Eli Lilly & Co. v. Perrigo Co.

FINDINGS OF FACT AND CONCLUSIONS OF LAW AND FINAL JUDGMENT BASED THEREON

SARAH EVANS BARKER, JUDGE

This matter is before the Court for decision on the issues of validity, enforceability, and infringement of three patents owned by Plaintiff Acrux DDS PTY Ltd. (“Acrux”). Plaintiff Eli Lilly Export S.A. is the exclusive worldwide licensee of the patents at issue in this litigation and has licensed its rights in the United States to Plaintiff Eli Lilly and Company (“Lilly”). Plaintiffs hold an approved New Drug Application (“NDA”) No. 022504 for the manufacture and sale of testosterone metered transdermal solution, 30 mg/1.5mL used to treat males for conditions associated with a deficiency or absence of endogenous testosterone. Lilly markets the product disclosed in NDA No. 022504 under the tradename Axiron®. Axiron® was approved by the Food and Drug Administration (“FDA”) on November 23, 2010. In connection with the NDA, Lilly listed nine patents in the Orange Book, including: U.S. Patent Nos. 6,299,900 (“the ’900 patent”); 6,818,226 (“the ’226 patent”); 6,923,- *927 983 (“the ’983 patent”); 8,071,075 (“the ’075 patent”); 8,419,307 (“the ’307 patent”); 8,435,944 (“the ’944 patent”); 8,177,449 (“the ’449 patent”); 8,807,861 (“the ’861 patent”); and 8,993,520 (“the ’520 patent”).

This action arises out of the Abbreviated New Drug Applications (“ANDA”) for the commercial manufacture, use, and sale of generic versions of Axiron® filed by Defendants Perrigo Company and Perrigo Israel Pharmaceuticals Ltd. (collectively, “Perri-go”); Actavis Láboratories UT, Inc. (“Acta-vis”); Amneal Pharmaceuticals LLC (“Am-neal”); and Lupin Pharmaceuticals, Inc. and Lupin Ltd. (collectively, “Lupin”), respectively. As will be described in more detail below, each Defendant sought FDA approval to market its generic transdermal testosterone product before expiration of the patents Lilly listed in the Orange Book, and, pursuant to 21 U.S.C. § 355 (j)(2)(A)(vii)(IV), each ANDA includes a “paragraph IV certification” to Plaintiffs’ patents, in which each Defendant has certified that certain patents are invalid and/or would not be infringed by Defendants’ manufacture, use, or sale, of their generic testosterone products.

Plaintiffs proceeded to trial on the following representative patent claims: claim 13 of the ’075 “formula” patent against Actavis; claim 20 of the ’944 “axilla” patent against all defendants; and claims 9 and 10 of the ’861 “applicator” patent against all defendants. Defendants contend that their proposed ANDA products would not infringe the asserted claims of the ’861 patent and that each of the asserted claims of the ’861 patent and the ’944 patent are invalid. Actavis also contends that the asserted claim of the ’075 patent is invalid.

A bench trial on these issues was conducted over nine (9) days, the first eight of which ran from June 16, 2016 to/through June 28, 2016, and a final day of trial occurred on July 21, 2016. Having now considered the evidence adduced at trial and the parties’ post-trial submissions, we hold, for the reasons set forth in detail below, as follows: (1) claim 13 of the ’075 patent is invalid for lack of written description and enablement; (2) claim 20 of the ’944 patent is invalid for obviousness; (3) the asserted claims of the ’861 patent are not infringed by Actavis’s, Perrigo’s or Lupin’s accused products; (4) claims 9 and 10 of the ’861 patent are neither anticipated nor obvious and are therefore valid and enforceable; and (5) Amneal’s applicator product and/or its use will directly and indirectly infringe the asserted claims of the ’861 patent.

Findings of Fact

I. The Parties

A. Plaintiffs

Lilly is an Indiana corporation that has its corporate offices and principal place of business in Indianapolis, Indiana. Lilly is engaged in the business of research, development, manufacture, and sale of pharmaceutical products throughout the world. Eli Lilly Export S.A. is a Swiss corporation and wholly-owned subsidiary of Lilly. Its corporate offices and principal place of business are located at 16 Chemin des Coquelicots, The Air Centre, 1214 Vernier/Geneva, Switzerland. Acrux is an Australian corporation and its corporate offices and principal place of business are located at 103-113 Stanley Street, West Melbourne VIC 3003, Australia. Acrux is engaged in the development and commercialization of pharmaceutical products.

B. Defendants

Perrigo Company is a Michigan corporation with its principal place of business in Allegan, Michigan. Perrigo Israel Pharam-ceuticals is an Israeli corporation with a principal place of business at 29 Lehi Street, Bnei Brak 51200, Israel. The Perri-go Defendants are engaged in the business of making and selling generic drugs, which they distribute in Indiana and throughout *928 the United States. On April 3, 2012, Perri-go Israel submitted ANDA No. 204255, pursuant to 21 U.S.C. § 355 (j), seeking approval from the FDA to sell “Testosterone Metered Transdermal Solution, 30 mg/ 1.5 mL.” By letter dated October 16, 2015, the FDA informed the Perrigo Defendants of its tentative approval of ANDA No. 204255.

Actavis (formerly known as Watson Laboratories, Inc.) is a Delaware corporation with its principal place of business in Salt Lake City, Utah. Actavis is engaged in the business of making and selling generic drugs, which it distributes in Indiana and throughout the United States. On January 29, 2013, Actavis filed ANDA No. 205328, pursuant to 21 U.S.C. § 355 (j), seeking approval from the FDA to sell “Testosterone Topical Solution, for Topical Use, 30 mg of Testosterone per Pump Actuation.” By letter dated July 29, 2015, the FDA informed Actavis of its tentative approval of ANDA No. 205328.

Amneal is a Delaware corporation with its principal place of business in Bridgewa-ter, New Jersey. Amneal is engaged in the business of making and selling generic drugs, which it distributes in Indiana and throughout the United States. On March 14, 2014, pursuant to 21 U.S.C. § 355 (j), Amneal filed ANDA No. 206998, seeking approval from the FDA to sell “Testosterone Topical Solution, 30 mg/1.5 mL.”

Lupin Pharmaceuticals is a Delaware corporation with its principal place of business in Baltimore, Maryland. Lupin Ltd, is an Indian corporation with its principal place of business located at B/4 Laxmi Towers, Bandra-Kurla Complex, Bandra (E), Mumbai 400 051, India. Lupin Pharmaceuticals is a wholly-owned subsidiary of Lupin Ltd. The Lupin Defendants are engaged in the business of making and selling generic drugs, which they distribute in Indiana and throughout the United States. On April 13, 2015, Lupin submitted ANDA No. 208061, pursuant to 21 U.S.C. § 355 (j), seeking approval from the FDA to sell “Testosterone Topical Solution, 30 mg/1.5 mL.”

Each of Defendants’ ANDA filings references Plaintiffs’ NDA No. 022504 for Axiron® (testosterone) Metered Transder-mal Solution 30 mg/1.5 mL as the referenced listed drug.

II. The Patents-In-Suit

A. The ’075 Patent

U.S. Patent No. 8,071,075, entitled “Dermal penetration enhancers and drug delivery systems involving the same,” issued on December 6, 2011, to named inventors Barry Leonard Reed, Timothy Mathias Morgan, and Barrie Charles Finnin. PTX-1 at 2. The ’075 patent was assigned to Acrux DDS Pty Ltd. upon issuance. Id.

The ’075 patent issued from U.S. Patent Application No. 11/905,926 filed on October 5, 2007. PTX-1 at 2. The ’926 application is a continuation of U.S. Patent Application No. 10/759,303 filed on January 20, 2004, which issued as U.S. Patent No. 7,438,203 . Id. The ’303 application is a continuation-in-part of U.S. Patent Application No. 09/910,780 filed on July 24, 2001, which issued as U.S. Patent No. 6,818,226 . Id. The ’780 application is a divisional of U.S. Patent Application No. 09/125,436, which was filed as International Patent Application No. PCT/AU97/00091, filed on February 19, 1997, which issued as U.S. Patent No. 6,299,900 . Id. The ’075 penetration enhancer patent claims priority to Australian Provisional Patent Application No. 8144 filed on February 19,1996. 1 Id.

*929 ’ Plaintiffs are asserting claim IB of the ’075 patent against Actavis. 2 Claim 13 depends from claims 1, 5, 9, 10, and 11. Claim 13 and the claims from which it depends recite as follows:

1. A transdermal drug delivery system comprising:

(a) a therapeutically effective amount of testosterone;

(b) at least one dermal penetration enhancer present in an amount of from 10 to 10,000 wt % based on the weight of the testosterone;' wherein the dermal penetration enhancer is at least one ester of formula (I):

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wherein R1 is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or NR3 R4; R2 is a C8 to C18 alkyl; R3 and R4 are each independently hydrogen, lower al-kyl or R3 and R4 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring; ri is 0 or 1, and q is 1 or 2, wherein, when n is 0 and R1 is NR3 R4, then NR3 R4 is para-substituted; and

(c)at least one volatile liquid present in an amount to act as a vehicle for the testosterone and penetration enhancer. 5. A method for the treatment of a testosterone deficient hypogonadal man which comprises administering to a dermal surface of said man in .need of such treatment a therapeutically effective amount of the drug delivery system according to claim 1.

9.The method according to claim 5, wherein said ester is a C8 to C18 alkyl para-aminobenzoate, C8 to C18 alkyl dimethyl-para-aminobenzoate, C8 to C18 al-kyl cinnamate, C8 to ⅞ alkyl methoxy-cinnamate or C8 to C18 alkyl salicylate.

10. The method according to claim 9, wherein said ester is octyl dimethyl-para-aminobenzoate, octyl para-methox-ycinnamate, or octyl salicylate.

11. The method according to claim 10, wherein said ester is octyl salicylate.

13. The method according to claim 11, wherein said volatile liquid is selected from the group consisting of ethanol, isopropanol, and a mixture thereof.

PTX-1 at 27.

Actavis has stipulated that it infringes the ’075 patent, if the patent is upheld as valid. Dkt. 264 at ¶¶ 1-3.

B. The ’944 Patent

U.S. Patent- No. 8,435,944, entitled “Method and composition for transdermal *930 drag delivery,” issued on May 7, 2013, to named inventors Tony Dipietro, Andrew Humberstone, Igor Gonda, Adam Watkin-son, Kerrie Setiawan, and Nina Wilkins. PTX-4 at 2. The ’944 patent was assigned to Acrux DDS Pty Ltd. upon issuance. Id.

The ’944 patent issued from U.S. Patent Application No. 11/445,463 filed on June 2006. PTX-4 at 2. The ’944 patent claims priority to U.S. Provisional Application No. 60/752,884 filed on December 23, 2005, and Australian Application No. 2005902902 filed on June 3, 2005. Id. The earliest date to which the ’944 patent may claim priority is June 3, 2005. Id.) Hadgraft Tr. 359:23-25.

Plaintiffs assert that defendants Perrigo, Actavis, Amneal, and Lupin infringe asserted claim 20 of the ’944 patent. 3 Had-graft Tr. 355:2-9. The asserted claim of the ’944 axilla patent and the claims to which it depends recite as follows:

13.A method of increasing the testosterone blood level of an adult male subject in need thereof comprising applying to at least one axilla of the subject, without occlusion by a patch device, a non-occlusive transdermal drug delivery composition consisting of: (a) a pharmaceutically effective amount of testosterone; (b) one or more lower alkyl alcohols, wherein the combined volume of the lower alkyl alcohol(s) is more than 60% (v/v) of the composition; (c) one or more penetration enhancers selected from the group consisting of octisalate, oetyldimethyl-para-aminobenzoate and octyl para-methoxy-cinnamate; (d) one or more viscosity modulating agents, in an amount effective to increase the viscosity of the composition to within the range of from greater than the viscosity of water to less than 300 centipoise; and (e) optionally, water, wherein the composition is applied in an amount effective to achieve a testosterone blood level in the subject of at least 200 ng/dL.

14. The method of claim 13 wherein the penetration enhancer is present in an amount of from 0.01% to 15% (w/v) of the composition.

15. The method of claim 14 wherein the penetration enhancer is octisalate.

16. The method of claim 15, wherein the lower alkyl alcohol is selected from the group consisting of ethanol, isopropanol, and mixtures thereof.

17. The method of claim 16 wherein the combined volume of lower alkyl alcohols) is more than 70% (v/v).

18. The method of claim 17 wherein the combined volume of lower alkyl alcohols/s) is more than 80% (v/v).

19. The method of claim 18 wherein the viscosity modulating agent is polyvinyl pyrrolidone.

20. The method of claim 19 wherein the polyvinyl pyrrolidone is present in an amount of from 1% to 3% (w/v) of the composition.

PTX-4 at 18.

Defendants stipulate that they infringe the ’944 patent, if the patent is upheld as valid. Dkt. 263, Joint Stipulation Between Plaintiffs and Perrigo Defendants, at ¶¶ 1-3; Dkt. 264, Joint Stipulation Between Plaintiffs and Defendant Actavis, at ¶¶ 1-3; Dkt. 272, Joint Stipulation Between Plaintiffs and Lupin Defendants as to U.S. Patent Nos. 8,435,944, 8,993,520, 8,177,449, and 8,419,307, at ¶ 13; Dkt. 284, Joint Stipulation Between Plaintiffs and Amneal as to U.S. Patent Nos. 8,435,944, 8,993,520, 8,177,449, and 8,419,307, at ¶¶ 1-3.

*931 The use of Axiron® is an embodiment of claim 20 of the ’944 patent.

C. The ’861 Patent

U.S. Patent Application No. 13/836,056 was filed on March 15, 2013, as a continuation of application No. 13/464,556 (now the ’307 patent) and issued as the ’861 patent,” entitled “Spreading Implement,” on August 19, 2014. PTX-5, ’861 patent, at 2. The ’861 patent names Peter Bayly, Mark Simon Bayly, Magnus Ahlstrom, and Adam Charles Watkinson as inventors. PTX-5, ’861 patent, at 2; Dkt. 359, Stipulated Faets, at ¶ 16.

The ’861 patent issued from U.S. Patent App. No. 13/836,056, filed on March 15, 2013, which is a continuation of U.S. Patent App. No. 13/464,556 filed on May 4, 2012, which is a continuation of U.S. Patent App. No. 11/678,673, filed on February 26, 2007, which claims priority to U.S. Provisional App. No. 60/884,482, filed on January 11, 2007.

Plaintiffs contend that Defendants’ applicators infringe dependent claims 9 and 10 of the ’861 patent. 4 These claims (and those from which they depend) recite as follows:

1. A system for transdermal administration of a physiologically active agent from a liquid composition, the system including a container containing the liquid composition including the physiologically active agent, a dispensing device for delivering liquid composition from the container; and an applicator for applying the liquid to an area of skin for transdermal administration said applicator including a support detachably contactable to the dispensing device or container being adapted to detach to permit said dispensing device to deliver said liquid composition, a receptacle mounted on the support defining a reservoir space which receives a volume of the liquid composition from the container, the receptacle having a base and a resiliently deformable wall, the wall being substantially transverse to the base and having a working surface that is used to spread the liquid composition over the area of the skin surface, the base having a surface such that the liquid composition cannot pass through the base.

9. A method of transdermal administration of a physiologically active agent to a subject including providing a system according to claim 1; applying the liquid composition including the physiologically active agent to the reservoir space; and deforming the wall of the receptacle containing the liquid composition against the skin of the subject and spreading the liquid composition over the area of the skin surface in at least one axilla.

10. A system according to claim 1 wherein the receptacle defining the reservoir space has an open top being configured to receive the liquid composition from the dispensing device through the open top.

(Id. at claims 1, 9,10.)

Plaintiffs assert that Actavis and Perri-go indirectly infringe the ’861 patent. Dkt. 142-1, Second Consolidated Amended Complaint for Patent Infringement, at ¶¶ 129-35, 180-90, 283-89, 378-88; Dkt. 264, Joint Stipulation Between Plaintiffs and *932 Defendant Actavis, at ¶¶ 4-6; Dkt. 263, Joint Stipulation Between Plaintiffs and Perrigo Defendants, at ¶¶4-6. Plaintiffs assert that Araneal and Lupin directly and indirectly infringe the ’861 patent. Dkt. 142-1, Second Consolidated Amended Complaint for Patent Infringement, at ¶¶ 433-43, 488-98; Case No. 1:15-CV-1047, Dkt. 1, Complaint for Patent Infringement, at ¶¶ 73-83,128-38.

III. The Experts

A. Plaintiffs’ Experts

At trial, Plaintiffs offered the testimony of the following experts: (1) Dr. Jonathan Hadgraft, an expert in transdermal formulation and skin barrier function; (2) Dr. Irwin Goldstein, an expert in urology and hypogonadism; and (3) Dr. Alexander Slocum, an expert in the field of mechanical engineering and the design of medical devices.

Jonathan Hadgraft, D.Sc.

Dr. Jonathan Hadgraft, Plaintiffs’ trans-dermal formulation and skin barrier function expert, has worked in the field of dermal and transdermal drug delivery for more than thirty-five years. Dr. Hadraft testified that in his opinion the asserted claims of the ’075 and ’944 patents are valid.

In 1973, Dr. Hadgraft received a B.A. and M.A. in Chemistry, with an emphasis on Chemical Pharmacology, from the University of Oxford. In 1975, he earned a doctorate in Physical Chemistry from the University of Oxford. In 1992, he was awarded a D.Sc. from the Faculty of Medicine at the University of Oxford in recognition of his research in dermal drug delivery. PTX-220; Hadgraft 102:2-104:17, 106:12-114:22, 116:20-123:23, 126:24-127:21.

Dr. Hadgraft founded the Prediction of Percutaneous Penetration Conference and Skin Forum, which is comprised of multiple academic and industrial research groups. In recognition of his contributions, he was named a Fellow of the American Association of Pharmaceutical Scientists, Academy of Pharmaceutical Sciences, and the Controlled Release Society. PTX-220; PDX-3001; Hadgraft 102:2-104:17, 106:12-114:22,116:20-123:23,126:24-127:21.

Dr. Hadgraft has conducted research, lectured extensively on skin barrier function and dermal and transdermal drug delivery, and published more than 500 peer-reviewed articles. Dr. Hadgraft currently holds the rank of Emeritus Professor of Biophysical Chemistry at the School of Pharmacy, the University of London. Prior to assuming Emeritus status, Dr. Hadgraft was a full-time Professor of Biophysical Chemistry at the School of Pharmacy. Since the 1980s, Dr. Hadgraft has served as an industry consultant for SmithKline Beecham, Eastman Kodak, Shire and others on formulations for dermal and trans-dermal therapies. Dr. Hadgraft worked on approved transdermal products, such as nitroglycerin, clonidine, estradiol, fentanyl, and nicotine. PTX-220; PDX-3000; PDX-3002; Hadgraft 102:2-104:17, 106:12-114:22, 116:20-123:23, 126:24-127:21; 142:25-143:5. However, he has never been the lead formulator of a transdermal product that has been approved by the FDA and has never worked on any actual experiments with testosterone or conducted any research and development of a transdermal testosterone product. Hadgraft 306:10-12, 307:23-308:6.

Irwin Goldstein, M.D.

Dr. Irwin Goldstein is a Board-certified urologist. The field of urology focuses on the organs associated with the urinary system and male reproduction. At trial, Dr. Goldstein opined that the asserted claim of the ’944 patent would not have been obvious.

Dr. Goldstein received his M.D.C.M. from McGill University Faculty of Medicine in 1975. He served as a surgical resi *933 dent and fellow at University Hospital in Boston. In 1982, Dr. Goldstein joined the faculty of Boston University School of Medicine, teaching courses in urology and gynecology until 2005. PDX-7000; PDX-7001; Goldstein 604:9-610:10.

Dr. Goldstein has been treating patients for more than forty years. He has taught and lectured widely and published in excess of 300 peer-reviewed papers. Dr. Goldstein currently holds the position of Clinical Professor of Surgery at the University of San Diego and Director of San Diego Sexual Medicine, where he diagnoses and treats patients with hypogonadism. He also serves as a consultant in the Surgical Service of the San Diego Veterans Administration Hospital. PDX-7000; PDX-7001; Goldstein 604:9-610:10.

Dr. Goldstein was a principal investigator or co-investigator for various clinical trials, and was a consultant on a clinical trial involving the FDA’s consideration of undecanoate as an oral testosterone therapy. Dr. Goldstein has been granted funding by the National Institutes of Health to study urologic complications of diabetes and sexual dysfunction. PDX-7000; PDX-7001; Goldstein 604:9-610:10.

Alexander H. Slocum, Ph.D.

Dr. Alexander Slocum is an expert in the field of mechanical engineering. He conducts research, has published in excess of 100 academic peer-reviewed journal papers, and lectures extensively in the field. PTX-222 at 2, 4-5; Slocum 525:22-24, 526:21-527:11, 532:3-8. Dr. Slocum opined at trial that the asserted claims of the ’861 patent are valid and infringed by Defendants’ products.

Dr. Slocum received his Bachelor of Science degree in mechanical engineering in 1982, a Master of Science degree in 1983, and a Ph.D. in mechanical engineering in 1985, all from the Massachusetts Institute of Technology (“MIT”). PTX-222 at 1; Slocum 526:13-15. He is currently the Pappa-lardo Professor of Mechanical Engineering at MIT. PTX-222 at 3; Slocum 527:10-11. He teaches and conducts research in the field of precision machine design. PTX-222; Slocum 527:12-19, 531:2-8, 533:15-535:2. He has a particular research focus on machine tools and manufacturing equipment, medical devices, renewable energy machines, and tools for the petroleum industry. PTX-222; Slocum 535:13-536:7. He has extensive experience studying and working with fluids and seals. Slocum 527:12-19.

From 1983 until 1986, he served as a mechanical engineer with the National Institute of Standards & Technology (“NIST”). PTX-222 at 2; Slocum 526:17-21. During his tenure at NIST, he assisted with the Charters of Freedom project to create the encasements to house and protect the Bill of Rights, Constitution, and Declaration of Independence in the National Archives. Slocum 527:24-528:14. In 1986, he received the U.S. Department of Commerce Bronze Medal Award for Outstanding Federal Service. PTX-222 at 3.

Dr. Slocum has been awarded more than 100 patents and has developed an important precision alignment standard for the semiconductor industry. PTX-222 at-1; Slocum 533:10-535:12. He has helped to create eleven products that have been awarded “R&D 100” awards, each for being one of the one hundred most technologically significant new products of the year. PTX-222 at 2-3; Slocum 533:1-8.

Dr. Slocum is the author of the books “Precision Machine Design” (Dearborn, MI, SME 1985) and “FUNdaMENTALS of Design” (Cambridge, MA, MIT 2005), http://pergatory.mit.edu/resources/FUN da MENTALS.html. PTX-222 at 2; Slocum 530:22-531:18. He has also received the SME Frederick W. Taylor Research Medal and the ASME Leonardo da Vinci and Machine Design Awards, which are the two most prestigious awards for machine *934 design bestowed by the American Society for Mechanical Engineers. PTX-222 at 2-3; Slocum 533:9-535:2.

B. Defendants’ Experts

At trial, Defendants presented the testimony of the following experts, each of whom appeared in person: (1) Dr. Russell Potts, an expert in the field of research and development for the transdermal delivery of active pharmaceutical ingredients into and through the skin; (2) Dr. Walter Chambliss, an expert in the field of pharmaceutical sciences and pharmaceutical formulations and related fields; (3) Dr. Peter Snyder, an expert in the field of endocrinology and the treatment of hypogonadism with testosterone; (4) Dr. Sher Singh, an expert in the field of the design and manufacturing of products and packaging for cosmetic, health and beauty aids and pharmaceutical applications; and (5) Dr. Steven MacLean, an expert appearing on behalf of Lupin regarding the fields of polymer science and mechanical engineering. Amneal offered the additional expert testimony of Mr. Hermann Plank, an expert in design and manufacture of products and packaging for cosmetic, health and beauty aids, and pharmaceutical applications, who appeared and testified through written submission.

Russell Potts, Ph.D.

Dr. Potts’s expertise relates to research and development for the transdermal delivery of active pharmaceutical ingredients into and through the skin. Potts 1304:13-16, 1306:2-9. He testified that, in his opinion, the asserted claims of the ’075 and the ’944 patents are invalid.

Dr. Potts received his Bachelor of Science degree in Chemistry at Michigan State University in 1968, his Masters of Science degree in Physical Chemistry at Cornell University in 1970, his Ph.D. in Biochemistry at the University of Massachusetts in Amherst in 1978, and undertook post-doctoral training in Chemistry at Yale University in 1979. DTX-1122 at 2. Dr. Potts accrued more than 30 years of professional experience relating to drug delivery into and through the skin, including conducting and leading research at Gillette Research Institute, Pfizer Central Research, and Cygnus Therapeutic Systems. Potts 1301:3-23. His industry work has led to several FDA-approved transder-mal drug products, including a nicotine patch and contraceptive patch. Id. at 1301:24-1302:11 . In 2002, Dr. Potts retired from full-time work in the pharmaceutical industry to become a full-time consultant.

Dr. Potts has published more than 115 papers in the area of skin transport and has been awarded 35 U.S. patents. Id. at 1302:12-19 . He is a recognized leader in the field of transdermal drug delivery, having served on the board of several prominent journals and was elected a fellow of significant industry organizations in the field of pharmaceutical sciences. Id. at 1302:23-1303:22 . Most notably, in 1991, Dr. Potts served as the Chairman of the Gordon Conference on topical and transdermal drug delivery. Id.

Walter Chambliss, Ph.D.

Dr. Chambliss is an expert in the field of pharmaceutical sciences and pharmaceutical formulations and related areas. Cham-bliss 1529:11-17; 1535:5-1536:7. At trial, he testified that in his opinion claim 20 of the ’944 patent is invalid. He also testified regarding certain aspects of the asserted claims 9 and 10 of the ’861 patent.

Dr. Chambliss accrued 30 years of experience in pharmaceutical research and development, both in industry and academia, including extensive experience in the formulation, development, and manufacturing of a variety of types of formulations that are applied to the skin for topical and/or transdermal use, including hydroalcoholic solution, lotion and gel formulations. *935 Chambliss 1530:21-1535:4; PGO DX 2-2, 2-3; PTX-224. Dr. Chambliss received a Bachelor of Science degree in Pharmacy in 1977, a Masters of Science degree in Pharmaceutics in 1980, and a Ph.D. in Pharmaceutics in 1982, all from the University of Mississippi. Chambliss 1529:18-1530:16; PTX-224. For seventeen years, Dr. Cham-bliss researched and developed various pharmaceutical products for G.D. Searle, Bristol-Myers, and Schering-Plough. Overall, he was involved in the formulation development and/or process development of more than 300 products. Chambliss 1530:21-1535:4; PGO DX 2-2, 2-3; PTX-224. In 1998, Dr. Chambliss retired from full-time work in the. pharmaceutical industry, following which he has worked as a consultant. Currently, he is a professor of pharmaceutics at the University of Mississippi. Chambliss 1531:9-21; PTX-224.

Peter Snyder, M.D.

Dr. Snyder testified as an expert in the field of endocrinology and the treatment of hypogonadism with testosterone. Snyder 912:25-913:8. He opined that the asserted secondary considerations do not provide compelling evidence of the nonobviousness of asserted claim 20 of the ’944 patent.

Dr. Snyder received his Bachelor’s degree from Williams College in 1961 and his M.D. from the Harvard Medical School in 1965. DTX-1121 at 2. He completed his residency in internal medicine at Beth Israel Hospital in Boston and received a fellowship in endocrinology at the University of Pennsylvania in 1971. Id, Following his fellowship, Dr. Snyder has been a member of the faculty at the University of Pennsylvania in the field of endocrinology, specializing in reproductive endocrinology, which is the study of conditions affecting reproductive organs. Snyder 909:3-13.

Dr. Snyder has conducted extensive research in the area of reproductive endocrinology, including the treatment of male hypogonadism with transdermal testosterone replacement therapies. Id. at 910:3-7, 911:20-22, 912:6-16 . He was involved with the pivotal clinical trials leading to FDA approval for Testoderm®, Testoderm® TTS, and AndroGel®. Id. at 912:6-16 . Dr. Snyder is currently heading up the largest clinical trial of testosterone replacement therapy, which involves approximately 800 patients located at 12 centers across the United States. Id. at 910:24-911:15 .

Sher Paul Singh, Ph.D.

Dr. Singh’s expertise is the design and manufacturing of products and packaging for cosmetic, health and beauty aids and pharmaceutical applications. See Singh 1010:5-7. At trial, he testified that in his opinion Defendants’ applicator products did not infringe on the ’861 patent. He also testified as to the invalidity of the ’861 patent.

Dr. Singh received a Bachelor of Science degree in Mechanical Engineering with Honors at Punjab University in Chandigarh, India in 1982, a Masters of Science degree in Packaging from Michigan State University in 1983, and a Doctorate in Agricultural Engineering from Michigan State University in 1987. See Singh 1006:23-1007:3. Dr. Singh is currently Professor Emeritus at Michigan State University and President of Packaging Forensics Associates Inc., a Michigan consulting company providing consulting services and expert testimony for transportation, packaging, and personal injury litigations. See Singh 1004:12-15. Dr. Singh has authored more than 150 peer-reviewed papers, and participated as a contributing author of two text books and eight book chapters in the areas of packaging, machinery, and forensics. See Singh 1008:21-23.

Dr. Singh has served as a consultant for various companies, including leading suppliers of health and beauty aids, pharmaceuticals, and medical device packaging systems, for whom he has designed, tested, *936 and evaluated various products and packaging systems. See Singh Tr. 1008:11-16. Dr. Singh currently serves as a member of several professional societies and associations representing the manufacturers of consumer products and packaging, including the International Association of Packaging Research Institutes and the American Society of Testing and Materials. See Singh Tr. 1009:15-20.

Steven MacLean, Ph.D,, P.E.

Dr. MacLean is Lupin’s expert based on his knowledge and experience in polymer science and mechanical engineering. Mac-Lean 1657:5-13. He opined at trial that asserted claims 9 and 10 of the ’861 applicator patent are invalid for indefiniteness. He further testified that Lupin’s applicator does not infringe claims 9 and 10 of the ’861 patent.

Dr. MacLean received his Ph.D. in Materials Science from the University of Rochester in 2007, following his completion of his Master of Science degree in Materials Science and Engineering from Rochester Institute of Technology in 2001. DTX-3002_001; MacLean 1645:7-13; DDX-502. His Master’s degree and Ph.D. were concentrated on the field of polymers. MacLean 1645:14-20. Dr. MacLean also received a Bachelor of Sciences degree and a Master of Engineering degree in Mechanical Engineering from Rensselaer Polytechnic Institute in 1993 and 1997, respectively. DTX-3002_001; MacLean 1645:7-13; DDX-502.

Dr. MacLean is a licensed, registered Professional Engineer in Mechanical Engineering in the States of New York and Maryland and a certified Six Sigma Black Belt. DTX-3002_002; MacLean 1646:1-1647:10; DDX 503. Currently, Dr. Mac-Lean is a Principal Engineer in the Polymer Science and Materials Chemistry Practice at Exponent Failure Analysis Associates, Inc., which is an engineering and scientific consulting firm. MacLean 1649:23-1650-6. Dr. MacLean conducts proactive as well as reactive investigations, assisting clients in developing or designing products and providing product failure analyses in areas including intellectual property matters. MacLean 1650:8-21. He has sixteen years of experience in materials selection as well as designing, testing, and manufacturing polymeric raw materials. MacLean 1648:16-1649-14; DDX 504. In his 20 years in the polymer industry, Dr. MacLean concentrated his work on numerous medical devices, including trocar tubes, syringes, surgical scalpels, vaginal speculums, tongue retractor implants, pelvic mesh implants, sleep apnea masks and devices. MacLean 1651:2-9.

Dr. MacLean is a voting member of the American Society for Testing Materials (“ASTM”), a professional organization that develops test standards for materials, and is a senior member of the Society of Plastics Engineers. MacLean 1651:12-1652:9; DDX-505; DTX-3002_004. Dr. MacLean has authored and presented approximately 25 publications and presentations in the fields of polymer science and polymer mechanics, including Designing for injection molded 'parts, General Electrics Plastics Customer Design Workshop (1998, 1999); Mechanical behavior of polymeric materials, General Electrics Plastics Engineering Workshop (1997); and The importance of polymer structure-property relationships in preventing failure in medical devices, Medical Grade Polymers Conference (2015). MacLean 1652:11-1653:20; DDX-506; DTX-3002_002-3.

Hermann Plank, MSc.

Mr. Plank, MSc. is Amneal’s expert in the design and manufacture of products and packaging for cosmetic, health and beauty aids, and pharmaceutical applications. He received his Masters of Science degree in Plastics Technology from Leo-ben University in Austria in 1985. He pres *937 ently is the President of TecnoKal LLC. For thirty years, he has been engaged in Plastics Technology, including product development and execution as well as plastics, thermoplastics, thermoset, composite materials, injection molding, extrusion, thermoforming, blow molding, and defining prototyping methods. Mr. Plank is credited for his work in designing several applicators for delivery of cosmetic and other products to the body, including underarm applicators. In his opinion, Amneal’s proposed applicator does not infringe any of the asserted' claims of the ’861 patent. 5

IV. The ’075 Formula Patent

The ’075 formula patent claims a trans-dermal drug delivery system comprising a therapeutically effective amount of testosterone and at least one dermal penetration enhancer selected from safe ester sunscreens. PTX-1 at 2. The drug delivery system claimed in the ’075 patent is used to treat various medical conditions, including testosterone deficiency in hypogonadal men. Id. at col. 28,11. 32-26.

Definition of a Person of Ordinary Skill in the Art for the ’075 Patent

A person of ordinary skill in the art (“POSA”) for the ’075 formula patent would have been. a pharmaceutical -formulator with a doctorate or master’s degree and with at least two years of experience in transdermal or topical formulation, working together with, or able- to rely on, the expertise of a clinician or physician. Hadgraft 250:23-251:5; 251:14-16. Both sides’ experts agree that their opinions on validity of the ’075 patent are the same regardless of which expert’s precise POSA definition is adopted. Hadgraft 219:1-5; Potts 1309:17-1310:9.

Hypogonadism

Hypogonadism is the medical term for the physical condition of low levels of testosterone in men. Goldstein 616:14-19. Testosterone is a 19 carbon sex-steroid that is a male hormone circulating in human blood that affects male androgen dependent tissues, e.g., the prostate, scrotum, and apoc-rine glands. PDX-7003; Goldstein 613:15-614:8. Testosterone also forms and develops secondary sex characteristics such as facial hair, muscle strength, deepening of the voice, bone growth, sperm maturation, and sexual desire. Goldstein 614:9-14. There are several organs involved in the production and secretion of testosterone, including the hypothalamus, pituitary gland, and testicles. PDX-7003; Goldstein 615:8-616:13.

Hypogonadism is generally classified as primary or secondary hypogonadism. Primary hypogonadism is a lack of function of the testes; anorchism, orchitis, cancer of the testicles, and Klinefelter syndrome are examples. PTX-390 at 1; PDX-7004; Gold-stein 617:3-12. Secondary hypogonadism involves a breakdown of the regulatory system that governs the hypothalamus and pituitary glands which regulates the production of testosterone. Tumors, diabetes, hypertension, high cholesterol, and HIV exemplify' conditions that can lead to secondary hypogonadism and interfere with or limit testosterone production. PDX-7006; Goldstein 618:5-22.

A hypogonadal male may suffer physical, metabolic, cognitive, psychological, and sexual symptoms, e.g,, decreased bone density, impaired memory, and reduced libido. PDX-7007; Goldstein 619:8-620:15. In 2005, it was estimated that approxi *938 mately 13 million men were hypogonadal. Goldstein 621:1-15.

The Invention and ’075 Patent

Although testosterone treatments have been available for many years, early treatment modalities involved the administration of drugs by intramuscular injection or oral administration, both of which had significant drawbacks. Transdermal delivery of testosterone, by contrast, offered a number of advantages, including reduced pain, ease of administration, and better bioavailability. PTX-390 at 1; PTX-253 at 1, 3; PDX-7008; Hadgraft 132:11-21; Gold-stein 621:16-24.

In the 1980s, Drs. Reed and Finnin, professors in Melbourne, Australia, were engaged in transdermal formulation research, studying formulations containing hydroquinone, a compound that causes depigmentation in the skin. Because they were concerned that the effects of sun exposure on skin would interfere with the effects of the hydroquinone formulations, they decided to add a sunscreen agent to the formulation. Upon adding the sunscreen agent, they were surprised to observe that a formulation without the normal penetration enhancer but with sunscreen substantially enhanced trans-dermal penetration of hydroquinone. PTX-1 at co. 11:41-45 (“Additionally the group of compounds of the invention surprisingly exhibited appreciable penetration into and substantivity for the outer layers of the skin, namely the stratum corneum which has previously presented a formidable barrier to percutaneous drug absorption.”).

Following this discovery, Drs. Reed and Finnin continued their research with Tim Morgan, then a Ph.D. student. Together, these inventors of the ’075 patent discovered that sunscreen compounds in combination with testosterone showed a significant improvement in skin penetration, and that the penetration enhancer, octyl salicylate, in particular, showed a substantial improvement in testosterone absorption through the skin. PTX-1 at col. 23, 11. 15-41; Hadgraft 165:14-24.

In 1998, the inventors of the ’075 patent along with a small group of founding members formed the company Acrux to develop pharmaceutical treatment based on their discovery. Their development work led to FDA approval of two products that include octyl salicylate as the dermal penetration enhancer—Evamist®, an estrogen product sold in the United States, and Axiron®, which is a transdermal testosterone formulation used to treat hypogonadal men. Axi-ron® is the product at issue in this litigation. 6

Contemporaneous Transdermal Drug Formulations

By February 1996, when the priority application for the ’075 patent was filed, several compounds were in use or otherwise known that delivered transdermally into systemic circulation: scopolamine, nitroglycerin, fentanyl, nicotine, estradiol, isosorbind dinitrate, clonidine, norethister-one, and testosterone. PTX-531 at 17; PTX-253 at 3; PDX-3004; Hadgraft 141:20-143:18. As of 1996, transdermal testosterone formulations were commercially available and known to be therapeutically effective in increasing testosterone blood levels. PDX-2064. These formulations included the marketed drugs Testoderm®; Andro-derm® (PTX-630); Percutacrine Androge-nique Forte (PTX-576 at 2); Testogel®; and a formulation that was not marketed *939 but had been tested by Heiber et al. PTX-409 at 21-22; Dkt. 367 ¶ 88.

Claim 13 of the ’075 Patent

Claim 13 of the ’075 patent claims a method for the treatment of a testosterone deficient hypogonadal man which comprises administering to a dermal surface of said man in need of such treatment a therapeutically effective amount of a trans-dermal drug delivery system comprising: (a) a therapeutically effective amount of testosterone, (b) octyl salicylate as a dermal penetration enhancer present in an amount of from 10 to 10,000 wt % based on the weight of the testosterone, 7 and (c) at least one volatile liquid selected from the group consisting of ethanol, isopropanol, and a mixture thereof present in an amount to act as a vehicle for the testosterone and penetration enhancer. PTX-1 at claims 1, 5, 9-11, 13. This description is consistent with Plaintiffs’ proffered description of the scope of claim 13 in their opening statement as well as their pre-trial submissions. See PDX 2019; Dkt. 364 at 51-53; 227-228.

A POSA would understand that the transdermal drug delivery system recited in asserted claim 13 must include the penetration enhancer octyl salicylate in an amount ranging from 10% to 10,000% reíar five to the weight of testosterone. Potts 1307:22-1308:11; 1310:16-1311:3; see Had-graft 340:21-341:15. The claimed upper limit of 10,000% corresponds to 100 times more octyl salicylate than testosterone by weight. Potts 1310:16-1311:3.

The Testosterone Formulation Examples in the ’075 Patent Specifícation

The specification of the ’075 penetration enhancer patent includes no exemplary testosterone formulation having 100-times more octyl salicylate than testosterone. Hadgraft 324:16-325:4; Potts 1321:11-1322:6. The parties’ experts are not aware of any transdermal formulation that includes 100 times more penetration enhancer than active ingredient and there is no evidence that the inventors ever made or tested such a formulation. Hadgraft 325:5-12. The specification instructs that “[t]he concentration of absorption/penetration enhancer may be in the range from 10-10,000 weight percent of absorption/penetration enhancer based upon the weight of the active ingredient.” PTX-1 at col. 12, 11. 35-45. But “[t]he ratio of penetration enhancer to active ingredient may vary considerably and' will be governed as much as anything, by the pharmacological results that are required to be achieved.” Id. “In principle, it is desirable that as little absorption enhancer as possible is used,” but, “for some actives, it may well be that the upper range of 10,000% by weight will be required.” Id. The specification lists approximately 700 active ingredients. Had-graft 341:23-342:20; PTX-1 at col. 5, 1. 23-col. 9, 1. 60. The specification does not name testosterone as an active ingredient for which the inventors believed 10,000% of penetration enhancer may be required. Potts 1319:13-22; PTX-1 at col. 12,11. 35-45.

The specification contains five examples disclosing transdermal formulations with testosterone, and all five have 12% w/v testosterone and 8% v/v of penetration enhancer—including Example 10 reciting 12% w/v testosterone and 8% v/v of octyl salicylate. PTX-1 at Examples 6,10,12,13, and 15; Potts 1320:8-17, 1321:11-1322:6; Hadgraft 348:5-8; DDX 212. This ratio in all of the testosterone examples corresponds to approximately 0.67-times (or *940 67%) of the penetration enhancer by weight of testosterone. Potts 1320:18-1321:10. Accordingly, the examples illustrate that a formulation comprising less octyl salicylate than testosterone is effective. There is no other indication in the specification that testosterone is an active ingredient that may require 10,000% of penetration enhancer. Id. at 1319:10-1322:6 .

Composition of Formula with 100 Times More Penetration Enhancer than Testosterone

Defendants’ expert. Dr. Potts, testified as to one way in which a POSA might make the claimed formulation with 100 times more penetration enhancer than testosterone. The first ingredient of the claimed formulation is a therapeutically effective amount of testosterone for treatment of a testosterone deficient hypogona-dal man. PTX-1 at claim 13. The patent specification teaches that in hormone replacement therapy, for example with the Androderm® testosterone patch, the goal is to deliver 5 to 6 mg of testosterone per day to a testosterone deficient hypogona-dal man. PTX-1 at col. 24, 11. 26-35; Potts 1327:14-1328:1. To deliver this amount of testosterone across the skin, Androderm® included 12.5 mg testosterone in its patch reservoir. Potts 1328:2-1329:14. The second ingredient of the claimed formulation is 100-times more octyl salicylate than testosterone at the upper claimed limit. PTX-1 at claim 13. If a POSA were to prepare a formulation having the same amount of testosterone as Androderm® and 100-times more octyl salicylate than testosterone, then the formulation would have 12.5 mg testosterone and 1,250 mg octyl salicy-late. Potts 1330:2-1331:5. The third ingredient of the claimed formulation is ethanol, isopropanol, or a mixture thereof in an amount sufficient to act as a vehicle for the testosterone and penetration enhancer. PTX-1 at claim 13. The testosterone examples of the ’075 penetration enhancer patent include a volatile liquid in an amount of four times the combined amount of testosterone and penetration enhancer (or 80% by weight of the final formulation). Id. at Examples 6, 10, 12, 13, 15. Accordingly, a POSA following the teachings of the ’075 penetration enhancer patent would add 5,050 mg of volatile liquid to the formulation containing 12.5 mg testosterone and I,250 mg octyl salicylate, for a total of 6,312.5 mg of material. Potts 1330:2-1331:5.

In transdermal drug delivery, typically only a few milligrams of material per square centimeter is spread across the skin. Id. Therefore, a formulation amounting to over 6,300 mg would need to be spread over thousands of square centimeters of the skin. Id.

Concents Identified in the ’075 Patent Specification Related to Skin Irritation and Application Time

The ’075 patent specification identifies the minimization of skin irritation and drying time following application of the testosterone composition as two objectives of the invention. At the time of the invention, it was well-known that effective dermal penetration enhancers may be irritating to the skin, and the potential for skin irritancy increases as the concentration of the dermal penetration enhancers increases. Potts 1322:7-1324:18; Hadgraft 148:8-21. Dr. Hadgraft testified that in some cases, effective penetration enhancers can be too irritating to the skin to be tolerated. Had-graft 323:18-21. To address the potential for skin irritation, the patent specification teaches that it is desirable to use as little enhancer as possible. Potts 1322:16-22 (referring to PTX-1 at col. 2, 11. 51-53, col. 4, II. 13-15, col. 12, 11. 41-42). The patent specification further teaches that it is desirable for the claimed invention to have a convenient application time. Potts 1323:4-1324:5 (referring to PTX-1 at col. 4,11. 1-6, col. 10, 11. 50-56). Preparing a formulation *941 that has 100 times more penetration enhancer than testosterone is at odds with the invention’s purposes of minimizing skin irritation and applying a formulation that dries quickly. Id. at 1322:7-1324:18, 1325:8-18 .

Testing Required to Ensure Efficacy of Formula Using 100 Times More Penetration Enhancer than Testosterone

Even if a POSA prepared a formulation having 100-times more octyl salicylate than testosterone, he would not know whether a formulation with such an extreme ratio of low active ingredient to high permeation enhancer would work without testing it first. Hadgraft 319:21-320:3. Dr. Potts is not aware of any evidence that anyone has ever made a formulation with 100 times more octyl salicylate than testosterone. Potts 1334:10-13. Dr. Hadgraft also is not aware of any indication that the inventors had actually made or tested a formulation that had 100 times more penetration enhancer than testosterone. Hadgraft 325:9-12. Nor is he aware of any person who has ever made a transdermal-formulation that had 100 times more penetration enhancer than testosterone. Hadgraft 319:8-18. In the absence of this information in the patent specification, a POSA would need to conduct further testing, such as skin penetration studies, stability studies, and skin irritancy studies. Id. at 320:4-23 .

As discussed above, more effective penetration enhancement typically correlates with increased skin irritation, and the potential for skin irritancy increases as the concentration of the dermal penetration enhancers increases. Potts 1322:16-22; Hadgraft 148:8-21. Octyl salicylate was generally recognized as safe for application to the skin in a concentration of up to 5%, but in Dr. Potts’s hypothetical formulation, the octyl salicylate is present in an amount of about 19.8%—equivalent to 1,250 mg out of 6,312.5 mg. Potts 1330:2-1331:5, 1439:2-15. Accordingly, a POSA would be particularly concerned that using 100 times more octyl salicylate than testosterone in a formulation that is spread across a very large area of the skin would be highly irritating to the skin. Potts 1336:3-9.

Dr. Hadgraft further explained that transitioning from these in vitro experiments to in vivo experiments can be an unpredictable process. Hadgraft 323:14-21. Theréfore, according to Dr. Hadgraft, even if a POSA knew how much testosterone he wanted to deliver into a patient’s bloodstream, such a person would not be able to formulate a transdermal product to deliver that amount of testosterone with any degree of certainty without further testing. Id; at 324:11-15.

V. The ’944 Axilla Patent

The ’944 axilla patent claims a method of treating hypogonadism by application of a non-occlusive (non-patch) transdermal testosterone formulation to the axilla. PTX-4 at claims 13-20. The relative time period for the validity analysis of the ’944 patent is June 2005.

Definition of a Person of Ordinary Skill in the Art for the ’944 Patent

A person of ordinary skill in the art (“POSA”) for the ’944 axilla patent would have been a pharmaceutical formulator with a doctorate or master’s degree in pharmaceutical sciences or a similar degree and with at least two years of experience in transdermal or topical pharmaceutical formulation, working together with, or able to rely on, the expertise of a clinician or physician. Hadgraft 250:23-251:5; 251:14-16. Both sides’ experts agree that their opinions on validity of the ’944 patent are the same regardless of which expert’s specific POSA definition is adopted. Had-graft 219:1-5; Potts 1339:14-1340:13; Chambliss 1538:22-1540:12.

General Background of the Invention

As of 2005, there were two types of transdermal testosterone replacement *942 therapies on the market: patches and gels. The patches were associated with skin irritation, and the scrotal patch in particular was associated with elevated dihydrotes-tosterone (“DHT”) levels. PTX-511 at 3; PTX-92 at 4; PTX-93 at 33; PTX-264; PTX-587; Hadgraft 197:19-22; Goldstein 622:20-23, 623:1-8, 635:9-636:22. Elevated DHT levels were associated with an increased risk of developing prostate cancer or enlarged prostate and because of the chronic or long-term nature of testosterone replacement therapy, such elevated DHT levels were of particular concern. PTX-511 at 3; PTX-92 at 4; Hadgraft 197:19-22; Goldstein 622:20-23; 636:23-637:16. The scrotal patch was withdrawn from the market in 2002 at least in part because of these concerns. PTX-587 at 4; Goldstein 623:12-15. The gels were applied to large areas, such as the upper arms, back, abdomen, thighs, buttocks, or shoulders. PDX-2064. Although gels were not associated with elevated DHT levels, it was reported that there was a risk of inadvertent transfer to a spouse or child by patients using the gels. Hadgraft 209:14-17.

Acrux sought to develop an improved testosterone replacement therapy with its sunscreen penetration enhancer formulation. In 2004, Acrux began clinical trials to assess the safety, efficacy, and feasibility of administering testosterone through the axilla. See, e.g., PTX-96; PTX-100; PTX-154; DTX-69; PTX-4, col. 20, 11. 32-67; Goldstein 668:23-669:20. The initial pilot study was conducted in women, and the follow-up study was conducted in healthy men with compressed testosterone. PTX-4 at 16, col. 20, 1. 32-col. 23, 1. 9; PTX-96; PTX-117. The results of the studies showed that applying testosterone to the axilla was effective at increasing testosterone blood levels and did not lead to abnormally high DHT levels or increase sweat or odor despite the increased perspiration usually associated with the use of testosterone. Hadgraft 296:10-300:15; Goldstein 612:17-613:8, 671:3-674:25, 682:17-683:17; PTX-4 at col. 22,1. 65-col. 23,1. 8. Based on the results of these studies, the inventors conceived of treating hypogonadism by application of transdermal testosterone to the axilla, which is the invention of the ’944 patent. PTX-1109 at 3.

Claim 20 of the ’944 Patent

Asserted claim 20 of the ’944 patent depends upon independent claim 13 and each of dependent claims 14-19. PTX-4 at Claims 13-20. The chart below maps each of the limitations of asserted claim 20, including each of the limitations of the claims from which it depends. M; Potts 1347:8-1348:24 (discussing demonstratives DDX 234-36); see also PDX 2022.

*943 [[Image here]]

*944

Occlusive and Non-Occlusive Transder-mal Testosterone Treatments for Hypo-gonadism Were Well-Known in the Prior Art

By June 2005, a number of transdermal testosterone products were commercially available in the United States as testosterone therapies to treat males experiencing a deficiency or absence of endogenous testosterone, as characterized by the condition known as hypogonadism. Snyder 915:19-917:22. Such products included occlusive (patch) treatments Testoderm® (PTX-511) and Androderm® (PTX-512), and nonocclusive (non-patch) treatments AndroGel® (PTX-1059), and Testim® (PTX-641). Other transdermal testosterone formulations were disclosed in the prior art literature, including U.S. Patent Application Publication No. 2004/0028725 (“Morgan ’725 Publication”) (PTX-483); U.S. Patent No. 6,299,900 (“Reed ’900 Patent”) (PTX-19); U.S. Patent No. 6,211,250 (“Tomlinson ’250 Patent”) (PTX-592); U.S. Patent No. 6,319,913 (“Mak ’913 Patent”) (PTX-453); and U.S. Patent Application Publication No. 2005/0042268 (“Aschkena-sy ’268 Publication”) (PTX-243). These products and formulations are all § 102(b) prior art to the ’944 axilla patent. We describe each in greater detail below:

A.Testoderm®

Testoderm® was first approved by the FDA in 1993 and was commercially sold in the United States prior to June 2005. PTX-511 at 2. Testoderm® was a commercially available patch for the transdermal delivery of testosterone for testosterone replacement therapy in hypogonadal men. Id. at 3. The Testoderm® system is a thin film about the size of a business card containing testosterone that was designed to be worn on the scrotum for 22 to 24 hours daily. Id.) Hadgraft 197:19-22; Gold-stein 622:20-23. Testoderm® was later withdrawn from the market because of concerns related to elevated DHT levels associated with use of the product. Gold-stein 623:12-15.

B. Androderm®

Androderm®, another transdermal testosterone patch product, was first approved by the FDA in 1995 and was commercially sold in the United States prior to June 2005. PTX-512 at 2. Androderm® is a commercially available testosterone patch for testosterone replacement therapy in men with conditions associated with a deficiency or absence of endogenous testosterone, such as hypogonadism. Id. at 3. The suggested starting dosage is two Andro-derm® patches applied to the back, abdomen, upper arm, or thigh, providing a total dose of 5 mg/day of testosterone. Id. at 4.

C. AndroGel® and U.S. Patent No. 6,503,894

AndroGel® was first approved by the FDA in 2000 and was commercially sold in the United States prior to June 2005. PTX-1059 at 1; Potts 1342:6-12. AndroGel® is § 102(b) prior art to the axilla patent. An-droGel® is a non-occlusive hydroalcoholic gel containing 1% testosterone as the active ingredient. PTX-1059 at 1. AndroGel® is a testosterone replacement therapy for males with a deficiency or absence of endogenous testosterone, as characterized by the condition known as hypogonadism. Id. at 11-12. An appropriate starting dosage of AndroGel® 1% is 5 grams applied once daily to clean, dry, intact skin of (i) the shoulders and upper arms (ii) and/or abdomen. Id. at 22.

U.S. Patent No. 6,503,894 (“Dudley ’894 patent”) (PTX-319), entitled “Pharmaceutical composition and method for treating hypogonadism,” issued on January 7, 2003. PTX-319 at 1; Potts 1342:6-12. The Dudley ’894 patent is § 102(b) prior art to the axilla patent. The Dudley ’894 patent discloses the AndroGel® composition and *945 teaches a method for treating hypogonadism by applying the AndroGel® composition to the skin. PTX-319 at Abstract, col. 13,11. 22-35, col. 14,11. 25-28.

D. Testim® and International Patent Application Publication No. WO 2003/088974

Testim® was first approved by the FDA in 2002 and was commercially sold in the United States prior to June 2005. PTX-641 at 1, 18; Potts Tr. 1342:6-12. Testim® is § 102(b) prior art to the axilla patent. Tes-tim® is a non-occlusive hydroalcoholic gel containing 1% testosterone as the active ingredient. PTX-641 at 1. Testim® is a testosterone replacement therapy for males with a deficiency or absence of endogenous testosterone, as characterized by the condition known as hypogonadism. Id. at 10. The recommended starting dosage of Testim® is “5 g of gel (one tube) containing 50 mg of testosterone applied once daily (preferably in the morning) to clean, dry intact skin of the shoulders and/or upper arms.” Id. at 17.

International Patent Application Publication No. WO 2003/088974 (“Gyurik ’974 publication”) (PTX-382), entitled “Pharmaceutical Composition,” was published on October 30, 2003. PTX-382 at 1; Potts 1342:6-12. Gyurik ’974 publication is § 102(b) prior art to the axilla patent. Gyu-rik ’974 publication discloses a variation of the Testim® formulation and teaches a method for treating hypogonadism by applying .the formulation to the skin. PTX-382 at Abstract, Example 1, Comparative Example C-l.

E. Morgan ’725 Publication

U.S. Patent Application Publication No. US 2004/0028725 (“the Morgan ’725 publication”), entitled “Transdermal Delivery Of Hormones,” is a patent application that was filed by Morgan, et al, no later than May 2, 2003, and was published on February 12, 2004. PTX-483. The Morgan ’725 publication issued as the Morgan ’983 patent. PTX-21.

The Morgan ’725 publication teaches a method of increasing testosterone blood levels of an adult male subject in need thereof. Potts 1349:4-23. The Morgan ’725 publication discloses a “transdermal drug delivery system which comprises: a therapeutically effective amount of a hormone; at least one dermal penetration enhancer, which is a safe skin-tolerant ester sunscreen ester; and at least one volatile liquid.” PTX-483 at Abstract. It further provides “a method for administering at least one systemic acting hormone to an animal which comprises applying an effective amount of the hormone in the form of the drug delivery system of the present invention,” Id. Specifically, ⅛ teaches that the transdermal drug delivery system may be used as “male hormone therapy in testosterone deficient hypogonadal men.”- Id. at [0057].

A POSA would understand that the Morgan ’725 publication’s teaching that its transdermal drug delivery system may be used as male hormone therapy in testosterone deficient hypogonadal men inherently discloses raising the testosterone blood levels of that hypogonadal male to at least 200 ng/dL. Potts 1349:4-23; Cham-bliss 1559:20-1560:17. By June 2005, methods for treating hypogonadal adult males by applying a non-occlusive transdermal testosterone composition with the objective of increasing testosterone blood levels to normal physiologic ranges were well-known in the art. Potts 1341:22-1342:12. For instance, AndroGel® and Testim® were FDA-approved transdermal testosterone compositions used to treat hypogo-nadism in adult males by transdermally delivering testosterone to maintain therapeutically effective testosterone blood levels. PTX-1059 at 11-12; PTX-641 at 10. AndroGel® and Testim® deliver a thera *946 peutically effective amount of testosterone across the skin to produce testosterone blood levels that approximate normal adult male blood levels of about 300 ng/dL to 1000 ng/dL. PTX-1059 at 2; PTX-641 at 1; Snyder 913:22-914:6. A POSA would have sought to return the testosterone blood levels of a hypogonadal man to the normal adult male levels, which is greater than 200 ng/dL. Id; Chambliss 1559:20-1560:17.

Composition 13A of the Morgan ’725 publication expressly teaches a nonocclu-sive transdermal drug delivery composition consisting of: (a) testosterone in an amount of 1% w/v, (b) 90% w/v aqueous ethanol, (c) the penetration enhancer octyl salicylate in an amount of 2.5% w/v, and (d) the viscosity modulating agent hydrox-yl propyl cellulose in an amount of 1.5% w/v. PTX-483 at Example 13. Composition 13B of the Morgan ’725 publication discloses a similar formulation containing the viscosity modulating agent ethyl cellulose in an amount of 1.5% w/v. Id. The Morgan ’725 publication teaches that the viscosity modulating agents in Compositions 13A and 13B are interchangeable with the claimed viscosity modulating agent polyvinyl pyrrolidone (also known as povidone). PTX-483 at [0024]; Potts 1350:23-1352:6. The Morgan ’725 publication also discloses that the preferred range of the thickening agent in such formulations is 0.5 to 5%. PTX-483 at [0027].

The Morgan ’725 publication also states that “[preferably the drug delivery system is applied to the skin of the animal covering a delivery surface area between about 10 and 800 cm2, more preferably between about 10 and 400 cm2, and most preferably between about 10 and 200 cm2.” PTX-483 ¶¶ 23, 30, 58; id. at claims 17-19. The Morgan ’725 publication further discloses that the claimed transdermal testosterone formulation may be applied to an area of the body on which it would be useful to use an applicator. PTX-483 ¶ 58; Chambliss 1564:11-1565:1.

F. Morgan ’983 Patent

U.S. Patent No. 6, 923, 983 (“Morgan ’983 patent”), entitled “Transdermal Delivery Of Hormones,” issued to Morgan, et al, on August 2, 2005, from an application filed no later than May 2, 2003. PTX-21. The Morgan ’983 patent is prior art to the axilla patent under 35 U.S.C. § 102 (e). Dkt. 208, ¶19. The Morgan ’983 patent issued from the Morgan ’725 publication and contains the same disclosures. See, e.g., Hadgraft 282:13-283:19, 486:10-16; Chambliss 1541:1-1542:8. 8

G. Reed ’900 Patent

The Reed ’900 patent, entitled “Dermal penetration enhancers and drug delivery systems involving same,” issued on October 9, 2001. PTX-19 at 1. The Reed ’900 patent is the grandparent of the ’075 penetration enhancer patent. Hadgraft Tr. 271:18-20. The Reed ’900 patent teaches a testosterone transdermal formulation. Potts 1342:16-1343:16; PTX-19 at Abstract, col. 4, 11. 20-45, col. 7, 11. 1-5, Example 15.

H. Tomlinson ’250 Patent

The Tomlinson ’250 patent, entitled “Percutaneous delivery system,” issued on April 3, 2001. PTX-592 at 1. The Tomlin-son ’250 patent teaches a testosterone transdermal formulation. Potts 1342:16-1343:16; PTX-592 at Abstract, col. 4,11. 39-48, col. 5,11. 35-40, col. 6,11. 39-40.

I. Mak ’913 Patent

The Mak ’913 patent, entitled “Penetration enhancing and irritation reducing *947 systems,” issued on November 20, 2001. PTX-453 at 1. The Mak ’913 patent teaches a testosterone transdermal formulation. Potts 1342:16-1343:16; PTX-453 at col. 2,11. 40-45, col. 4,11.1-9, Example 9.

J. Aschkenasy ’268 Publication

The Aschkenasy ’268 publication, entitled “Pharmaceutical composition and method for transdermal drug delivery,” was published on February 24, 2005, from U.S. Patent Application No. 10/891,489 filed on July 15, 2004. PTX-243 at 1. The Aschkenasy ’268 publication is § 102(a) and (e) prior art to the ’944 axilla patent. See Dkt. 208 ¶ 31.

The Aschkenasy ’268 publication teaches a testosterone transdermal formulation. Potts 1364:13-1366:6. The Aschkenasy ’268 publication discloses “[a] pharmaceutical composition for transdermal administration of a hormone (e.g., testosterone), which includes urea and/or a derivative thereof as a penetration enhancer, and methods utilizing same for treating medical conditions in which elevating a hormone serum level is beneficial.” Id.; PTX-243 at Abstract.

The Aschkenasy ’268 publication teaches that applying the pharmaceutical composition, such as testosterone and a penetration enhancer, to a biological surface can “elevat[e] a blood serum concentration of the hormone in the subject from a sub-potent concentration to a potent concentration within about 24 hours after application. For testosterone, in a human male, a potent concentration ranges between about 300 ng/dl and 1100 ng/dl in serum.” PTX-243 at [0065]; Potts 1365:6-15.

The PT considered the Aschkenasy ’268 publication prior to allowance of the ’944 patent. PTX-4 at 2.

Based on at least these afore-mentioned prior art references, a POSA would have understood that transdermal testosterone formulas to treat hypogonadal men were well-disclosed in the prior art to the ’944 axilla patent.

Characteristics of the Axilla

The axilla is the area of the body commonly referred to as the “armpit.” Had-graft 362:8-10. The axilla is a region located under the shoulder joint that forms a depressed or hollow region, ie., a bowl, that contains, inter alia, apocrine and ec-crine glands, lymph nodes, fat, loose connective tissue, skin folds, and the brachial plexus. There are both hairy and non-hairy portions of the axilla. Hadgraft 362:14-17; 364:17-365:5. The axilla is known to be sweaty and is often treated with antiperspirants and deodorants to offset odors. Hadgraft 177:23-25,178:1-5.

Known Permeability Studies of Various Anatomical Sites, Including the Axilla

By June 2005, it was well-known in the art that the speed and extent of transder-mal drug delivery varies by the surface area of application, the anatomical site upon which the drug formulation is applied, as well as the nature of the compound being applied to the skin. Potts 1355:20-1358:1; 1505:6-10; Hadgraft 136:22-24; 229:22-230:6, 236:17-237:6, 499:10-501:7. In studies comparing the relative permeability of different areas of skin for trans-dermal drug delivery, such as Feldmann (1967) and Maibach (1971), the axilla was consistently found to be a site of high permeability for various compounds in comparison to other potential application sites, including the back, shoulders, abdomen, and forearms. Potts 1354:16-1355:4; PTX-340; PTX 449. At the time of the invention of the ’944 patent, the axilla was also known to have reduced barrier properties. PTX-607 at 1; see Potts 1361:18-22.

A. Feldmann (1967)

Feldmann et al., Regional Variation in Percutaneous Penetration of 14 C Cortisol in Man, The Journal of Investigative Der *948 matology, 48(2):181-83 (1967) (“Feldmann (1967)”) was published in 1967. PTX-340 at 1. Feldmann (1967) is § 102(b) prior art to the axilla patent.

Feldmann (1967) conducted a study that “quantitates the effect of regional variation on percutaneous penetration of hydrocorti-sone ” PTX-340 at 1; Potts 1355:20-23. The study authors delineated a 13 cm2 area on different skin sites for application of hy-drocortisone and measured the amount of drug delivery per unit area. PTX-340 at 1; Potts 1355:24-1356:18. By pre-marking the exact size of the application site, the Feld-mann study accurately determined the amount of drug delivery per unit area. Id. As shown in table 1 of Feldmann (1967), the absorption of hydrocortisone is 3.6-fold greater across the axilla than the forearm (ventral). PTX-340 at 2; Potts 1356:19-1357:2; Hadgraft 228:9-229:2. The permeability of the axilla was the second greatest among the sites tested, with the scrotum having the highest permeability, which was 42 times more permeable than the forearm. 9

The PTO considered Feldmann (1967) prior to allowing the ’944 patent. PTX-4 at 3.

B. Maibach (1971)

Maibach HI et al, Regional Variation in Percutaneous Penetration in Man, Arch Environ Health, 23:208-211 (1971) (“Maibach (1971)”) was published in 1971. PTX-449 at 2. Maibach (1971) is § 102(b) prior art to the axilla patent.

Maibach (1971) conducted a study of the systemic absorption of the pesticides parathion and malathion when topically applied to different anatomical regions. PTX-449 at 3-4. As shown in Tables 1-3 of Maibach (1971), the axilla demonstrated greater absorption than many of the anatomical regions tested, including a 7.4-fold greater absorption of parathion than the forearm and a 4.2-fold greater absorption of malathion than the forearm. Id. at Tables 1-3; Potts 1357:3-20; Hadgraft 231:20-232:4.

Maibach (1971) was considered by the PTO prior to allowance of the ’944 patent. PTX-4 at 2-3.

C. Watkinson (2002)

Watkinson A et al, Reduced Barrier Efficiency in Axillary Stratum Comeum, International Journal of Cosmetic Science 24:151-161 (2002) (“Watkinson 2000”) was published in 2002. PTX-607 at 1. Watkin-son (2002) is § 102(b) prior art to the axilla patent.

Watkinson (2002) reports a study to characterize the axillary skin and evaluate its composition and function, particularly its barrier properties, as compared to other body sites. PTX-607 at 2. Watkinson (2002) conducted a study of transepidermal water loss (“TEWL”), which is a measure of how rapidly water is released from the skin and reflects the strength of the skin site to act as a barrier to drug delivery. Id.; Potts 1360:15-25. As illustrated in Figure 1 of Watkinson (2002), in a head-to-head comparison of the same subjects serving as their own control, the “axillary TEWL measurements were significantly greater than those of the volar forearm (Fig. 1).” PTX-607 at 5; Potts 1361:1-13. Watkinson (2002) ultimately concluded that the study “revealed a reduced barrier function in the axilla.” PTX-607 at 1.

Watkinson (2002) also described the axil-la as a “major recipient tissue for sweat secretion,” a factor in providing the “ideal growth conditions for the commensal skin bacteria.” PTX-607 at 2. Watkinson (2002) *949 further reported that “we know virtually nothing about axillary skin or how antiperspirant (AP) use impacts upon it.” PTX-607 at 1.

D. Berti (1995)

Citing the data from Feldmann (1967) and Maibach (1971), Berti et al, Transcu-taneous Drug Delivery: A Practical Review, Mayo. Clin. Proc., Vol. 70:581-586 (1995) (“Berti 1995”), reported that the axilla is approximately four times more permeable than the forearm to transcuta-neous absoiption of the active ingredient hydrocortisone. PTX-264 at Fig. 3. Berti (1995) further reported that “[although not all drugs have the same degree of absorption as hydrocortisone, the relative ratio of absorption at various skin sites (Fig. 3) is likely similar and correlates with the thickness and lipid content of the stratum corneum.” PTX-264 at Fig. 3. Berti (1995) also noted that “the areas of greatest transcutaneous absorption” (including the axilla) were “also those subjected to the greatest application of cosmetics, antiperspirants, and deodorants.” PTX-264 at 4.

Berti (1995) was considered by the USP-TO prior to allowance of the ’520 patent (related to the ’944 patent). PTX-6 at 4.

Potential Application Sites for Transder-mal Testosterone Formulations Known in the Art

In June 2005, there were no transdermal testosterone products that were applied to the axilla. Rather, transdermal treatments as of 2005 were applied to the following sites: (1) scrotum (Testoderm®); (2) upper buttocks, upper arms, back (Testoderm® TTS); (3) abdomen, upper arms, back, thighs (Androderm®); (4) abdomen, shoulders, upper arms (AndroGel®); (5) shoulders, upper arms, upper torso (Testim®); and (6) abdomen and trunk (Percutacrine Androgenique Forte (“PAF”)). Axiron® is currently still the only transdermal testosterone product that is applied through the axilla. Hadgraft 218:1-9.

The armpit or axillary; area was, however, recognized as a potential application site for transdermal testosterone treatment in the prior art, and as of June 2005 a POSA would have been aware of the following references that teach administration of testosterone to the axilla for delivery of .testosterone into the systemic bloodstream:

A. Aschkenasy ’268 Publication

As discussed above, the Aschkena-sy ’268 publication discloses pharmaceutical compositions for transdermal drug delivery, including testosterone. Potts 1365:2-15. The Aschkenasy ’268 publication is directed to “a pharmaceutical composition for topical application, which comprises a pharmaceutically active ingredient, a penetration enhancer, and a phar-maceutically acceptable carrier, wherein the pharmaceutically active ingredient is.a hormone, and the penetration enhancer is urea and/or a derivative thereof’” PTX-243 at [0048]. This transdermal drug delivery composition may be used to deliver a therapeutically effective amount of testosterone across a biological surface of the subject to raise testosterone blood levels within the normal adult male range of 300-1100 ng/dL testosterone:

[0065] The pharmaceutical composition of the present invention is capable, upon application of an amount of the composition onto at least one biological surface of a subject, of elevating a blood serum concentration of the hormone in the subject from a subpotent concentration to a potent concentration within about 24 hours .after application. For testosterone, in a human male, a potent concentration ranges between about 300 ng/dl and 1100 ng/dl in serum.

*950 Id. at [0065]; Hadgraft 431:2-18. One of the express objectives of the Aschkenasy ’268 publication is the topical administration of a testosterone gel for use in hormone replacement therapy in hypogonadal males. Hadgraft Tr. 428:4-429:2, 429:23-431:1; PTX-243 at [0024]-[0027], [0047], [0057].

The Aschkenasy ’268 publication further teaches that its topical formulations (which include testosterone formulations) may be applied to one of seven biological surfaces of the skin, including the armpit:

[0066] The biological surface can be, for example, the abdomen, an armpit, an inside arm, the back, a thigh, a shoulder, or the scrotum.

PTX-243 at [0066] (emphasis added); Had-graft 431:19-432:4, 447:5-12. The Aschken-asy ’268 publication also claims application of the testosterone formulation to only these seven biological surfaces. PTX-243 at claims 88, 93, 113, 142, 147, 167. A POSA would understand that the Aschkena-sy ’268 publication teaches application of testosterone to the axilla for transdermal drug delivery. Potts 1365:2-1366:6.

A POSA would understand that the Aschkenasy ’268 publication provides a curated list of appropriate sites for transder-mal delivery of testosterone. Potts 1365:2-1366:6. A POSA also would have known that the FDA-approved testosterone products prior to June 2005 were applied to several of the biological surfaces listed in Aschkenasy ’268 publication—namely, the abdomen (Androderm® and AndroGel®), an inside arm (AndroGel® and Testim®), the back (Androderm®), a thigh (Andro-derm®), a shoulder (AndroGel® and Tes-tim®), or the scrotum (Testoderm®). Had-graft 447:5-452:16 (discussing DDX 1001). If a POSA wanted to apply a testosterone topical formulation to a biological surface listed in Aschkenasy ’268 publication that would be commercially differentiated from the FDA-approved transdermal testosterone products, as Drs. Potts and Chambliss explained that a POSA would have been motivated to do, the only choice for application site would have been the armpit. Hadgraft 452:11-16; see Potts 1473:5-14; Chambliss 1611:10-1612:10.

The Aschkenasy ’268 publication further teaches that the topical testosterone formulation may contain additional additives, including humectants, deodorant agents, antiperspirants, pH adjusting agents, preservatives, emulsifiers, occlusive agents, solubilizing agents, colorants, and surfactants. PTX-243 at [0139]. The axilla patent identifies these same inactive ingredients in the same order as the Aschkenasy ’268 publication. PTX-243 at [0139]; PTX-4 at col. 18, 11. 14-23; Hadgraft 438:19-439:4. The Aschkenasy ’268 publication also provides an extensive list of deodorant agents and antiperspirants (agents that are commonly applied to the axilla) for addition to the topical testosterone formulation. PTX-243 at [0141], [0142]; Hadgraft 433:10-434:18.

The Aschkenasy ’268 publication was considered by the PTO prior to allowance of the ’944 patent. PTX-4, ’944 patent, at 2; PDX-3031, Aschkenasy ’268 Publication (2005); PTX-243; Hadgraft 267:24-268:1.

B. Cutter (2000)

Cutter CB, Compounded Testosterone Gels: A Guide for Clinicians and Pharmacists, Int’l J. of Pharm. Compounding, 4(6):432-437 (2000) (“Cutter 2000”) published in 2000. PTX-301 at 3. Cutter (2000) is § 102(b) prior art to the axilla patent.

Cutter (2000) reviews the role of compounding pharmacists in developing testosterone replacement therapies for the care of patients with hypogonadism. PTX-301 at 3. Cutter (2000) teaches that when administering testosterone gel for transdermal delivery, “the choice of the application site is quite important.” Id. at 6. Cutter (2000) recommends administering testosterone *951 replacement therapies to the trunk or “axillary area” to provide the normal physiologic balance of testosterone, DHT, and estradiol:

When the gel is applied to the trunk or axillary area, the resulting balance of testosterone, DHT, and E2 will be very much in the normal physiologic range. However, when the gel is applied to the scrotum, the level of DHT becomes much higher because of the presence of a much higher level of the enzyme 5-alpha reductase.

Id. A POSA would understand that Cutter (2000)’s discussion of the axillary area is a reference to a part of the axilla. Potts 1380:21-1381:22, 1486:12-1487:25; 1489:5-17; Chambliss 1569:6-17,1614:4-24.

C. Cutter (2001)

Cutter CB, Compounded Percutaneous Testosterone Gel: Use and Effects in Hy-pogonadal Men, J. of the Am. Board of Family Practice, 14(l):22-32 (2001) (“Cutter 2001”) was published in 2001. (PTX-302 at 1.) Cutter (2001) is § 102(b) prior art to the axilla patent.

Cutter (2001) reports the results from administering compounded percutaneous testosterone gel to ten hypogonadal men (characterized as “a testosterone level of less than 300 ng/dL on repeat morning serum testing”). PTX-302 at 1, 4. Patients were provided a “testosterone gel in a dosing syringe and instructed on administration, the site of application (either the upper inner arm or chest near the axilla or the inner thigh and scrotum), and the amount of gel (1-3 mL).” Id. at 3. A POSA would understand that Dr. Cutter is describing application of the testosterone gel to a portion of the axilla as one of the sites of application. Potts 1367:21-1368:24; Snyder 966:20-967:7. A POSA would understand that the armpit or axilla includes areas above and below the hairline of the axilla. Chambliss 1614:4-1615:19; see also Hadgraft 419:1-420:9. A POSA would understand that Dr. Cutter’s site of application represents the non-hairy area of the axilla. Id. Indeed, consistent with his description of the study design, Dr. Cutter later identifies the site of application as the “axilla” when presenting the results from the study. PTX-302 at 4; Potts 1367:21-1368:24, 1487:3-25; Chambliss 1569:12-17.

Cutter (2001) further explains that he has “treated many men since the beginning of this study.” PTX-302 at 9. In describing his clinical practice beyond the ten men treated in his study, Dr. Cutter recommends that “the most useful starting dose for most men is a 6% gel, 2.5 mL applied to the nonhairy area of the axil-la.” Id.) Hadgraft 420:18-421:4. A POSA would understand that the axilla has both hairy and nonhairy areas. Hadgraft 362:14-17. The nonhairy area of the axilla, where Dr. Cutter recommends administering testosterone gel based on his clinical practice, is a part of the axilla. Potts 1368:25-1369:20; Snyder 938:14-17; Chambliss 1614:4-1615:19.

Cutter (2001) further warns that “inadvertent transmission of the gels could occur if the patient did not exercise caution in application and usage.” PTX-302 at 10. Inadvertent transmission of testosterone is a particular concern for any children, sexual partners, or pregnant women who may come into contact with the patient. Id. Cutter (2001) recommends that “[b]y using the gel in the axillary area, at bedtime, transmission can be avoided.” Id. (emphasis added). A POSA would understand that Cutter (2001) teaches administration of testosterone gel to the remote area of the axilla to avoid inadvertent transmission of testosterone to others. Potts 1376:1-14.

Cutter (2001) was considered by the PTO prior to allowance of the ’944 patent. PTX-4, ’944 patent, at 2; PDX-3037, Cutter (2001): PTX-302; Hadgraft 255:17-18.

*952 D. Chein 790 Patent

U.S. Patent No. 6,562,790 (“Chein 790 patent”), entitled “Hormone therapy methods and hormone products for abating coronary artery blockage,” issued on May 13, 2003. (PTX-283 at 1.) The Chein 790 patent is § 102(b) prior art to the axilla patent.

The Chein 790 patent discloses “methods and products to abate coronary artery blockage in men and in women” by “administering a combination of natural hormones, including human growth hormone or recombinant human growth hormone, one or more sex hormones, such as testosterone, estrogen or progesterone and other naturally occurring hormones, as appropriate.” PTX-283 at col. 1, 11. 5-11. For those men “with below optimal testosterone levels, these methods call for administering natural testosterone in gel form, preferably applied topically to under arm pits.” Id. at col. 1, 11. 22-25. A POSA would understand the Chein 790 patent’s instruction to apply the testosterone composition to the “under arm pits” to refer to application to the axilla. Potts 1371:2-21.

The Chein 790 patent was considered by the USPTO prior to allowance of the related ’520 axilla patent. PTX-6, ’520 patent, at 2; PDX-3034, Chein 790 Patent (2003): PTX-283.

E. Ben-Galim (1980)

Ben-Galim E et al., Topically Applied Testosterone And Phallic Growth, Am. J. Dis. Child, Vol. 134:296-298 (1980) (“Ben-Galim (1980)”) was published in 1980. (PTX-263 at 1.) Ben-Galim (1980) is § 102(b) prior art to the axilla patent.

Ben-Galim (1980) reports the results of a study of “the effect of topical application of testosterone cream in five boys with micro-penis and hypopituitarism.” PTX-263 at 1. In this study, “all subjects were treated with 5% testosterone propionate in hydro-philic ointment USP. Average dosage was between 2.5 and 4.0 mg of testosterone (50 to 75 mg of ointment) applied three times a day for three weeks, on an approximate area of 9 sq cm. In four patients (1 through 4), the ointment was applied directly to the phallus, and in one patient (5) to his right axilla.” Id. For the patient that administered the testosterone propionate to his right axilla, the total plasma testosterone increased from <20 ng/dL before treatment to 573 ng/dL on the last day of treatment. Id. at 2. A POSA would understand that Ben-Galim (1980) reports an example of administering testosterone to the skin of the axilla to elevate systemic testosterone blood levels. Potts 1372:5-18; Hadgraft 403:25-404:21, 405:7-25, 407:9-15, 408:4-16.

Ben-Galim (1980) was considered by the PTO prior to allowance of the ’944 patent. PTX-4, ’944 patent, at 3; Hadgraft 225:23-226:1.

F.Papa (1967)

Papa CM et al., Effect of Topical Hormones on Aging Human Skin, Journal of the Society of Cosmetic Chemists, 18(8):549-62 (1967) was published in 1967 (“Papa (1967)”). PTX-502 at 1. Papa (1967) is § 102(b) prior art to the axilla patent.

Papa (1967) reviews the effect of administering topical hormones, including testosterone propionate (a testosterone derivative) to aging human skin. PTX-502 at 1-2. Papa (1967) applied the topical hormones to the “face, extensor forearm, and back of the hand” and “axilla,” using “hydrophilic ointment base or alcoholic solution” formulations. Id. at 2. Papa (1967) found that administering testosterone propionate to the axilla of elderly men and women had a noticeable rejuvenating effect on the appearance of the axilla skin. Id. at 3-5.

Papa (1967) is directed to studying the effectiveness of hormones, like testosterone propionate, “to ameliorate the degra- *953 dative changes” in aging human skin. PTX-502 at 12. Papa (1967) explains that the observed rejuvenating effect is limited to the local areas of the skin topically treated with hormones, and that the systemic administration of hormones (ie., drug delivery to the entire body through the bloodstream) has been found to be ineffective in rejuvenating the appearance of aging skin. Id. Papa (1967) does not suggest that transdermal delivery of testosterone into systemic circulation would be ineffectual through the axilla, however. Id. Instead, a POSA would have known that to even have a local rejuvenating effect on the skin, the testosterone propionate must bypass the stratum corneum (the main barrier to transdermal drug delivery) to reach the deeper layers of the skin—in other words, it must penetrate the skin. (Potts Tr. 1373:3-21) A POSA would understand that topical administration of testosterone propionate to the axilla was effective in delivering the drug across the skin for a local effect and would have expected that applying a greater amount of testosterone propionate would have increased the amount of testosterone delivered into the bloodstream. Id.

Papa (1967) was considered by the PTO during prosecution of the ’944 patent.

Known Concern Regarding Inadvertent Transference of Testosterone

By June 2005, the inadvertent transference of testosterone was a known risk associated with transdermal testosterone formulations. Both the AndroGel® - and Testim® labels cautioned that pregnant and nursing women should avoid skin contact with the testosterone gels and warned of the risk of inadvertent transference of testosterone. PTX-1059 at 12; PTX-641 at 10; Potts 1376:15-1377:8. Cutter (2001) further warned that inadvertent transmission of the testosterone gels could occur if patients did not exercise caution in application and usage. PTX-302 at 10; Potts 1375:23-1376:14; Hadgraft 421:23-422:22. A 2-year old boy experienced serious virilization symptoms after coming into contact with his father who was using a testosterone gel on his arms and back. Id. Cutter (2001) recommended that “by using the gel in the axillary area, at bedtime, transmission can be avoided.” Id. A POSA would have understood that application of a testosterone gel to the axilla—an area that infrequently comes into contact with others—would avoid inadvertent transference of testosterone from the user to other individuals. Id.

Elevated DHT Levels Associated With Transdermal Testosterone Treatment Applied to Scrotum

Testosterone is converted in the body to DHT via the enzyme 5-alpha reductase. Goldstein 626:11-13; PDX-7010. The metabolite, DHT, is a potent androgen that targets androgen-dependent tissues: testes, prostate, apocrine glands, and hair follicles. Goldstein 627:3-629:24. The enzyme 5-alpha reductase catalyzes the conversion of testosterone to DHT. The relevant measurement is the DHT-to-T (DHT to testosterone) ratio. Goldstein 628:15-629:24.

Exogenous testosterone permeating across the skin is metabolized to DHT prior to reaching the dermal capillaries. PTX-464 at 12; Goldstein 627:3-12, 629:17-24. Once reaching the dermal capillaries, DHT travels to the prostate via systemic circulation. PTX-462 at 5; Goldstein 629:17-24; Snyder 965:13-18. The prior art recognized that elevated DHT levels were found in men using scrotal patches. It was theorized in the prior art that exogenous application of testosterone to a site rich in 5-alpha reductase activity, like the scrotum, was what caused the abnormally high DHT levels. PDX-7013; Goldstein 632:4-15. The prior art further recognized a concern regarding the possible link between elevat *954 ed DHT and DHT-to-T levels and negative side effects such as benign prostatic hypertrophy (“BPH”) (enlargement of the prostate that can lead to kidney failure and morbidity) and prostate cancer. Goldstein 628:21-629:16.

Despite the prior art recognizing a concern regarding elevated DHT levels associated with transdermal application of testosterone to the scrotum, the FDA approved the Testoderm® scrotal patch in 1993 as safe and effective for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone. Id. at 622:20-623:8; PTX-511 at 3. The FDA approved Testoderm® even though the literature prior to 1993 (which Dr. Goldstein relied on) reported that administration of the scrotal patch resulted in elevated DHT levels. Goldstein Tr. 635:9-636:14. Even after the Testoderm® patch was discontinued, 10 the prior art still recommended administration of testosterone to the scrotum for transdermal drug delivery. See, e.g., PTX-431 (“Kryger ’448 patent”) at col. 4, 11. 36-50 (patent issued on June 1, 2004, teaching the application of a testosterone formulation “to the scrotal skin” in order to “achieve a serum testosterone level of from about 600 ng/dl to about 1200 ng/dl”); PTX-243 (Aschkenasy ’268 publication, which published on February 24, 2005, teaching topical administration of a testosterone composition to the scrotum to achieve potent testosterone compositions in men.). Indeed, the ’944 axilla patent itself lists the scrotum as a preferred area of skin where the claimed composition may be applied; nowhere states to avoid application of the disclosed formulation to the scrotum; and nowhere purports to solve any alleged problem with DHT levels. PTX-4 at col. 7, 11. 39-42.

At most, by June 2005, the clinical significance of elevated DHT levels on the prostate gland was the subject of debate among physicians. Snyder 921:6-22. In its normal function, the prostate converts testosterone taken from the bloodstream to DHT. Id. There is a distinction between DHT levels in the prostate and DHT blood levels, with levels in the prostate gland being far higher than those in the bloodstream. Id. Diseases of the prostate, like BPH, depend on the conversion of testosterone to DHT that occurred in the prostate. Id. To a physician in 2005, therefore, there was no particular reason to believe that the blood concentrations of DHT had any clinical effect or medical significance on prostate disease. Id.

The teachings of the prior art relevant to elevated DHT levels associated with transdermal testosterone treatment applied to the scrotal skin are summarized below. Each of the references cited is prior art to the ’944 patent.

A. Ahmed (1988)

Ahmed et ah, “Transdermal Testosterone Therapy in the Treatment of Male Hypogonadism,” J. Clin. Endocrin, & Me-tab., Vol. 66(3):546-51 (1988) (“Ahmed (1988)”) reported on a study testing the efficacy of using a testosterone patch on the scrotal skin. PTX-235 at Abstract. Ahmed (1988) found a “disproportionate increase in serum DHT levels” which “probably resulted from the conversion of testosterone to DHT in the scrotal skin” related to 5a-reductase activity known to *955 be present there. Id. at 6-7. Ahmed (1988) recognized that while short-term DHT elevations were not known to be related to adverse clinical effects, “the effects of chronically elevated serum DHT concentrations coupled with normal serum testosterone levels are unknown.” Id. at 7. Although Ahmed (1988) noted that the long-term effects of increased serum DHT concentrations on the prostate “need to be systematically studied,” the authors concluded that transdermal testosterone therapy using a scrotal patch was “an effective long term treatment for hypogonadism in men.” Id. at 7-8.

B. Findlay (1989)

Like Ahmed (1988), Findlay et al., “Treatment of Primary Hypogonadism in Men by the Transdermal Administration of Testosterone,” J. Clin. Endocrin. & Metab., Vol. 68(2):369-73 (1989) (“Findlay (1989)”) reported on a study testing the efficacy of using a scrotal patch for the long term treatment of hypogondadal men. PTX-343 at Abstract. Findley (1989) stated that an “unexpected finding” following the study was “the increase in the serum [DHT] concentration in each of the 10 men from subnormal or low normal to supranormal during trans-dermal testosterone administration.” Id. at 7. Findlay (1989) speculated that “the reason for this increase is the high concentration in the scrotal skin of 50-re-ductase, the enzyme that catalyzes the conversion of testosterone to [DHT].” Id. Findlay (1989) recognized that such abnormally high levels of DHT “raise the issue as to whether transdermal administration of testosterone would be more likely than other methods of replacement to accelerate the development of [BPH], since BPH is probably dependent on [DHT] formation.” Id. However, Findlay (1989) observed that the DHT upon which BPH is dependent “is normally formed within prostatic cells from testosterone taken up from the systemic circulation.” Id. Findlay (1989) advised that in the absence of definitive information about the “hormonal mechanisms of BPH development,” prostatic examination of subjects should be performed before starting and annually during transdermal testosterone treatment. Findlay (1989) nonetheless concluded that the transder-mal administration of testosterone via scrotal patch “is an- effective means of treating testosterone deficiency in hypo-gonadal men, except in those who have a very small or irregular scrotal surface.” Id.

C. McClure (1991)

McClure et ah, “Hypogonadal Impotence Treated by Transdermal Testosterone,” Urology, Vol. 37(3):224-28 (1991) (“McClure (1991)”) reported the results of a clinical study of Testoderm® with four men in which the DHT:T ratio was more than double the upper value in normal men. PTX-468. McClure concluded that high concentration of 5-alpha reductase in scrotal skin was likely the reason for this increase. However, despite observing elevated DHT levels, McClure (1991) reported that “[n]one of our patients, 2 of whom were older than fifty-five, had any subjective evidence of changes in urine flow or frequency or an increase in the size of the prostate.” Id. at 4. McClure (1991) noted that the “etiology of the supposed large increases in DHT in BPH became a major focus of research during the last decade,” and that, following that research, “[t]oday, less credence is given to the simple concept that elevated DHT levels may be a factor in BPH ....’’Id. McClure (1991) concluded that transdermal testosterone therapy applied to the scrotal skin “is convenient, reliable, and more closely mimics normal physiology than do conventional methods of testosterone replacement for hypogondal men.” Id. at 5.

*956 D. Confrancesco (1996)

Confrancesco & Dobs., “Transdermal Testosterone Delivery Systems,” The Endocrinologist 6(3): 207-13 (1996) (“Confran-cesco (1996)”) compares studies of patients using the Testoderm® and Androderm® transdermal testosterone patches. PTX-290. Confrancesco (1996) reports that patients using Testoderm® (applied to the scrotal skin), unlike patients using Adro-derm® (applied to nonscrotal skin), were found to have elevated serum DHT levels following treatment. Confrancesco (1996) concluded this was “likely due to the high level of 5 a-reductase activity in scrotal skin,” noting that “[t]he clinical significance of the increased DHT is unknown.” Id. at 3.

E. Amory (1998)

Amory & Matsumoto, “The therapeutic potential of testosterone patches.” Exp. Opin. Invest. Drugs 7(11) (1998) (“Amory (1998)”) is a review of various transdermal testosterone patches. PTX-238. Amory (1998) reported that in a study of Testo-derm® treatment for an extended period of time DHT-to-T ratios were elevated but “[i]mportantly, there were no adverse effects such as gynaecomastia, prostatic hypertrophy, or oedema.” Id. at 4 (emphasis added).

F. Cutter (2001)

Cutter 2001 reported that long-term studies with Testoderm® do not support the concerns that DHT may be linked to increased prostate growth:

The published findings on the long-term use of the scrotal application of the Tes-toderm patch (ALZA Corporation, Palo Alto, California) indicate that the level of DHT was several-fold higher in subjects who used the patch than it was in those treated with nonscrotal patches. However, the incidence of prostate problems in those who wore scrotal patches was no greater than that in subjects given placebo. Additional studies have indicated a 15% decrease in size of the prostate in men treated with pure DHT gels, probably as a result of an inhibition of the normal production of DHT and E2 that occurs in the prostate itself.

PTX-301 at 7 (emphasis added).

Prior Art Related to Connection Between Application of Testosterone to the Axilla and Elevated DHT Levels

As discussed above, the prior art attributed the elevated DHT levels and DHT:T ratio associated with use of transdermal testosterone treatments applied to scrotal skin to the high 5-alpha reductase activity in that area. It was known at the time of the invention of the ’944 patent that high concentrations of 5-alpha reductase are predominately found in skin where there are apocrine sweat glands, such as the scrotum and axilla. Goldstein 632:16-634:17, 711:16-25. Apocrine glands have highly regionalized locations and are found only in the axillae (armpits), in anogenital regions, and around the nipples. 11 Gold-stein 625:15-626:7; Potts 1481:8-1482:6.

Dr. Goldstein opined that the prior art taught away from the application of testosterone to the axilla due to concerns of increases in DHT levels and increased DHT-to-T ratios to above supraphysiologic levels. Goldstein 632:4-15. Yet, in arriving at his opinion, Dr. Goldstein relied on no prior art data showing that the administration of testosterone to the axilla actually *957 resulted in elevated DHT levels or elevated DHT-to-T ratios. Id. at 692:11-693:5. Nor did he rely on any prior art reference describing that administration of testosterone to the axilla would result in elevated DHT levels. Id. at 694:3-11. To the contrary, the Cutter (2000) and Cutter (2001) references disclose that application of testosterone to the “axillary area” did not result in elevated DHT levels. PTX-301 at 6; PTX-302 at 4.

Likewise, Dr. Goldstein presented no data or experimental results showing that administration of testosterone to the axilla would result in increased risk of prostate cancer. Id. at 694:12-22. Dr. Goldstein conceded that for his opinion on teaching away he did not rely on any - prior art reference that actually criticizes the administration of testosterone to the axilla. Id. at 703:1-5. He is not aware of any prior art literature stating that the axilla would not be a good site for transdermal delivery of testosterone. Id. at 701:4-20.

In the absence of any prior art reference that actually criticizes the administration of testosterone to the axilla due to concerns of elevated DHT levels (Goldstein 703:1-5), Dr. Goldstein’s opinion relied upon only one study that concerned axilla skin —the in vitro study described in Ta-kayasu (1980). Id. at 705:13-15. None of the studies Dr. Goldstein relied on studied application of testosterone to the axilla of a living human. Goldstein 704:11-24. None of the other prior art references that Dr. Goldstein relied upon for his opinion studied or otherwise discussed DHT levels after application of testosterone to the axilla of a human, or activity of the enzyme 5a- reductase in the axilla. Id. at 726:14-24 (referring to demonstrative PDX 7013).

The prior art relevant to this issue includes the following references:

A. Takayasu (1980)

• Takayasu S. et al, Activity of Testosterone 5a-Reductase in Various Tissues of Human Skin, Journal of Investigative Dermatology, 74:187-91 (1980) reports a study of 5a-reductase activity—the enzyme involved with converting testosterone to DHT—in various skin components derived from various human skin sites. PTX-583 at 1. In this study, samples of skin were collected from surgery and the authors collected a 5 mm punch biopsy. Potts 1389:16-1390:7; PTX-583 at 1. The punch biopsy was further.dissected under a microscope into separate components— ie., glands, hair follicles, dermis, and epidermis. Id. • Each individual component (but not the whole, intact skin samples) was tested for 5a-reductase activity. Id. In total, Dr. Takayasu evaluated components of axillary skin taken from two patients— Subject I, a 22-year-old female and Subject J, a 41-year-old female. Potts Tr. 1391:8-22; PTX-583 .at 4. No skin samples were collected from any anatomical region other than the axilla for these two patients. Id. Table II of Takayasu (1980) reports that the 5a-reductase activity of the sebaceous glands or the dermis obtained from the axilla was in about the middle of the range for these components obtained from other skin samples of other patients, whereas the 5a-reductase activity of the sweat gland obtained from the axilla was higher than the sweat glands obtained from the scalp and forehead of other patients. Potts Tr. 1391:23-1392:5; Watkinson Dep. Tr. 152:10-24; PTX-583 at 4.

In the Takayasu study, only two subjects provided axillary skin samples, and no skin samples from other anatomic regions from these subjects were studied. Potts 1391:8-22; PTX-583 at 4. The study collected a 5 mm punch biopsy from the skin samples, which is about the diameter of a pencil eraser, representing less than 0.1% of the total area of the axilla. Potts *958 Tr. 1389:16-1390:7; PTX-583 at 1. The 5a-reductase activity, as reported by Dr. Ta-kayasu, was then adjusted by dry weight of the sample of the component studied. PTX-583 at 2, 4. Dr. Takayasu does not provide data regarding the relative abundance of the components in the skin sam ples—ie., how much sweat gland was in the skin sample relative to the total amount of all components in the punch ' biopsy. Potts 1392:6-16; Goldstein 715:24-716:2. In the absence of this information, a POSA would not be able to determine the level of 5a-reductase activity in the entire axillary skin sample. Id. Dr. Goldstein attempts to fill in this missing information regarding the composition of the skin by offering his opinion that the “majority” of the skin of the axilla is comprised of sweat glands, but this opinion was not included in his expert report nor did it rely upon any prior art for corroboration. Goldstein 711:16-712:4, 715:9-23.

Takayasu (1980) is the only prior art reference upon which Dr. Goldstein relied for his opinion regarding the level of 5a-reductase activity in the axilla. Goldstein Tr. 705:13-15. Dr. Goldstein’s opinion assumes that the axilla has similar 5a-reduc-tase activity as the scrotum. Id. at 701:21-702:14; 717:8-13, 723:9-19. Takayasu (1980) did not measure the 5a-reductase activity of the scrotum, however. Potts 1396:10-14; Goldstein 706:17-21. Instead, Takayasu (1980) discloses that “[o]ur knowledge of the localization of 5a-reductase activity in the skin largely depends upon indirect evidence obtainable from a study with whole skin: the activity is high in genital [2] and axillary skin [4].” PTX-583 at 2; Potts 1480:5-1481:3. Takayasu (1980) plainly cites to one study for genital skin and another study for axillary skin. See PTX-583 at 2. Dr. Potts is not aware of any reference that directly compares the 5a-reductase activity of the axilla and that of the scrotum. Potts at 1397:6-25. Dr. Gold-stein also is not aware of any data in the prior art literature that directly compares the 5a-reductase activity of the axilla and that of the scrotum. Goldstein 702:16-20; see also Watkinson Dep Tr. 161:6-10, 161:12-14,161:22-162:3.

Since there is no study directly comparing those two skin sites, there is no way to evaluate what “high” activity in genital skin means versus in axillary skin. Potts 1480:5-1481:3. Indeed, Dr. Takayasu warned against drawing this parallel between 5a-reductase activity of the axilla and scrotum from two different studies. Id.; PTX-583 at 2. Specifically, he stated that, “in addition to complexity of the skin constituents, different experimental conditions used in these studies, which may possibly have affected the in vitro testosterone metabolism, does not permit us to draw a parallel between various components of the skin from different regions or those in diseased state in terms of 5a-reductase activity. PTX-583 at 2 (emphasis added).) A POSA would understand that Dr. Takayasu cautions against making comparisons between two studies because of these methodological difficulties. Potts 1480:5-1481:3.

B. Scheuplein (1971)

Takayasu (1980) does not address whether the 5a-reductase activity of isolated axillary sweat glands is representative of the 5a-reductase activity of intact living human axilla. As Dr. Potts explained with Scheuplein & Blank, “Permeability of the Skin,” Physiological Reviews, Vol. 51 (1971) (“Scheuplein (1971)”) and his demonstrative exhibit DDX 248 (which was admitted into evidence), there are different routes of drug transport through the skin, including drug delivery directly through the outermost layer of skin (the stratum corneum) and through skin appendages that pierce the stratum corneum (the hair follicles and sweat ducts).

*959 [[Image here]]

Id. at 1393:7-20, 1394:18-1395:13 (referring to demonstrative DDX 248); Watkinson Dep Tr. 154:9-15, 156:1-9, 156:16-21; PTX-563 at 7.) For a drug applied to the top of the skin to reach the sweat glands in intact skin, the drug must go through the skin appendage route by diffusing through a sweat pore and down the sweat duct to reach the sweat gland. Id. As was well-known, drug delivery through the skin appendages is minimal due to the relatively small total surface area of these appendages, with total transport through the sweat glands and hair follicles on the order of about 10'3 (0.1%). Id. Scheuplein (1971) in Table 6 compared the fractional diffusional volume of these separate pathways as reported in the literature. Potts 1393:21-1394:10; PTX-563 at 22. There are about 200-250 sweat ducts/cm2 of the skin and the fractional diffusion volume of the collective sweat ducts is about 3-5 x 10"4 (0.03-0.05%) of the skin. Id. Even accounting for regional variations of areas of high sweat—such as the palms of the hands and soles of the feet that have about two to four times greater the amount of sweat ducts than the average body surface—the fractional diffusion volume of the collective sweat ducts in these areas of high sweat remains small. Potts 1483:21-1484:12; PTX-563 at 22.

A POSA with an understanding of the structure of the skin and the routes of drug delivery through the skin would not extrapolate the data reported in Takayasu (1980) for individual components of the skin to draw conclusions about the 5a-reductase activity of intact living human axilla. Potts Tr. 1395:14-1396:22. Dr. Ta-kayasu harvested individual sweat glands away from the skin. Id. at 1395:14-21. His study was not designed to take into account the amount of testosterone that would follow the narrow pathway through the sweat pores and sweat ducts to reach the sweat glands. Id. at 1396:3-22. A POSA would know that drug delivery through the sweat ducts into the sweat glands comprises a minor fraction of the total volume and *960 is not a major route for drug delivery through the skin. Id. at 1394:11-17; see also Hadgraft Tr. 183:6-184:10 (explaining that drug delivery through the hair follicle is “really insignificant”).

C. Cutter (2000) and Cutter (2001)

Cutter (2000) teaches a POSA that applying a testosterone gel to the axillary area, unlike the scrotum, will result in a balance of testosterone, DHT, and estra-diol that is very much in the normal physiologic range:

The choice of application site is quite important. When the gel is applied to the trunk or axillary area, the resulting balance of testosterone, DHT, and E% will be very much in the normal physiologic range. However, when the gel is applied to the scrotum, the level of DHT becomes much higher because of the presence of a much higher level of the enzyme 6-alpha reductase.

PTX-301 at 6 (emphasis added); Potts 1380:17-1381:7. A POSA would understand that Dr. Cutter’s reference to the “axillary area” would by definition include the axilla. Id. At 1381:16-22.

Cutter (2001) further presents clinical data demonstrating that administration of testosterone to the axilla as an application site did not result in elevated DHT levels. Potts 1381:23-1383:7. In Table 2 of Cutter (2001), reproduced below, Dr. Cutter provided measurements of the DHT levels of ten patients, which included seven patients administering testosterone gel to the scrotum and three patients administering testosterone gel to the axilla. PTX-302 at 4. Each of the three subjects who had the drug administered to the axilla demonstrated DHT levels within the normal physiological range of 30-100 ng/dL, whereas each of the seven subjects who had the drug administered to the scrotum demonstrated DHT levels above 100 ng/ dL. Id.

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PTX-302 at 4. A POSA would understand that Dr. Cutter’s description of the “axilla” as the site of application in Table 2 to refer to part of the axilla. Potts 1381:23-1383:7; see Chambliss 1614:4-24. Cutter (2001) therefore teaches that it would be appropriate to apply a testosterone gel to the axilla and that elevated DHT levels would not be expected. Potts 1382:4-1383:7.

Internal Acrux Correspondence Related to DHT and the Axilla

In internal documents from 2004, Acrux noted certain concerns regarding applica *961 tion of testosterone to the axilla. For example, in a March 2004 email, Acrux recognized: “[T]here is still concern re DHT levels, even after application, because DHT is a 5-fold more potent androgen than [testosterone]. Need to make sure this is measured in any [pharmacokinetic] studies that Acrux completes.” PTX-1033, March 9, 2004, Email from Charman, at 1. Acrux meeting minutes from December 2004 also reflect discussion of potential concerns regarding applying testosterone to the axilla, including increased hair growth, increased sweating or smell, increased 5-alpha reductase and DHT:T ratio, and interaction from shaving and cosmetics. PTX-657, Acrux Dec. 15, 2004, Meeting Minutes, at 1.

However, in an April 26, 2006 email from Ms. Paulina Hall (Acrux’s FDA consultant) to Acrux recounting a conversation she had with Mr. John Kim (the FDA’s representative) occurring earlier that day, Ms. Hall clearly states that the FDA was “not concern[ed] with using the axilla as the application site for the proposed IND study.” PTX-1035 at 1. In his direct testimony, Dr. Goldstein offered an opinion as to why the FDA would have had no concern with selecting the axilla as an application site, (Goldstein 670:8-23), stating that the FDA was at first concerned about DHT levels, but that the FDA was subsequently convinced that there were no concerns, because “data shown to [the FDA of any earlier Acrux clinical study] did not show elevations in DHT when a testosterone formulation was applied to a region with high 5-alpha reductase activity, the axilla.” Id. However, the email correspondence from Ms. Hall does not state that the FDA ever had any concerns with elevated DHT levels from application of testosterone to the axilla. PTX-1035 at 1. Nor does Ms. Hall explain the reason the FDA had no concerns. Id.

Further, the premise of Dr. Goldstein’s opinion on the FDA correspondence is that the FDA had reviewed the data from Acrux clinical study MTE04 in evaluating whether there was any concern with applying testosterone to the axilla. Goldstein 670:8-23. But it is not clear whether the FDA had actually reviewed the data at the point, it expressed no concern regarding application of testosterone to the axilla. In the April 11, 2006 correspondence, Ms. Hall inquired of the FDA as to whether it had “any concerns about the use of the axilla as the proposed application site, potentially the levels of DHT.” Id. at 664:17-23, 668:5-22; PTX-1034 at 1. Ms. Hall attached to her letter a protocol for clinical study MTE04 (PTX-1034 at 1), noting that “the results from this study will be available at the end of April/06” and asking whether the FDA would “recommend Acrux to submit the results from study MTE04 for review prior to submitting the IND.” PTX-1034 at 1. In the later April 26, 2006 email, when Ms. Hill reported that the FDA had no concern, she did not state that the FDA had reviewed any patient data from MTE04. PTX-1035 at 1. Rather, in response to Acrux’s earlier question as to when the FDA recommended that Acrux submit the results from the study, Ms. Hall reported that the “[r]esults from study MTE04 will be included in the initial IND for review.” Id. In fact, the clinical study dates for MTE04 extended to May 5, 2006 (subsequent to the April 26, 2006 email from Ms. Hall) and the final report was dated April 20, 2007. PTX-100, MTE04 Clinical Study Report at 5. Thus, it is not clear whether, at the time of the April 26, 2006 email from Ms. Hall, the FDA had received the clinical study MTE04 data or if that data impacted the FDA’s opinion regarding whether the axil-la was expected to raise DHT levels.

*962

Impact of the Axilla’s Characteristics on Its Suitability as an Application Site for Transdermal Drug Delivery

Plaintiffs maintain that a POSA in June 2005 would have been discouraged from administering a transdermal drug to the axilla because of concerns regarding hair, creases and folds in the skin,'sweat, bacteria, and interference with deodorants and antiperspirants that are regularly applied to the area. However, the prior art does not support either this contention or these concerns and does not teach away from the axilla as an application site for non-occlusive testosterone formulations based on any of these concerns.

Prior Art Belated to the Presence of Hair and Creases and Folds of the Skin

A.Berti (1995)

Dr. Hadgraft relied on a set of guidelines for transdermally delivered drugs described in Berti (1995) to support his opinion that the prior art taught away from topical administration to a hairy area of the skin. Hadgraft 189:8-190:10; PTX-264 at 5. Berti (1995) states that “[t]he device should be applied to a region that has the least amount of hair possible; otherwise, hair may be clipped rather than shaved.” Hadgraft 457:18-22; PTX-264 at 5. As Dr. Hadgraft conceded on cross-examination, however, a POSA would have understood that the guidelines referencing a “device” is specific to transdermal patch products, where the presence of hair may limit the ability of the patch device to adhere to the skin and maintain contact for drug delivery. Hadgraft 458:10-459:5; see also Snyder 915:16-916:6. By contrast, the claimed transdermal testosterone formulations are limited to formulations that are applied to the skin “without occlusion by a patch device.” PTX-4 at Claim 13, 20; Potts 1402:18-21.

B. Tomlinson ’250 Patent

These known disadvantages of transder-mal patch products are consistent with the teachings of the Tomlinson ’250 patent. Potts 1401:1-1402:17. The Tomlinson ’250 patent is a second reference upon which Dr. Hadgraft relied for his opinion that the prior art teaches away from transdermal drug delivery to areas of the skin with ham and significant creasing and folding. Had-graft 276:10-20; PTX-592. However, the Tomlinson ’250 patent teaches that these factors are the limitations of the prior art relating to adhesive patches which may be applied to only “a non-hairy area of the skin that is substantially free of wrinkles, creases, and folds.” PTX-592 at col. 2,11. 7-16; Potts Tr. 1401:1-22. The Tomlinson ’250 patent further teaches that for non-occlusive compositions, “the presence of hair does not create as significant a problem as is the case with adhesive patches” and “the presence of wrinkles, creases and folds in the skin are not an impediment to the application of the composition of the invention to a particular area of the body.” PTX-592 at col. 2, 11. 25-32, col. 2, 1. 63 - col. 3,1. 5; Potts 1401:23-1402:11. A POSA would understand from the Tomlinson ’250 patent that, since the claimed testosterone formulations are applied without occlusion by a patch device, the presence of hair or creases and folds in the skin would not present a significant problem. (Potts Tr. 1402:12-17.)

The Tomlinson ’250 patent was considered by the PTO prior to allowance of the ’944 patent. PTX-4, ’944 patent, at 2; PDX-3049, Tomlinson ’250 Patent (2001): PTX-592; Hadgraft 276:19-20.

C. AndroGel® and Testim®

The two prior art non-occlusive testosterone gels, AndroGel® and Testim®, are also applied to skin sites where men often grow hair such as the shoulders, upper *963 arms, and abdomen. Potts 1400:1-15. Unlike with patches, the presence of hair does not present an obstacle for testosterone gels or solutions, which can flow past the hair and be absorbed through the axilla skin. Snyder 931:7-14.

Prior Art Related to Sweat and Bacteria in Axilla

Dr, Hadgraft further opined that a POSA would have been discouraged from application of testosterone to the axilla due to the presence of sweat. Hadgraft 176:17-177:8, 178:10-14, 179:22-180:10, 279:13-280:13.. But Dr. Hadgraft testified on direct examination that the impact of sweat on transdermal drug delivery is “unpredictable.” Id. at 279:13-280:13. Further, he does not identify any prior art reference that discusses any adverse effect of sweat on transdermal delivery of testosterone. See id. at 176:17-177:8, 178:10-14, 179:22-180:10, 279:13-280:13.

Dr. Hadgraft also opined that “if you have bacteria in the armpit, then you have the potential for breaking down any active ... [and] then it will never get through to the skin in the systemic blood supply.” Hadgraft 122:2-13; see also id. at 177:23-178:1, 180:22-181:3. However, he failed to identify any specific bacteria that had been shown to have this effect or any prior art reference discussing the effect of skin bacteria on the transdermal delivery of testosterone. Id.

Even if this were a real concern regarding sweat or bacteria in the axilla, the prior art testosterone gels, AndroGel® and Testim®, recommended application of the testosterone product to “intact, clean, dry skin.” PTX-1059 at 1; PTX-641 at 1. These instructions to wash and dry the skin prior to application of a testosterone product would likely avoid any issues with the presence of excessive sweat or bacteria on the skin. Potts 1404:11-22. Axiron® includes a similar instruction to apply the testosterone composition when the axilla is clean, dry, and intact. PTX-633 at 1; PTX-1061 at 1.

Prior Art Related to Presence of Deodorants and Antiperspirants

Dr. Hadgraft further opined that a POSA would have been discouraged from application of testosterone to the axilla which is repeatedly treated with both deodorants and antiperspirants. Hadgraft 176:8-177:8, 188:24-189:7, 279:9-280:13. Likewise, Dr. Goldstein opined that a physician would expect that the presence of antiperspirants and deodorants would affect testosterone blood levels. Goldstein 675:11-676:13. But Drs. Hadgraft and Goldstein did not identify any specific deodorant or antiperspirant agent that has been shown to interact or counteract with testosterone or otherwise impede trans-dermal drug delivery. Id. Nor did Dr. Hadgraft rely on any prior art reference warning that deodorants and antiperspirants were expected to affect transdermal delivery of testosterone. Id. To the contrary, the prior art contemplates adding deodorants and antiperspirants to trans-dermal testosterone formulations, as shown below.

A. Aschkenasy ’268 Publication

The Aschkenasy ’268 publication, for example, anticipates that deodorants and antiperspirants may be added to its transder-mal testosterone composition. PTX-243 at [0139]. Specifically, the Aschkenasy ’268 publication, like the axilla patent, teaches that the testosterone composition may comprise additives, including deodorants and antiperspirants. Hadgraft 437:22-439:4; PTX-243 at [0139], PTX-4 at col. 18, 11. 14-23. The Aschkenasy ’268 publication provides an extensive list of deodorant agents and antiperspirants—agents that are commonly applied to the axilla—for addition to the topical testosterone formu *964 lation. PTX-243 at [0141], [0142]; Hadgraft 433:10-434:18.

B. AndroGel® and Testim®H

As discussed above, the prior art testosterone gels, AndroGel® and Testim® recommended application of the testosterone product to “intact, clean, dry skin.” PTX-1059 at 1; PTX-641 at 1. These instructions to wash and dry the skin prior to application of a testosterone product avoid the issues that might present with a deodorant agent or antiperspirant on the skin. Potts 1404:11-22. Axiron® includes a similar instruction to apply the testosterone composition when the axilla is clean, dry, and intact. PTX-633 at 1; PTX-1061 at 1.

Acrux’s Clinical Studies Applying Its Transdermal Testosterone Formulation to the Axilla

In 2004, Acrux began clinical trials to assess the safety, efficacy, and feasibility of transdermal testosterone application to the axilla. The initial pilot study was conducted in women, and the follow-up study was conducted in healthy men with compressed testosterone. PTX-4 at 16, col. 20, 1. 32-col. 23, 1. 9; PTX-96; PTX-117. The results of the studies showed that applying testosterone to the axilla was effective at increasing testosterone blood levels and did not lead to abnormally high DHT levels or increase sweat or odor despite the increased perspiration usually associated with the use of testosterone. Hadgraft 296:10-300:15; Goldstein 612:17-613:8, 671:3-674:25, 682:17-683:17; PTX-4 at col. 22,1. 65-col. 23,1. 8.

One of Acrux’s initial studies, Clinical Trial No. DDS16, showed efficacy without elevated DHT levels following application to the axilla. PTX-14; PTX-96; PTX-133; PDX-7032; PDX-7033; Goldstein 669:15-20, 676:23-677:9. In fact, the reported DHT levels were lower than those seen in the forearm. Goldstein 669:13-20; PTX-133 at 46 (“Whilst the inner arm treatment showed no significant change in T:DHT ratio over the 72 hour time course, the average ratio of 5:1 was significantly higher than the average ratio for the axilla treatment (3.7)”).) Later studies by Acrux confirmed this finding, including, for example, Clinical Trial No. MTE04 (mean DHT:T ratio within the normal physiological range). PTX-14; PTX-100 at 76; PDX-7032; PDX-7033; Goldstein 677:10-14.

Alleged Unexpected and Surprising Results of the Method Claimed in the ’944 Patent

No Increased Sweating

Dr. Goldstein opined that a POSA would expect that testosterone increases the activity of the apocrine glands and should result in increased sweating and odor in the axilla. It therefore was surprising that application of testosterone to the axilla in Plaintiffs’ clinical studies did not increase sweat or odor. 12 Goldstein 675:11-676:13. However, because a hypogonadal man has decreased testosterone blood levels, a physician would expect that his sweating *965 would also be less than normal. Snyder 930:1-23. If testosterone replacement therapy returns a hypogonadal man to normal physiologic ranges, a physician would then expect the amount of sweating to increase to normal levels. Id. A physician would further understand that perspiration is a systemic effect of testosterone. Id. Increased testosterone blood levels increases sweating in all areas where men normally perspire. Id. Sweating does not increase just at the local site of application of testosterone. Id. Regardless of the site of application, a physician would expect that returning testosterone blood levels to normal physiologic ranges would result in normal amounts of sweating. Id.

Seven-Fold Increase in Permeability Across the Axilla

Dr. Hadgraft opined that it was unexpected that drug delivery .across the axilla provided a seven-fold greater absorption of testosterone per unit surface area of the skin than that of the forearm. Hadgraft 514:5-515:4. Dr. Hadgraft’s opinion relied upon the results from plaintiff Acrux’s Clinical Study DDS16 comparing drug delivery of testosterone across the skin of the axilla and the inner forearm, which results were later adjusted by inventor Dr. Adam Watkinson to account for the surface areas of the respective application sites. Based on his calculations, Dr. Watkinson asserted that the drug delivery across the axilla was seven-fold greater per unit surface area than that across the forearm. Id.

Clinical Study DDS16 is entitled:' “A pharmacokinetic phase I study to assess the effect of different application sites on the pharmacokinetics of testosterone from a Testosterone Metered Dose (MD) Lo-tionTM.” PTX-96 at 1. In this study, a trans dermal testosterone composition was applied to the skin of the axilla and the inner forearm. Id. at 7; Potts Tr. 1406:6-21. The study investigators did not measure the surface area of the application site on the axilla or the forearm or otherwise control for the size of the surface area of the application site. Id. The study found that “mean baseline-corrected total testosterone AUCo-72 for the axilla was 5617 ng. hr/mL, a result , almost double that achieved for the inner arm (2979 ng. hr/mL).” PTX-96 at 45; Potts Tr. 1406:22-1407:5. The study investigators found that “the different extents of absorption observed for the two application sites in this study are consistent with a previous investigation of variations in skin penetration where the extent of hydrocortisone absorption from the axilla was 3.6 times greater than from the ventral forearm,” as reported in Feldmann (1967). PTX-96 at 45, 77 (emphasis added); Potts Tr. 1406:22-1407:7. Dr. Hadgraft does not dispute that the two-fold enhanced permeation of the axilla relative to the forearm as measured in Clinical Study DDS16 would have been expected. Hadgraft Tr. 459:10-25; see also Watkinson Dep. Tr. 114:22-116:14. His opinion on unexpected results based on enhanced permeation is limited to the seven-fold size adjustment made by Dr. Wat-kinson. Id.

In his 2010 declaration, Dr. Watkinson relied on a measurement of the median size of the female axilla obtained from the measurements of 60 women who had their axillae measured for a deodorant/antiperspirant study reported in Cowan-Ellsberry (2008) (PTX-299) and a measurement of the median size of the inner forearm of 15 women from Acrucx’s offices who had their forearms measured by Dr. Watkinson in order to calculate the “flux” per unit surface area of testosterone across the skin in the axilla and inner forearm of the subjects in DDS16. PTX-14 at 5-6, ¶¶ 13-15. Flux is a term used to describe the rate of transfer of a drug across the skin. Had-graft 303:23-304:3. When Dr. Watkinson performed this calculation correcting for the surface area of the two administration *966 sites in DDS16, he determined that there was a seven-fold increase in flux for the axilla as compared to the inner arm. PTX-14 at 8, ¶ 21; Hadgraft 299:18-304:6. In making this comparison, Dr. Watkinson relied upon the assumption that the areas of the axillae and forearms measured represented the areas of application in the original Clinical Study DDS16. Potts 1411:12-20,1411:24-1412:7. In his 2010 declaration to the PTO regarding unexpected results, Dr. Watkinson explained that the seven-fold greater absorption of testosterone in the axilla was unpredictable in view of the variability in the prior art, depending on the compound and site of application. PTX-14 at 9, ¶ 22.

Clinical Study DDS16 did not include any discussion of the axilla providing a seven-fold greater permeation than the forearm. Potts 1407:8-11. None of the publications of the Clinical Study DDS16 results, other than Dr. Watkinson’s declaration to the PTO, included any discussion of the axilla providing a seven-fold greater permeation than the forearm. Id. at 1407:12-1410:3. Specifically, the results of Clinical Study DDS16 are reported in Example 1 of the axilla patent, but the inventors did not make any claim in the specification that the axilla resulted in a sevenfold greater permeation than the forearm. Id. at 1407:19-1408:4; PTX-4 at Example 1. The study investigators later published the results of Clinical Study DDS16 in a 2014 peer-reviewed article by lead author Dr. Susan Davis. Potts 1408:5-1409:5; PTX-303. The authors report that administration of testosterone to the axilla resulted in two-fold greater absorption than across the forearm. Potts 1409:9-17; PTX-303 at 1, 6. The authors did not make any claim that absorption across the axilla was seven-fold greater than across the forearm. Id.

VI. The Applicator Patent

The ’861 applicator patent, entitled “Spreading Implement,” claims an implement for topical delivery of a therapeutic liquid or lotion—here, the claimed trans-dermal testosterone lotion—to the “axilla area of the user.” PTX-5 at Abstract.

Deñnition of a Person of Ordinary Skill in the Art for the ’861 Patent

A person of ordinary skill in the art (“POSA”) for the ’861 applicator patent would have been someone with a bachelor of science degree in mechanical engineering or the packaging fields and one to three years of experience, or equivalent education and/or experience, in the design of medical products and/or design and manufacture of products and packaging for pharmaceutical applications. Slocum 565:11-567:17; DDX-418 (Singh definition of POSA for ’861 patent).

The Invention and the ’861 Patent

For safety and efficacy, Acrux needed to show that its patented testosterone solution could be applied accurately and consistently. PTX-75 at 30-32 (listing requests from FDA regarding the applicator). Since there were no similar products on the market at the time (ie., a low-viscosity transdermal testosterone formulation applied to the axilla), Acrux did not believe an applicator was then in existence that was suitable for its purpose. PTX-1093 at 7 (providing market research on known applicators for other products to the axilla).

To assist in developing a no-touch applicator implement to apply its testosterone formulation to the axilla, Acrux engaged the Bayly Group. PTX-1066 at 3; PTX-1093; PTX-1153; Slocum 541:12-24. The inventors considered numerous possible designs for the applicator. PTX-1093 at 6-7, 10; PTX-1148 at 4; Slocum 545:3-16, 548:11-549:25. Their first design attempts embodied applicators with convex heads, similar to roll-on and ball-shaped applica *967 tors for the axilla known at the time. PTX-1148 at 4, 6; Slocum 548:4-549:25. Because the axilla is primarily a concave surface, the general wisdom at the time was to use an applicator with a complementary shape: a convex applicator to fit the concave surface. PTX-1093 at 7; Slocum 546:15-22.

The first design pursued by the inventors was a dome-shaped applicator referred to as the “mushroom” applicator. E.g., PTX-1093 at 6-7; Slocum 545:3-546:2, 549:19-25. As previously noted, the mushroom applicator had a convex head and was designed to apply the solution in a manner similar to the known roll-on deodorant applicators. PTX-1066 at 6, 8. The mushroom applicator concept was eventually abandoned, however, for several reasons. PTX-1066 at 7. Importantly, the metered-dose testosterone lotion was not effectively retained on the surface of the head; the solution would run down the bottle and did not reliably deliver the required dose. PTX-1066 at 6, 7; PTX-1144 at 2; Slocum 552:3-15, 559:18-23.

The inventors began to pursue a design of a “simple axilla applicator.” (PTX-1066 at 6, 7, 10). The “simple axilla applicator” was so named because it was made with fewer parts than the mushroom applicator. PTX-1066 at 7, 10. Ultimately, the inventors struck upon the idea of an applicator with a concave receptacle. PTX-1066 at 17; PTX-1157 at 3-5; PTX-1158 at 2, 4-6; Slocum 554:4-555:3. The simple axilla applicator: (1) retains the solution dispensed from the pump and allows for the applicator to be tilted to angles up to 45 degrees without spilling the dose; (2) includes a soft, collapsible head to aid in the smooth and effective dosing to the axilla; (3) delivers a full dose; and (4) is easy to clean. PTX-1066 at 6,10,17. Those applicator concepts were the foundation of the patent application that issued as the ’861 patent. Slocum 554:4-555:3.

An overview of the preferred applicator embodiment is shown in Figure 1 (PTX-5 at col. 3, 11. 6-17 and Fig. 1.); a cross-sectional view of the applicator with additional detail is shown in Figure 2 (Id. at col. 3, 11. 18-33 and Fig. 2). The applicator is used as follows: therapeutic liquid is dispensed into the applicator reservoir (4) (Figure 1), after which the user places the applicator in contact with the skin surface to deposit and spread the liquid onto the skin. See id. at col. 3, 11. 6-17. The ’861 patent claims describe the applicator and its components, various therapeutic compositions, and the application method. PTX-5.

*968 [[Image here]]

[[Image here]]

[[Image here]]

PTX-5 at col. 3, 11. 6-17 and Fig. 1; id. at col. 3,11.18-33 and Fig. 2.

Claims 9 and 10 of the ’861 Patent

As discussed above, in this litigation, Plaintiffs have asserted against Defendants dependent claims 9 and 10 of the ’861 patent. These claims (and those from which they depend) recite as follows:

1. A system for transdermal administration of a physiologically active agent from a liquid composition, the system including a container containing the liquid composition including the physiologically active agent, a dispensing device for delivering liquid composition from the container; and an applicator for applying the liquid to an area of skin for *969 transdermal administration said applicator including a support detachably contactable to the dispensing device or container being adapted to detach to permit said dispensing device to deliver said liquid composition, a receptacle mounted on the support defining a reservoir space which receives a volume of the liquid composition from the container, the receptacle having a base and a resiliently deformable wall, the wall being substantially transverse to the base and having a working surface that is used to spread the liquid composition over the area of the skin surface, the base having a surface such that the liquid composition cannot pass through the base.

9. A method of transdermal administration of a physiologically active agent to a subject including providing a system according to claim 1; applying the liquid composition including the physiologically active agent to the reservoir space; and deforming the wall of the receptacle containing the liquid composition against the skin of the subject and spreading the liquid composition over the area of the skin surface in at least one axilla.

10. A system according to claim 1 wherein the receptacle defining the reservoir space has an open top being configured to receive the liquid composition from the dispensing device through the open top.

PTX-5 at claims 1, 9,10.

Claim Construction of the ’861 Patent

The parties have agreed that the claimed “wall” is defined as “[p]art of the receptacle having an inner portion and an outer skirt portion which form a double-wall structure.” Dkt. 105 at 2. The “double-wall structure” is “[a] structure having two walls, i.e., not the two surfaces of a single wall.” Id. In the context of the ’861 applicator patent, the claimed wall must comprise an inner portion (“[o]ne of the two walls of the double-wall structure that is closest to the reservoir space”) and an outer skirt portion (“[o]ne of the two walls of the double-wall structure that is furthest from the reservoir space”) that together form a double-wall structure. Id. at 1-2; PTX-5 at claim 1. The parties agree that the asserted claims of the ’861 patent require a wall that is “substantially transverse to the base.”

The parties have also agreed that the terms “has a continuous surface such that liquid cannot pass through the base” and “having a surface such that the liquid composition cannot pass through the base,” mean “[the] surface does not contain openings or pores that would permit liquid to pass through the base.”

A. The Actavis and Perrigo Applicators 13

The Actavis Applicator

Actavis’s ANDA applicator is depicted in the schematics below:

*970 [[Image here]]

PTX-218 at 1658-59; see PTX-1174; DTX-1277. Detail B depicts the single wall of Actavis’s applicator that Plaintiffs allege folds over to form a double-wall structure when used in accordance with Actavis’s labeling instructions.

The Perrigo Applicator

Perrigo Israel submitted ANDA No. 204255 to FDA on April 3, 2012. Dkt. 134 ¶58; DTX-13 at 1-4. As originally submitted, Perrigo Israel’s ANDA included information regarding an original proposed applicator device including*

*971 [[Image here]]

DTX-13 at 756; see also DTX-13 at 753-55.

In 2014, Perrigo Israel’s ANDA was amended to include information regarding the current proposed applicator device, which is the applicator that Perrigo intends to include as part of the its ANDA Product. See PTX-206 at 992-95.

The Perrigo ANDA applicator is depicted in the schematics below:

Schematics of the Perrigo Applicator

*972 [[Image here]]

DTX-32 at 1-3; PTX-206 at 992, 994-95; DTX-30 at 1-3; see PTX-1175.

The “Wall” Limitation 14

As discussed above, the “wall” limitation in the asserted claims has been construed to require a double-walled structure. Plaintiffs concede that both the Actavis and Perrigo applicators have only a single wall at rest, and therefore neither applicator meets the limitations of claims 9 and 10 of the ’861 patent at rest. See, e.g., Slocum 774:14-17, 978:18-20; Slocum 817:16-20, 856:8-22. Plaintiffs contend, however, that the wall of both the Actavis and Perrigo applicators folds over when used in accordance with the devices’ respective labeling instructions to form the infringing double-walled structure.

The Basis of Dr, Slocum’s Testimony Regarding the Wall Limitation

Plaintiffs rely in support of this contention solely on Dr. Slocum’s testimony that the Actavis and Perrigo applicators form a claimed double-wall structure in use. Dr. Slocum based his opinion that the Actavis and Perrigo applicators form a claimed double-wall structure in use on:

• portions of the Actavis and Perrigo labeling (Slocum 778:20-779:15; PDX 4088; Slocum 819:13-820:1; PDX 4067; PDX 4068);

• his theoretical understanding of the materials used in the wall (Slocum 781:14-23);

• his manipulation of the applicators in the offices of the Finnegan lawyers *973 (“Finnegan testing”) (Slocum 783:5-25); and

• his March 2016 at-home testing in his shower (“wet testing”) (id.)

See id. at 817:9-11, 818:1-14. In reaching his conclusions, Dr. Slocum never saw a patient or any other person actually use the Actavis or Perrigo applicator. Id. at 895:2-4; 979:8-981:4.

The Structure and Materials Used in the Walls of the Actavis and Perrigo Applicators

The wall of Actavis’s applicator is made of a thermoplastic elastomer; Perrigo’s áp-plicator has a wall made of silicone. Both thermoplastic elastomer and silicone are flexible plastics. Dr. Slocum testified, and Dr. Singh did not dispute, that the walls of both the Actavis and Perrigo applicators can be deformed when force is applied to them and will then return to their original shape when the force is removed. Slocum 798:23-794:6, 827:6-16; Singh 1015:24-1016:4,1116:18-1118:14.

Dr. Slocum further testified that, when Actavis’s and Perrigo’s applicators are used as directed in the labeling instructions, the flexible walls are pressed against the axilla. He also opined that the instructions included with the Actavis and Perrigo applicators teach the patient' to use the applicators in a manner that would avoid leakage of the testosterone formulation. According to Dr. Slocum, the force created when the devices are pressed against the surface of the axilla with enough pressure to prevent leakage causes the walls of the respective applicators to ' double over on themselves, forming a double-walled structure as disclosed in claims 9 and 10 of the ’861 patent. To support this testimony, Dr. Slocum relies on Actavis’s and Perri-go’s labeling instructions as well as his personal observations during his hands-on testing of the accused applicators.

Dr. Slocum ⅛ Finnegan Testing

Prior to submitting his January 2016 infringement reports, in which he opined that the Actavis and Perrigo applicators would form a claimed double wall in use, Dr. Slocum met at the law offices of Plaintiffs’ counsel which provided him an opportunity to. handle the accused applicators; this visit was referenced at trial as the “Finnegan testing.” Slocum 783:5-25, 862:14-863:8, 870:5-11, 872:25-873:3; 979:8-981:4. Dr. Slocum’s Finnegan testing consisted of him manipulating by hand- in a fashion he described as “playing with” the Actavis and Perrigo applicators there in Plaintiffs’ counsel’s office. Id. at 783:5-17, 862:14-863:8, 863:18-864:10, 864:19-865:11, 865:19-866:21, 979:8-981:4. Dr. Slocum was uncertain as to whether he used liquid in the applicators during the testing, but he testified that, if he had, it would have been “just a little bit of water.” Id. at 863:18-23, 864:1-10, 1172:8-16. Dr. Slocum’s Finnegan testing process did not include placement of the Actavis or Perrigo applicators against the axilla, nor did it include utilizing the applicators according the Actavis or Perrigo labeling. Id. at 864:1-10, 864:19-865:11, 865:19-24. Dr. Slocum admitted that his Finnegan testing was not performed in a way that a typical user would use the applicators, and that a typical user would not have Dr. Slocum’s level of knowledge regarding sealing structures. Id. at 865:25-866:14.

Dr. Slocum took no photographs, video, or contemporaneous notes to document or otherwise record his Finnegan testing on the Actavis and Perrigo applicators. Slocum 866:15-21, 867:7-25. Generally, in his testing conducted outside a litigation context, Dr. Slocum keeps notes, photographs, video, computer records, or other documentation of his testing procedures, data, and results. Id. 856:23-857:5, 860:21-861:11.

*974

Dr. Slocum’s Wet Testing

After reading defendants’ expert reports rebutting his January 2016 infringement report opinions, Dr. Slocum performed his “wet testing” experiment in March 2016 for purposes of preparing his reply report. Slocum 783:5-25, 862:14-863:17, 870:5-11, 872:25-873:8, 979:8-981:4. Dr. Slocum’s wet testing consisted of his using the Actavis and Perrigo applicators to apply a homemade contrived liquid formulated by him from ingredients he found at his personal residence (consisting of a combination of cranberry juice and household rubbing alcohol in unknown amounts) to his own axilla, while standing in his bathroom shower. See, e.g., id. at 783:5-784:9, 863:14-17, 874:17-19, 875:24-876:6, 877:13-21, 878:13-18; 979:8-981:4. He testified that he “pretend[ed]” to be “a typical user” during his wet testing and that he did not intend for the wet testing to be a scientifically reliable experiment, rather he simply wanted to do a “quick play” with the accused applicators. Id. at 783:5-25, 786:17-21, 863:14-17, 891:9-892:2.

At trial, Dr. Slocum could not recall various details about his wet testing. For example, he was unable to remember the date on which he performed his wet testing. Slocum 873:4-12. He also testified that he could not remember the length of time it took him to perform the wet testing on each applicator because “he did not record the time,” but he believed that it took “less than an horn- and more than a minute.” Id. at 875:14-23. He could not recall precisely how many times he tested the Actavis or Perrigo applicators during the wet testing, (see, e.g., Slocum 884:4-16), stating that it was “a bunch of times,” and “probably around ten” times, but was “more than one time and less than 20” times. Id. Additionally, although Dr. Slocum reportedly tested all four applicators on the same day, one after the other, he did not recall the order in which he tested defendants’ accused applicators. See Slocum 874:17-875:9. Dr. Slocum testified that he was “pretty sure [he] did Lupin last, but [he doesn’t] recall,” nor does he recall whether he tested Actavis’s, Perrigo’s, or Amneal’s applicator first. 15 Id.

When conducting his wet testing, Dr. Slocum did not use either Actavis’s or Perrigo’s ANDA formulation that will be sold with the applicators, or even an accurate substitute for those formulations. See, e.g., Slocum 783:5-784:9, 875:24-876:15, 877:13-21, 878:13-18, 878:21-879:2; see also id. at 979:8-981:4. Dr. Slocum conceded that he could have asked for and used an Axiron placebo formulation, but he did not. Id. at 876:3-17. He also admitted that he had access to Perrigo’s ANDA and the formulation described therein, but he did not use that information to make a placebo formulation because he is “not a chemist” and “wouldn’t know what to do with [that information] anyway.” Id. at 876:18-877:3; see also id. at 877:8-12. Instead, Dr. Slocum used a homemade mixture of his own devising—cranberry juice and “household rubbing alcohol that [he] found at [his] house”—as a substitute for Actavis’s and Perrigo’s ANDA formulations. See, e.g., id. at 875:24-876:15, 877:13-21. Dr. Slocum did not know how the rubbing alcohol he used in his cranberry juice/alcohol mixture compared to the isopropyl alcohol in the ANDA formulations. See id. at 877:4-7.

Despite knowing that Actavis’s and Per-rigo’s ANDA formulations contain a thickening agent, Dr. Slocum did not include any thickener, in his cranberry juice/rubbing alcohol mixture. Slocum 877:18-878:7; see also id. at 979:8-981:4. He admitted that a formulation containing a thickener would have a higher viscosity than his cranberry juice/alcohol mixture, and that *975 his cranberry juice/alcohol mixture is “more sensitive to detecting leakage from the applicator.” Id. at 878:8-18. Dr. Slocum did not measure the viscosity of the cranberry juice/alcohol mixture used in his wet testing of the Actavis and Perrigo applicators, but he estimated that it would be “about one centipoise” and “very close to water.” Id. at 879:4-9. Plaintiffs’ expert, Dr. Hadgraft, testified that, based on the ingredients in the Axiron formulation, the viscosity of the Axiron formulation is “between 14 and 35 centipoise,” which is “roughly the viscosity of something like vegetable oil.” Hadgraft 171:3-18. Actavis’s ANDA formulation and Perrigo’s ANDA formulation have the same ingredients in roughly the same amounts as the Axiron formulation. Cf PTX-218 at 239 (Actavis ANDA formulation) and DTX-14 at 20 (Perrigo ANDA formulation) with PTX-75 at 211 (Axiron formulation); see Hadgraft 168:14-169:22.

Thus, according to the testimony of plaintiffs’ experts, the viscosity of Dr. Slocum’s cranberry juice/alcohol mixture differed significantly from the viscosity of the Actavis and Perrigo ANDA formulations, and Dr. Slocum’s wet testing exaggerated the leakage that one would expect from use of Actavis’s and Perrigo’s applicators by patients according to the Actavis or Perrigo labeling to apply the Actavis or Perrigo ANDA formulations. See Hadgraft 171:3-18; Slocum 877:18-878:18, 879:4-9, 979:8-981:4.

Dr. Slocum also failed to use the amount of liquid directed in Actavis’s and Perrigo’s labeling instructions when he performed his wet testing. Both Actavis’s and Perri-go’s labeling specifies that only 1.5 ml of liquid (one pump) at a time is to be transferred into the Actavis and Perrigo applicators for application to the axilla. See, e.g., PTX-218 at 2614-15, 2623; PTX-216 at 16-17. Dr. Slocum admitted that the Actavis and Perrigo labeling tells the patient “exactly” how much liquid to. use. Slocum 881:17-19.

Dr. Slocum, however, did not precisely measure the amount of liquid he used in Actavis’s and Perrigo’s applicators during his wet testing. He testified that he did not use any type of medical syringe or accurate measuring device to measure the amount of liquid he transferred to the Actavis and Perrigo applicators during his wet testing. Slocum 881:6-8. Rather, he used a common kitchen teaspoon that “[they] eat with,” which holds approximately “4 to 5 mL total.” 16 Id. at 880:9-881:5, 785:7-21, 882:16-883:5.

At his deposition, Dr. Slocum first testified that he used 3 ccs per application for his wet testing, which is 3 ml and double the amount of liquid called for in Actavis’s and Perrigo’s labeling. Slocum 881:20-22, 979:8-981:4. Later in his deposition, he testified that he used 1.5 ccs per application for his wet testing. Id. at 881:23-882:3. At trial, Dr. Slocum could not recall the exact amount of liquid he used in Actavis’s and Perrigo’s applicators during the wet testing. He testified variously that he used “what looked like a reasonable amount” of liquid for his wet testing, (id. at 785:7-21, 882:13-15); “a fraction of a teaspoon,” (id. at 785:7-14), “about a third of a teaspoon,” (id. at 879:10-880:6), “a reasonable guesstimate,” (id. at 882:13-21), “a few milliliters lower than the rim” of the teaspoon, (id.), “less than [4 to 5 mL], on the order of the one and a half, (id. at 882:16-883:2), and “a third to a half, probably.” Id. at 883:3-5.

*976 As with his Finnegan testing, Dr. Slocum took no photographs, video, or contemporaneous notes to document his wet testing on the Actavis and Perrigo applicators. Slocum 873:13-16, 875:10-23, 880:24-881:5, 888:1-6, 894:20-21, 895:11-19. Because he elected to perform his wet testing in the bathroom of his home, without anyone witnessing his use or otherwise documenting the testing with photographs or video, Dr. Slocum was able to determine whether a double-wall formed only by looking at himself directly while using the applicators, and, for parts he could not observe in that way, by looking at himself in his bathroom mirror while standing in his shower about five or six feet away from the mirror. See, e.g., Slocum 885:15-886:16.

Based on his wet testing, Dr. Slocum testified that users will “learn” to form a double wall when using the Actavis and Perrigo applicators because they are instructed to prevent all leakage during application. See, e.g., Slocum 783:5-785:6, 883:12-884:3, 890:5-891:4. He testified that the applicators would not be “working right” if there were any amount of leakage more than “a drip now and then.” Id. at 892:19-893:21, Thus, Dr. Slocum testified that patients will press the Actavis and Perrigo applicators with sufficient force to form a double wall simply because he did so to ayoid excessive leakage, which he defines as anything more than “a drip now and then.” Dr. Slocum did not test the Axiron® applicator as a control, in order to compare the leakage experienced with the Actavis and Perrigo applicators with leakage associated with the Axiron® applicator. With regard to his belief as to the acceptable amount of leakage, Dr. Slocum testified that “if it was drippy, runny, ineffective ... I don’t think the FDA would have approved it as a product.” Slocum Tr. 869:5-870:4, 902:3-903:2.

Dr. Slocum testified that he cannot say precisely the amount of force he applied in order for the single wall of Perrigo’s applicator to fold over in use. Slocum 884:17-885:14, 890:11-891:8, 979:8-981:4. Although Dr. Slocum testified that the amount of force with which the applicator is pressed against the axilla can affect whether a double wall is formed, he utilized no special instrument to control (or measure) the amount of force that he used when wet testing Actavis’s and Perrigo’s applicators. Id. at 884:17-885:14, 890:11-891:8. Dr. Slocum testified that he himself pressed Acta-vis’s and Perrigo’s applicators to his axilla with enough force to create a so-called “rolling diaphragm” seal in order to avoid what he deemed to be excessive leakage, but he conceded that typical users do not have his level of knowledge regarding sealing structures. See id. at 777:18-778:8, 783:5-785:6, 866:12-14.

Dr. Slocum also testified that he followed the instructions on Actavis’s and Perrigo’s labeling “as closely as possible.” Dkt. 318 at 11. He concedes that néither Actavis’s nor Perrigo’s labeling contains express instructions to apply sufficient force to avoid all leakage or to create a seal. See Dkt. 318 at 10. The instructions direct patients only to “keep[ ] the applicator upright” and to “place [the applicator] up into the axilla and wipe steadily down and up into the axilla.” E.g., DTX-258. Actavis’s and Perrigo’s labeling both warn patients about the risk of secondary exposure to testosterone and instruct the user to apply the testosterone lotion only to the axilla and not to touch the solution with their hands. With regard to possible leakage, the instructions direct that “[i]f the solution drips or runs, it can be wiped back up with the applicator cup.” Id.

Dr. Slocum’s Animation of the Accused Applicators

During cross examination, Dr. Slocum admitted that an animation he used in connection with his infringement testimony *977 (PDX 4084), which demonstrated the wall of Actavis’ applicator folding over to form a double wall in use, depicted the axilla as a “simple,” “upside-down bowl” that lacked any “other stuff that’s in the axilla,” such as hair. Slocum 1214:25-1215:23, 1216:7-15; see also id. at 817:6-11, 818:1-819:7; PDX 4063. However, Dr. Slocum had previously testified that the axilla is a “very complex” surface, is “not just a smooth bowl,” and has “all kinds of stuff going on in there.” Slocum 1214:12-24; see id. at 794:22-795:6. Dr. Slocum admitted that his animation does not show the applicator being wiped up and down according to the labeling or moving laterally across the skin surface. Id. at 1217:1-4,11-13. Dr. Slocum provided no pictures or video of the Actavis or Perrigo applicators actually being used in a human axilla, nor did he demonstrate use of the applicators on a human axilla. Slocum 1216:16-25.

Dr, Singh’s Testimony Regarding the Wall Limitation

At trial, Dr. Singh opined that the Acta-vis and Perrigo applicators, when used in accordance with the Actavis and Perrigo labeling, do not form a double wall and therefore do not infringe claims 9 and 10 of the ’861 patent. His opinions were based on, among other things, his review of the ’861 applicator patent and its prosecution history, the Actavis (and Perrigo) ANDA labeling, Lilly’s demonstrative videos of the Axiron applicator, information regarding the Actavis (and Perrigo) applicator including schematics, and a sample of the Actavis (and Perrigo) applicator. Singh 1013:2-17, 1015:6-8; see Dkt. 410 at ¶1.

Dr. Singh testified that the Actavis and Perrigo labeling does not include any requirements or directions that, in using the Actavis or Perrigo applicators, the patient should or must use them in such a way to form a double wall, apply a certain amount of force against the axilla, or form a seal against the axilla. Singh 1018:4-1019:2; PTX-218; see also Dkt. 410 ¶ 1; PTX-206; PTX-216. He further testified that, contrary to Dr. Slocum’s opinion, the labeling does not instruct the patient to push the applicators with enough pressure against the axilla to cause the single wall to fold over onto itself. Singh Tr. 1019:13-19. According to Dr. Singh, a patient using the Actavis or Perrigo applicators consistent with the labeling will not form a seal or double wall against the axilla. Singh 1019:3-12,1023:14-16,1024:4-16.

In support of this opinion, Dr. Singh testified that, contrary to Dr. Slocum’s description, the surface of the armpit is relatively flat (rather than concave) when the applicators first make contact with the skin. Singh 1019:20-1020:5. Dr. Singh pointed to Figure 3 of the Actavis labeling as showing the relatively flat surface to which the applicator is initially applied:

*978 [[Image here]]

PTX-218 at 2633; see Singh 1019:20-1020:5. Figure 3 of the Perrigo labeling also shows the relatively flat surface to which the Perrigo applicator is initially applied:

[[Image here]]

PTX-216 at 19; see Singh 1019:20-1020:5; Dkt. 410 at ¶ 1.

Dr. Singh also referenced Lilly’s Axi-ron® video (DTX-1283), entitled “Application Video,” which purports to provide patients with “step by step instructions on how to properly apply Axiron,” according to the Axiron® labeling. DTX-1283 at 00:00 to 00:06, available at http://axiron. com/how-to-apply-axiron-for-testosterone-treatmentaspx. As Dr. Slocum admitted, the Axiron labeling and the Actavis and Perrigo labeling are substantively the same. Slocum Tr. 904:22-905:6; see also id, at 979:8-25. Thus, Lilly’s Axiron video also illustrates the proper application of the Actavis and Perrigo applicators according to the Actavis and Perrigo labeling. Indeed, Dr. Singh testified that Lilly’s Axi-ron video is representative of applications using Actavis’ and Perrigo’s applicators according to the Actavis and Perrigo label *979 ing. See id. at 1022:20-1023:16, 1025:23-1026:5; see also Dkt. 410 ¶ 1.

During Lilly’s Axiron video, patients are instructed to “start swiping a little above and ending a little below your underarms to help avoid spilling and to speed drying.” DTX-1283 at 01:19 to 01:25. Excerpted photographs from video show the following:

[[Image here]]

DDX 405; see DTX-1283.

[[Image here]]

DDX 408; see DTX-1283.

Using Lilly’s Axiron video (DTX-1283), specifically at the 1:24 mark to the 1:39 mark, Dr. Singh explained that the applicator is first placed up against a relatively flat surface of the axilla (as opposed to a relatively concave or convex surface), then is swiped down and steadily up. Singh *980 1020:24-1022:7; DTX-1283. He also testified that, as the applicator is swiped down and up, the leading portion of the wall is folded inwards into the receptacle while the trailing wall portion is not deformed at all. Id. at 1021:14-1022:19; DDX 405, 408; DTX-1283.

Dr. Singh opined that the Actavis and Perrigo applicators would behave similarly during application according to the Actavis and Perrigo labeling. Singh 1022:20-1023:16; DDX 407; see also Dkt. 410 ¶ 1. Specifically, Dr. Singh testified that, during application, the leading edge of the Actavis and Perrigo applicators would fold inward (therefore not forming a double wall even according to Dr. Slocum’s theory) and the trailing edge would not defo

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