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Eli lilly and Co. v. Perrigo Co.

United States District Court, S.D. Indiana, Indianapolis Division

August 22, 2016

ELI LILLY AND COMPANY, ELI LILLY EXPORT S.A., ACRUX DDS PTY LTD., Plaintiffs,
v.
PERRIGO COMPANY, PERRIGO ISRAEL PHARMACEUTICALS LTD., ACTAVIS LABORATORIES UT, INC. formerly known as WATSON LABORATORIES INC., AMNEAL PHARMACEUTICALS LLC, LUPIN PHARMACEUTICALS, INC., and LUPIN LTD., Defendants.

          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, 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, “Perrigo”); Actavis Laboratories UT, Inc. (“Actavis”); Amneal Pharmaceuticals LLC (“Amneal”); 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 Pharamceuticals is an Israeli corporation with a principal place of business at 29 Lehi Street, Bnei Brak 51200, Israel. The Perrigo Defendants are engaged in the business of making and selling generic drugs, which they distribute in Indiana and throughout the United States. On April 3, 2012, Perrigo 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 Bridgewater, 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 Transdermal 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.

         Plaintiffs are asserting claim 13 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):
Image Omitted.
wherein R1 is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or NR3R4; R2 is a C8 to C18 alkyl; R3 and R4 are each independently hydrogen, lower alkyl or R3 and R4 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring; n is 0 or 1, and q is 1 or 2, wherein, when n is 0 and R1 is NR3R4, then NR3R4 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 alkyl cinnamate, C8 to C18 alkyl methoxycinnamate or C8 to C18 alkyl salicylate.
10. The method according to claim 9, wherein said ester is octyl dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, 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 drug delivery, ” issued on May 7, 2013, to named inventors Tony Dipietro, Andrew Humberstone, Igor Gonda, Adam Watkinson, 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 2, 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] Hadgraft 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, octyldimethyl-para-aminobenzoate and octyl para-methoxycinnamate; (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 alcohol(s) 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. 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 Facts, 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 Perrigo 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 Defendant Actavis, at ¶¶ 4-6; Dkt. 263, Joint Stipulation Between Plaintiffs and Perrigo Defendants, at ¶¶ 4-6. Plaintiffs assert that Amneal 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’ transdermal 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 BA. and MA. 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 transdermal 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.CM. from McGill University Faculty of Medicine in 1975. He served as a surgical resident 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 Pappalardo 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-222at3.

         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/FUNdaMENTALS.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 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 transdermal 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 Ckambliss, Ph.D.

         Dr. Chambliss is an expert in the field of pharmaceutical sciences and pharmaceutical formulations and related areas. Chambliss 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 thet861 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. 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. Chambliss 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 thet861 patent. He also testified as to the invalidity of thet861 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, 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. MacLean 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-3002001; 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-3002001; 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-3002002; MacLean 1646:1-1647:10; DDX 503. Currently, Dr. MacLean 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-3002004. 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-3002002-3.

         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 Leoben University in Austria in 1985. He presently 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 transdermal 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, ll. 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 apocrine 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; Goldstein 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 approximately 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; Goldstein 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 transdermal 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, ll. 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. Axiron® 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, norethisterone, and testosterone. PTX-531 at 17; PTX-253 at 3; PDX-3004; Hadgraft 141:20-143:18. As of 1996, transdermal testosterone fonnulations were commercially available and known to be therapeutically effective in increasing testosterone blood levels. PDX-2064. These fonnulations included the marketed drugs Testoderm®; Androderm® (PTX-630); Percutacrine Androgenique Forte (PTX-576 at 2); Testogel®; and a formulation that was not marketed 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 transdermal 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% relative to the weight of testosterone. Potts 1307:22-1308:11; 1310:16-1311:3; see Hadgraft 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 Specification

         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. Hadgraft 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 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 hypogonadal 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 hypogonadal man. PTX-1 at col. 24, 11. 25-35; 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 salicylate. 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 1, 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.

         Concerns 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. Hadgraft 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, 11. 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 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. Therefore, 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. Hadgraft 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 therapies on the market: patches and gels. The patches were associated with skin irritation, and the scrotal patch in particular was associated with elevated dihydrotestosterone (“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, ll. 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, l. 32-col. 23, l. 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, l. 65-col. 23, l. 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. Id.; Potts 1347:8-1348:24 (discussing demonstratives DDX 234-36); see also PDX 2022.

Claim 13 of the Axilla Patent

Dependent Claims 14-20 of the Axilla Patent

Compilation of Claim 20 of the Axilla Patent

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 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;

(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;

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

’944 claim 17 - The method of claim 16, wherein the combined volume of lower alkyl alcohol(s) is more than 70% (v/v).

’944 claim 18 - The method of claim 17, wherein the combined volume of lower alkyl alcohol(s) is more than 80% (v/v).

(b) one or more lower alkyl alcohols selected from a group consisting of ethanol, isopropanol, and mixtures thereof, wherein the combined volume of the lower alkyl alcohol(s) is more than 80% (v/v) of the composition;

(c) one or more penetration enhancers selected from the group consisting of octisalate, octyldimethyl-para-aminobenzoate and octyl para-methoxycinnamate;

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

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

(c) the penetration enhancer octisalate in an amount of from 0.01% to 15% (w/v)

(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

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

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

(d) the viscosity modulating agent polyvinyl pyrrolidone present in an amount from 1% to 3% (w/v) of the composition, 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

(e) optionally, water

(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.

wherein the composition is applied in an amount effective to achieve a testosterone blood level in the subject of at least 200 ng/dL.

         Occlusive and Non-Occlusive Transdermal Testosterone Treatments for Hypogonadism 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 non-occlusive (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 (“Aschkenasy ‘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; Goldstein 622:20-23. Testoderm® was later withdrawn from the market because of concerns related to elevated DHT levels associated with use of the product. Goldstein 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 Androderm® 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. AndroGel® 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 teaches a method for treating hypogonadism by applying the AndroGel® composition to the skin. PTX-319 at Abstract, col. 13, ll. 22-35, col. 14, ll. 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. Testim® 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. Gyurik ’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-1.

         E. Morgan ‘725 Publication

         U.S. Patent Application Publication No. U.S. 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, it 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; Chambliss 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 hypogonadism 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 therapeutically 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 non-occlusive 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 hydroxyl 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 “[p]referably 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, ll. 20-45, col. 7, ll. 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 Tomlinson ’250 patent teaches a testosterone transdermal formulation. Potts 1342:16-1343:16; PTX-592 at Abstract, col. 4, ll. 39-48, col. 5, ll. 35-40, col. 6, ll. 39-40.

         I. Mak ‘913 Patent

         The Mak ’913 patent, entitled “Penetration enhancing and irritation reducing 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, ll. 40-45, col. 4, ll. 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 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.” 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.” Hadgraft 362:8-10. The axilla is a region located under the shoulder joint that forms a depressed or hollow region, i.e., a bowl, that contains, inter alia, apocrine and eccrine 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 transdermal 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 transdermal 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 14C Cortisol in Man, The Journal of Investigative Dermatology, 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 hydrocortisone.” PTX-340 at 1; Potts 1355:20-23. The study authors delineated a 13 cm2 area on different skin sites for application of hydrocortisone 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 Feldmann 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 Corneum, International Journal of Cosmetic Science 24:151-161 (2002) (“Watkinson 2000”) was published in 2002. PTX-607 at 1. Watkinson (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 axilla 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) 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., Transcutaneous 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 transcutaneous absorption of the active ingredient hydrocortisone. PTX-264 at Fig. 3. Berti (1995) further reported that “[a]lthough 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 USPTO prior to allowance of the ‘520 patent (related to the ‘944 patent). PTX-6 at 4.

         Potential Application Sites for Transdermal 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 Aschkenasy ’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 pharmaceutically 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.

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); Hadgraft 431:19-432:4, 447:5-12. The Aschkenasy ’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 Aschkenasy ’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 transdermal 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 (Androderm®), a shoulder (AndroGel® and Testim®), or the scrotum (Testoderm®). Hadgraft 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, ll. 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. ...


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