UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD. ACTELION PHARMACEUTICALS LTD, Petitioner,

Transcription

1 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD ACTELION PHARMACEUTICALS LTD, Petitioner, v. ICOS CORPORATION, Patent Owner. CASE UNASSIGNED Patent 6,821,975 PETITION FOR INTER PARTES REVIEW

2 TABLE OF CONTENTS TABLE OF AUTHORITIES LIST OF EXHIBITS i iii I. MANDATORY NOTICES... 1 A. Real Party-In-Interest... 1 B. Related Matters... 1 C. Lead and Back-up Counsel/Service Information... 2 D. Payment of Fees... 2 II. GROUNDS FOR STANDING... 2 III. IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE PRECISE RELIEF REQUESTED... 2 IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW... 3 V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED... 3 A. Prosecution Background and Summary of Argument The Drug Compound is Old and Its Uses Were Already Known The Compound s Poor Water Solubility Was Known The Inventors Applied a Known Technique: Finely Ground Drug Dissolves Faster and is Absorbed at a Faster Rate Into a Patient s Bloodstream Lack of Cited Art Concerning Particle Size Reduction Led to a First Action Allowance of the 463 Application... 10

3 5. Seth Suggested Particle Size Reduction But Was Not Considered by the Examiner of the 463 Application Seth Was Cited Against Co-Pending Application Ser. No. 10/031,464 as Teaching Particle Size Reduction to Improve Dissolution and Absorption But It Was Not Disclosed to the Examiner of the 463 Application B. Level of Ordinary Skill in the Art Legal Principles Education and Experience Types of Problems Encountered in the Art Poor Drug Dissolution and Absorption Prior Art Solutions to Poor Drug Solubility Particle Size Reduction Applications of Particle Size Reduction to Improve Bioavailability C. Claim Construction Free Drug Particle Size Nomenclature Compound Having the Structural Formula D. Scope and Content of the Prior Art Patents and Printed Publications Relied Upon Applicants Admissions Daugan 675 (Ex. 1006) Butler 131 (Ex. 1008) Wadke (Ex. 1014)... 26

4 5. Seth (Ex. 1011) Martin (Ex. 1010) E. Ground 1: Claims 1-11 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke Claim 1 is Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke Claims 2-4 and 9 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke Claims 6-8 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke Claims 5, 10, and 11 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke F. Ground 2: Claims 5, 10 and 11 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke, Additionally In View of Martin G. There are No Unexpected Results Or Other Secondary Indicia that Rebut the Strong Case of Obviousness VI. CONCLUSION... 50

5 TABLE OF AUTHORITIES Page(s) Federal Cases Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369 (Fed. Cir. 2013) In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) Eli Lilly and Co., v. Synthon Pharms., Inc., Civ. No. 5:10-CV D (E.D.N.C. Western Division)... 1 Ex parte Erlich, 22 U.S.P.Q.2d 1463 (Bd. Pat. App. & Inter. 1992) In re Farrenkopf, 713 F.2d 714 (Fed. Cir. 1983) In re Geisler, 116 F.3d 1465 (Fed. Cir. 1997)... 8, 50 In re GPAC, 57 F.3d 1573 (Fed. Cir. 1995) , 50 Ex parte Hiyamizu, 10 U.S.P.Q. 2d 1393 (Bd. Pat. App. & Inter. 1988) In re Kahn, 441 F.3d 977 (Fed. Cir. 2006) KSR Int l. Co. v. Teleflex Inc., 550 U.S. 398 (2007) In re Kulling, 897 F.2d 1147 (Fed. Cir. 1990)... 8, 50 In re O Farrell, 853 F.2d 894 (Fed. Cir. 1988) i

6 Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007)...passim SAP America, Inc. v. Versata Dev. Group, Inc., CBM (MPT) Paper 70 (P.T.A.B. 2013) Synthon Pharms., Inc. v. Eli Lilly and Co., Civ. No. 5:10-CV D (E.D.N.C. Western Division)... 1 Thomas & Betts Corp., v. Litton Sys., Inc., 720 F.2d 1572 (Fed. Cir. 1983) In re Trans Texas Holdings Corp., 498 F.3d 1290 (Fed. Cir. 2007) Vanderbilt Univ. v. ICOS Corp., 601 F.3d 1297 (Fed. Cir. 2010)... 5, 6 Federal Statutes 35 U.S.C. 102(b)... 4, 5 35 U.S.C. 102(e)... 5, 8 35 U.S.C U.S.C U.S.C. 314(a)... 3 Regulations 37 C.F.R. 42.6(c) C.F.R. 42.8(b)(1) C.F.R. 42.8(b)(2) C.F.R. 42.8(b)(3) and (4) C.F.R (b) C.F.R (a) C.F.R (b) ii

7 PETITIONER S EXHIBIT LIST Inter Partes Review Actelion Ex. No. Description 1001 U.S. Patent No. 6,821,975 to Neil R. Anderson, Kerry J. Hartauer, Martha A. Kral and Gregory A. Stephenson, titled Beta Carboline Drug Products, issued on Nov. 23, 2004 Anderson 975 or 975 patent 1002 Declaration of Harry G. Brittain, PhD, FRSC dated January 8, U.S. Patent No. 7,182,958 to Peter L. Oren, Neil R. Anderson and Martha A. Kral, titled β-carboline Pharmaceutical Compositions, issued Feb. 27, 2007 Oren 958 or 958 patent 1004 Prosecution History of U.S. Application Ser. No. 10/031, application 1005 Prosecution History of U.S. Application Ser. No. 10/031, application 1006 WO 97/03675, titled Use of cgmp-phosphodiesterase Inhibitors To Treat Impotence, published Feb. 6, 1997 Daugan U.S. Patent No. 5,859,006, titled Tetracyclic Derivatives; Process of Preparation and Use, issued Jan. 12, 1999 Daugan 006 iii

8 Actelion Ex. No. Description 1008 WO 96/38131, titled Method of Producing a Solid Dispersion of a Poorly Water Soluble Drug, published Dec. 5, 1996 Butler U.S. Patent No. 5,985,326, titled Method of Producing a Solid Dispersion of a Poorly Water Soluble Drug, issued Nov. 16, 1999 Butler U.S. Patent No. 4,344,934, titled Therapeutic Compositions With Enhanced Bioavailability, issued Aug. 17, 1982 Martin 1011 U.S. Patent No. 4,721,709, titled Novel Pharmaceutical Compositions Containing Hydrophobic Practically Water-Insoluble Drugs Adsorbed On Pharmaceutical Excipients as Carriers; Process for their Preparation and The Use of Said Compositions, issued Jan. 26, 1988 Seth 1012 U.S. Patent No. 4,895,726, titled Novel Dosage Form of Fenofibrate, issued Jan. 23, 1990 Curtet 1013 Edward M. Rudnic and Mary Kathryn Kottke, Tablet Dosage Forms in MODERN PHARMACEUTICS, Chpt. 10, pp , Marcel Dekker (Gilbert S. Banker and Christopher T. Rhodes, Eds., 3rd Ed. 1996) Rudnic iv

9 Actelion Ex. No. Description 1014 Deodatt A. Wadke, Abu T. M. Serajuddin, and Harold Jacobson, Preformulation Testing in PHARMACEUTICAL DOSAGE FORMS: TABLETS, VOL. 1, Chpt. 1, pp. 1-73, Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed., rev. and expanded 1989) Wadke 1015 Garnet E. Peck, George J. Baley, Vincent E. McCurdy and Gilbert S. Banker, Tablet Formulation and Design in PHARMACEUTICAL DOSAGE FORMS: TABLETS, VOL. 1, Chpt. 2, pp , Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds. 2nd ed., rev. and expanded 1989) Peck 1016 Fred J. Bandelin, Compressed Tablets by Wet Granulation in PHARMACEUTICAL DOSAGE FORMS: TABLETS, VOL. 1, Chpt. 3, pp , Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed., rev. and expanded 1989) Bandelin 1017 Ralph F. Shangraw, Compressed Tablets by Direct Compression in PHARMACEUTICAL DOSAGE FORMS: TABLETS, VOL. 1, Chpt. 4, pp , Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed., rev. and expanded 1989) Shangraw v

10 Actelion Ex. No. Description 1018 Gilbert S. Banker and Neil R. Anderson, Tablets in THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY, 3d Ed., Chpt. 11, pp. 293, , Lea & Febiger (Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, Eds. 1986) Banker 1019 Gerry Steele, Preformulation as an Aid to Product Design in Early Drug Development in PHARMACEUTICAL PREFORMULATION AND FORMULATION: A PRACTICAL GUIDE FROM CANDIDATE DRUG SELECTION TO COMMERCIAL DOSAGE FORM, Chpt. 6, pp , Interpharm/CRC (Mark Gibson, Ed. 2004) Steele 1020 Peter Davies, Oral Solid Dosage Forms in PHARMACEUTICAL PREFORMULATION AND FORMULATION: A PRACTICAL GUIDE FROM CANDIDATE DRUG SELECTION TO COMMERCIAL DOSAGE FORM, Chpt. 11, pp , Interpharm/CRC (Mark Gibson, Ed. 2004) Davies 1021 J. C. Chaumeil, Micronization: A Method of Improving the Bioavailability of Poorly Soluble Drugs, METH FIND EXP. CLIN. PHARMACOL, 20(3): (1998) Chaumeil 1022 N. Midoux, P. Hošek, L. Pailleres, and J. R. Authelin, Micronization of Pharmaceutical Substances in a Spiral Jet Mill, POWDER TECH., 104: (1999) Midoux vi

11 Actelion Ex. No. Description 1023 Artistides Dokoumetzidis, et al., A Century of Dissolution Research: From Noyes and Whitney to the Biopharmaceutics Classification System, INT L. J. PHARMACEUTICS, 321: 1-11 (2006) Dokoumetzidis 1024 Arthur A. Noyes and Willis R. Whitney, The Rate of Solution of Solid Substances in Their Own Solutions, J. AM. CHEM. SOC., 19: (1897) Noyes and Whitney 1025 A. J. Jounela, P.J. Pentrikäinen and A. Sothmann, Effect of Particle Size On the Bioavailability of Digoxin, EUR. J. CLIN. PHARMACOL., 8: (1975) Jounela 1026 Gordon T. McInnes, Michael J. Asbury, Lawrence E. Ramsay and John R. Shelton, Effect of Micronization on the Bioavailability and Pharmacologic Activity of Spironolactone, J. CLIN. PHARMACOL., 22: (1982) McInnes 1027 Julian H. Fincher, Particle Size Reduction and Its Relationship to Absorption and Activity, J. PHARM. SCI., 57: (1968) Fincher 1028 GB 2,293,103 (Cephalon Inc as applicant), titled Modafinil Composition of Defined Particle Size, published on March 20, 1996 vii

12 Actelion Ex. No. Description 1029 Judgment of the UK High Court of Justice, Chancery Division, Patents Court, in Cephalon, Inc. v. Orchid Europe Ltd., [2011] EWHC 1591 (Pat) (June 24, 2011) 1030 Sissel Solvang and Per Finholt, Effect of Tablet Processing and Formulation Factors on Dissolution Rate of the Active Ingredient in Human Gastric Juice, J. PHARM. SCI., 59:49-52 (1970) Solvang 1031 Russell J. Lantz, Jr., Size Reduction in PHARMACEUTICAL DOSAGE FORMS: TABLETS, VOL. 2, Chpt. 3, pp. 107, , Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed., rev. and expanded 1989) Lantz 1032 Eugene L. Parrott, Milling in THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY, 3d Ed., Chpt. 11, pp. 21, 37-43, Lea & Febiger (Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, Eds. 1986) Parrott viii

13 Pursuant to 35 U.S.C. 311, Petitioner Actelion Pharmaceuticals Ltd ( Petitioner or Actelion ) respectfully petitions for inter partes review of claims 1-11 of Ex. 1001,, which was issued on November 23, 2004 ( 975 patent or Anderson 975 ). The challenged claims are unpatentable under 35 U.S.C. 103 over the prior art publications identified in this Petition. Concurrently filed herewith is a Power of Attorney under 37 C.F.R (b). I. MANDATORY NOTICES A. Real Party-In-Interest Pursuant to 37 C.F.R. 42.8(b)(1), Actelion Pharmaceuticals Ltd is the real party-in-interest. Petitioner is a wholly-owned subsidiary of Actelion Ltd. B. Related Matters Pursuant to 37 C.F.R. 42.8(b)(2), to the best of Petitioner s knowledge the 975 patent has been at issue in the following pending lawsuits involving third parties not involved with this petition: 1. Synthon Pharms., Inc. v. Eli Lilly and Co., Civ. No. 5:10-CV D (E.D.N.C. Western Division); proceedings stayed until 5/22/15 (see Dkt. 27) and 2. Eli Lilly and Co., v. Synthon Pharms., Inc., Civ. No. 5:10-CV D (E.D.N.C. Western Division) consolidated with Civ. No. 5:10-CV D, above (see Dkts. 54 and 56). To the best of Petitioner s knowledge there are no related administrative matters that would affect, or be affected by, a decision in this proceeding. 1

14 C. Lead and Back-up Counsel/Service Information Inter Partes Review Pursuant to 37 C.F.R. 42.8(b)(3) and (4), the signature block of this petition designates lead counsel, back-up counsel and service information for Petitioner. Petitioner consents to electronic service. D. Payment of Fees The Office is authorized to charge Deposit Account for the fee set forth in 37 C.F.R (a), and is authorized to charge any additional fees to the same account. II. GROUNDS FOR STANDING Petitioner certifies that the 975 patent is available for inter partes review and that neither Petitioner (or its corporate parent Actelion Ltd) is barred or estopped from requesting inter partes review challenging the patent claims of the 975 patent on the grounds identified in this petition. III. IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE PRECISE RELIEF REQUESTED Petitioner requests inter partes review and cancellation of claims 1-11 of the 975 patent on one or more of the grounds under 35 U.S.C. 103 set forth herein. The 975 patent is to be reviewed under pre-aia 102 and 103. Petitioner s detailed statement of the reasons for the relief requested is set forth below in the section titled Statement of Reasons for Relief Requested. In accordance with 37 2

15 C.F.R. 42.6(c), copies of the exhibits are filed herewith. In addition, this Petition is accompanied by the Declaration of Harry Brittain, Ph.D., FRSC, Ex IV. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW A petition for inter partes review must demonstrate a reasonable likelihood that the petitioner would prevail with respect to at least 1 of the claims challenged in the petition. 35 U.S.C. 314(a). This Petition meets this threshold. As explained below, for each of the grounds of unpatentability proposed, there is a reasonable likelihood that Petitioner will prevail with respect to at least one of the challenged claims. V. STATEMENT OF REASONS FOR THE RELIEF REQUESTED The challenged claims of the 975 patent are generally directed to the application of prior art particle size reduction technology to an old compound that was known to be poorly water-soluble. The inventors claim that particle size reduction improves the rate at and extent to which the drug dissolves and is absorbed into a patient s bloodstream following oral administration of the drug. The claims are thus directed to the drug in its finely ground state (with varying levels of size reduction recited), a general method for its manufacture, and methods of using the finely ground drug for its previously disclosed uses. Claims 1-11 of the 975 patent are unpatentable based on the following grounds: Ground 1: Claims 1-11 are unpatentable as obvious over 3

16 Daugan 675, Ex. 1006, Butler 131, Ex. 1008, Seth, Ex and Wadke, Ex Ground 2: Claims 5, 10 and 11 are unpatentable as obvious over Daugan 675, Ex. 1006, Butler 131, Ex. 1008, Seth, Ex. 1011, Wadke, Ex and Martin, Ex A. Prosecution Background and Summary of Argument The 975 patent, Ex. 1001, was issued on November 23, 2004 from U.S. Patent Application Serial No. 10/031,463 (the 463 application ), Ex. 1004, filed July 19, The 463 application is a national phase application based on PCT/US00/20981, filed August 1, 2000, and claims the benefit of U.S. Provisional Application Serial No. 60/147,048, filed August 3, Petitioner will treat August 3, 1999 as the earliest effective filing date to which the 975 patent could be entitled. This makes one year earlier - August 3, the critical date for assessing the availability of prior art under 35 U.S.C. 102(b). 1. The Drug Compound is Old and Its Uses Were Already Known The 975 patent, Ex. 1001, cites Daugan, U.S. Patent 5,859,006 ( Daugan 006 ), Ex. 1007, as disclosing a class of β-carboline compounds and their use in the treatment of sexual dysfunction. 975 patent, Ex at pg , 1:

17 The claims of the 975 patent, Ex. 1001, are all directed to a compound having the structural formula: This compound is also known by alternate chemical names and was disclosed in Daugan 006, Ex patent, Ex at pg , 4: As noted below, the compound was also disclosed in Daugan 675, Ex Daugan 006, Ex. 1007, has a 35 U.S.C. 102(e) date of July 17, 1996 and was issued on Jan. 12, 1999 from a PCT application that was published as WO 95/19978 on July 27, Daugan 675 was published February 6, 1997 and is prior art under 35 U.S.C. 102(b). First, by way of technical background, Dr. Alain Claude-Marie Daugan discovered the drug tadalafil over twenty years ago while employed as a research chemist at Glaxo. Vanderbilt Univ. v. ICOS Corp., 601 F.3d 1297, 1301 (Fed. Cir. 2010). Tadalafil is a PDE5 inhibitor and is the active ingredient in two marketed drugs, Cialis and Adcirca. PDE5 is a phosphodiesterase enzyme found in smooth muscle cells. These cells are relaxed and dilated as a result of PDE5 inhibition, which makes tadalafil useful for treating conditions such as erectile 5

18 dysfunction. Vanderbilt, 601 F.3d at 1299; see WO 97/03675, titled Use of cgmp-phosphodiesterase Inhibitors To Treat Impotence, published Feb. 6, 1997 Daugan 675, Ex. 1006; Brittain Decl., Ex. 1002, 31. In 1991, Glaxo assigned all of its right, title, and interest in its PDE5 inhibitor compounds to ICOS Corp ( ICOS ). Vanderbilt, 601 F.3d at Among the rights transferred, was Glaxo s original U.S. patent covering tadalafil Daugan 006, Ex. 1007, which was granted in 1999 and will expire in Subject of the Petition - This Petition concerns the 975 patent, Ex. 1001, a follow-on patent filed by ICOS in 2000 which is directed to pharmaceutical compositions containing tadalafil in finely divided particulate form 1. Tadalafil was 1 In a separate petition for inter partes review, Petitioner is also challenging U.S. Patent No. 7,182,958, Ex. 1003, another follow-on patent filed by ICOS in 2000 which is directed to the same finely divided form of tadalafil. The 958 patent, Ex is terminally disclaimed over the 975 patent, Ex Ex at pgs Because the ICOS patents are closely related (see Id. at pgs , DOUBLE PATENTING REJECTION ), Dr. Brittain addresses them in a combined declaration, Ex. 1002, which is being filed in support of both petitions. 6

19 known. The 975 patent merely discloses the results of routine optimization of that known compound for its known uses. The ICOS inventors applied a well-known micronization technique to reduce the particle size of the drug. Micronization is often utilized in scale-up during the preformulation testing stage particularly when as here the drug was found to be poorly soluble. See Wadke, Ex. 1014, which explains at pgs that all new drugs with a coarse particle size should be ground to the micron size range for preformulation testing and thence to maintain and control it. See Id. at pg This basic concept is the only significant difference between the instant patent claims and the tadalafil prior art, but merely represents the routine application of a common scale-up practice well known in the art. The question raised by this Petition is analogous to that in Pfizer v. Apotex, in which it was held obvious to optimize a known compound by formulating it as a different salt form to improve its manufacturing properties. Creating a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient to enhance commercial opportunities is universal-and even common-sensical. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (quoting DyStar Textilfarben GmbH v. C.H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006)). Claims which are directed to nothing more than routine optimization that would have been obvious 7

20 to one of ordinary skill in the art are not patentable. Id. (citing In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955) ( it is not inventive to discover the optimum or workable ranges by routine experimentation )); see also In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (same) and In re Kulling, 897 F.2d 1147, 1149 (Fed. Cir. 1990) (affirming obviousness conclusion that amount of eluent to be used in a washing sequence was a matter of routine optimization known in the art). 2. The Compound s Poor Water Solubility Was Known The 975 patent inventors stated that the β-carboline compounds were known to be poorly soluble. 975 patent, Ex at 00003, 1:44-47 (citing Butler 131, Ex and Butler 326, Ex ). These cited references are directed to making a coprecipitate form of the drug to enhance its bioavailability. Id. 3. The Inventors Applied a Known Technique: Finely Ground Drug Dissolves Faster and is Absorbed at a Faster Rate Into a Patient s Bloodstream According to the 975 patent inventors, coprecipitate tablets yielded slow onset of action from 3 to 4 hours in preliminary clinical trials (with the average 2 Ex. 1008, WO 96/38131, titled Method of Producing a Solid Dispersion of a Poorly Water Soluble Drug ( Butler 131 ), published on Dec. 5, Ex. 1009, U.S. Patent No. 5,985,326, titled Method of Producing a Solid Dispersion of a Poorly Water Soluble Drug ( Butler 326 ), which has a 35 U.S.C. 102(e) date of Feb. 6,

21 time for onset of therapeutic effect not precisely determined). This allegedly did not meet the need of those patients desiring more immediate onset of action and/or less prolonged effects. 975 patent, Ex. 1001, 1: More specifically, the 975 patent addresses an alleged need in the art for orally administrable β-carboline compounds and 5-carboline-containing pharmaceutical compositions having an ability to provide a therapeutic effect within a desirable, or at least acceptable, time frame. 975 patent, Ex at pg , 1:65-2:2. The 975 patent inventors claim that they solved this problem by providing a free drug form of a β-carboline compound having specific and defined particle size characteristics. Id., 2:5-7. According to the patent, [t]he defined particle size permits a uniform formulation of stable pharmaceutical compositions. In particular, the present invention provides compositions that exhibit a rapid achievement of maximum blood concentration of PDE5 inhibitor and/or a rapid onset of a therapeutic PDE5 inhibitory effect. Id., 2:7-12. But, as discussed below, it was common pharmaceutical knowledge that poorly soluble drugs should be ground to reduce their particle size. This micronization process was the most commonly employed technique in the art for improving drug dissolution and absorption. (Seth, Ex at pg , 2:9-11; Wadke, Ex at pg ). Brittain Decl., Ex. 9

22 1002, 34 and 53, sentence preceding Example 3. But none of this art was considered by the Examiner who allowed the 975 patent. 4. Lack of Cited Art Concerning Particle Size Reduction Led to a First Action Allowance of the 463 Application The 975 patent, Ex. 1001, was issued from the 463 application, Ex. 1004, after the examiner failed to uncover or apply prior art suggesting that the compound be finely ground to improve its poor aqueous solubility. Claim 1 of the 975 patent, Ex at pg , 13:14-14:60, which is illustrative reads as follows (emphasis added): 1. A free drug particulate form of a compound having a formula or pharmaceutically acceptable salts and solvates thereof, comprising particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns. First Action Allowance: During prosecution of the 463 application, pending application claims 1-9 and were allowed in the first office action over the art of record and from a 10

23 search in the pertinent art area which lacks a teaching of modifying instant compounds to a narrow range of particle sizes. First Non-Final Rejection, Ex at pg , January 7, 2004 (emphasis added). 5. Seth Suggested Particle Size Reduction But Was Not Considered by the Examiner of the 463 Application There is a fundamental omission in the examiner s reasoning that is addressed by this petition. It was and is common knowledge in the pharmaceutical art that particle size reduction improves a poorly soluble drug by increasing its surface area and fostering better dissolution and drug absorption properties. Brittain Decl., Ex. 1002, 47. This general pharmaceutical knowledge is exemplified in U.S. Patent 4,721,709, Seth, Ex Seth was cited by a different examiner in support of an obviousness rejection against similar claims then pending in applicants co-pending application USSN 10/031,464 (discussed below). 464 application, Ex at pg However, Seth was never made of record during examination of the 463 application which lead to the 975 patent. The Notice of Allowance in the 463 application was mailed on April 28, , application, Ex at pg Applicants paid the issue fee on July 20, 2004, roughly seven weeks after Seth had been cited by another examiner in their co-pending application. 463 application, Ex at pg and 464 application, Ex at pgs

24 6. Seth Was Cited Against Co-Pending Application Ser. No. 10/031,464 as Teaching Particle Size Reduction to Improve Dissolution and Absorption But It Was Not Disclosed to the Examiner of the 463 Application Two of the 975 patent s named co-inventors had filed a second application, USSN 10/031,464, Ex. 1005, directed to pharmaceutical compositions of the same drug. All claims were initially rejected on June 2, 2004 in a First Non-Final Office Action. 464 application, Ex at pg Certain claims incorporated the same 40 micron particle size limitation that appears in the allowed claims of the 975 patent. See, dependent claim 17 in Ex (Original 464 Application) at pg The examiner found claims reciting the particle size limitation obvious over Daugan 675, Ex. 1006, Butler 131, Ex. 1008, and Seth, Ex Ex. 1005, pg According to the Examiner of the 464 application, Daugan 675 disclosed the same active ingredient and its uses, dosage range, and formulation into pharmaceutical compositions using common excipients. June 2, 2004 First Non- Final Rejection, 464 application, Ex at pg Daugan 675, Ex. 1006, does not state the particle sizes recited in the rejected claims. However, Butler 131, Ex teaches that the active compound is poorly soluble. 464 application, Ex at pg And, Seth teaches a particle size reduction method which is practically applicable to all water insoluble drugs. Id. at pg

25 Seth was cited against applicants in the 464 application on June 2, Roughly seven weeks later, they paid the issue fee in the 463 application on July 20, 2004, Ex at pg , without making Seth of record in that application and without alerting the Examiner of the 463 application to the rejection over Daugan 675, Ex. 1006, Butler 131, Ex and Seth, Ex B. Level of Ordinary Skill in the Art In brief, the patents and scientific literature cited in this section demonstrate these key points: (1) there is a high level of skill in the pharmaceutical art; (2) persons of ordinary skill in the art knew that a drug s dissolution rate and bioavailability are influenced by the surface area of the drug particles; and (3) persons of ordinary skill in the art were very experienced in using particle size reduction techniques to increase drug particle surface area, improve drug dissolution, and increase the bioavailability of poorly soluble drugs. Brittain Decl., Ex. 1002, Legal Principles The level of ordinary skill in the art is that of a hypothetical person presumed to have known the relevant art at the time of the invention. Factors that may be considered are: (1) type of problems encountered in the art, (2) prior art solutions to those problems, (3) rapidity with which innovations are made, (4) sophistication of the technology, and (5) educational level of active workers in 13

26 the field. In a given case, every factor may not be present, and one or more factors may predominate. In re GPAC, 57 F.3d 1573, 1579 (Fed. Cir. 1995). The hypothetical person having ordinary skill in the art to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art. Ex parte Hiyamizu, 10 U.S.P.Q. 2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). 2. Education and Experience The person of ordinary skill in the art would have background and experience relating to oral dosage formulations. Such a person would have either a Ph.D. in Chemistry, Pharmaceutics, or Chemical Engineering (with a few years of experience in the preparation, formulation, and characterization of orally administered formulations), or a Bachelor s or Master s degree in Chemistry, Pharmaceutics, or Chemical Engineering with a proportionately greater degree of work experience. Brittain Decl., Ex. 1002, 46. That person would also have to have knowledge of particle size reduction and the expression of particle size distributions, and be able to understand the effect of particle size on the absorption of drug substances. Id., Types of Problems Encountered in the Art Poor Drug Dissolution and Absorption 14

27 Rudnic 4, Ex. 1013, includes an illustration that summarizes the disintegration/dissolution/absorption process associated with tablet dosage forms: As graphically illustrated in the preceding figure, it is generally understood by the person of ordinary skill in the art that if one desires fast dissolution of a drug substance, then the best formulation will be the one that yields fine (i.e., very small) particles of free drug in the dissolution medium. Brittain Decl., Ex. 1002, Ex. 1013, Edward M. Rudnic and Mary Kathryn Kottke, Tablet Dosage Forms in MODERN PHARMACEUTICS, Chpt. 10, pp , Marcel Dekker (Gilbert S. Banker and Christopher T. Rhodes, Eds., 3rd Ed. 1996) ( Rudnic ). 15

28 The absorption of a drug substance can only take place after the compound enters the dissolved state. For drug substances that are poorly soluble in water or water-based dissolution media, then the rate at which the substance dissolves will be slow. Since only dissolved drug can be absorbed by the body, a slow dissolution rate results in poor absorption of a drug substance. Brittain Decl., Ex. 1002, Prior Art Solutions to Poor Drug Solubility Particle Size Reduction It is an established tenet in pharmaceutics that one method which can be used to improve the dissolution rate of a relatively insoluble substance is to reduce the particle size of its component particles. Brittain Decl., Ex. 1002, 82. Peck 5, Ex. 1015, teaches that, [w]ith certain drugs (e.g., griseofulvin), the efficiency of absorption has been shown to depend on the particle size and specific surface area of the drug. By reducing the particle size of such drugs, the dosage level may be reduced by one-half or more and still produce the same biological 5 Ex. 1015, Garnet E. Peck, George J. Baley, Vincent E. McCurdy and Gilbert S. Banker, Tablet Formulation and Design in PHARMACEUTICAL DOSAGE FORMS: TABLETS, Vol. 1, Chpt. 2, pp , Marcel Decker (Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz, Eds., 2nd ed., rev. and expanded 1989). 16

29 response. Id. at pg See also Brittain Decl., Ex. 1002, 43 and 76 citing Parrott, Ex To understand this phenomenon, one must consider the processes that take place at the surface of a dissolving particle, which can be illustrated using the following figure: a) The first step in the dissolution process is the formation of a thin film around the particle that contains molecules of the dissolving substance. This layer is formed rapidly, and the layer of solution contains as much dissolved substance as the solvent can hold. Since this condition represents a saturated solution, the concentration of dissolving molecules in the film layer will be termed Cs. Brittain Decl., Ex. 1002, 83. b) The second step in the dissolution process consists of the diffusion of dissolved molecules from this boundary layer into the bulk fluid. Since this layer is characterized by the motion of dissolved molecules from the saturated layer into the bulk solution, it is known as the diffusion layer. 17

30 Molecules leaving the diffusion layer accumulate in the bulk solution, where their concentration at a specified time is termed Ct. Id. As molecules of the dissolving drug substance diffuse away from the dissolving particle, more molecules leave the solid particle and enter the solution phase. This process continues until the particle is completely dissolved. In a majority of dissolution phenomena, initial step (a) is almost instantaneous, while the second step (b) is much slower. Consequently, the rate of dissolution associated with particulate solids is most often determined by diffusion processes, and is obviously a time-dependent process. Brittain Decl., Ex. 1002, 84. The basic theory describing this process was first outlined in 1897 by Arthur Noyes and Willis Whitney, Ex. 1024, who used diffusion theory to describe the dissolution of particulate solids. Their original equation has been refined somewhat, but has the form: Rate = (D/h) S (Cs-Ct) In the Noyes-Whitney equation, the quantity of interest is the rate of drug dissolution (at a time equal to t) that is yielding a concentration of dissolved substance in the bulk solution equal to Ct. Three factors in the equation {the diffusion coefficient (D), the thickness of the saturation layer (h), and the concentration of dissolving substance in the saturation layer (Cs)} are determined entirely by the identity of the dissolving substance, and are not subject to 18

31 modification by an experimenter. The only quantity in the Noyes-Whitney equation that can be controlled is the surface area of the dissolving particle (S). Brittain Decl., Ex. 1002, 85. The Noyes-Whitney equation makes it clear and obvious that if one seeks to increase the dissolution rate of a substance, one must increase the surface area of the dissolving particles. Since it is well known that there is an inverse relationship between the surface area of a particle and the particle diameter, it was well-known that an increase in the surface area of the dissolving particles would be achieved by causing a decrease in the size of the particles. Brittain Decl., Ex. 1002, 86. The effect of particle size on the dissolution rate of sparingly soluble drug substances was also well known to pharmaceutical scientists. Brittain Decl., Ex. 1002, 87; see also Fincher, Ex (Fincher, a 1968 review article that documented and reviewed a number of published studies concerning the relationship between particle size and drug absorption). The level of skill in the art may also be demonstrated by post-filing date articles. References which do not qualify as prior art because they postdate the claimed invention may be relied upon to show the level of ordinary skill in the art at around the time the invention was made. Ex parte Erlich, 22 U.S.P.Q.2d 1463 (Bd. Pat. App. & Inter. 1992); Thomas & Betts Corp., v. Litton Sys., Inc., 720 F.2d 1572, 1581 (Fed. Cir. 1983) ( [references] though not technically prior art, were, in effect, 19

32 properly used as indicators of the level of the ordinary skill in the art to which the invention pertained ); In re Farrenkopf, 713 F.2d 714 (Fed. Cir. 1983). According to Steele, Ex. 1019, published in 2004, micronization was a common technique known in the art for improving dissolution and absorption of poorly soluble drugs. Ex at pg ; see also, Dokoumetzidis, Ex. 1023, published in 2006 (same). Steele reflects the common understanding in the art that [m]icronized particles are typically less than 10 µm in diameter. Steele, Ex at pg (citing, Midoux, Ex. 1022) (micronization using a spiral jet mill); see also, Chaumeil, Ex at pg (discussion of fluid energy mills). Brittain Decl., Ex. 1002, Applications of Particle Size Reduction to Improve Bioavailability Prior art patents and printed publications from the 1970 s and 1980 s evidence the well-known relationship between particle size, dissolution rate, and bioavailability. These patents and printed publications all reflect the understanding in the art that particle size reduction is a general solution to poor drug dissolution. For example, Jounela, Ex. 1025, reported that the dissolution rate and bioavailability (expressed as AUC, and C max ) of digoxin was improved by increasing the surface area of the particles through micronization - 7, 13, and 102 micron average particle size fractions were tested. Jounela, Ex at pg

33 McInnes, Ex. 1026, reported significantly higher bioavailability of micronized spironolactone having a median particle size of 2.21 microns compared to 78.8 micron- size particles. McInnes, Ex at pg Seth, Ex. 1011, which is relied on in support of this petition, states: It is a common observation that when poorly soluble, hydrophobic drug substances are employed in the preparation of solid dosage forms such as tablets or capsules, their rate of dissolution is rather slow. As a result, their absorption from the gastrointestinal tract into systemic blood of the body is slow. However, if such drugs are to be administered in oral dosage forms and to be used for clinical indications where a rapid onset of therapeutic activity is desirable, the slow rate of dissolution and slow rate of absorption can put very great limitations on their therapeutic utility. Seth, Ex at pg , 1:65 2:8 (emphasis added). Seth states further: A frequently used method to overcome such problems is to finely grind or micronise drug substances so as to reduce their particle size. For example high speed running pin mills or air-jet mills are used to reduce the particle-size to a range of 5-10 microns. Id., 2:9-13 (emphasis added); see also Curtet, Ex at pg , 1:28-30 ( It is known that the micronization of an active principle is capable of improving the dissolution of the said active principle in vivo, and hence its bioavailability. ) 21

34 C. Claim Construction Inter Partes Review In accordance with 37 C.F.R (b), the challenged claim must be given its broadest reasonable construction in light of the specification of the 975 patent. In SAP America, Inc. v. Versata Dev. Group, Inc., CBM (MPT) Paper 70 (P.T.A.B. 2013) the Patent Trial and Appeal Board confirmed that the broadest reasonable construction standard for claim construction applies to the newly implemented America Invents Act review proceedings. See also In re Trans Texas Holdings Corp., 498 F.3d 1290, 1295 (Fed. Cir. 2007) (giving claims their broadest reasonable interpretation consistent with the specification. ) Relevant here, three claim terms were defined by applicants in their written description: (i) the term free drug, (ii) particle size nomenclature, and (iii) compound having the structural formula. Petitioner believes that all other claim terms are to be given their broadest reasonable interpretation, as understood by one of ordinary skill in the art and consistent with the disclosure. 1. Free Drug According to the 975 patent, [t]he term free drug refers to solid particles of Compound (I) not intimately embedded in a polymeric coprecipitate. 975 patent, Ex at 00004, 4:5-6. Brittain Decl., Ex. 1002, Particle Size Nomenclature The 975 patent, Ex states at pg , 4:25-29: 22

35 The nomenclature describing the particle size of compound (I) is commonly referred to, and is herein, as the d90. For example, a d90 of 40 (or d90=40) means that at least 90% of particles have a particle size of less than 40 microns. 3. Compound Having the Structural Formula The claims all refer to the drug as a compound having the structural formula: The written description of the 975 patent refers to this structure as Compound (I), and by the alternate chemical names: (6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2- methylpyrazino[1,2 :1,6]pyrido[3,4-b]indole-1,4-dione, 975 patent, Ex at pg , 4:35-37; or alternatively 23

36 (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2,1 :6.1]pyrido[3,4-b]indole-1,4-dione, as disclosed in Daugan U.S. Pat. No. 5,859,006, Id., 4: D. Scope and Content of the Prior Art Patents and Printed Publications Relied Upon 1. Applicants Admissions Applicants made the following admissions in the written description of the 975 patent, Ex at pg : Admission I: Type 5 cgmp-specific phosphodiesterase (PDE5) was known in the art as an attractive target in the treatment of sexual dysfunction. Id., 1:30-35 (prior art citation omitted). Admission II: Daugan U.S. Pat. No. 5,859,006 [Ex. 1007] discloses a class of β-carboline compounds, and pharmaceutical compositions containing the β- carbolines, which are useful in the treatment of conditions wherein inhibition of PDE5 is desired. PCT publication WO 97/03675 [Ex. 1006] discloses use of this class of β-carboline compounds in the treatment of sexual dysfunction. Id., 1: This same compound is referred to as Compound A in Daugan 675, Ex at pg , 3:

37 Admission III: Inter Partes Review The poor solubility of many β-carboline compounds useful as PDE5 inhibitors prompted the development of coprecipitate preparations, as disclosed in PCT publication WO 96/38131 [Ex. 1008] and Butler U.S. Pat. No. 5,985,326 [Ex. 1009]. Id., 1: Admission IV: [M]ethodologies to prepare particles as described herein are readily available, including a variety of milling techniques, such as hammer or fluid energy mills. Id. at pg , 5: Admission V: Any pharmaceutically acceptable excipients can be used to formulate tablets. Id. at pg , 7: Admission VI: The pharmaceutical compositions are prepared by standard pharmaceutical manufacturing techniques. Id., 7: Daugan 675 (Ex. 1006) Daugan 675, Ex discloses the compound of the invention as Compound A at pg , 3: The compound may be used for treating male or female sexual dysfunction. Id. at pg , 4: Oral administration is the preferred route. Id., 4: Individual tablet or capsule dosages could be in the range of mg, the appropriate dose to be determined by a physician in accordance with the patient s age, weight, and response to treatment. Id. at pg , 5:5-11. Compound A may be admixed with pharmaceutical excipients and administered as tablets or capsules. Id., 5: There are examples of 50 mg 25

38 tablets made using either direct compression or wet granulation. Id. at pgs , 12:15-14:14. In the examples, the active ingredient was sieved and blended with the other excipients. Id. at pg , 12:22-23; pg , 13:8-9; pg :9. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the other excipients. Id. at pg , 14: See also Brittain Decl., Ex. 1002, Butler 131 (Ex. 1008) Butler 131, Ex discloses the compound of the invention as Compound A at pg , 4: As noted above, applicants admitted that Butler 131 discloses the poor solubility of Compound A. See Admission III, above. According to applicants, this prompted the development of coprecipitate preparations disclosed in Butler 131, Ex patent, Ex at pg , 1: See also Brittain Decl., Ex. 1002, Wadke (Ex. 1014) Wadke, Ex. 1014, explains at pg , that the absorption of solid drugs administered orally may be visualized as a two-step process: (1) dissolution of the drug into the gastrointestinal fluid, and (2) absorption of the dissolved drug through the intestinal wall into systemic circulation. Ex at pg When dissolution is substantially slower than absorption, the absorption is described as dissolution rate-limited. Id. 26

39 It was common pharmaceutical knowledge in 1989 that particle size reduction is beneficial for drugs that are poorly absorbed. According to Wadke, Ex, 1014 at pg (emphasis added): Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. For example, the bioavailability of griseofulvin and phenacetin is directly related to the particle size distributions of these drugs. It is now generally recognized that poorly soluble drugs showing a dissolution ratelimiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state than as a coarse material. Ex at pg See also Brittain Decl., Ex. 1002, 34 and 53, sentence before Example 3. In addition, Wadke, Ex discloses at pgs , that it would have been routine to grind the drug particles to the 10 to 40 micron range specified in the 975 patent (italics added): It is probably safest to grind most new drugs having particles that are above approximately 100 µm in diameter. If the material consists of particles primarily 30 µm or less in diameter, then grinding is unnecessary, except if the material exists as needles where grinding may improve flow and handling properties, or if the material is poorly water soluble where grinding increases dissolution rate. Grinding 27

40 should reduce coarse material to, preferably the 10- to 40- µm range. Once this is accomplished, controlled testing can be performed both for subsequent in vivo studies and for in-depth preformulation studies. Ex at pg See also Brittain Decl., Ex. 1002, 34. Wadke, Ex. 1014, was cited with approval in, Cephalon, Inc., v. Orchid Europe Ltd., [2011] EWHC 1591 (Pat) (UK High Court of Justice, June 24, 2011), Ex. 1029, where Justice Floyd wrote: I have no doubt that grinding into the μm range represented a common general knowledge approach to pre-formulation testing. That is not to say that everyone would have adopted it. But the skilled person would know that it was one of the practical approaches. Id. at pg , 27, (Invalidating GB 2,293,103, Ex. 1028, Modafinil Composition of Defined Particle Size ). Wadke, Ex. 1014, further states at 00025, when dissolution is considered to be slow, a means of enhancing it may be sought. In the absence of a more soluble physical or chemical form of the drug, particle size reduction is the most commonly employed practice. (emphasis added). See also Brittain Decl., Ex. 1002, 34. Wadke mentions that other less common techniques include coprecipitation (e.g. as in Butler 131, Ex. 1008). Id. 5. Seth (Ex. 1011) Seth, Ex. 1011, discloses dry powder pharmaceutical compositions of a hydrophobic poorly soluble drug adsorbed onto an inert pharmaceutical carrier. 28

41 See, Seth, Ex at pg , 4:44-52, wherein (1) the drug is present in particulate form, (2) the drug particles have a mean particle size of less than 10 microns, and (3) the particle size distribution is such that at least 95% of particles are smaller than 15 microns. Seth states that the particle size distribution is preferably where at least 95% of the particles are less than 9 microns. Id. at pg , 6: The compositions may be compressed into tablets for oral administration. Id. at pg , 8: See also Brittain Decl., Ex. 1002, Martin (Ex. 1010) Martin, Ex. 1010, teaches that formulations of griseofulvin (or other poorly soluble drugs) with (a) hydrophilic polymers, and (b) wetting agents, such as sodium lauryl sulfate, have improved drug dissolution and absorption. Martin, Ex at pg , 3:14-31 and 4: The formulations in Martin can be formed by mixing the drug with a water-soluble polymer and coating the mixture onto lactose. Id. at pg , 5: A powdered drug-polymer mixture may then be treated with the wetting agent. Id., 5: If necessary, the mixture may be milled, screened or ground prior to formulating into suitable dosage forms with pharmaceutically acceptable excipients. Id., 6:9-12. The mixture could be compressed to form solid dosage forms with good dissolution characteristics, e.g. Example 17. Id. at pg , 15:1-30. See also Brittain Decl., Ex. 1002,

42 E. Ground 1: Claims 1-11 are Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke 1. Claim 1 is Unpatentable as Obvious Over Daugan 675, Butler 131, Seth, and Wadke The claim chart below shows where each limitation of claim 1 of the 975 patent is met by Daugan 675, Ex. 1006, Butler 131, Ex. 1008, Seth, Ex and Wadke, Ex A free drug particulate form of a drug having a formula Daugan 675, Butler 131, Seth, and Wadke Claim 1 Daugan 675 discloses the compound of the invention. Ex at pg , 3: Seth teaches a micronization technique (see below) that provides a drug present in particulate form. Ex at pg , 4:49. or pharmaceutically acceptable salts and solvates thereof, comprising particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns. Ex at pg , 13: Butler applicants admitted that Ex (Butler 131) discloses the poor solubility of the compound. Ex at pg , 1:44-47 (Admission III, supra.) Wadke teaches that when dissolution is considered to be slow particle size reduction is the most commonly employed practice. Ex at pg Seth teaches micronization of a hydrophobic poorly soluble drug to improve its dissolution and bioavailability. 30

43 Ex at pg , 4: Inter Partes Review Seth further teaches (1) the drug is present in particulate form, (2) the drug particles have a mean particle size of less than 10 microns, and (3) the particle size distribution is such that at least 95% of particles are smaller than 15 microns. Id. In addition, Seth teaches that commonly employed micronization techniques reduce the particle size to a range of 5-10 microns. Id. at pg , 2:9-13. Daugan 675, Ex discloses the compound of the invention at pg , 3: The claim has two elements that purport to distinguish it from the prior art. Both relate to the physical form of the compound: (a) the drug is in a free drug particulate form, and (b) at least 90% of the drug particles have a particle size of less than about 40 microns. Brittain Decl., Ex. 1002, 32. Both limitations are met by modifying Daugan 675, Ex. 1006, in accordance with the teachings of Seth, Ex See also Brittain Decl., Ex. 1002, 37. Seth teaches micronization of a hydrophobic poorly soluble drug to improve its dissolution and bioavailability. Id. at pg , 4: Seth further teaches (1) the drug is present in particulate form, (2) the drug particles have a mean particle size of less than 10 microns, and (3) the particle size distribution is such that at least 95% of particles are smaller than 15 microns. Id. Daugan 675, Ex. 31