Thus, Dr. Expert2 was unable to produce or pure” “pure” “substantially crystalline Form B tapentadol HCl in accordance with the procedures set forth in Example 24/25 of Even when varying the addition time of TMSCl/water EP 475. in accordance with common practice, Dr. Expert2 always produced at least some tapentadol HCl Form A. (Ex. XX. ¶ XX.) Next, Dr. Expert2 attempted to produce pure Form B tapentadol HCl using other alternative crystallization techniques described in For instance, EP 475. examples in describe the preparation of actives via the free base solution’s EP 475 a TMSCl/water mixture as opposed adding TMSCl/water to the free addition to – base/2-butanone solution as described in Example 24/25. (See, Ex. 1006 at 7 e.g., (Example 1).) In accordance with those general procedures, Dr. Expert2 carried out the following crystallization procedures: Dr. Expert2 dissolved the tapentadol free base (30 mg, 0.16 mmol) in (0.45 mL) and added this solution to a mixture of TMSCl (22.7 µL, 0.180 mmol) and water (3.3 µL). (Ex. XX. ¶ XX.) After about 18 hours at 5 °C, Dr. Expert2 collected the precipitate, rinsed it with 2-butanone, and dried it in air to obtain tapentadol hydrochloride (XX mg, XX % yield). (Ex. XX. ¶ XX.) Dr. Expert conducted an XRPD analysis of the resulting tapentadol HCl using Cu Kα radiation. (Ex. XX. ¶ XX.) The XRPD pattern
Thus, Dr. Expert2 was unable to produce “pure” or “substantially pure” crystalline Form B tapentadol HCl in accordance with the procedures set forth in Example 24/25 of EP 475. Even when varying the addition time of TMSCl/water in accordance with common practice, Dr. Expert2 always produced at least some tapentadol HCl Form A. (Ex. XX. ¶ XX.) Next, Dr. Expert2 attempted to produce pure Form B tapentadol HCl using other alternative crystallization techniques described in EP 475. For instance, examples in EP 475 describe the preparation of actives via the free base solution’s addition to a TMSCl/water mixture – as opposed adding TMSCl/water to the free base/2-butanone solution as described in Example 24/25. (See, e.g., Ex. 1006 at 7 (Example 1).) In accordance with those general procedures, Dr. Expert2 carried out the following crystallization procedures: Dr. Expert2 dissolved the tapentadol free base (30 mg, 0.16 mmol) in (0.45 mL) and added this solution to a mixture of TMSCl (22.7 µL, 0.180 mmol) and water (3.3 µL). (Ex. XX. ¶ XX.) After about 18 hours at 5 °C, Dr. Expert2 collected the precipitate, rinsed it with 2-butanone, and dried it in air to obtain tapentadol hydrochloride (XX mg, XX % yield). (Ex. XX. ¶ XX.) Dr. Expert conducted an XRPD analysis of the resulting tapentadol HCl using Cu Kα radiation. (Ex. XX. ¶ XX.) The XRPD pattern
DepoMed-Nucynta-7994364-IPR-draft.docx