# Appendix — Tanabe Seiyaku Co. v. International Trade Commission > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40386013_1344%3A2 ## Record - **Collection:** Supreme Court brief - **Document type:** Appendix - **Published:** January 1, 1997 - **Citation:** 522 U.S. 1027 ## Text (2) ete ea “No. F_ 2° 395 SEP - 4 1997, OFFICE OF THE CLERK” In The Supreme Court of the United States October Term, 1996 ’ TANABE SEITYAKU CO., LTD. AND MARION MERRELL DOW, INC., Petitioners, V. UNITED STATES INTERNATIONAL TRADE COMMISSION, Respondent, -and- ORION CORPORATION FERMION, COPLEY PHARMACEUTICALS, INC., INTERCHEM CORPORATION AND RHONE-POULENC RORER, INC., Respondents. + On Petition For A Writ Of Certiorari To The United States Court Of Appeals For The Federal Circuit * APPENDIX TO PETITION FOR A WRIT OF CERTIORARI VOLUME II, PAGES 251-462 + LAWRENCE G. MEYER MicHaet A. Carvin* James M. SPEARS Davip H. THOMPSON THomas B. PAHL Cooper & Carvin, PLLC Gapssy & HANNAH, LLP 2000 K Street, N.W. 1747 Pennsylvania Washington, D.C. 20006 Ave., N.W. (202) 822-8950 Washington, D.C. 20006 e (202) pe, ei Counsel of Record WiiuraM J. Sirio, PHD. PENNIE & EDMONDS 1155 Avenue of the Americas New York, NY 10036 (212) 790-9090 COCKLE LAW BRIEF PRINTING CO., (800) 225-6964 OR CALL COLLECT (402) 342-2831 INDEX TO APPENDIX VOLUME i OF II Opinion, Tanabe Seiyaku Co., Ltd. v. United States International Trade Comm'n, No. 95-1448 (Fed. Se ee Fp Re ic 6k de Ranke e eee cee ndebens App. Order, Tanabe Seiyaku Co., Ltd. v. United States International Trade Comm'n, No. 95-1448 (Fed. Cor. Tee FU Ge Bee i no's cece. cht vaneukees App. Commission Opinion, In the Matter of Certain Diltiazem Hydrochloride and Preparations, Interna- tional Trade Comm'n, Investigation No. 337- TA-349 (filed June 8, 1995 ITC)............. App. Initial Determination (Public Version), In the Mat- ter of Certain Diltiazem Hydrochloride and Prepara- tions, International Trade Comm’n, Investigation No. 337-TA-349 (filed Feb. 14, i Bn 8 BRR RAs tag iar ag cn am seg eae rere App. VOLUME II OF II Initial Determination (Public Version), In the Mat- ter of Certain Diltiazem Hydrochloride and Prepara- tions, International Trade Comm’n, Investigation No. 337-TA-349 (filed Feb. 14, BOGS TER Oe ks oe si vec eee a gia seesseannvees App 19 U.S.C. § 1337(a) (relevant portions) ........ App. Warner-Jenkinson v. Hilton Davis Chem. Co., 117 Se SOE POE Da oe ich ks hos tan oka es es App Page 20 22 33 ae ) . 435 App. 251 Ill. INFRINGEMENT A. The Profarmaco Process Does Not Infringe Claim 1 of the ‘035 Patent 1. The Development of the Profarmaco Pro- cess FF CP 1. In approximately late 1982, Profarmaco began work to synthesize diltiazem. Piselli, Tr. 1966. FF CP 2. Using the German counterpart to the ‘257 patent, one of the Profarmaco scientists, Dr. Piselli, ran several experiments involving the N-alkylation step. Pis- elli, Tr. 1967-1969, 1998. FF CP 3. In these, he used sodium hydride and anhydrous (“DMF”) to become more familiar with the N-alkylation of TZP. Piselli, Tr. 1967-1969, 1998-99. FF CP 4. Knowing that sodium hydride is unaccept- able for commercial scale synthesis, Dr. Piselli almost immediately tried potassium carbonate and DMF. Piselli, Tr. 1967-69. FF CP 5. The potassium carbonate/DMF combina- tion - which was the first one that Dr. Piselli tried - was selected based on a 1978 article by Professor Makosza, an organic chemist known as the “inventor of phase trans- fer,” which specifically disclosed the use of potassium carbonate and DMF in similar reactions. Piselli, Tr. 1967-69; RX 3025. FF CP 6. The Makosza article described the possi- bility of replacing the reagents described in the ‘257 pat- ent with potassium carbonate and DMF. Piselli, Tr. 1967; RX 3025. App. 252 FF CP 7. The article specifically described the advantages of potassium carbonate/DMF over sodium hydride, including the eliminations of potentially dan- gerous reactions caused by anhydrous organic solvents. Piselli, Tr. 1968; RX 3025. FF CP 8. Dr. Piselli had previously used such a system at Profarmaco and he therefore followed Makosza’s suggestions and tried potassium carbonate/ DMF in his first experiments. Piselli, Tr. 1969. FF CP 9. This potassium carbonate/DMF process - the first one that Dr. Piselli tried — was successful. Piselli, Tr. 1969. FF CP 10. Within two months, Dr. Piselli had devel- oped an industrial process using potassium carbonate/ DMF. Piselli, lr. 1969. FF CP 11. Profarmaco used this process for produc- ing bulk diltiazem from approximately mid-1983 to July 15, 1986. Piselli, Tr. 1970; RPX 4026. FF CP 12. In order to increase the consistency of the yield, Profarmaco experimented with the addition of water to the reaction and found that [C] % by volume of water caused more consistent yields. During the summer of 1986, Profarmaco therefore modified its process to include the addition of [C] % water to its potassium carbonate/DMF process. Piselli, Tr. 1969-1970, 2001-2002; RPX 4026. : FF CP 13. Shortly after December 30, 1986, Profar- maco first learned from a French pharmaceutical firm, App. 253 Sanofi, of the Tanabe European Patent Application corre- sponding to the ‘035 patent. Russolo, Tr. 1924; Piselli, Tr. 2001; RX 3930C. FF CP 14. This was the first time anyone at Profar- maco became aware of the existence of the ‘035 patent or any of its counterparts. Russolo, Tr. 1924; Piselli, Tr. 1970, 2001. FF CP 15. Profarmaco reviewed this patent applica- tion and after such review concluded that its potassium carbonate/DMF process did not infringe. Russolo, Tr. 1934. FF CP 16. Profarmaco therefore continued using this process for five additional years. Russolo, Tr. 1934. FF CP 17. In April 1989, after expiration of the ’257 patent and with the end of MMD’s Waxman-Hatch exclu- Sivity on the horizon, Gyma, Profarmaco’s exclusive agent in the United States, wrote to MMD requesting disclosure of any process patents which MMD contended might cover processes for the manufacture of diltiazem. RX 3947C at 214-215; Russolo, Tr. 1924-25. FF CP 18. MMD responded shortly thereafter by identifying four patents, including the ‘035 patent. RX 3947C at 216; Russolo, Tr. 1924-25. FF CP 19. Gyma forwarded MMD’s process patent disclosure letter to Profarmaco for review. Russolo, Tr. 1924-25. FF CP 20. Profarmaco, after reviewing the ‘035 pat- ent, continued to use its potassium carbonate/DMF pro- cess. Russolo, Tr. 1934. App. 254 Receipt by Profarmaco of the EPO Comparative Test Report FF CP 21. On June 13, 1991, Profarmaco received from its Italian patent attorneys (in connection with an inquiry from Profarmaco on a different matter) Tanabe’s October 1, 1984 submission to the European Patent Office, including the Comparative Test Report. Russolo, Tr. 1925-27; RX 4032-C. FF CP 22. Dr. Russolo, Profarmaco’s Managing Director and General Manager, testified that, Profarmaco is a conservative company, and immediately decided to ascertain whether it could develop a process using a base not specified in the ‘035 patent claims and, particularly, bases and solvents that Tanabe had expressly represented to the EPO not to be the subject of its invention. Russolo, Tr. 1916-1917, 1925-1927. FF CP 23. On June 27, 1991, two weeks after receipt of the Comparative Test Report, Profarmaco held an R&D meeting attended by, among others, Drs. Russolo and Piselli. Russolo, Tr. 1927-29; Piselli, Tr. 1970-71; RX 3928- aa FF CP 24. At that meeting, Dr. Piselli was directed to try to develop an N-alkylation process using sodium carbonate as the base. Russolo, Tr. 1927-29; Piselli, Tr. 1970-71. FF CP 25. Specifically, the meeting minutes state: “try the attachment of the chlorobase [i.e., 2-dimet- hylaminoethyl-chloride (“DMC”)] with sodium carbo- nate/DMF with different percentages of water.” RX 3928- C; Russolo, Tr. 1928-29; Piselli, Tr. 1970-71. App. 255 FF CP 26. Sodium carbonate was chosen as a target base because Tanabe had identified the base in the Com- parative Test Report as being outside the scope of its invention. Russolo, Tr. 1928-29. FF CP 27. Profarmaco therefore viewed the use of sodium carbonate as a “zero-risk situation by using what inventors were saying not to be part of the invention.” Russolo, Tr. 1926-1927. FF CP 28. DMF was identified because that was the solvent that Profarmaco was then using in its current potassium carbonate/DMF process which was “a very good process.” Russolo, Tr. 1928-29; Piselli, Tr. 1973. FF CP 29. Four days after this R&D meeting, on July 1, 1991, Dr. Piselli conducted the first experiment using sodium carbonate in the period following receipt of the Comparative Test Report. Piselli, Tr. 1972; RX 3926C; RX 3932C. FF CP 30. Dr. Piselli used sodium carbonate and DMF with C percent water. RX 3926 at Prof 436; Russolo, Tr. 1929-30; Piselli, Tr. 1972. FF CP 31. During approximately the next eight months, Profarmaco was able to develop a new process for N-alkylating TZP using sodium carbonate as the base. Piselli, Tr. 1971-1972; RX 3926C; RX 3932C. re Cr 32. in developing this process, Profarmaco conducted approximately 100 experiments. Piselli, Tr. 1972; RX 3932C. FF CP 33. Profarmaco experimented by including and not including a phase transfer catalyst, by conduct- ing the reaction at various temperatures, by varying App. 256 times, by using various solvents, and by adding or removing water. Piselli, Tr. 1973-74; RX 3932-C. FF CP 34. Experimental evidence provided by com- plainants in this investigation shows that water removal is not critical in order to get a low yield from the Profar- maco process. Taber Tr. 2094-95. FF CP 35. Profarmaco discovered during the course of these experiments that only by removing water (through azeotropic distillation) could Profarmaco achieve an industrially valid high-yield process. Piselli, Tr. 1975. FF CP 36. Dr. Piselli characterized the removal of water as very important and essential. Piselli, Tr. 1975. FF CP 37. If water is not removed from the current Profarmaco process, the reaction is “never complete” and there are by-products and impurities. Piselli, Tr. at 1975. FF CP 38. Profarmaco also discovered that if the temperature of the reaction is less than [C] °[C], then the N-alkylation reaction cannot be completed. Piselli, Tr. at 1976. FF CP 39. During the next eight months, Profar- maco scientists conducted approximately 100 experi- ments with different base/solvent combinations, and by February 1992, determined to use sodium carbonate and toluene, a base and a solvent, both of which were expressly identified by Tanabe in the Comparative Test Report as not included within its invention. Russolo, Tr. 1930; RX 3928C at 312, 315. App. 257 FF CP 40. On March 6, 1992, the sodium carbonate and toluene process went to the Pilot Plant. RX 3016C at Prof 166. FF CP 41. By June 4, 1992, that process had been prepared for production and was ready for use. Piselli, Tr. 1978; RX 3928C at 316. The Profarmaco Sodium Carbonate/Toluene Process FF CP 42. Profarmaco conducts its process for man- ufacturing bulk diltiazem in a [C] reactor vessel with a volume of [C] cubic meters. Piselli, Tr. 1979-80. FF CP 43. The reactor vessel contains a distillation column, [C], and a variety of other equipment. The distil- lation device which allows for azeotropically distilled vapors to be cooled, condensed, and then either removed from the system, or returned to the reactor vessel is —— known as a Markusson trap. Piselli, Tr. 1978-1980; RX 3996. FF CP 44. In the step immediately preceding N-alkylation, Profarmaco carries out the [C]. Profarmaco first charges [C]. Profarmaco then [C]. Following this step, Profarmaco allows the contents of the reactor vessel [C], which results in the formation of two phases: a lower aqueous phase and an upper phase containing [C]. The Profarmaco operator, following the separation, [C]. Fol- lowing this procedure, the operator causes [C], thus removing any last traces or droplets of water which may have adhered to the sides of the reactor vessel. Any water that is gathered as a resuit of [C] is then discharged by the operator [C]. Piselli, Tr. 1979-1980; RX 3996(a). App. 258 FF CP 45. The next step is the N-alkylation. That process is carried out in the same reactor vessel. The reactor vessel already contains DMC free base in a toluene solution. To that solution Profarmaco adds sodium carbonate which, by its specification, may not contain more than [C]% water by weight. It also adds TZP, which is prepared at Profarmaco, and which is heated by Profarmaco to remove all water. Piselli, Tr. 1980-82, 1986; RX 3996(b). FF CP 46. Once the TZP and sodium carbonate have been added to the toluene solution containing DMC base, the operator heats the reactor vessel as quickly as possi- ble using the maximum amount of steam flowing through the jackets surrounding the reactor vessel. At [C]°, the operator reduces the steam flow so that the inside tem- perature will reach about [C]°[C] without the reactor’s contents overflowing. Through thermal inertia, the reac- tion mixture increases in temperature to approximately [C]° and the reaction mixture is then heated to [C]°. It takes [C] for the reaction mixture to reach [C]°; [C] for the reaction mixture to reach [C]°; and the reaction mixture is then heated at a [C]° for [C] hours. Piselli, Tr. 1982-83; RX 3996(b). FF CP 47. At the [C]° range, the water/toluene solu- tion begins to distill azeotropically. Profarmaco begins to see carbon dioxide evolution at approximately [C]° and begins to see water collecting in the Markusson trap also at approximately [C]°. Because water is heavier than toluene, the water collects in the Markusson trap while the toluene returns to the reaction vessel. Piselli, Tr. 1983-84. App. 259 FF CP 48. Profarmaco observed in the R&D labora- tory a relationship between carbon dioxide evolution and N-alkylation. Profarmaco has observed that the N-alkyla- tion reaction takes place while carbon dioxide evolution is occurring. Piselli, Tr. 1984-85. FF CP 49. Profarmaco takes five separate steps to prevent water from entering the reactor vessel and to remove water created during N-alkylation step. RX 4024- C; RX 3996(a); RX 3996(b); Piselli, Tr. 1985-87, 1977-81. Specifically: 1. during the [C] step, which immediately pre- cedes N-alkylation, the Profarmaco operator [C] and to settle into two phases, the lower of which is water. That aqueous phase is then discharged [C]. RPX 4024-C; RX 3996(a); Piselli, Tr. 1980. 2. The operator then causes [C].” These last traces of water are then discharged [C] to make sure that there is no water in the reac- tor. RPX 4024(c); RX 3996(a); Piselli, Tr. 1980. 3. During the N-alkylation step, Profarmaco adds to the reactor vessel (which already contains a toluene solution containing [C]) TZP which Profarmaco has dried by heating. Piselli, Tr. 1981-82; RX 4024-C; RX 3996(a). 4. [C]. Piselli, Tr. 1981-82; RPX 4024-C; RPX 3996(a). 5. [C] Piselli, Tr. 1985-86, 1978-79; RX P4024-C. App. 260 2. Differences Between the Profarmaco Pro- cess and the ‘035 Process FF CP 50. The differences between the Profarmaco process currently employed to manufacture bulk diltiazem in the N-alkylation step and the processes claimed in the 035 patent (and in the Examples contained in the patent) include the following: a) Profarmaco uses sodium carbonate as a base; the ‘035 patent specifies potassium carbonate and potassium hydroxide; b) Profarmaco uses toluene as a solvent; the ‘035 patent uses acetone and lower alkyl acetates, or mixtures of those solvents and water; c) according to complainants’ theory of the case, the ‘035 patent process operates in the presence of water, and calls for the optional addition of water; Profarmaco’s process requires that water be removed constantly throughout the N-alkylation reaction and no water is specifically added. d) Profarmaco’s process is conducted at a tem- perature of approximately [C]°; the ‘035 pro- cesses are conducted at a maximum of 77°. CX 1 (“035 patent, col. 2, line 62). e) in the Profarmaco process, Profarmaco arrives at a solution in toluene of the inter- mediate; Profarmaco is therefore ready to conduct the subsequent acetylation reaction in the same reactor vessel using the same reactants. By contrast, in the ‘035 process the intermediate is isolated. See Piselli, Tr. 1986-87. ee er alia a App. 261 a. Solvents FF CP 51. In comparing the solvent system of toluene to either acetone or ethyl acetate, “there are cer- tainly differences that one can point to in the properties of these solvents.” Gokel, Tr. 698. FF CP 52. According to complainant’s expert Dr. Gokel, “the key difference” of the Profarmaco process from the 035 process is the use of toluene as the solvent. Gokel, Tr. 764. FF CP 53. The information reported in Dr. Gokel’s report entitled “Fermion and Profarmaco Versions of Tan- abe Diltiazem Synthesis” reflects what Dr. Gokel “con- structed to aid [his] thinking at an early stage” in the present litigation. In determining the equivalence between the Fermion and Profarmaco processes with the ‘035 process, Dr. Gokel considered many parameters relating to the solvents used for the N-alkylation reaction. One of the parameters that Dr. Gokel considered and thought might influence his opinion was solvent polarity parameters, while another was a comparison of the water miscibilities of the different solvents. Dr. Gokel also listed and considered dipole moments and dielectric constants for the different solvents. Dr. Gokel summarized all of the different values in a solvent table on pages 13-15 of his report. CX 606; Gokel, Tr. 810-15. FF CP 54. When looking at the solvent tables included in Dr. Gokel’s report eniitled “Fermion and Profarmaco Versions of Tanabe Diltiazem Synthesis,” Dr. Gokel compared the relevant values of one solvent with a App. 262 second solvent, as determined by the same methodology, same tester, same equipment, etc. for the different sol- vents. CX 606; Gokel, Tr. 814-15. Toluene is Substantially Different in Structure From the ‘035 Carbonyl Solvents FF CP 55. The predominant structural feature of each of the solvents claimed in the ‘035 patent is the presence of a carbonyl group, which is shown enclosed by the dotted lines in the following formulas: [Diagram Omitted In Printing] RRX 3983; Taber, Tr. 2058-59. FF CP 56. Toluene is an aromatic hydrocarbon whose structure is illustrated by the formula: [Diagram Omitted In Printing] RPX 3987. FF CP 57. Toluene contains neither a carbonyl group nor any structure analogous to a carbonyl. Toluene is not a ketone (like acetone) or an ester (like an alkyl acetate). Taber, Tr. 2145; Gokel, Tr. 702. FF CP 58. The oxygen atoms in the carbonyls of the solvents claimed in the ‘035 patent have two unbonded pairs of electrons which can be donated to positively charged species (“cations”), such as potassium ions (K+), as depicted below: [Diagram Omitted In Printing] RX 3983; Taber, Tr. 2059. App. 263 FF CP 59. The second oxygen atom in an alkyl acetate also possesses two pairs of unbonded electrons that can be donated. RX 3983; Taber, Tr. 2059. The ‘035 Carbonyl Solvents Are Good Donor Solvents Whereas Toluene Is Not FF CP 60. A donor solvent is a solvent which can donate electron density to stabilize an electron deficient species such as a cation. A donor solvent provides stabi- lization to an electron deficient species, such as a sodium or potassium cation, which are both electron deficient. Gokel, Tr. 702. 3 FF CP 61. The ’035 carbonyl solvents are good donor solvents. RPX 3984; Taber, Tr. 2060; Taylor, Tr. 2606. FF CP 62. Toluene is a very poor donor solvent. RPX 3984; Taber, Tr. 2060, 2145. FF CP 63. A donor solvent is “a material that has a polar functional group that can solvate a Lewis acid entity.” A Lewis acid entity would include a potassium ion. Gokel, Tr. 802. FF CP 64. Acetone and lower alky] acetates are stron- ger donors than toluene. Gokel. Tr. 806. FF CP 65. Because ‘035 carbonyl solvents can donate electrons, particularly when they contain water, they are able to solvate (or solubilize) and thus stabilize cations of inorganic bases, such as the potassium bases of the ‘035 patent. Taber, Tr. 2058, 2059. App. 264 FF CP 66. Potassium bases are more soluble in car- bonyl solvents than are sodium bases. RX 4038C; Taber, Tr. 2147; Kende, Tr. 1455. FF CP 67. Because of its poor donorability, toluene cannot effectively solvate (or solubilize) and thus stabi- lize cations of inorganic bases, such as potassium ions or sodium ions. RX 4034; Taber, Tr. 2061-2065. FF CP 68. Sodium carbonate is not soluble in toluene. Taber, Tr. 2093. The ‘035 Carbonyl Solvents Possess Medium Polarity Whereas Toluene Is Nonpolar FF CP 69. The ‘035 carbonyl solvents, methyl acetate, acetone and ethyl acetate range in donor number from 16.4 to 17.1. RPX 3984; Taber, Tr. 2060. FF CP 70. The donor number for toluene is 0.1. RPX 3984; Taber, Tr. 2060. FF CP 71. The ‘035 carbonyl solvents are more than 160 times better donors than is toluene. RPX 3984 FF CP 72. The ‘035 carbonyl solvents, methyl acetate, ethyl acetate and acetone, are of medium polarity, having dipole moments ranging between 5.7 and 9.0 and dielectric constants ranging from 6.0 to 20.56. RPX 3985 FF CP 73. Toluene is a non-polar solvent, having a dipole moment of 1.0 and dielectric constant of 2.38. RPX 3985; Taber, Tr. 2145; Gokel, Tr. 810. FF CP 74. Because water is soluble in the ‘035 car- bony] solvents, it increases the dielectric constant of the ‘035 carbonyl solvents. Taber, Tr. 2067. i ia 2 App. 265 FF CP 75. Ionic species are solvated and stabilized better by polar solvents than by non-polar solvents. Gokel, Tr. 810. FF CP 76. Toluene, being a non-polar solvent, lacks the ability to dissolve inorganic bases. Taber, Tr. 2064-65. The ‘035 Solvents and Water Are Substantially Soluble Within Each Other Whereas Toluene and Water Are Not FF CP 77. The ‘035 carbonyl solvents are substantially soluble in water, and water is substantially soluble in those solvents. RPX 3986; Taber, Tr. 2068. FF CP 78. Acetone is infinitely soluble in water, and water is infinitely soluble in acetone. RPX 3986 FF CP 79. Methyl acetate is very soluble in water (approximately 23%), and water is very soluble in methyl acetate. RPX 3986 FF CP 80. Ethyl acetate is soluble in water at 2.94%, and water is soluble in ethyl acetate at 8.08%. RPX 3986 FF CP 81. Toluene is soluble in water at 0.052% and water is soluble in toluene at 0.033%. RPX 3986 FF CP 82. The solubility of water in the “wet toluene” used in the Profarmaco process is .03%. Taber, Tr. 2068. FF CP 83. It is “well-known” that water is immiscible in toluene. Taylor, Tr. 2607. FF CP 84. The least soluble of the ‘035 carbonyl solvents (ethyl acetate) is more than 50 times more sol- uble in water than toluene, and water is more than 200 times more soluble in ethyl acetate than in toluene. RPX 3986. App. 266 Water Can Solvate Inorganic Bases FF CP 85. The solubility of water in the ‘035 carbonyl solvents, and vice versa, contributes to the ability of the ‘035 carbonyl solvents to solvate (or solubilize) the potassium bases disclosed in the ‘035 patent. Taber, Tr. 2145-46. FF CP 86. One of ordinary skill in the art in 1981 would have known that the solubility of potassium salts in acetone would be enhanced by the addition of water. Taylor. Tr. 2606. FF CP 87. Water stabilizes and thus makes more soluble negatively charged hydroxide and carbonate ions (“anions”) in a reaction solution. RPX 3994; Taber, Tr. 2057-58. The ‘035 Carbonyl Solvents Are Both Hydrophilic and Lipophilic Whereas Toluene Is Only Lipophilic FF CP 88. The ‘035 carbonyl solvents possess both hydrophilic (water-loving) and lipophilic (oil-loving) properties. RPX 3993; Taber, Tr. 2058; 2068-69. FF CP 89. Because the ‘035 carbonyl solvents have both hydrophilic and lipophilic properties, they are able to bring together in solution TZP, the inorganic base, and DMC (in the form of aziridinium). Taber, Tr. 2146. FF CP 90. Because the ‘035 carbonyl solvents have both hydrophilic and lipophilic properties, the TZP, inor- ganic base, and DMC all dissolve in the organic-aqueous phase surrounding the inorganic base particles. Taber, Tr. 2083, 2146. App. 267 FF CP 91. Toluene has strongly lipophilic properties with little or no hydrophilic properties. RX 3993; Taber, Tr. 2069, 2077, 2146. FF CP 92. Because Toluene has very little hydrophilic properties, most water included in the Profarmaco pro- cess is associated with the surface of the sodium carbo- nate base particle. Taber, Tr. 2146. b. Bases Sodium and Potassium Bases Are Not Interchangeable in the ‘035 Process, but Are Interchangeable in Profar- maco’s Process FF CP 93. Sodium carbonate is not equivalent to the potassium bases claimed in claim 1 of the ‘035 patent. Taber, Tr. 2150. FF CP 94. The carbonyl containing solvents of the ‘035 patent are known to be able to solvate at least to some degree potassium. This same phenomenon is not known, however, with sodium, at least not to the same degree. Thus, especially given the teachings of the ‘035 patent, a person skilled in the art at the time of the alleged ‘035 invention would have believed that the spec- ific carbonyl containing solvents of the ‘035 patent were linked with and were capable of providing some sol- ubility only to potassium hydroxide and potassium car- bonate. Taylor, Tr. 2604-05. FF CP 95. Potassium salts are generally more soluble in solvating organic solvents than are sodium salts. Gokel, Tr. 844; Taylor, Tr. 2604-05. App. 268 FF CP 96. The sodium cation is more charge dense than the potassium cation. Gokel, Tr. 844. FF CP 97. Whereas sodium carbonate does not work in the same way as the potassium bases in the ‘035 patent, sodium carbonate would work in the same way as potassium carbonate in the Profarmaco process. This is because sodium and potassium bases are often inter- changeable when dealing with reaction solutions contain- ing pure water, as in the aqueous phase surrounding the inorganic base particle in the Profarmaco process. Taber, Tr. 2146-47. FF CP 98. Potassium salts and sodium salts are inter- changeable in aqueous systems. Taber, Tr. 2117-18. c. Reaction Mechanisms The Profarmaco and ‘035 Processes Operate with Sub- stantially Different Reaction Mechanisms FF CP 99. The Profarmaco process proceeds with a different mechanism than does the ‘035 process. Taber, Tr. 2111-12. FF CP 100. The ‘035 process is one in which the inorganic base particles (potassium base particles) are surrounded by a solvent-water mixture, wherein the con- centration of water is greatest at the surface of the parti- cle and decreases with distance from the particle. Some water is dissolved in the bulk organic phase. Taber, Tr. 2069-71; Gokel, Tr. 705. FF CP 101. Complainants’ expert, Dr. Gokel, has car- ried out no experiments and is unaware of any experi- ments carried out by others, comparing a surface solvent App. 269 phase formed in the ‘035 process with a surface solvent phase formed in any of the Respondents’ processes. Gokel, Tr. 1053. FF CP 102. Dr. Baldwin would expect to find more dissolved base in the solvent system of the ‘035 process than he would in the toluene phase of the Profarmaco process. RX 3048C. FF CP 103. The pH of the carbonate buffer contained in the aqueous phase of the Profarmaco process is the same, whether sodium carbonate or potassium carbonate is used as the base. Because a dramatic difference is obtained in the ‘035 process when using a sodium base instead of a potassium base, this indicates that the ‘035 reaction system is a mixed solvent system, comprising water, organic solvents and potassium base. This mixed solvent system is further evidenced by the knowledge that potassium bases are more soluble than sodium bases in the ‘035 carbonyl solvents, due to the ability of the carbonyl solvents to solvate potassium ions more effi- ciently than sodium ions. Taber, Tr. 2147. FF CP 104. The ratio of water to organic solvent in the ‘035 process is a gradient or continuum extending outward from the solid base particles of the ‘035 patent. Taber, Tr. 2069-71. In the ‘035 system, there exists a “phase boundary” between the ethyl acetate and water phases “which is on the ethyl acetate side more like ethyl acetate; on the water side, more like water. And in the middle there is a progression from one to the other. Gokel, Tr. 705. FF CP 105. Complainants’ expert Dr. Gokel “would certainly expect” that the difference between toluene and App. 270 ethyl acetate would alter the phase boundary present in the respective systems. Gokel, Tr. 707. FF CP 106. The TZP in the ‘035 process is deproto- nated by carbonate or hydroxide ions and the resulting amide anion reacts with the aziridinium ion to yield the alkylated product. Taber, Tr. 2074-75. FF CP 107. No direct experimental evidence exists that the claimed N-alkylation process of the ‘035 patent using potassium carbonate as a base is hydroxide-medi- ated. Gokel, Tr. 1028. If anything, there are indications that it is not hydroxide-mediated. Taylor, Tr. 2674. FF CP 108. The particular base-solvent combinations of the ‘035 patent result in the reactants coming together in solution and thus allow the reaction to proceed at relatively low temperatures with good yields. Kende, Tr. 1194. FF CP 109. Complainants’ expert, Dr. Gokel, was unsure whether the actual alkylating agent in either the Profarmaco or the ‘035 processes is the aziridinium ion. Specifically, the only thing Dr. Gokel knows is that in both reactions some aziridinium ion is formed, but he does not know whether the aziridinium ion is the actual alkylating agent or not. Although he “think(s], it is rea- sonable that it could be, . . . [he] can’t rule out the other possibility.” That the alkylation of TZP occurs predom- inately through the aziridinium ion would be a “guess” to Dr. Gokel. Gokel, Tr. 849-51. App. 271 FF CP 110. Dr. Gokel also agreed that the aziridinium ion would be likely involved in the ’257 process, in addi- tion to its likely involvement in both the ‘035 and Profar- maco processes. Gokel, Tr. 850-51. FF CP 111. Dr. Baldwin’s labeling experiments in JEB1-JEB4 do not prove that the aziridinium ion is the alkylating species. RX 3963; RX 4038C. FF CP 112. Profarmaco’s expert testified that in the Profarmaco reaction, the aziridinium ion acts as a phase transfer agent between the thin water layer surrounding the inorganic base particle and the bulk toluene phase. Taber, Tr. 2081, 2109-12; RPX 4000, 4001. Substantially Lower Amounts of Water Are Present in the Profarmaco Process FF CP 113. In the Profarmaco process, the amounts of water present are much smaller than the amounts of water present in the ‘035 process. Specifically, in Example 3 of the 035 patent, the amount of water associated with potassium carbonate is about 1.1 moles of water per mole of potassium carbonate. RX 1688 (Liotta Dep. Tr. 977-78). In contrast, in the Profarmaco process wherein the water concentration of the water-extracted toluene is [C]%, the molar ratio of water to sodium carbonate is about [C]% or [C] times less than in the ’035 process. RX 1688. FF CP 114. The small amount of dissolved water in the toluene of the Profarmaco process exists in aggregates of molecules. Taber, Tr. 2077; RPX 4000. App. 272 FF CP 115. The minuscule amounts of water in the toluene associate with the surface of the sodium carbo- nate base in the Profarmaco process, whereas in the pro- cess of the ‘035 patent significant amounts of water are dissolved in the carbonyl solvent and the water partici- pates in the solvation and dissolution of the inorganic potassium base. RPX 4000; Taber, Tr. 2069-71, 2076-78. FF CP 116. No mention is made of azeotropic removal of water in any of the examples of the ‘035 patent. Instead, the ‘035 patent teaches in the examples that the reaction is carried out under reflux conditions, meaning that the vapors of solvent released from the reaction mixture during boiling are condensed to a liquid in a reflux condenser and returned to the reaction vessel. Gokel, Tr. 904-06. The Profarmaco Process Is More Like the ’257 Process Than the ‘035 Process FF CP 117. The Profarmaco process is much more like the ‘257 process than the ‘035 process because where reversible deprotonation of the TZP starting material occurs in the ‘035 process, the TZP starting material in the Profarmaco process is directly alkylated after deprotona- tion occurs. Thus, no equilibrium (or reversibility) exists in the Profarmaco process between the TZP starting mate- rial and its anion. Taber, Tr. 2112-14; RPX 4001. More Energy Is Required to Carry Out Profarmaco Pro- cess FF CP 118. A higher amount of energy is required for the reaction occurring in the Profarmaco process than for App. 273 the reaction occurring in the process of the 035 patent, as reflected by the higher reaction temperatures required for obtaining good yields in the Profarmaco process. Taber, Tr. 2109. FF CP 119. The Profarmaco process is carried out at a temperature of [C] °[C] versus 77°[C] or less in the ‘035 process. CX 1; Piselli, Tr. 1987. Evolution of Carbon Dioxide Occurs in the Profarmaco Process, But Not in the ‘035 Process FF CP 120. Because of the higher reaction tempera- tures necessary to carry out the Profarmaco process, car- bon dioxide is evolved during the Profarmaco process, thereby also producing sodium hydroxide. Taber, Tr. 2088. FF CP 121. Nothing in the ‘035 patent indicates that carbon dioxide is evolved during the ‘035 process. Taber, Tr. 2088; Gokel, Tr. 1043-1044. FF CP 122. The fact that the evolution of carbon dioxide in the Profarmaco process coincides with the production of the product indicates that the hydroxide ion formation, which occurs simultaneously with carbon dioxide evolution, is important to the Profarmaco pro- cess. Taber, Tr. 2089. Different pH Levels Exist in Profarmaco and ’035 Pro- cesses FF CP 123. While the pH in the ‘035 process drops from an initial pH of 11.5 to 8.5, the pH in the Profarmaco App. 274 process is maintained at a minimum level of 11.5. Taber, Tr. 2088-89. FF CP 124. One pH interval level represents a differ- ence in hydroxide ion concentration of a factor of 10. Thus, there is 1000 times more hydroxide ion present in the Profarmaco process than in the ‘035 process. Taber, Tr. 2089. FF CP 125. The Profarmaco process operates at a much higher pH level than the process of the ‘035 patent, due to the higher hydroxide ion concentration and signif- icantly lower amount of water present in the Profarmaco process. Taber, Tr. 2089-90. d. Experimental Evidence Demonstrates That the Profarmaco Process Works in A Substantially Different Way Than the ‘035 Process FF CP 126. At least four different sets of experiments have been made of record in the present investigation demonstrating that when the solvent toluene is substi- tuted for the ‘035 carbonyl] solvents in the ‘035 process the reaction proceeds very differently: (1) the experiments underlying the EPO Comparative Test Report submitted by Tanabe during the prosecution of the European appli- cation corresponding to the ‘035 patent; (2) experiments conducted by Tanabe scientists in the early 1980's; (3) experiments conducted by complainants’ expert Dr. Bald- win; and (4) experiments conducted by Profarmaco. RX 3929, 3494, 3963, 3936; Taber, Tr. 2120-23, 2131-2145. App. 275 FF CP 127. At least four different sets of experimental data demonstrate that sodium carbonate reacts quite dif- ferently than potassium carbonate in the ‘035 process: (1) the EPO Comparative Test Report submitted by Tanabe during the prosecution of the European application corre- sponding to the ‘035 patent; (2) research reports by the ‘035 inventors; (3) experimental tests by complainants’ expert Dr. Baldwin; and (4) experiments conducted by Profarmaco. RX 3929, 3361, 3963, 3936; Taber, Tr. 2119-23, 2131-2145. Comparative Test Report FF CP 128. In Experiment No. 1 of Table 1, a yield of 86.2% was reported when using potassium hydroxide and acetone at a reaction temperature of 50°[C] for a reaction period of 7 hours. RX 3929C. The reaction temperature of 50-60°[C] was within the range described in the ‘035 patent specification. RX 3048C. FF CP 129. In Experiment No. 2 of Table 1, a yield of 94.5% was reported when using potassium carbonate and acetone under reflux conditions for a reaction period of 9 hours. RX 3929C. FF CP 130. In experiment No. 3 of Table 1, a yield of 90.2% was reported when using potassium carbonate and ethyl acetate under reflux conditions for a reaction period of 23 hours. RX 3929C. FF CP 131. In Experiment No. 4 of Table 1, a yield of 90.7% was reported when using potassium carbonate and acetone/water under reflux conditions for a reaction period of 3 hours. RX 3929C. App. 276 FF CP 132. In Experiment No. 5 of Table 1, a yield of 92.7% was reported when using potassium carbonate and ethyl acetate/ water under reflux conditions for a reaction period of 6 hours. RX 3929C. FF CP 133. In Experiment No. 6 of Table 1, a yield of 87.3% was obtained when using potassium carbonate and methyl acetate/water under reflux conditions for a reac- tion period of 30 hours. RX 3929C. FF CP 134. The base and solvent systems, reactions temperatures, reaction times and yields obtained in Experiment Nos. 1-6 in Table 1 of the EPO Comparative Test Report correspond with the bases and solvents, reac- tion conditions and yields obtained in Examples 1, 4, 5, 2, 3 and 7, respectively, of the ‘035 patent. CX 1; RX 3929-C. FF CP 135. In Experiment No. 8 of Table 1, the yield of product was reported as “no reaction” when potassium hydroxide and toluene were used at a reaction tempera- ture of 50-60°[C] for a reaction period of 7 hours. RX 3929C. The reaction temperature of 50-60°[C] was within the range described in the ‘035 patent. RX 3048C. FF CP 136. In Experiment No. 11 of Table 1, a yield of 10% was reported when using sodium hydroxide and acetone under reflux conditions for a reaction period of 15 to 20 hours. RX 3929C. FF CP 137. In Experiment No. 12 of Table 1, the yield of product was reported as “no reaction” when sodium carbonate and acetone were used under reflux conditions for a reaction period of 15 to 20 hours. RX 3929C. FF CP 138. Where “no reaction” is reported in Experi- ments 8 and 12 of the Comparative Test Report, Tanabe paw eee ee App. 277 did not necessarily mean zero yield but rather meant a poor yield. Taber, Tr. 2281. FF CP 139. Complainants’ expert, Dr. Gokel, pro- vided as an explanation for why a 86.2% yield was obtained in Experiment No. 1 (KOH / Acetone) of Table 1, whereas only a 10% yield was obtained in Experiment No. 11 (NaOH/Acetone) of Table 1, was that “[i]t can be explained by the fact this is sodium hydroxide and that’s potassium hydroxide. . . . ” Another possible explanation for why different yields were obtained in Experiments Nos. 1 and 11 is that in a theoretical sense there exists a difference in the solubilities of potassium hydroxide and sodium hydroxide, which thus could account for the dif- ferences in the reaction yields obtained. Dr. Gokel recog- nized this to be a “well-known phenomenon.” Gokel, Tr. 845-47. Experiments Performed by Tanabe Scientists Toluene Did Not Work in ‘035 Process FF CP 140. In a Tanabe technology department report, dated October 1981 (approximately two months prior to the December 1981 date of the Japanese priority patent application upon which the ‘035 patent is based), Tanabe scientists reported that the N-alkylation of TZP at a reaction temperature of [C] °[C] using [C] as the base and [C] as the solvent did not work. Tanabe repeated the reaction several times, varying the reaction temperature and amount of water added, but were unable to obtain an appreciable product. Taber, Tr. 2136-37; Gokel. Tr. 779-84- RX 3494. App. 278 FF CP 141. Dr. Gaino, one of the co-inventors named on the face of the ‘035 patent, reported in his notebook that N-alkylating TZP using [C] as the base and [C] as the solvent failed to work. Taber, Tr. 2138-39; RX 3368C. FF CP 142. The Tanabe research reports reflect the Tanabe scientists’ finding that toluene is not a useful solvent for the ‘035 process. Taber, Tr. 2139. Sodium Carbonate Did Not Work in the ‘035 Process FF CP 143. Tanabe performed experiments about three months prior to the December 1981 date of the Japanese priority patent application upon which the ‘035 patent is based wherein [C] and [C] were substituted for [C] as the base for N-alkylating TZP in [C] . When using either [C] or [C] , tanabe scientists were unable to make the N-alkylation reaction work. The experiment using sodium carbonate and acetone corresponded with Experi- ment No. 12 in Table 1 of the European Comparative Test Report using sodium carbonate and acetone wherein “no reaction” is reported. Thus, Experiment 12 may be based on this test. RX 3362C, RX 3361C; Taber, Tr. 2123, 2131-35. FF CP 144. Tanabe Research Reports reflect the find- ing of Tanabe scientists that sodium carbonate is not useful as a base in the ‘035 process. Taber, Tr. 2139. Experiments Performed by Complainants’ Expert, Dr. Baldwin, During the Investigation FF CP 145. Experiments carried out by Complainant's expert Dr. Baldwin demonstrate that toluene does not Se TE ci aR ee e App. 279 work as a solvent in the ‘035 process. Taber, Tr. 2143-44; RX 3963, RPX 3991C. FF CP 146. Experiments carried out by Complainant's expert Dr. Baldwin demonstrate that sodium carbonate does not work efficiently as a base in the ‘035 process, as that process is taught in the patent's examples. Taber, Tr. 2143-2144; RX 3963, RPX 3991C. FF CP 147. In Experiment JEB15, which was designed to simulate a process of the ‘035 patent in which toluene was interchanged for a solvent of the ‘035 patent, a yield of 24% was obtained when N-alkylating TZP with potassium hydroxide as the base and toluene as the sol- vent at a reaction temperature of 111°[C]. RX 3963; RX 3048C. FF CP 148. In Experiment JEB16, which was designed to simulate a process of the ‘035 patent in which toluene was interchanged for a solvent of the ‘035 patent, a yield of 56% was obtained when N-alkylating TZP with potassium carbonate as the base and toluene as the sol- vent at a reaction temperature of 111°[C]. RX 3963; RX 3048C. FF CP 149. In Experiment JEB17, the yield of product obtained dropped from 90.7% to 35% when sodium car- bonate was substituted for potassium carbonate under some reaction conditions of Example 2 of the ‘035 patent. RX 3963; RPX 3991C. FF CP 150. In Experiment JEB18, the yield of product obtained dropped from 92.7% to 65% when sodium car- bonate was substituted for potassium carbonate under App. 280 some reaction conditions of Example 3 of the ‘035 patent. RX 3963; RPX 3991C. FF CP 151. In Experiment JEB19, the yield of product obtained dropped from 90.7% to 10% when sodium car- bonate was substituted for potassium carbonate under some reaction conditions of Example 2 of the ‘035 patent. RX 3963; RPX 3991C. FF CP 152. In Experiment JEB20, a yield of 97% was obtained whe. sodium carbonate was substituted for potassium carbonate under some reaction conditions of Example 3 of the ‘035 patent, but only after heating the reaction mixture at reflux temperature for 23 hours (almost 4 times the reaction time in Example 3). RX 3963; RPX 3991C. FF CP 153. Experiment No. 12 in Table 1 of the Comparative Test Report, in which “no reaction” was reported for an N-alkylation reaction using sodium car- bonate and acetone, is consistent with the 10% yield that the complainants’ expert Dr. Baldwin obtained in JEB 19, wherein sodium carbonate and acetone also were used. Taber, Tr. 2281. FF CP 154. Experiment No. 8 in Table 1 of the Com- parative Test Report, in which “no reaction” was reported for an N-alkylation reaction using potassium hydroxide and toluene, is consistent with the 24% yield that the complainants’ expert Dr. Baldwin obtained in JEB 15, wherein potassium hydroxide and toluene also were used. Taber, Tr. 2281. App. 281 FF CP 155. Dr. Baldwin’s experiments also demon- strated the importance of water removal during the Pro- farmaco process. RPX 3992; RX 3963. FF CP 156. In Experiment JEB2 (which sought to mimic the Profarmaco process), Dr. Baldwin’s assistants failed to follow his instruction that steps be taken to remove water during the reaction. RX 4038C; Gokel, Tr. 866-67. FF CP 157. Without taking steps to remove water in JEB2, a yield of only 32% was obtained. RX 3963. FF CP 158. When Dr. Baldwin repeated Experiments JEB2 with azeotropic water removal, the yield increased from 32% to 98%. RX 3963. FF CP 159. Complainants’ expert, Dr. Gokel, agreed that “an effort was made to remove water” during Dr. Baldwin’s repeat of JEB2, including transferring the reac- tion mixture to a clean Wheaton vile after the neutraliza- tion step, as well as using a heat gun to heat the distillation head to ensure that any water adhering to its walls was driven over into the condenser. In addition, a clean condenser was attached to the reaction system prior to completing the reaction. The effort made to remove water in the repeat of Experiment JEB2 was consistent with Profarmaco’s effort to remove water during its pro- cess by azeotropic distillation. Gokel, Tr. 867-69. FF CP 160. No attempt also was made to remove water azeotropically during Experiments JEB 15 and JEB 16. Gokel, Tr. 801; RX 3048C. FF CP 161. Complainants’ expert, Dr. Gokel, had no ideal whether Dr. Baldwin’s Experiment Nos. JEB1-JEB20 App. 282 had been optimized; in other words, they may have been or they may not have been. Gokel, Tr. 616-617. FF CP 162. If Dr. Baldwin’s experiments were not already optimized, they could have been optimized if complainants’ counsel chose to have it done. Gokel, Tr. 1113-15. Experiments Performed by Profarmaco During Investi- gation FF CP 163. During the course of this investigation, Dr. Piselli of Profarmaco conducted certain experiments. Those experiments are summarized at page 703 of RX 3936. Trial Tr. at 1987-88. FF CP 164. In Experiments 1-3, Dr. Piselli repeated Example 3 of the ‘035 process. These experiments were run in triplicate. Piselli, Tr. 1988; RX 3936. FF CP 165. The yields obtained by Dr. Piselli in these three repetitions of Example 3 of the ‘035 patent were virtually identical to the yield indicated in the ‘035 patent itself. Similarly, the product produced, based on TLC analysis and melting point range, appears to be identical to that indicated in Example 3 of the ‘035 patent. Piselli, Tr. 1988; RX 3936; CX 1. FF CP 166. In Experiments 4-6, Dr. Piselli used Exam- ple 3 of the ‘035 patent as a starting point for three experiments, in which he substituted sodium carbonate for potassium carbonate. Dr. Piselli ascertained that after a period of time that was slightly longer than that speci- fied in Example 3 of the ‘035 patent, each of the three App. 283 experiments provided a low yield. Piselli, Tr. 1989-1990; RX 3936. FF CP 167. In Experiment 4, Dr. Piselli therefore extended the reaction time to 15 hours, and in Experi- ment 6 extended the reaction time to 30 hours and changed a number of other factors. In each instance, the yield remained low. Piselli, Tr. 1989; RX 3936. FF CP 168. Also, in Experiments 5 and 6, the purity of the product obtained was poor, as characterized by a “NEG” indication in the “Purity by TLC” column. RX 3936 at 703. FF CP 169. Similarly, the melting points of the prod- uct obtained in Experiments 5 and 6 were significantly lower than the melting range for the product obtained by a simple replication of the Example 3 of the ‘035 patent. Piselli, Tr. 1988-1990; RX 3936 at 703. FF CP 170. With respect to Experiments 4-6, Dr. Pis- elli testified that the yields reflected in those experiments “is not a process. It’s something that should be aban- doned.” Piselli, Tr. 1990. FF CP 171. In Experiments 7 and 8, Dr. Piselli repli- cated Example 4 of the ‘035 patent. Piselli, Tr. 1990; RX 3936. FF CP 172. The yields and quality obtained in Experi- ments 7 and 8 compare favorably with the yields and quality reflected in Example 4 of the ‘035 patent. Piselli, Tr. 1990-1991; RX 3996 at 703. FF CP 173. In Experiments 10 and 11, Dr. Piselli replicated Example 4 of the ‘035 patent, except that he App. 284 substituted sodium carbonate for potassium carbonate. Piselli, Tr. 1991; RX 3936. FF CP 174. Experiments 10 and 11 produced a low yield and a poor quality product, as reflected by the “neg” comment in the purity by TLC column. These results were not improved by continuing the reaction for 18 hours. Piselli, Tr. 1991; RX 3936 at 703. FF CP 175. Experiments 4-6 and 10-11 demonstrate that sodium carbonate is not a useful base in the ‘035 process. Taber, Tr. 2142. FF CP 176. In Experiment 15, Dr. Piselli replicated Example 3 of the ‘035 patent except that he substituted toluene as the solvent in the place of ethyl acetate. Dr. Piselli used the reflux temperature of ethyl acetate, as used in the patent example. The yield was extremely low and the product was not pure. Piselli, Tr. 1991-1992, 2031; RX 3936 at 703. FF CP 177. In Experiment 16, Dr. Piselli replicated Example 3 of the ‘035 patent except that he substituted toluene for acetone. There was no yield in this reaction at all. Dr. Piselli used the boiling temperature of acetone. Piselli, Tr. 1992, 2031; RX 3936 at 703. Optimization Defined FF CP 178. Optimization is not the same thing as experimentation. A process is optimized only after it has been found to be a “consistent” process, specifically a process from which “a well-defined product with a well- defined yield” is obtained. It is only at this point in time 6 OE ES OPS Oa App. 285 that “technological optimization” (i.e., trying “small vari- ations in the operating parameters”) of a process is con- ducted. For example, if an experiment using the same reactants and reaction conditioner was repeated ten times, any variation in yield would be minimal. Piselli, Tr. 2017-18, 2021. FF CP 197. Dr. Piselli testified that one could not “optimize” the Profarmaco experiments: “Optimization is one thing, the process is another. You optimize a process that has a certain consistency and is valid, but if the process doesn’t exist, you don’t optimize it.” Piselli, Tr. 1990. e. The Profarmaco Process Also Performs A Substantially Different Function and Achieves A Substantially Different Result Than the ’035 Process FF CP 180. Because claim 1 of the ‘035 patent does not include a recovery step, the product of claim 1 is N-alkylated TZP in a reaction mixture containing water, a polar, water-miscible carbonyl solvent and various salts. CX 1; Taber, Tr. 2183. FF CP 181. The Profarmaco process produces a solu- tion of N-alkylated TZP in toluene taber, TR. 2183-2184. FFCP 182. The examples of the ‘035 patent teach that the N-alkylated TZP obtained as the product of claim 1 of the ‘035 patent must be isolated, purified, and transferred to another reaction vessel before the manufacture of diltiazem can proceed. CX 1; Piselli, Tr. 1987. App. 286 FF CP 183. The product of Profarmaco’s sodium car- bonate/toluene N-alkylation process provides commer- cial advantages, for example, convenience, unobtainable using the product of the N-alkylation process claimed in the claim 1 of the ‘035 patent. Taber, Tr. 2183-2185. FF CP 184. Because toluene is immiscible with water, the solution of N-alkylatedTZP in toluene produced from the N-alkylation step of the Profarmaco process can be directly washed with water to remove byproducts and unreacted DMC, leaving behind a solution in which one can directly carry out the subsequent acetylation reaction. Taber, Tr. 2185. FF CP 185. The function of the process of claim 1 of the ‘035 patent is to produce an organic reaction mixture containing N-alkylated TZP in a carbonyl solvent-water mixture. This product will contain water, dissolved base and salts along with alkylated TZP. To utilize the sol- ubilized N-alkylated TZP, the reaction mixture must be (i) extracted, (ii) washed, (iii) filtered, (iv) concentrated, (v) redissolved, and (vi) transferred to another reactor prior to the subsequently applied steps, including, inter alia, the acetylation and salt-forming steps. RX 3348; Taber, Tr. 2183; Piselli, Tr. 1987. B. The Abic Process Does Not Infringe Claim 1 of the ‘035 Patent 1. The Abic Process Is Not Equivalent to Any Process Disclosed Or Claimed By The ‘035 Patent FF CA 1. The Abic process does not employ either of the two bases or either of the two organic solvents or any App. 287 of the five specific base-solvent combinations identified in the ‘035 patent. See RX 1194; RX 1195. FF CA 2. Abic’s commercial process uses barium hydroxide octahydrate as a base, a biphasic solvent sys- tem of methylene chloride and water, and tri- ethylbenzylammonium chloride (TEBA) and is similar to the process described in example 4 of its United States Patent No. 4,466,995 (“the ‘995 patent”). RX 1701C. FF CA 3. All the processes used by Abic to manufac- ture diltiazem hydrochloride were disclosed in the Abic DMF. [C]. RX 1701. The Bases Are Not Equivalent FF CA 4. Abic’s base is barium hydroxide octahy- drate, and not potassium hydroxide or potassium carbo- nate. RX 1194; Taylor Tr. 2638; RX 1701C. FF CA 5. The ‘035 patent does not disclose or suggest barium hydroxide to a person of ordinary skill. Taylor Tr. 2609. FF CA 6. Barium is an alkaline earth metal, and as such forms divalent cations. Taylor Tr. 2609. FF CA 7. Among other things, barium hydroxide is less soluble than potassium hydroxide in carbonyl sol- vents such as acetone and lower alkyl acetates. Taylor Tr. 2610. FF CA 8. If one of ordinary skill in the art were investigating the interchangeability of other bases with the potassium bases of the ‘035 patent, one would likely first try sodium hydroxide (NaOH) because sodium App. 288 hydroxide is more common and substantially less expen- sive than potassium hydroxide. Taylor Tr. 2626. FF CA 9. Tanabe tried and abandoned sodium hydroxide in combination with DMSO. RX 1589C. FF CA 10. As is shown by the Comparative Test Report, Tanabe did try the base/solvent combination of sodium hydroxide and acetone, and concluded that it was not part of the method of the invention of the ‘035 patent. Tr. 2636; RPX 1146; RX 1096; RX 1344; RX 3225. FF CA 11. Barium hydroxide would be expected to be less effective than sodium hydroxide in the ‘035 process because barium is even less soluble than sodium in the carbonyl solvents acetone or ethyl acetate of the ‘035 patent. Taylor Tr. 2627. FF CA 12. Consequently, if sodium hydroxide were found to be not as good as potassium hydroxide, one of ordinary skill in the art would not be led to try barium hydroxide, since barium hydroxide would be expected to be even worse in the ‘035 process, which discloses solva- tion of the solid base in a carbonyl solvent. Taylor Tr. 2627. FF CA 13. Accordingly, one of ordinary skill in the art, knowing that even sodium hydroxide was not inter- changeable with potassium hydroxide would not have expected that barium hydroxide would be interchange- able with potassium hydroxide or potassium carbonate. Taylor Tr. 2609-10. App. 289 The Organic Solvents Are Not Equivalent FF CA 14. The organic solvent in Abic’s process is methylene chloride. RX 1195; Taylor Tr. 2641; RX 1701C. FF CA 15. The ‘035 patent does not teach the use of methylene chloride as an oroganic solvent to be used in the N-alkylation of the ‘035 process. See Taylor Tr. 2612. FF CA 16. The ‘035 patent disclosed chloroform, a chlorinated hydrocarbon like methylene chloride, but did not disclose its use or the use of any other chlorinated hydrocarbon solvent in its N-alkylation process. CX 1; Gokel Tr. 769-70. FF CA 17. Acetone is a ketone. Taylor Tr. 2621. FF CA 18. One of ordinary skill in the art looking to investigate the scope of potentially interchangeable sol- vents to replace acetone in the ‘035 process would have looked for solvents which shared the important structural and functional characteristics of the carbonyl solvents of the ‘035 patent. i.e, would have looked at oxygen-con- taining, cation-solvating, water-miscible solvents. Taylor Tr. 2624. FF CA 19. Some common solvents which one might have investigated include methyl ethyl ketone, dioxane, methanol, and DMSO. Taylor Tr. 2621-24; RPX 1155. FF CA 20. Methylene chloride would not be one of the solvents one would first try since it does not solvate cations well, has no oxygen atoms to act as donors, and is nearly totally immiscible with water. Taylor Tr. 2624. FF CA 21. If solvents such as dioxane, methanol, and methyl ethyl ketone were not as effective as acetone in a App. 290 reaction, one would not be led to try methylene chloride, since that would be going in the “wrong direction,” to even more inferior water-immiscible solvents. Taylor Tr. 2624-25. Tanabe Tried to Extend the Scope of It’s Invention in 1981 and Failed FF CA 22. Tanabe tried sodium carbonate instead of potassium carbonate, but it did not work as well as the ‘035 bases. RX 3368; Taber Tr. 2134-36. FF CA 23. Tanabe tried structurally and functionally similar solvents, such as dioxane, methyl ethyl ketone, methanol, and DEMSO, and they didn’t work as well as the ‘035 solvents. RX 3361, Gokel Tr. 928-31; RX 2046; Gokel Tr. 676-79; RX 3368; Taber Tr. 2138; RX 1272C; Taylor Tr. 2629-31. FF CA 24. In fact, Tanabe tested and abandoned the base-solvent combination of potassium carbonate-methyl ethyl ketone (the combination currently employed by fermiomion) because Tanabe could not get that combina- tion to work. Taylor Tr. 2629; Gokel Tr. 676-79; RPX-10161a; and RX-2046. FF CA 25. Tanabe did not try barium hydroxide as a base, methylene chloride as a solvent, or the combination of barium hydroxide and methylene chloride. See Taylor Tr. 2633; RX 1703. App. 291 The Liquid-Solid Process of the ‘035 Patent and the Abic Liquid-Liquid Process Are Not Equivalent FF CA 26. Each of the organic solvent-water mixtures of the 035 patent forms a single liquid phase, i.e., it is a solution of water in the acetone or lower alkyl acetate organic solvent. Taylor 1804, 2666-68. FF CA 27. Abic’s solvent system is a biphasic solvent system — it consists of two distinct liquid phases — meth- ylene chloride and water. RX 1195; Liotta Tr. 1804-05; Taylor Tr. 2664, 2666-67. FF CA 28. There is no solid phase present in the Abic process. Schwartz Tr. 2520-21. FF CA 29. Liquid-liquid phase transfer catalyst pro- cesses such as that used by Abic and solid-liquid pro- cesses such as those of the’035 patent are not chemically equivalent. Taylor Tr. 2667; RX-3969 at 108. FF CA 30. Dr. Liotta wrote in his book that, even when a solid-liquid process and a liquid-liquid process are both phase transfer catalyzed, they are by no means equivalent. RX 3969 at 108. Abic’s Process Is Phase Transfer Catalyzed by TEBA FF CA 31. Dr. Charles Liotta, complainants’ expert with respect to infringement of the ‘035 patent by the Abic process, submitted a declaration in this investiga- tion in which he stated that: Convincing evidence has not been presented by Abic to date that (TEBA) is operating as a phase App. 292 transfer catalyst in their N-alkylation process step. RX 1333C, { 6d. FF CA 32. At his deposition, Dr. Liotta explained how such evidence could be generated: Q If Ihave two experiments, one where I have a phase transfer catalyst present and one where it is exactly the same but I leave out the phase transfer catalyst, and the rate in the one with the phase transfer catalyst is faster than the one without it, does that indicate that a phase transfer catalysis is taking place? A_ If you have repeated the experiments so you have reproductibility and stirring speeds are the same in both and everything was the same, the indication is that you have evi- dence for the operation of phase transfer catalysis. Liotta Tr. 1832-33. FF CA 33. Abic carried out a series of such experi- ments, as described by Dr. Liotta, which are identified as experiments 1, 10, and 14-20 on RPX 105la. Taylor Tr. 2642-45. FF CA 34. In experiments 1, 14, 17, 18, the N-alkyla- tion was performed in the presence of TEBA catalyst; experiments 10, 13, 15, 16, 19 and 20 did not use the TEBA phase transfer catalyst. RPX 1051a. FF CA 35. The TZP and DMC were allowed to react in the methylene chloride-water biphasic solvent system for 1.5, 3, 6, or 12 hours. RPX 1051la. Te See ee es Se I ae Oe Ee eee Ret Pep 2 a eee App. 293 FF CA 36. Experiments 14 and 17, 15 and 16 are repeats of each other, and the similar results indicate that the results were reproducible. Taylor Tr. 2645-47. FF CA 37. The stirring speeds were carefully con- trolled, and were essentially the same in all experiments. Schwartz Tr. 2524, 2532. FF CA 38. The Abic experiments met the criteria set forth by Dr. Liotta. Taylor Tr. 2650. FF CA 39. The results were plotted on a graph which shows that the phase-transfer catalyzed reaction was at least twice as fast as the uncatalyzed reaction. Taylor Tr. 2647-49; RPX 1058. The Abic Process Functions in a Different Way Than the ‘035 Process FF CA 40. In the Abic liquid-liquid biphasic solvent process, the TZP and DMC are in the organic phase (the methylene chloride layer), while the barium hydroxide remains dissolved in the aqueous phase. TEBA, the phase transfer catalyst, is soluble in both phases. The aziridinium ion which, as a cation, is insoluble in meth- ylene chloride, remains in the aqueous layer. Taylor, Tr. 2638; RPX 1156. FF CA 41. The hydroxide ion in the water layer cannot efficiently deprotonate the TZP in the methylene chloride layer, because they are in separate layers, organic and aqueous. The TEBA phase transfer catalyst carries the hydroxide ion as TEBA hydroxide into the methylene chloride layer, where it deprotonates the TZP. App. 294 The TZP anion can then react with DMC to N-alkylate the TZP N-aryl amide. Taylor Tr. 2638; RPX 1099. FF CA 42. The methylene chloride phase has an addi- tional function in the Abic process over and above the function of acetone in the ‘035 process. Taylor Tr. 2641. FF CA 43. The water-immiscible solvent methylene chloride keeps the TZP and DMC separate from dissolved aqueous barium hydroxide. Taylor Tr. 2641 FF CA 44. Kugita I discloses that TZP can hydrolyze in the presence of aqueous sodium hydroxide, especially at higher temperatures. RX 3806; Kende Tr. 1452-54. FF CA 45. Abic’s experience with biphasic toluena- aqueous hydroxide processes is in accord; at higher tem- peratures, hydrolysis of TZP was seen. RX 1007C; Haber Tr. 2417-20. FF CA 46. In the Abic process, the methylene chlo- ride, operating at 40° C, protects the TZP and DMC from hydrolysis by aqueous barium hydroxide. Taylor Tr. 2641. FF CA 47. Because there is no aqueous hydroxide in the ’035 solid-liquid potassium hydroxide/acetone pro- cess, hydrolysis is not a problem in the ‘035 process. Taylor Tr. 2666; Taber Tr. 2173. Abic’s Process Is Not Equivalent to the Potassium Hydroxide-Acetone Process of the ‘035 Patent FF CA 48. Abic’s expert compared the potassium hydroxide (KOH) /acetone system of the ‘035 patent and the barium hydroxide/methylene chloride system of Abic’s process. Taylor Tr. 2664-65; RPX 1157. EE EE eee App. 295 FF CA 49. The bases and solvents are different. Id. FF CA 50. There is no water in the ‘035 potassium hydroxide process; thee is a separate aqueous layer in the Abic barium hydroxide process. Id. FF CA 51. There is one solvent phase in the ‘035 process; there are two solvent phases in the Abic process. Id. FF CA 52. The alkylating agent in the ‘035 process is aziridinium ion, and is located in the acetone single sol- vent phase in the ‘035 process. CPX 14; RPX 1157; Taylor Tr. 2664. FF CA 53. In Abic’s process, the active alkylating agent, DMC itself, is located in the methylene chloride phase. Taylor Tr. 2665. FF CA 54. In the ‘035 process, potassium hydroxide is able to deprotonate TZP because it is somewhat soluble in the acetone solvent. In the Abic process, barium hydroxide, which is not soluble in methylene chloride, is able to deprotonate TZP via phase transfer catalysis. Tay- lor Tr. 2656, 2668. FF CA 55. The potassium hydroxide in the ‘035 sys- tem and barium hydroxide in Abic’s system do not func- tion the same way to deprotonate TZP. Taylor Ir. 2665. FF CA 56. The organic solvents in the ‘035 and the Abic processes have different functions: the function of acetone in the ‘035 process is to solubilize the KOH base in the organic phase; the solvents in Abic’s process have the important function of separating the reagents. Taylor Tr. 2665-66. App. 296 FF CA 57. The ‘035 process is a solid-liquid system while the Abic process is a liquid-liquid system. Taylor Tr. 2666. FF CA 58. The Abic process uses the phase transfer catalyst TEBA, but there is no phase transfer catalyst in the ‘035 process. Taylor Tr. 2665. FF CA 59. Solid-liquid phase-transfer-catalyzed sys- tems and liquid-liquid phase transfer catalyzed systems are not regarded as equivalent in the art. Taylor Tr. 2666-67; RX 3969. FF CA 60. Abic’s liquid-liquid phase-transfer-cata- lyzed system is even less equivalent to a simple solid- liquid system, i.e., a solid-liquid system without a phase transfer catalyst, such as that of the ‘035 process. Taylor Tr. 2667; RX 3969. FF CA 61. Phase transfer of the hydroxide ion could be effected by heating Abic’s system. Unlike catalysis, which selectively increases the rate of hydroxide ion transfer, heating indiscriminately speeds up everything that is going on, thus increasing the potential for side reactions. Taylor Tr. 2668-69; RX 3969. FF CA 62. Examples of side reactions which could occur in the Abic system as a result of heating to speed up the reaction are: dimer formation, hydrolysis of DMC, and hydrolysis of TZP. Taylor Tr. 2669-70; RPX 1051a. FF CA 63. In Abic’s process, dimer formation is inhibited by use of a phase transfer catalyst. Taylor Tr. 2669-70; RPX-1051a. App. 297 FF CA 64. Use of a phase transfer catalyst in Abic’s system also enables a reduction in the volume of solvent used. Taylor Tr. 2670-71; RX-1024. FF CA 65. The elements of Abic’s barium hydroxide process, i.e., the base, the two solvents, the alkylating agent, and the phase transfer catalyst, are not the same as the elements of the potassium hydroxide/acetone base/ solvent combination of the ‘035 patent, and the two pro- cesses do not function in the same way and are not equivalent. See Taylor Tr. 2672. FF CA 66. Even if the alkylating agents were the same, and phase transfer catalysis were not taking place, the two processes would still not be equivalent. See Tay- lor Tr. 2672. FF CA 67. That the ‘035 process starts with the same substrate, employe the same alkylating agent, and obtains the same product has no bearing on the equivalence of the base/solvent combinations to the claimed process, because the starting material, alkylating agent and the product are the prior art, not the elements of the claimed improvement. See Taylor Tr. 2672-73. The Abic Process System Is Not Equivalent to the Potassium Carbonate/Acetone or Potassium Carbonate/ Ethyl Acetate Processes of the ‘035 Patent FF CA 68. The Abic process is even less similar to the potassium carbonate/acetone or potassium carbonate / ethyl acetate processes of the ‘035 patent, because the Abic base, barium hydroxide (Ba(OH),), is not a carbo- nate base, but a hydroxide base. RPX 1157; Taylor Tr. 2673. App. 298 FF CA 69. The Abic process is not equivalent to the potassium carbonate/acetone or potassium carbonate/ lower alkyl acetate processes of the ‘035 patent because those processes cannot be made to work as they are disclosed by the ‘035 patent. See Taylor Tr. 2675. FF CA 70. Attempts by Abic to replicate Examples 4 and 5 of the ‘035 patent (powdery potassium carbo- nate=acetone and powdery potassium carbonate-ethyl acetate, with no added water) failed. Taylor Tr. 2675; RPX-1051A. FF CA 71. Abic found that the potassium carbonate/ acetone and potassium carbonate/ethyl acetae base/sol- vent combination is do not work without added water. Taylor Tr. 2676, 2680-81; RX 1272. FF CA 72. The Tanabe laboratory notebooks pro- duced by Tanabe and in evidence showed that Tanabe knew from experiments conducted in 1981, before it filed its patent application on December 7, 1991, that the potassium carbonate/acetone and potassium carbonate/ ethyl acetate combinations did not work consistently without added water. Taylor Tr. 2677; Taber Tr. 2099, 2148. FF CA 73. Abic’s process, which consistently works, is not equivalent to the ‘035 systems of potassium carbo- nate/acetone and potassium carbonate/ethyl acetate, which do not work. Taylor Tr. 2678; RX 1272C. FF CA 74. If, contrary to the evidence, it were assumed that the ‘035 processes of potassium carbonate/ acetone and potassium carbonate/lower alkyl aceate did work, the Abic process would not be equivalent to either process. See Taylor Tr. 2673, 2680. App. 299 FF CA 75. Barium hydroxide and potassium carbo- nate bases are different, and are non-equivalent ways of deprotonating TZP, because the deprotonating species is hydroxide (OH’) in the one case, and carbonate ion (CO,>) in the other. Taylor Tr. 2673-74. FF CA 76. To make the potassium carbonate and barium hydroxide bases seem more similar, complainants have postulated that the potassium carbonate processes are “hydroxide mediated”; that is, that potassium carbo- nate forms some hydroxide ion, which then deprotonates TZP. CPX 14; Gokel Tr. 709. FF CA 77. There is no evidence that the potassium carbonate processes of the ‘035 patent are hydroxide mediated. Taylor Tr. 2674. FF CA 78. Dr. Kende testified that he didn’t know whether the processes were hydroxide mediated or not, and didn’t even know how one would carry out an exper- iment to determine this. Kende Tr. 3415-16. FF CA 79. Abic’s process is not equivalent to the potassium carbonate/acetone combination; and for the additional reasons that these ‘035 processes employ a different base, and are not hydroxide mediated. See Tay- lor Tr. 2679. Abic’s Process Is Not Equivalent to the Potassium Car- bonate/Acetone-Water and Potassium Carbonate/Lower Acetate-Water System of the ‘035 Patent FE CA 80. Potassium carbonate processes with added water are similar to the potassium carbonate/acetone of potassium carbonate/ethyl acetate processes of the ‘035 App. 300 patent, except that with the small added amount of water they produce satisfactory results. Taylor Tr. 2681-82; RPX 1051A. FF CA 81. Although there is a small amount of water in the potassium carbonate/acetone-water and potassium carbonate/ethyl acetate-water processes, they are still solid-liquid processes, because the water (a) reacts with potassium carbonate to form solid potassium car- bonatesesquihydrate, or (b) dissolves in the acetone or lower alkyl acetate solvent. Taylor Tr. 2682-3; 2687-98. FF CA 82. For the same reasons that the Abic process is not equivalent to the KOH/ACETONE processes, or the potassium carbonate/acetone and potassium carbo- nate-lower alkyl acetate processes, it is not equivalent to the potassium carbonate-acetone-water or potassium car- bonate-lower alkyl acetate-water processes. Taylor 2681-82. FF CA 83. Abic repeated Examples 3 and 7 of the ‘035 patent, with yields similar to those reported by the ‘035 patent, and observed only one solid phase and one liquid phase. Schwartz Tr. 2513-15; RX 1175; Taylor Tr. 2692-82; RPX1051a. FF CA 84. Abic also performed some experiments which showed that the ‘035 solid-liquid processes, even with added water, and the Abic liquid-liquid processes were fundamentally different. RPX 1051a; Taylor Tr. 2682-86. FF CA 85. Abic performed an experiment repeating Example 3 of the ‘035 patent (potassium carbonate/ethyl App. 301 acetate-water) but in which methylene chloride was sub- stituted for ethyl acetate. After 6 hours (as specified in the ‘035 example), there was 21.5 percent of unreacted TZP and 77 percent of product. Taylor Tr. 2684; RPX-1051a. FF CA 86. The yield of ’035 Example 3 is reported to be 92.7%. RX 1194. FF CA 87. The yield of the process is important in determining the equivalence of commercial processes, which require high yields. Gokel Tr. 1116-17. FF CA 88. Abix performed as identical experiment with the sale difference that a small amount of TEBA phase transfer catalyst was added. After 6 hours, there remained 77 percent of product, but only 2.7 percent of unreacted starting material and a large amount of the dimer side product. Taylor Tr. 2684; RPX1051a. FF CA 89. Abix also repeated Example 4 of Abic’s ‘995 patent, with and without the TEBA phase transfer catalyst. In Abic’s liquid-liquid biphasic solvent process, the results were exactly the reverse, a dimer was formed in the absence of phase transfer catalyst, but no dimer was formed in the presence of the phase transfer catalyst. Taylor Tr. 2685-86; RPX 1051a. FF CA 90. It is not surprising that the two systems behave in opposite ways, since they are completely differ- ent systems. Taylor Tr. 2686. FF CA 91. Complainants assert that the small amount of water present in these base/solvent combinations of the ‘035 patent is present as a “surface solvent phase” which complainants attempt to liken to the aqueous App. 302 phase of Abic’s biphasic solvent process. See Taylor Tr. 2698-99. FF CA 92. Complainants introduced no evidence of such a surface solvent phase under the base-solvent con- ditions of the ‘035 patent. See Liotta Tr. 1762-64, and 1779-81. FF CA 93. The “surface solvent phase” is postulated by complainants to be a very thin layer, approximately 100 angstroms (A) thick, of indeterminate composition associated with the solid. Gokel Tr. 707, 1053. FF CA 94. It would take 50,000 of the postulated 100 A surface solvent phases laid one on top of the other to make up the thickness of a pencil line. The surface sol- vent phase would be invisible to the naked eye. Wrighton Tr. 1610. FF CA 95. Even if there were a surface solvent phase, the two processes would still be non-equivalent, for the reasons set forth above. See Taylor Tr. 2698-99. FF CA 96. Professor Wrighton of M.I.T., an expert on surface chemistry, testified that the term “surface solvent phase” was not customarily used in surface chemistry, and had no recognized meaning. Wrighton Tr. 1608. FF CA 97. Before this investigation, Dr. Liotta had never used the term “surface solvent phase” in any pub- lication. Liotta Tr. 1749. FF CA 98. Before this investigation, Dr. Liotta had never called a surface solvent phase a “biphasic solvent system.” It appears that he used that terminology as and analogy to Abic’s biphasic solvent system. Liotta Tr. 1705-06. — U!U!Cd@Y App. 303 FF CA 99. The postulated surface solvent phase film, of indeterminant composition, and only 1/50,000th of the thickness of a pencil line, is not the chemical equivalent of the aqueous phase of the Abic methylene chloride- water biphasic solvent system. Taylor Tr. 2700. FF CA 100. Dr. Liotta performed experiments attempting to prove the presence of a surface solvent phase when water was added to a mixture of potassium carbonate and ethyl acetate. Liotta Tr. 1812-13; CX 636. FF CA 101. Dr. Liotta’s experiments established that the potassium carbonate and water did not form a “sur- face solvent phase”, but formed the well known solid compound potassium carbonate sesquihydrate (K,CO,1.5H,O). Taylor Tr. 2687-2697. FF CA 102. Potassium carbonate sesquihydrate is not a surface solvent phase. Gokel Tr. 1052; Wrighton Tr. 1622; Taylo: Tr. 2688. FF CA 103. Abic repeated Dr. Liotta’s experiments, and tested the products by differential scanning calorime- try (DSC). RX 1702. FF CA 104. Dr. Wrighton testified that the DSC results established that when potassium carbonate was treated with water in ethyl acetate as Dr. Liotta had done, the products were potassium carbonate sesquihydrate, or potassium carbonate sesquihydrate with some residual potassium carbonate. Wrighton Tr. 1602-22. FF CA 105. Dr. Ronald Jenkins of the International Center for Diffraction Data testified as to analyses he had performed on the same material that Dr. Wrighton testi- fied about. Dr. Jenkins concluded that the products were App. 304 potassium carbonate sesquihydrate, or potassium carbo- nate sesquihydrate, with some residual potassium carbo- nate. Jenkins Tr. 2945-2953. 2. Abic Independently Developed Its Own Process - It Did Not Copy the Process of the ‘035 Patent Abic’s Initial Experiments FF CA 106. In 1982 Abic decided to market a calcium channel blocker, and chose diltiazem as its goal. Haber Tr. 1401. FF CA 107. Although thee was no patent on diltiazem in Isreal, Abic sought a license from Tanabe for sale to other countries. Haber Tr. 2402. FF CA 108. Tanabe refused to license Abic, or to supply raw material. Haber Tr. 2402-2403. FF CA 109. As a consequence, Abic began research and development of the overall process for synthesizing diltiazem hydrochloride in December 1982 or very early in 1983. Habert Tr. 2402. FF CA 110. By early 1983, Abic knew of the ‘257 patent and its foreign counterparts, but not of the ‘035 patent or any foreign counterpart of it. Haber Tr. 2403-04. FF CA 111. There are about seven or eight steps in Abic’s procedure to manufacture diltiazem hydro- chloride, and the N-alkylation is the fifth or sixth step. Haber Tr. 2404. FF CA 112. Therefore, it wasn’t until May of 1983 that Abic had the starting material in hand to enable it to begin working on the N-alkylation step. Haber Tr. 2408. App. 305 FF CA 113. Abic’s work on the synthesis of diltiazem hydrochloride, particularly the N-alkylation step, is reflected in Abic’s internal periodic reports for 1982 and 1983. Haber Tr. 2409-10; RX 1007C; RX 1008C; RX 1009C; RX 1010C; RX 1013C; RX 1015C. History of Abic Work on N-Alkylation Date Event May 1983 First N-alkylation NaH/DMSO August 1983 First phase transfer catalyst work KOH + Methylene Chloride + Water + TBABr Fix on methylene chloride as sol- vent E Fix on TEBA as PTC 3 Try NaOH as base September - NovemberNaOH + Methylene 1983 Chloride + Water + TEBA December 1983 Try other than alkali metal bases Mg(OH), Ca(OH), NH,OH CaCO, MEt, Knowledge of EPO ‘035 coun- terpart FORA BA inal Eatbad tng February 1984 Test Ba(OH),-H,O a RPX 1144 eee wewet se ge BE App. 306 FF CA 114. Based on the literature, Abic believed that alkylating the nitrogen on the seven-membered ring would be a straightforward procedure. Haber Tr. 2406-07. FF CA 115. Because Abic needed diltiazem precur- sor for study of the acetylation step, and for further pharmaceutical testing, Abic began alkylating TZP under the conditions already reported in the ‘257 patent and the Kugita publications, sodium hydride and DMSO. Haber Tr. 2411. The Early Development of Abic’s Phase-Transfer Cata- lyzed, Methylene-Chloride-Water Processes FF CA 116. Abic quickly moved away from the sodium hydride-DMSO base-solvent combination by replacing DMSO with DMF. Haber Tr. 2411-12. FF CA 117. Abic then began to look for alkylation processes which did not employ sodium hydride. Haber Tr. 2412. FF CA 118. It was known at that time, the summer of 1983, that one could alkylate carbon atoms (C-alkyla- tion) using either harsh conditions or the milder condi- tions of phase transfer catalysis, in the presence of water, and it was felt that those milder phase transfer catalysis methods could be adapted to the N-alkylation of TZP. Haber Tr. 2412. FF CA 119. Abic believed that alkylating under mil- der conditions would minimize the possibility of side reactions. Haber Tr. 2412-13. FF CA 120. Although there is a large amount of water present in classical phase transfer conditions, Abic App. 307 was not concerned with potential hydrolysis of the TZP. Haber Tr. 2413-14. FF CA 121. Similarly, Abic was not concerned with the potential retro-Michael reactions under phase transfer catalyzed conditions because of the particular structure of the TZP molecule. Haber Tr. 2414-15. FF CA 122. Because Tanabe had not observed O-alkylation at the 3-hydroxyl group of TZP under the harsher conditions of the ‘257 patent, Abic was not con- cerned that such O-alkylation was likely to take place under the milder phase-transfer conditions. Haber Tr. 2415. FF CA 123. Abic was not concerned about the potential for alkylation at the carbonyl oxygen because in the presence of a base, alkylation occurs almost exclu- sively at the nitrogen. Haber Tr. 2416. FF CA 124. Abic was not concerned that DMC would be unstable under Abic’s phase transfer conditions because, as with all alkylating agents, conditions can be ‘modified to minimize instability. Haber Tr. 2416-17. FF CA 125. In August, 1983, Abic tried two phase transfer catalyzed processes, one using potassium hydroxide-methylene chloride-water and the other using potassium hydroxide-toluene-water, both with TEBA bro- mide as the phase transfer catalyst. Haber Tr. 2413. FF CA 126. In August, 1983 Abic was not aware of the ‘035 patent or any of its foreign counterparts. Haber Tr. 2413. FF CA 127. The phase transfer catalyzed reaction in toluene did not work at low temperatures, and at high App. 308 temperatures there was some hydrolysis of the lactam. Haber Tr. 2418-19; RX 1007C. FF CA 128. However, the phase transfer catalyzed reaction in methylene chloride worked well at low tem- perature, so hydrolysis which could occur at high tem- perature was not a problem. Haber Tr. 2418-19; RX 1007C. FF CA 129. Although Abic tried a number of other solvents, none were as good as methylene chloride, so from August, 1983, Abic concentrated on developing the methylene chloride-water phase transfer catalyzed pro- cess. Haber Tr. 2422-23. FF CA 130. Abic also experimented with several phase transfer catalysts, but rapidly settled on TEBA because it gave the best results. Haber Tr. 2423-24. FF CA 131. The product of the alkylation using potassium hydroxide as the base was somewhat impure. Haber Tr. 2423-25. FF CA 132. In August 1983, therefore, Abic tried sodium hydroxide as the base, since it was the most similar base to potassium hydroxide. RX 1008; RPX 1144; Haber Tr. 2424-25. FF CA 133. Sodium hydroxide gave a purer prod- uct, but it still contained about 10% of the unidentified impurity. Haber Tr. 2425. FF CA 134. Abic continued using sodium hydroxide as a base for two to three months to make precursor for use in studying the subsequent acetylation, hydro- chlorination and purification processes. Haber Tr. 2425-26. App. 309 Abic’s Development of Its Phase-Transfer-Catalyzed Barium Hydroxide-Methylene Chloride-Water Process FF CA 135. Eventually Abic discovered that the impurity obtained with potassium hydroxide and sodium hydroxide was “dimer”, which was formed by an alkyla- tion reaction between the solvent methylene chloride and two molecules of TZP. Haber Tr. 2426. FF CA 136. Abic also was aware of British Patent No. 1,236,467, a counterpart of the ‘257 patent, as well as other counterparts, claiming alkylation processes employ- ing alkali metal salts. RX 1010C; RX 1700; Haber Tr. 2432. FF CA 137. In an effort to avoid the formation of dimer, and in an attempt to develop a process using bases other than alkali metal bases which would not infringe the ‘257 foreign counterpart process patents, Abic in December, 1983 began experimenting with ammonium hydroxide, magnesium hydroxide and calcium hydrox- ide. Haber Tr. 2429-31, 2434. FF CA 138. Abic also apparently became aware in December of 1983, for the first time, of the European patent application that was the counterpart of the ’035 patent. Haber Tr. 2429-30. FF CA 139. Abic was not concerned with potential infringement in Europe, because the European applica- tion was restricted to potassium bases, and Abic at the time was using sodium hydroxide. Haber Tr. 2435. FF CA 140. Ammonium hydroxide and magnesium hydroxide bases did not work in the Abic phase transfer catalyzed methylene chloride-water process. Haber Tr. 2431. App. 310 FF CA 141. However, calcium hydroxide in the phase transfer catalyzed methylene chloride-water pro- cess gave high purity product without the formation of the unwanted dimer. Haber Tr. 2431-32. FF CA 142. Neither calcium hydroxide nor calcium carbonate in acetone resulted in N-alkylation. RX 1010C; Haber Tr. 2430-31. FF CA 143. In February 1984, Abic tested barium hydroxide with its methylene chloride-water-TEBA sys- tem and found that barium hydroxide gave good yields, practically no formation of dimer, and fewer side reac- tions with DMC. Haber Tr. 2436. FF CA 144. Abic repeated tests of other bases in the methylene chloride-water system with a phase transfer catalyst, and confirmed that potassium hydroxide and potassium carbonate yielded large amounts (20%-30%) of the dimer under those conditions. Haber Tr. 2436-37; RX 1015C. FF CA 145. For comparative purposes, Abic also tried some of the base-solvent combinations of the EPO 81234 application, but Abic did not pursue those combi- nations because Abic has a policy of not infringing valid patents. Haber Tr. 2438-39; RX 1013C. FF CA 146. Abic tried numerous bases in the meth- ylene chloride-water-TEBA system, including, in chrono- logical order, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium bicarbonate, calcium carbo- nate, magnesium hydroxide, ammonium hydroxide, tri- ethylamine, and alumina, but in every case Abic obtained either low yields of N-alkylated product or high yields of App. 311 the unwanted dimer formation. Haber Tr. 2439-40; RPX-1145. FF CA 147. [C] Haber Tr. 2440, 2443-43; RX 1145, RX 1024C. FF CA 148. [C] Haber Tr. 2443-44; RX 1024C. FF CA 149. [C] Haber Tr. 2445-46; RX 1024C. FF CA 150. [C] Haber Tr. 2447-48; RX 1024C. FF CA 151. [C] Haber Tr. 2449; RX 1024C. FF CA 152. Abic’s process is not a copy of the Tanabe process. Haber Tr. 2452. FF CA 153. Abic’s effort to develop its own process was wholly independent, and was not stimulated by knowledge of the ‘035 patent or of any counterpart. Haber Tr. 2452. FF CA 154. Abic obtained patents on its process in the United States of America, Israel, Japan, Canada and Europe. Haber Tr. 2450. FF CA 155. In the United States, Abic’s patent appli- cation was examined by Examiner Bond, who cited the ‘257 patent and the ‘035 patent as prior art, and con- cluded that Abic’s process was patentable over those references. Haber Tr. 2450; RX 1195 [CX 632]. FF CA 156. Professor Taylor is an organic chemist specializing in organic synthesis, synthetic methodology, and heterocyclic chemistry with emphasis on the devel- opment of new synthetic methods in heterocyclic and medicinal chemistry. Taylor Tr. 2586-87. App. 312 FF CA 157. Professor Taylor has been a professor of organic chemistry at Princeton for 41 years. He is cur- rently the A. Barton Hepburn Professor of Organic Chem- istry at Princeton. Taylor Tr. 2586. FF CA 158. Professor Taylor has published over 400 articles, written three books in the field of heterocyclic chemistry, and is editor of a 60-volume series called Chemistry of Heterocyclic Compounds that is generally rec- ognized as the reference series in heterocyclic com- pounds. He has obtained about 40 patents, and is a past Chairman of the Organic Division of the American Chem- ical Society. Taylor Tr. 2587-89. FF CA 159. Professor Taylor is a consultant to chem- ical companies in the area of process development. Taylor Tr. 2592. FF CA 160. Professor Taylor was awarded the American Chemical Society Award for Creative Work in Synthetic Organic Chemistry, the Gowland Hopkins Medal, the Fifth International Award in Heterocyclic Chemistry, and recently the C.Cope Scholar Award for his work in heterocyclic chemistry. Taylor Tr. 2592. FF CA 161. Professor Taylor was accepted as an expert in the field of organic chemistry, including the subfields of organic chemistry and heterocyclic chemistry, including the seven-membered ring of heterocyclic amide compounds. Taylor Tr. 2593-94. FF CA 162. Professor Mark S. Wrighton is an expert in surface chemistry and in the interpretation of differential scanning calorimetry curves. Wrighton Tr. 1607; RX 1679. i é 0] f+ ie App. 313 FF CA 163. Professor Wrighton is Provost and Pro- fessor of Chemistry at the Massachusetts Institute of Tech- nology. He has been on the MIT faculty since 1972, and has been a full professor since 1977. Wrighton Tr. 1605. FF CA 164. Professor Wrighton’s general area of research involves surface chemistry, photochemistry and electric chemistry. Virtually all of his current research concerns the property of surfaces. Wrighton Tr. 1605-06. FF CA 165. Professor Wrighton has published more than 400 scientific papers. Wrighton Tr. 1605. FF CA 166. Professor Wrighton has published papers which contain the results of differential scanning calorimetry analyses. Wrighton Tr. 1606-07. FF CA 167. Professor Wrighton was accepted as an expert in surface chemistry and in the interpretation of DSC curves. Wrighton Tr. 1607. 3. The Experts Professor Liotta FF CA 168. Dr. Liotta submitted a declaration in this investigation, which admittedly had some inaccuracies. The declaration also confused the claims of the patent with the examples cited in the specification. Liotta Tr. 1710-17. In an effort to show that the yield of Abic’s process is not affected by the use of TEBA, the phase transfer catalyst, he reported incorrect yields (id. at 1713-15). Although Dr. Liotta declared that he had reviewed the prior art relating to the claims, he had only examined the prior art of phase transfer catalysis. Id. at Tr. 1712-13. App. 314 FF CA 169. Dr. Liotta referred to his postulated “surface solvent phase” as a “biphasic solvent system” only for purposes of this litigation; he had never referred to it before in those terms, and did it only to draw a comparison between Abic’s solvent system and examples in the ‘035 patent. Liotta Tr. 1705-06. FF CA 170. Dr. Liotta first concluded that the KOH- DMSO process was not equivalent to the ‘035 processes; then concluded that the KOH-DMSO process was equiva- lent; and then changed his mind again and said that they were not equivalent. Liotta Tr. 1708-09. FF CA 171. Dr. Liotta obtained a patent on his the- ory of the “omega phase,” a “surface solvent phase” which contained a phase transfer catalyst. Id. at 1750. In his patent he distinguished such omega phase systems as patentably distinct from conventional phase transfer cata- lyst processes. Id. at 1750-52. He admitted at his deposi- tion that the Abic process is en example of such a conventional phase transfer catalyst process. Id. at 1753. But he also alleged that his theory of the omega phase was wrong, and that his patent was wrong. Id. at 1755. FF CA 172. Dr. Liotta could not bring himself to admit that TEBA is a phase transfer catalyst, and kept calling it a “quat” and a “surfactant”. Not only did Dr. Taylor testify that it is a phase transfer catalyst but Dr. Baldwin, an expert for complainant, referred to it as a phase transfer catalyst, as did Dr. Kende. CX 635; Liotta Tr. 1703-04; Kende Tr. 1340. FF CA 173. Eventually Dr. Liotta admitted that TEBA is one of the most commonly used phase transfer catalysts (Liotta Tr. 1702), because he had written that in App. 315 his book. RX 3969; Taylor Tr. 2654; RX 3969; Liotta Tr. 1676, 1701; Taylor Tr. 2653. FF CA 174. Dr. Liotta was forced to admit that there is no experimental data supporting his surfactant theory (Liotta Tr. 1676). He further admitted that he had not done any experiments of his own to show that TEBA is not acting as a phase transfer catalyst in the Abic system, and refused to accept Abic’s data which shows increased yield when TEBA is used. Liotta Tr. 1835-37. FF CA 175. For the above reasons, the Administra- tive Law Judge declines to accept the opinions of Dr. Liotta in support of complainants’ positions. Professor Atwood FF CA 176. Dr. Atwood is primarily a single-crystal x-ray crystallographer. Atwood Tr. 3311. FF CA 177. None of Dr. Atwood’s publications is about x-ray powder diffraction. Atwood Tr. 3315, 3260. FF CA 178. Unlike Dr. Jenkins, he hasn’t written text-books about x-ray powder diffraction. Atwood Tr. 3260. FF CA 179. Unlike Dr. Jenkins, Dr. Atwood does not belong to any organization devoted to x-ray powder dif- fraction. Atwood Tr. 3311. FF CA 180. Unlike Dr. Jenkins, Dr. Atwood does not have any patents on x-ray powder diffraction equipment. Atwood Tr. 3317-18, 3260. App. 316 FF CA 181. Unlike Dr. Jenkins, Dr. Atwood does not design his own x-ray powder diffraction equipment. Atwood Tr. 3322-3323. FF CA 182. Because the materials which are of inter- est in this investigation are powders, x-ray powder dif- fraction is the more pertinent expertise. Atwood Tr. 3313-14. Dr. Jenkins’ Qualifications FF CA 183. Dr. Jenkins is currently employed as the principle scientist at the International Center for X-Ray Product Direction Data, a not-for-profit data base organi- zation that archives and supplies about 65,000 powdered refraction patterns. Jenkins Tr. 2936-2937. FF CA 184. Dr. Jenkins has been involved in X-ray powder refraction for about 35 years. Jenkins Tr. 2937. FF CA 185. Dr. Jenkins worked for ESSO Research, Limited for 10 years, the last years spent in X-ray powder refraction analysis. He then worked at North American Phillips, where he was involved with the development of instrumentation and software for X-ray powder refrac- tion. He also was involved in the application of the technique and teaching of the method of powder refrac- tion. Jenkins Tr. 2937-2938. FF CA 186. Dr. Jenkins obtained 6 patents for devel- opmental work at North American Phillips, of which three were on equipment for X-ray powder refraction. Jenkins Tr. 2938 FF CA 187. Dr. Jenkins has published about 80 papers on X-ray powder refraction, and written three as a. x Ss App. 317 books targeted at an audience of material scientists (geol- ogists, mineralogists, chemists). The first book was writ- ten in 1972, and sold about 8,000 copies. The second was an audio course done in connection with the American Chemical Society. The third is coming out in March. Jenkins Tr. 2939 FF CA 188. Dr. Jenkins was accepted as an expert in X-ray powder refraction. Jenkins Tr. 2940. 4. TEBA/Phase Transfer Catalysis FF CA 189. Dr. Liotta does not have any experimen- tal evidence to support his opinion that TEBA in Abic’s process acts as a surfactant. Liotta Tr. 1676. FF CA 190. There is no documentary evidence of record in this investigation that TEBA acts as a surfactant or is regarded as a surfactant by people of ordinary skill in the art. Liotta Tr. 1701. FF CA 191. TEBA is one of the most commonly used phase transfer catalysts in chemistry. Liotta Tr. 1701. FF CA 192. Dr. Baldwin regards TEBA in Abic’s system as a phase transfer catalyst. Liotta Tr. 1704-03. FF CA 193. When TEBA is used in Abic’s system, no dimer is formed, whereas when TEBA is not used, dimer is formed. Liotta Tr. 1801-03. FF CA 194. In example 3 of the ‘035 patent, if meth- ylene chloride is substituted for ethyl acetate, and no TEBA is present, no dimer forms, whereas, if TEBA is present, dimer forms. Liotta Tr. 1803-04. App. 318 FF CA 195. Solid-liquid phase transfer catalysis is different than liquid-liquid phase transfer catalysis. Lio- tta Tr. 1838. C. The Fermion Process FF CF 1. In February 1983, Dr. Lindholm (a Fermion development manager) assigned the project of develop- ing a process for manufacturing diltiazem to Mr. Hyténen (who was then a product development chemist). Hyt6nen Tr. 2992-2993; Lindho!m Tr. 3067. FF CF 2. Dr. Lindholm testified at the hearing in part as an expert witness. Dr. Lindholm was accepted as an expert in chemical process design. Lindholm Tr. 3068-3069. FF CF 3. Fermion’s process development effort involved more than the single N-alkylation step. The Fermion diltiazem synthesis procedure today includes nine processing steps. The development effort com- menced with the early steps in synthesis. Hyt6nen Tr. 2994. FF CF 4. In early September 1983, Mr. Hytdnen began working on the N-alkylation step of the diltiazem process. RPX 2022C, RX 2114C and RX 2115C, identified at Hytdnen Tr. 2994-2995. FF CF 5. The first N-alkylation experiment con- ducted by Mr. Hytdnen was using ‘257 conditions so that he could obtain some N-alkylated TZP and learn how the ‘257 process worked. Hyténen Tr. 2994-2995. cal FE MEL SEE BAR MR SAT ST ARTE. App. 319 FF CF 6. Mr. Hyténen conducted many tests with various base/solvent combinations for about one year. In _ September and October 1984, Fermion experimented with 2-butanone or methy ethyl ketone (MEK), [C] in Septem- ber and October 1984. Hyt6nen Tr. 2995-3004; RX 2114C and RX 2115C. FF CF 7. Mr. Hytdnen read the ‘035 patent to exclude the use of MEK as a solvent. He testified as follows: Q When you reviewed the ‘035 patent, was there anything which suggested the use of MEK? A No, there was not. Why not? —O A They had only mentioned acetone, and they had — not even ketone mentioned. On the other hand, they had determined that the lower alkaline acetate, in the same way they could have determined - described also the lower ketones, if they had known that the reaction can be done with other ketones than acetone. —O Is MEK a homolog of acetone? A Yes. Q Do I understand that despite the facts that MEK is a homolog of acetone, the ‘035 pat- ent still do not suggest the use of MEK to you? * * * THE WITNESS: It did not suggest any other ketone than acetone. App. 320 BY MR. KELLEY: Q Why not? * * * THE WITNESS: I understand that Tanabe’s researchers thought that other ketones cannot be used in this reaction. Hytonen Tr. 3014-3015. FF CF 8. Butanone is a homolog of acetone, 1.e., butanone has an additional methylene group.’ It is not a lower alkyl acetate. Because of the additional methylene group, butanone has different properties from acetone. At the least, it can be said that butanone is more solvable in hydrocarbons than acetone; it is less solvable in water than acetone, it has a higher boiling point than acetone; it is less polar than acetone. Gokel Tr. 635, 637. FF CF 9. Normally, if one of ordinary skill in the art wanted to seek how far one could extend the N-alkyla- tion of ‘035 patent, one would try another ketone besides acetone, possibly 2-butanone (or MEK). By the same token, one of ordinary skill in the art familiar with a range of ketones would read the ‘035 patent, notice the specificity and exclusivity of the claim to the use of acetone, and conclude that other ketones were not 1 A homolog(ue) is defined as: Member of a series of compounds whose structure differs regularly by some radical, e.g., =CH2, from that of its adjacent neighbors in the series. R. Grant & C. Grant, eds. Grants & Hackh’s Chemical Dictionary 287 (1987). : P ; os 4 =. sl ql ) App. 321 included because they did not work. Taylor Tr. 2620-2621, 2784-85. FF CF 10. While at university, Mr. Hytdnen tried alternatives to acetone in an alkylation with potassium carbonate. One of the substitutions he tried was MEK for the acetone. He later had better success with another chemical. Although he tried these substitutions, Mr. Hytonen believes that many researchers (including his professor) think that certain alkylation reactions are spec- ific to acetone. Hytdnen Tr. 3015-3016, 3045-3046. FF CF 11. Mr. Hytonen had experience with MEK at Fermion before starting his diltiazem development work. Hyt6nen Tr. 3016. FF CF 12. Fermion conducts pilot tests on a scale that is smaller than industrial scale yet larger than labora- tory scale, using instruments similar to those used for commercial manufacturing. Hytdnen Tr. 3005. FF CF 13. In October 1984, Fermion conducted a pilot plant test on the N-alkylation process using potassium carbonate/MEK as the base/solvent combina- tion. This pilot plant test was a failure. RPX 2022C; Hyténen Tr. 3004-3005. FF CF 14. After the October pilot plant failure with MEK, Fermion conducted additional experiments with a mixture of [C] as the solvent and [C] as the base; [C] and either [C], with and without [C]; [C] and either [C]; [C] with either [C]; [C] with [C]; [C] with [C]; and [C] with [C]. RX 2114C and RX 2115C (experiments B2449, B2454, B3367(a) and (b), B3371(a) and (b), B3372(a) and (b), B1048, B1049 and B3370). App. 322 FF CF 15. In 1985 Fermion conducted additional testing with the combination of [C] as the base/solvent combination for the N-alkylation step. RX 2114C and RX 2115C (experiments B1054, B3275(a) and (b), B1058(a) and (b), B3376(a), (b), (c) and (d), B1061, B1062(a), (b) and (c), B1064 and B1065(a), (b), (c) and (d)). FF CF 16. Mr. Hyténen conducted further experi- ments in 1985 with the MEK and potassium carbonate process to determine why it had failed in the pilot plant. Hyténen Tr. 3007. FF CF 17. Fermion also developed an alternative process using potassium carbonate/ethyl acetate, and produced diltiazem for commercial use. Hyténen Tr. 3005-3007. FF CF 18. Fermion found the potassium carbonate/ ethyl acetate combination to be unreliable on a commer- cial scale because potassium carbonate had to be added twice and one had to follow the reaction to completion, and to add DMC-HC1 in different amounts based upon an analysis of the reaction. These procedures required the presence of a skilled chemist. Hyténen Tr. 3006-3007, 3047-3048. FF CF 19. The operators of Fermion’s process are not chemists, or laboratory technicians. They are individuals without formal chemical education. The skill of the oper- ators is taken into account when developing a commercial process. Lindholm Tr. 3089-3090. FF CF 20. The Finnish counterpart of the ‘035 patent was not in effect during the time period that Fermion UNS ETT ttt App. 323 used the potassium carbonate/ethyl acetate combination. Hytonen Tr. 3007, 3047-48. FF CF 21. In late 1985, Mr. Hytodnen thought he had solved the problem with the MEK and potassium carbo- nate system, and conducted a second pilot plant test. Hyténen Tr. 3007. FF CF 22. The second MEK and potassium carbo- nate pilot plant test was also a failure. Hytonen Tr. 3007. FF CF 23. Fermion conducted further experiments with the MEK and potassium carbonate process, and conducted a third pilot plant test in January 1986 which was a success. Hytdnen Tr. 3008. FF CF 24. In the accused Fermion process, the N-alkylation step uses TZP, DMC-HCI, K,CO,, butanone (or “MEK”) and water. Gokel Tr. 624; Cx 192¢. FF CF 25. Fermion learned that the amount of [C] Present in the MEK and potassium carbonate process was critical. Mr. Hytodnen testified to this point as follows: 4 ‘ f a li ad on ees Te yes os " 2 7 - - . sa Sa . i patna 4 nai ane pitas ~ ae oF ‘ le Si a a as is i rg -: ae ; Q Did you determine what the cause of the problem was with your MEK process? ) ; A Yes, we found out. What did you determine caused the failure on the first pilot run? A In the first pilot experiment, we had too much [C] in the reaction mixture. App. 324 Q Did you determine what the problem was in the second experiment? A_ Yes. It had too little [C]. Hytoénen Tr. 3008. FF CF 26. The ‘035 patent contains no teachings that the amount of [C] in the process is critical. For example, complainants’ expert testified as follows: Q Nowhere in the ‘035 patent is there any explicit teaching that [C] is critical to the success of the reaction, is there? A I think that’s a fair statement. Kende Tr. 1428. FF CF 27. The ‘035 patent provided no guidance to Fermion and Mr. Hyténen in solving the problems encountered with the MEK and potassium carbonate pro- cess. In this regard, Mr. Hyt6nen testified as follows: Q You testified a few minutes ago that the ‘035 patent did not provide any help in develop- ing the present Fermion process. Do you recall that? A That is true. Q Why didn’t it provide you with any help? A For instance, there was no mention about — they did not mention the critical nature of [C]. On the contrary, they had examples in which there were reactions that had no [C] in them. > oi c See ee ee ee ee ee BRE Siates 6 -e re tee ses Re hte Sy eee wiras wigs a Sas P a Aad ata ie. seks Sebamed ete Ret te hey cig A hoy *s ¥. App. 325 Q Did the ’035 patent provide you with any help in determining the cause of the failures in the first two pilot plant runs with MEK? A No, it did not. Hytdnen Tr. 3013-3014. FF CF 28. Fermion learned that the MEK and potassium carbonate process did not work with either too much or too little added [C]. Hytdnen Tr. 3008. FF CF 29. After Fermion’s success with the MEK and potassium carbonate N-alkylation process in the pilot plant, Mr. Hytonen began to experiment with making the Process less sensitive to the amount of [C] present, and therefore “more reliable.” Hyténen Tr. 3009-3010. FF CF 30. Mr. Hyt6nen discovered that by reducing the ratio of [C], it was possible to reduce the sensitivity of the MEK and potassium carbonate to the amount of [C] present. Hytdnen Tr. 3010. FF CF 31. The present Fermion process has [C] added to the MEK. Hytédnen Tr. 3008-3009, Lindholm Tr. 3090. FF CF 32. Fermion discovered that its present process is extremely reliable, always proceeding to completion, i.e., all the TZP is consumed. Hyténen Tr. 3011; Lindholm Tr. 3075. FF CF 33. The ’035 patent does not provide any teaching that the [C] [C] will have any effect on the reaction. Mr. Hyténen testified as follows: Q During the time that you were improving the MEK process, did the ’035 patent pro- vide any help? App. 326 A No, it did not. Q Does the ‘035 patent teach a chemist what the effect of varying the relative amount of [C] will have on the process? JUDGE HARRIS:You better ask that again. BY MR. KELLY: Q Let me break it into pieces and try to ask that again. Is there any description or teach- ing in the ‘035 patent that you will get a more reliable process by reducing the [C] [C]? A No. Tr. 3011-3012. FF CF 34. The ‘035 patent provided no guidance to Fermion in reducing the ratio of iC) . Tr. 3011. FF CF 35. Fermion’s experts, Dr. Lindholm and Pro- fessor Magnus, testified that Fermion’s process works in a different way than the process of the ‘035 patent claims. Lindholm Tr. 3075, Magnus Tr. 3178. FE CF 36. Fermion conducted over [C] N-alkylation experiments between October 1983 and early 1986 in developing its process. Lindholm Tr. 3101; RX 2114C. FF CF 37. In 1981, Tanabe attempted to use MEK as the solvent in the N-alkylation of TZP. RX 2047C, RX 2046C, RX 2094C and RX 3494C. FF CF 38. In 1981, Tanabe tested and rejected MEK as the solvent for the N-alkylation of TZP. RX 2047C, RX 2046C, RX 2094C, RX 3494C. App. 327 FF CF 39. In 1981, Tanabe’s experiments with MEK either resulted in no product or impure product. RX 2047C, RX 2046C, RX 2094C and RX 3494C. FF CF 40. Fermion introduced evidence that a process which produced impure product would be considered a failure. See Hyténen Tr. 2999. FF CF 41. The adverse consequence of too little or too much [C] in the ‘035 patent’s potassium carbonate /ethyl acetate process was experienced by Tanabe in its commer- cial process, and is demonstrated by Tanabe’s later 1991 testing. RX 2237C; Nakao Tr. 384, 420. FF CF 42. Complainants’ expert, Professor Gokel, testified that the way in which the process of the ‘035 patent claims worked was through a so-called “surface solvent phase” or a boundary phase. Gokel Tr. 941-942, 982. FF CF 43. Complainants offered no evidence that a surface solvent phase was present in the Fermion process. The only tests offered by complainants were not N-alkylations and lacked both the TZP and DMC.HC1. CX 636, CX 680C and CX 681C. FF CF 44. Dr. Lindholm testified as follows: Q Have you reviewed any experiments which were conducted by Professor Gokel and Lio- tta in connection with this litigation? A Yes, I have. Q In Your opinion are those experiments rele- vant in any way to the matters involved in this litigation? App. 328 > They are not in my opinion. Why not? @) A_ In these experiments there were no starting material, no reagent that’s the TZP or DMC. So in my opinion these experiments does not show anything about what happens when you do the real reaction. Q Do you recall the testimony by Dr. Gokel that in his experiments he saw or observed a clump of potassium carbonate forming in the experiments with MEK? > Yes, I remember. Q Based upon your experience in the Fermion process, does the potassium carbonate form a hard clump upon the addition of water? A_ No, it does not. We have not seen the thing occur either in laboratory or on the indus- trial scale. Dr. Lindholm Tr. 3095-3096. FF CF 45. In all of its experiments and commercial experience, Fermion has never observed the results obtained by complainants in complainants’ tests in which neither TZP nor DMC.HC1 were present. Lindholm Tr. 3095-3096. FF CF 46. Fermion’s expert, Dr. Lindholm, testified that complainants’ testing provides no basis for conclud- ing that the Fermion process works in the same way as the process of the ‘035 patent. Lindholm Tr. 3095-3096. FF CF 47. Fermion duplicated examples found in the ‘035 patent, and compared the results obtained with the is erent App. 329 ‘035 patent solvents to those obtained when MEK was used as the solvent. CX 394 FF CF 48. Dr. Lindholm, one of Fermion’s experts, concluded that based on these experiments, MEK was not equivalent to the ’035 patent claim solvents in the N-alkylation of TZP. Dr. Lindholm testified as follows: Q What is it about Cx 394 that further sup- ports your opinion? A This CX 394 is a test series we run in the laboratory using the ‘035 patent examples, just as they are described in the patent. And for comparison, these examples, we substi- tuted the solvent mentioned in the examples with MEK. And if we look at page 3, we see here a comparison of patent example 2 using either acetone or MEK. From these experiments, we see that these two reactions run rather Similarly. The butanone is a little bit faster than acetone. If we then go two Pages forward and look at patent Example 4, this is now a dry system. We can see here that the acetone process works. After nine hours, there is really nearly no starting material left in the reac- tion. But on the other hand, we can see that using MEK, we have Virtually no reaction. Taking these two examples together, as we should do, if these two solvents were equiv- alent, we would get the same results. We would even have a slightly faster reaction in MEK, as the boiling poin, is higher. But as we do not have that, this means that these solvents can’t be equivalent. If we turn one page back, we have patent Example 3. App. 330 This is with ethyl acetate. From the numbers here, we can see that the reaction grows nicely in ethyl acetate. But on the other hand, we can see that using MEK, the reaction proceeds, but to a very small extent. After six hours reaction time, we have still roughly about 60 percent of the starting material left. This indicates that or at least shows that MEK and ethyl acetate are not equivalent. Q When you said the reaction went rather nicely in ethyl acetate, what did you mean? A I mean that the consumption of starting material was nearly complete. Lindholm Tr. 3077-3078. FF CF 49. Dr. Lindholm testified, that with the excep- tion of ‘035 patent example 2, in all cases the substitution of MEK for the solvent of the patent example provided substantially different results. Lindholm Tr. 3077-3078. FF CF 50. In patent example 3, the use of ground potassium carbonate in combination with ethyl acetate resulted in an N-alkylation reaction which proceeded to completion as described in the patent, i.e., within six hours. In contrast, with MEK and ground potassium car- bonate, after six hours roughly 60% of the starting TZP remained. Lindholm Tr. 3077-3078, Hyténen Tr. 3138-3139. FF CF 51. In patent example 4, Fermion was able to duplicate the results reported for acetone and powdery potassium carbonate, essentially complete TZP conver- sion within nine hours. However, when MEK was substi- tuted for the acetone, the reaction did not proceed at all, App. 331 essentially all TZP remained unreacted. Hyténen Tr. 3077-3078. FF CF 52. Patent example 5 did not Proceed as writ- ten. CX 394. N-alkylation which Proceeded to completion in two hours, while with methyl acetate the reactior took thirty hours. CX 394. FF CF 54. Fermion chose to use patent example 3 as exemplary of the ‘035 patent claim process because this was the sole ‘035 patent example repeated by complain- ants’ expert, Professor Baldwin. Lindholm Tr 3086. FF CF 55. Subsequently, Fermion learned that patent example [C] closely resembles [C] process. Lindholm Tr. 3087. FF CF 56. Complainants had testing conducted by Professors Baldwin, Gokel and Liotta. Cx 635, CX 636 Cx 680C and CX 681C. FF CF 57 Professor Baldwin testified that he could not have predicted the results he obtained with MEK, 2-butanone: Q Is there any way before this experiment you could have predicted this result? A What result? App. 332 Q That increasing [C] [with 2-butanone] would increase yield. A In the particular butanone system, no, I couldn’t have predicted that. RX 2238C. FF CF 58. The only tests offered by complainants concerning the so-called “surface solvent phase” were not N-alkylations and lacked both the TZP and DMC.HC1. CX 636, CX 680C and CX 681C; Lindholm Tr. 3095-3096. FF CF 59. Professor Baldwin’s tests demonstrate that the mere substitution of MEK for the ‘035 patent’s sol- vents did not result in an N-alkylation process which achieved yields and/or productivity comparable to that achieved by the Fermion commercial process. RPX 2004C- A. Lindholm Tr. 3092-3093. IV. INVALIDITY - CLAIM 1 OF THE ‘035 PATENT IS INVALID UNDER 35 U.S.C. § 103 A. Background FF D 1. During the United States prosecution of the ‘035 patent, Tanabe submitted to the PTO a Statement of Art in which Tanabe described its alleged invention as involving only certain specified base/solvent combina- tions, specifically stating that the “Applicants’ invention” was N-alkylation: “[In] the presence of potassium hydroxide in acetone or potassium carbonate in acetone, SY MEE MEE pect SAG OPA As SOLE OEE eI eT I A A Re a Te, ok Re Sey A EE ee en a an a ee App. 333 lower alkyl acetate, water-acetone, or water- lower alkyl acetate.” CX 2, paper 4 at 2-3. FF D 2. In the Statement of Art Tanabe distinguished its alleged invention over the prior art by arguing that the invention produced yields of no less than 87% as opposed to 65-70% obtained with prior art processes.2 XC 2, paper 4 at 2-3. FF D 3. On December 21, 1981, Tanabe filed an appli- cation in Europe corresponding to the ‘035 patent appli- cation. RX 3325. On June 1, 1984, Tanabe’s EPO application was rejected over the ’967 and ‘257 patents. RX 3325. FF D 4. The ‘967 patent taught the use of “alkali metal hydroxides” in a variety of solvents including toluene to attach DMC to a benzothiazepinone differing from TZP by only a single R group at the three Position of the seven-membered ring. Potassium hydroxide and sodium hydroxide are examples of alkali metal hydrox- ides. RX 1103; Gokel, Tr. 870-82, 877-78, 881; Taber, Tr. 2159-60. In response to that rejection, on October 1, 1984, Tanabe submitted a twelve page document urging that the application be approved over the ‘257 and ’967 pat- ents. Included in this response were five pages of attor- ney argument and what Tanabe referred to as a “Comparative Test Report” which, Tanabe claimed, dem- onstrated the patentability of its claimed process over * Tanabe did not disclose Krapcho’s U.S. Patent 3,075,967 (the “ ‘967 patent”) to the U.S. Patent and Trademark Office (“PTO”) during the original prosecution of the ‘035 patent. CX 2. App. 334 prior art disclosures that used, inter alia, sodium carbo- nate and toluene. RX 3929C. Specifically, Tanabe repre- sented that the Comparative Test Report “[S]hows that the specific combination of bases and solvents, i.e., potassium hydroxide in acetone or potassium carbonate a solvent selected from acetone, lower alkyl acetate, a mixture of ace- tone and water and a mixture of lower alkyl acetate and water, leads to surprising results of the method according to the invention.” RX 3929C at 705 (emphasis added). FF D 5. Tanabe’s submission analyzed the experimen- tal data reflected in the Comparative Test Report and explained as follows to the EPO: For example, when the condensation reaction was carried out by the use of sodium hydroxide or sodium carbonate as the base, the yield of the product was less than 10% even if acetone was used as the solvent. Moreover, when sodium amide or sodium hydride was used as the base, the yield of the product was not more than 12.4% in the case where toluene or dioxane was used as the solvent. Furthermore, even if potassium hydroxide or potassium carbonate was used as the base, the yield of the product was less than 30% in the case where dioxane, toluene or meth- anol was used. (RX 3929C at 706.) Tanabe further explained that: [judging from the facts (i) that the refer- ences cited by the Examining Division teach neither the use of potassium carbonate as the base nor the use of the specific base- solvent combinations to be employed in the method of the present invention; (ii) that, App. 335 when the condensation reaction was carried out by the use of sodium hydroxide or sodium carbonate as the base, the yield of the product was less than 10%; and (iii) that, even if potassium hydroxide or potassium carbonate was used as the base, the yield of the product was less than 30% in the case where dioxane, toluene or methanol was used, it is obvious that the above-mentioned advantageous features of the present inven- tion have never been taught nor suggested in the references cited by the Examining Division. Thus, the replacement of sodium hydride and dimethylsulfoxide by the speci- fic base-solvent combinations of the present invention is unobvious over the cited refer- ences. Due to the superior and surprising results obtained by the method of the invention, the present application possesses level of inventiveness necessary for its patentability. RX 3929C (emphasis added). FF D 6. Tanabe made identical arguments to numerous other patent offices, including those of Israel and Finland. 3338C; 3233C. FF D 7. Reexamination of the ‘035 patent was requested by Respondent Abic, and supported by a decla- ration of Dr. Taylor. RX 1085 (See RX 2193). FF D 8. The examiner initially agreed with Dr. Taylor, and rejected all the claims of the ’035 patent. RX 1603 (RX 2193, RX 2204). The bases for the rejection included: (a) The ’257 patent showed a conventional method of N-alkylation; App. 336 (b) Pachter and subsequent references showed the “widely used” N-alkylation of N-aryl amides with the same bases (potassium hydrox- ide, potassium carbonate) and the same solvent (acetone) as the ‘035 patent; (c) British ‘119 and Nagarajan showed dimet- hylaminoethylation (i.e., reaction with DMC) of dibenzoxazepinones; (d) Johnstone “further illustrat[ed] the value of the Pachter et al [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40386013_1344%3A2. Public record. Not legal advice.