that the drug was safe enough to proceed to Phase II and III clinical trials in patients with the disease. (See Tr. at 1242:10-20 (Dr. Orlow describing the cumulative irritation test as a “gating step”)) A skilled person would understand that data from these Phase I studies conducted in healthy skin cannot be extrapolated to how the product will work in acne patients. (Tr. at 1796:15-1797:12 (Dr. Czernielewski testified, “[Y]ou cannot extrapolate from those tests to what will happen in [a] given patient population.”)) 135. A skilled person would understand that “[rjesults obtained via patch-testing methods that involve application to the back cannot be assumed to reliably predict facial irritation.” (PTX 205 at S17) As Dr. Orlow testified, a skilled person would know that patch testing on the backs of healthy volunteers is a “poor predictor” of the irritation experienced by facial skin damaged by acne. (Tr. at 1244:19-1245:6) 136. Even Dr. Maibach had previously written that the 21-day cumulative irritation test “had failed to predict adverse reactions to skin damaged by acne or shaving, or sensitive areas such as the face” (PTX 165 at 49-50 (emphasis added)) 137. Those of ordinary skill in the art would have known that applying a product on the back under occlusion is very different from application of the product to inflamed lesions on the patient’s face in the clinical setting. (See Tr. at 1242:21-1243:3; 1796:6-1797:4) As Dr. Czernielewski testified, those of ordinary skill would also know that back skin and forearm skin are thicker and less sensitive than facial skin, which is “more thin, more delicate, and ... [has] more inflammatory response.” (Tr. at 1796:10-14) 138. The type of tes