UNITED STATES PATENT AND TRADEMARK OFFICE
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`COALITION FOR AFFORDABLE DRUGS VI LLC
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`COALITION FOR AFFORDABLE DRUGS VI LLC
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`PETITIONER
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`V.
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`GRÜNENTHAL GMBH
`GRUNENTHAL GMBH
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`PATENT OWNER
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`___________________
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`CASE NO.: UNASSIGNED
`PATENT NO. 7,994,364
`PATENT NO. 7,994,364
`FILED: DECEMBER 10, 2009
`FILED: DECEMBER 10, 2009
`ISSUED: AUGUST 9, 2011
`ISSUED: AUGUST 9, 2011
`INVENTORS: ANDREAS FISCHER, ET AL.
`INVENTORS: ANDREAS FISCHER, ET AL.
`
`TITLE: CRYSTALLINE FORMS OF (-)-(1R,2R)-3-(3-DIMETHYLAMINO-1-
`TITLE: CRYSTALLINE FORMS OF (—)—(1R,2R)—3—(3—DIMETHYLAMINO-1-
`ETHYL-2-METHYLPROPYL)-PHENOL HYDROCHLORIDE
`ETHYL-2—METHYLPROPYL)-PHENOL HYDROCHLORIDE
`___________________
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`PETITIONER
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`V.
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`PATENT OWNER
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`CASE NO.: UNASSIGNED
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`DECLARATION OF RON BIHOVSKY, PH. D
`DECLARATION OF RON BIHOVSKY, PH. D
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`I, Ron Bihovsky, declare as follows:
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`I.
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`PROFESSIONAL BACKGROUND
`1.
`I make this declaration based on my personal knowledge,
`consideration of the materials I discuss herein, and my expert opinions.
`2.
`I am an organic chemistry and medicinal chemistry expert. I have
`served as an expert in numerous biotechnology and pharmaceutical cases, many
`requiring laboratory investigation. In my laboratory, I also synthesize organic
`compounds for the pharmaceutical, biotechnology, and agrochemical industries. I
`have more than 35 years of academic and industrial chemistry experience. My
`research has resulted in 50 publications in refereed journals, 15 granted U.S.
`Patents, and numerous foreign patents.
`3.
`I obtained my Bachelor of Science degree in chemistry from the State
`University of New York, Stony Brook in 1970. I earned a Ph.D. in organic
`chemistry from the University of California, Berkeley, and was a National Institute
`of Health postdoctoral fellow at the University of Wisconsin, Madison. My
`research included synthesis and structure elucidation of biologically-active
`molecules. Subsequently, I worked as a professor of organic chemistry at Stony
`Brook University, where I preformed organic chemistry research, synthesized
`natural products, supervised graduate students and postdoctoral fellows, and taught
`classes including graduate level organic synthesis.
`4.
`I then worked in the pharmaceutical industry as a medicinal chemist
`in roles of increasing responsibility at Berlex Laboratories and Cephalon Inc.
`where I synthesized numerous classes of small molecules ranging from
`heterocycles to peptide mimetics as potential pharmaceuticals.
`5.
`In 2001, I founded Key Synthesis LLC, an organic chemistry
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`laboratory located in the Philadelphia, Pennsylvania metropolitan area. Key
`Synthesis is fully equipped to conduct custom organic synthesis, contract
`medicinal chemistry research and process research for the pharmaceutical and
`biotechnology industries. I am currently the president of Key Synthesis LLC. I
`also utilize my laboratory to conduct experiments to investigate the validity of
`pharmaceutical patent claims.
`6. My qualifications are further detailed in my curriculum vitae, a copy
`of which is attached hereto as Exhibit 1015.
`7.
`I have been asked to provide my opinions and views based upon my
`review and analysis of the literature cited below, as well as my education, training,
`and experience in organic synthesis.
`II.
`FEES
`8.
`I have no financial interest in the outcome of this litigation. I invoice
`at a rate of $300 per hour for consulting and $350 per hour plus expenses for
`laboratory work or testimony.
`III. MATERIALS REVIEWED
`9.
`I have reviewed certain patents pertaining to tapentadol hydrochloride
`and crystalline forms thereof: U.S. Patent No. 7,994,364 (“the ’364 patent”)
`(Ex. 1001); U.S. Patent No. 6,344,558 (“the ‘558 patent”) (Ex. 1018); EP 0 693
`475 (“the ’475 patent”) (Ex. 1006); WO 03/035053 (Ex. 1009); and EP 1612203
`(Ex. 1022).
`IV. LEVEL OF ORDINARY SKILL IN THE ART
`10. A person of ordinary skill in the art (“POSA”) in connection with the
`’364 patent would typically have a Ph.D. in fields relevant to small molecule drug
`development, such as biochemistry, medicinal chemistry, organic chemistry, or the
`equivalent, or a bachelor’s degree in the same field(s) with four to six years of
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`practical experience.
`V.
`TAPENTADOL HYDROCHLORIDE SYNTHESIS
`11.
`I was asked in May 2015, to prepare Form B of tapentadol
`hydrochloride according to the examples in the ’364 and ’475 patents. The ’364
`patent describes Form A (Examples 1 - 6) and Form B (Examples 7 – 9 and 16).
`The ’364 patent (Examples 1 – 7) states that tapentadol hydrochloride was
`prepared according to Example 25 (which references Examples 1, 2, and 24) of the
`’475 patent. The examples in the ’475 and ’364 patents have also been published in
`U.S. Patent No. 6,344,558 and EP 1612203, respectively.
`12. Specifically, according to the ’364 patent (Examples 1 – 4 and 6),
`Form A of tapentadol hydrochloride was prepared by recrystallization from various
`solvents or (Example 5) by cooling to - 40 °C.
`13. Additionally, according to the ’364 patent, Form B of tapentadol
`hydrochloride was prepared in Example 7 by treating a solution of tapentadol
`dissolved in 2-butanone with trimethylchlorosilane (TMSCl) and water. Example
`7 of the ’364 patent states that Form B was prepared according to Example 25 of
`the ’475 patent, which in turn refers to Example 24 of the ’475 patent.
`14.
`I note that the ’364 patent provides no evidence that the crystalline
`solid obtained from the Example 7 procedure produced the XRPD pattern in Figure
`4 of the ’364 patent which is attributed to the Form B polymorph. Furthermore, the
`’364 patent contains no indication of how the polymorph identified as Form B in
`Figure 4 was prepared. Example 7 of the ‘364 patent is the only example for
`preparation of Form B which follows the ’475 patent’s method for obtaining
`tapentadol HCl, but it does not explicitly link the ‘364 patent’s Figure 4 XRPD
`pattern to Example 7 and the synthetic procedure of the ’475 patent. At best,
`Example 7 confirms that “Form B … was generated as proven by X-ray powder
`diffraction and by RAMAN microscopic analysis,” without any indication of yield
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`or percent purity. Thus, a POSA would not reasonably conclude that the Form B
`XRPD pattern of the ’364 patent’s Figure 4 was produced using the ’364 patent’s
`procedure of Example 7, as derived from the ’475 patent’s Example 25. In
`contrast, as described below, when I repeated the procedure described in Example
`7, I obtained Form A or a mixture of Form A and Form B.
`15. Further, according to the ’364 patent, Examples 8, 9, and 16, Form B
`of tapentadol hydrochloride was also prepared by heating milled or cryoground
`(cryogrinded) Form A of tapentadol hydrochloride.
`16. The ratios of Form A to Form B, summarized in this declaration, were
`determined by Dr. William Mayo and his colleagues at H&M Analytical Services.
`The reported ratios of A:B were determined by the ratios of the strong peak areas
`at 18.045° and 18.240° respectively.
`17.
`In the experiments which follow, my notebook reference number is
`included in parentheses.
`A. Obtaining tapentadol hydrochloride (Form A) for use in synthesizing
`Form B
`18.
`I obtained tapentadol hydrochloride (Form A) from Dr. William Mayo
`at H&M Analytical Services. This sample was supplied by MedChem Express,
`catalog number HY-70042 / CY-0879, batch number 03046. Documentation
`supplied with the sample included NMR and mass spectra which are consistent
`with the structure. Purity and enantiomeric excess were stated to be greater than
`99%. I also obtained the NMR of the sample and confirmed that it was consistent
`with the NMR provided by MedChem Express. I observed that the sample was a
`fine white solid, melting at 204–207 °C. Dr. Mayo obtained the X-Ray Diffraction
`(“XRD”) pattern from this sample and informed me that the X-ray powder pattern
`was consistent with Form A of tapentadol hydrochloride. I stored the sample at 5
`°C. (No. 10-194-1)
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`B. Attempts to Prepare Tapentadol hydrochloride (Form B)
`19.
`I attempted to prepare Form B of tapentadol hydrochloride by
`utilizing the procedures specified in the ’364 and ’475 patents.
`1.
`Heating experiments
`20. According to the ‘364 patent, Examples 8, 9 and 16, Form B of
`tapentadol hydrochloride can be prepared by heating milled or cryoground Form A
`of tapentadol hydrochloride. Initially, I investigated whether heating Form A
`which had not been milled or cryoground would produce Form B.
`21.
`I heated tapentadol hydrochloride Form A (34 mg) to 50 °C for 24
`hours under a nitrogen atmosphere in a capped vial according to Example 16 of the
`‘364 patent which states that Form A is converted to Form B at 40 to 50 °C. A
`POSA would utilize a nitrogen atmosphere to exclude oxygen which could cause
`the tapentadol hydrochloride decompose. The X-ray powder pattern indicated a
`100:0 ratio of Form A to Form B. (10-194-2)
`22. Next, I heated tapentadol hydrochloride Form A (41 mg) to 130 °C for
`80 minutes under a nitrogen atmosphere in a capped vial, as in Example 8 of the
`’364 patent. The X-ray powder pattern obtained by Dr. Mayo indicated a 100:0
`ratio of Form A to Form B. (10-194-3)
`23. Then, I heated tapentadol hydrochloride Form A (35 mg) to 215 °C
`for 1 minute under a nitrogen atmosphere in a capped vial. I performed this
`experiment in order to determine whether tapentadol hydrochloride would melt and
`then form new crystals of Form B. The sample melted. Off-white crystals formed
`when I allowed the sample to cool to 70 °C over 30 minutes, and then to room
`temperature. The X-ray powder pattern obtained by Dr. Mayo indicated a 93:7
`ratio of Form A to Form B. (10-194-5)
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`2.
`Heating experiments on cryomilled sample
`24. According to the ’364 patent, Examples 8, 9 and 16, Form B of
`tapentadol hydrochloride can be prepared by heating milled or cryoground Form A
`of tapentadol hydrochloride. Therefore, I investigated whether heating Form A
`which had been cryoground would produce Form B.
`25. Dr. Mayo cryomilled tapentadol hydrochloride Form A for one hour
`at -78 °C as in Example 9 of the ’364 patent. The X-ray powder pattern obtained
`by Dr. Mayo indicated a 100:0 ratio of Form A to Form B. (10-197-1)
`26.
`I then heated the cryomilled tapentadol hydrochloride Form A (30
`mg) to 65 °C for 24 hours under a nitrogen atmosphere in a capped vial according
`to Example 16 of the ’364 patent which states that Form A is converted to Form B
`at 40 to 50 °C. The X-ray powder pattern obtained by Dr. Mayo indicated a 52:48
`ratio of Form A to Form B. (10-197-4)
`27.
`I heated the cryomilled tapentadol hydrochloride Form A (30 mg) to
`130 °C for 80 minutes under a nitrogen atmosphere in a capped vial, as in Example
`8 of the ’364 patent. The X-ray powder pattern obtained by Dr. Mayo indicated a
`53:47 ratio of Form A to Form B. (10-197-2)
`28.
`I heated the cryomilled tapentadol hydrochloride Form A (30 mg) to
`214 °C for 5 minutes under a nitrogen atmosphere in a capped vial. I performed
`this experiment in order to determine whether tapentadol hydrochloride would melt
`and then form new crystals of Form B. The sample melted. Off-white crystals
`formed when I allowed the sample to cool to 70 °C over 1 hour, and then to room
`temperature. The X-ray powder pattern obtained by Dr. Mayo indicated a 75:25
`ratio of Form A to Form B. (10-197-3)
`3.
`Preparation of tapentadol free base
`29. Examples 24 and 25 of the ’475 patent describe the synthesis of the
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`free base of tapendatol and its conversion into tapentadol hydrochloride.
`Specifically, the hydrobromide salt of tapentadol was converted into the free base
`of tapendatol by treatment with a solution of sodium bicarbonate (also known as
`sodium hydrogen carbonate) followed by extraction into dichloromethane.
`Therefore, I utilized the same procedure to prepare the free base of tapendatol from
`tapentadol hydrochloride.
`30.
`I followed the procedure specified in Examples 24 and 25 of the ’475
`patent (also as directed by Example 7 of the ’364 patent). In doing so, I mixed
`tapentadol hydrochloride Form A (300 mg) with freshly prepared saturated
`aqueous sodium bicarbonate (4.5 mL) then extracted this mixture three times with
`3 mL of dichloromethane. I dried the combined dichloromethane extracts over
`sodium sulfate, filtered, and evaporated the solvent in vacuo to give the free base
`of tapentadol (252 mg, 98% yield) as a colorless oil which crystallized after
`storage at 5 °C. These crystals melted at 86 – 88 °C. I prepared two other batches
`of the free base in a similar manner. (10-195-1).
`31.
`I note that the polymorphic crystalline form of tapentadol HCl
`produced in Example 25 of the ’475 patent, via the synthetic procedure set forth in
`Example 24, will be determined by the final step of the procedure. In particular, the
`only step in the synthesis that will impart a polymorphic form to tapentadol HCl is
`the latter half of the 3rd Step of Example 24, wherein the free base of tapentadol
`(generated in situ) is taken up (dissolved) in 2-butanone and treated with
`trimethylchlorosilane (TMSCl) and water. The preceding steps will not influence
`or determine the polymorphic form of tapentadol HCl because the free base of
`tapentadol is completely dissolved in 2-butanone and therefore has no crystalline
`form since it is in solution. The fact that the Example 24 procedure is long and
`includes the production of at least 2 intermediates over 3 steps is completely
`irrelevant to the polymorphic form of tapentadol HCl which is produced.
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`4.
`Preparation of tapentadol hydrochloride with TMSCl in butanone
`32. Examples 24 and 25 of the ’475 patent state that TMSCl and water
`were added to a solution of tapentadol (free base) in 2-butanone to produce
`tapentadol hydrochloride, but give no further details such as the quantities or the
`time over which the addition was performed.
`33. The quantities of 2-butanone, TMSCl, and water required to produce a
`related hydrochloride salt are described in Example 1 of the ’475 patent and
`Example 1 of the ’558 patent. According to these examples, I calculated that the
`free base of the amine was dissolved in 15.1 volumes of 2-butanone and mixed
`with 1.32 molar equivalents of TMSCl and 1.32 molar equivalents of water. A
`POSA would know to use these approximate quantities of 2-butanone, TMSCl and
`water to convert tapendatol into tapentadol hydrochloride.
`34. Details for formation of a related hydrochloride are given in Example
`1 of the ’558 patent which indicates that a solution of the compound in 2-butanone
`was added to TMSCl and water. In contrast, Examples 1, 24, and 25 of the ’475
`patent state that TMSCl and water were added to the 2-butanone solution. I note
`that a literal reading of the ’475 patent may seem to suggest adding a mixture of
`TMSCl and water to the 2-butanone solution. However, a POSA would understand
`that it is impractical to add a mixture of water and TMSCl at the same time
`because they are immiscible, and because water will cause the TMSCl to
`decompose. Thus, a POSA would not interpret Example 24 to mean addition of a
`mixture of water and TMSCl, but instead would interpret this to mean addition of
`water, followed by TMSCl.
`35.
` In my experimental attempts to obtain Form B (see below), I utilized
`both addition methods: that described in Example 1 of the ’558 patent and that
`described in Examples 1, 24, and 25 of the ’475 patent.
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`a. Addition of TMSCl to Solution of Tapentadol (The Addition
`Method of the ’475 Patent)
`36. First following the addition method of the ’475 patent, I dissolved the
`free base of tapentadol (109 mg, 0.49 mmol) in 2-butanone (1.0 mL) and added
`water (15 mg), followed by TMSCl (67 mg, 0.62 mmol) in one portion. An oily
`precipitate formed immediately which became crystalline in about 1 minute. After
`10 minutes, precipitation appeared to be complete. Therefore, I collected the
`precipitate, rinsed it with 2-butanone, and dried it in air to obtain tapentadol
`hydrochloride (111 mg, 87 % yield). The X-ray powder pattern obtained by Dr.
`Mayo indicated a 83:17 ratio of Form A to Form B. (10-194-4)
`37. Repeating this experiment with an extended addition time, I dissolved
`the free base of tapentadol (35 mg, 0.16 mmol) in 2-butanone (0.5 mL) and added
`water (5 mg), followed by TMSCl (22 µL, 0.174 mmol) over 10 minutes while
`stirring and scratching the reaction container. After 30 minutes, precipitation
`appeared to be complete. Therefore, I collected the precipitate, rinsed it with 2-
`butanone, and dried it in air to obtain tapentadol hydrochloride (31 mg, 76 %
`yield). The X-ray powder pattern obtained by Dr. Mayo indicated a 65:35 ratio of
`Form A to Form B. (10-195-2).
`38.
`I repeated this experiment without the addition of water. Water was
`omitted in case the 2-butanone contained a trace of adventitious water. I dissolved
`the free base of tapentadol (35 mg, 0.16 mmol) in 2-butanone (0.5 mL) and then
`added TMSCl (22 µL, 0.174 mmol) over 30 minutes while stirring the reaction
`container. After 18 hours, precipitation appeared to be complete. Therefore, I
`collected the precipitate, rinsed it with 2-butanone, and dried it in air to obtain
`tapentadol hydrochloride (23 mg, 56 % yield). The X-ray powder pattern obtained
`by Dr. Mayo indicated a 90:10 ratio of Form A to Form B. (10-195-5).
`39. Again repeating this experiment without the addition of water, I
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`dissolved the free base of tapentadol (30 mg, 0.136 mmol) in 2-butanone (0.5 mL)
`and then added TMSCl (22.7 µL, 0.180 mmol) over 10 minutes while stirring the
`reaction container. After 3 days at 5 °C, precipitation appeared to be complete.
`Therefore, I collected the precipitate, rinsed it with 2-butanone, and dried it in air
`to obtain tapentadol hydrochloride (23 mg, 66 % yield). The X-ray powder pattern
`obtained by Dr. Mayo indicated a 90:10 ratio of Form A to Form B. (10-196-6).
`b. Addition of Solution of Tapentadol to TMSCl (The Addition
`Method of Example 1 of the ’558 Patent)
`40. Following the addition method of Example 1 of the ’558 patent, as
`discussed above, I dissolved the free base of tapentadol (30 mg, 0.136 mmol) in 2-
`butanone (0.45 mL) and added this solution to a mixture of TMSCl (22.7 µL, 0.180
`mmol) and water (3.3 µL). After about 18 hours at 5 °C, precipitation appeared to
`be complete. Therefore, I collected the precipitate, rinsed it with 2-butanone, and
`dried it in air to obtain tapentadol hydrochloride (11 mg, 31 % yield). The X-ray
`powder pattern obtained by Dr. Mayo indicated a 100:0 ratio of Form A to Form B.
`(10-196-3).
`41. When I repeated this procedure, I obtained tapentadol hydrochloride
`(7 mg, 20 % yield). The X-ray powder pattern obtained by Dr. Mayo indicated a
`100:0 ratio of Form A to Form B. (10-196-4).
`42. When I repeated this procedure again, but cooled the mixture to 5 °C
`for 3 days, I obtained tapentadol hydrochloride (8 mg, 23 % yield). A POSA
`would utilize this longer crystallization period to determine if it produced a higher
`yield. The X-ray powder pattern obtained by Dr. Mayo indicated a 100:0 ratio of
`Form A to Form B. (10-196-5).
`43. When I repeated this procedure again with a different batch of
`TMSCl, and cooled the mixture to 5 °C for 3 days, I obtained tapentadol
`hydrochloride (30 mg, 86 % yield). The X-ray powder pattern obtained by Dr.
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`Mayo indicated a 79:21 ratio of Form A to Form B. (10-196-5a).
`5.
`Other experiments
`44. When I was not able to obtain pure Form B of tapentadol
`hydrochloride by following the examples of the ’475 patent, I attempted various
`variations on the ’475 patent examples that a POSA would have known to try in
`attempting to produce Form B, such as by replacing TMSCl and water with
`aqueous hydrochloric acid or hydrogen chloride gas (HCl). Thus, a POSA would
`know that TMSCl reacts with water to generate HCl, so TMSCl and water might
`be replaced by HCl. However, the following procedures are distinct from those
`described in the ’475 examples.
`45. First, I dissolved the free base of tapentadol (35 mg, 0.16 mmol) in 2-
`butanone (0.5 mL) and then added 12 M aqueous HCl (15 µL, 0.18 mmol) over 10
`minutes while stirring and scratching the reaction container. After 30 minutes,
`precipitation appeared to be complete. Therefore, I collected the precipitate, rinsed
`it with 2-butanone, and dried it in air to obtain tapentadol hydrochloride (23 mg, 56
`% yield). The X-ray powder pattern obtained by Dr. Mayo indicated a 67:33 ratio
`of Form A to Form B. (10-195-3).
`46. Next, I dissolved the free base of tapentadol (35 mg, 0.16 mmol) in 2-
`butanone (0.5 mL) and then added a freshly prepared 2.5 M solution of HCl gas in
`2-butanone (75 µL, 0.188 mmol) over 15 minutes while stirring the reaction
`container. After 30 minutes, precipitation appeared to be complete. Therefore, I
`collected the precipitate, rinsed it with 2-butanone, and dried it in air to obtain
`tapentadol hydrochloride (32 mg, 78 % yield). The X-ray powder pattern obtained
`by Dr. Mayo indicated a 31:69 ratio of Form A to Form B. (10-195-4).
`47. Then, I dissolved the free base of tapentadol (35 mg, 0.16 mmol) in 2-
`butanone (0.5 mL) and allowed HCl from a concentric vial of aqueous HCl to
`diffuse into the reaction container. After 18 hours, half of the 2-butanone had
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`evaporated and I collected the precipitate, rinsed it with 2-butanone, and dried it in
`air to obtain tapentadol hydrochloride (32 mg, 78 % yield). A POSA would know
`that this diffusion method would introduce HCl slowly into the tapentadol solution.
`The X-ray powder pattern obtained by Dr. Mayo indicated a 100:0 ratio of Form A
`to Form B. (10-196-1).
`48. Finally, I dissolved the free base of tapentadol (35 mg, 0.16 mmol) in
`acetone (0.5 mL) and then added TMSCl (22 µL, 0.174 mmol) over 1 hour while
`stirring the reaction container. After 1 hour, precipitation appeared to be complete.
`Therefore, I collected the precipitate, rinsed it with acetone, and dried it in air to
`obtain tapentadol hydrochloride (25 mg, 61 % yield). A POSA would understand
`that use of acetone rather than 2-butanone might produce a different ratio of Form
`A to B. The X-ray powder pattern indicated an 88:12 ratio of Form A to Form B.
`(10-196-2).
`VI. CONCLUSIONS
`49.
`In summary, when a solution of tapentadol in 2-butanone is mixed
`with TMSCl and water according to Example 7 of the ’364 patent which refers to
`Example 25 of the ’475 patent, Form A of tapentadol hydrochloride is produced
`exclusively or predominantly. Variations on this procedure also gave Form A
`exclusively or predominantly. Of all the methods I evaluated for production of
`tapentadol hydrochloride, the highest proportion of Form B, a 31:69 ratio of Form
`A to Form B, was produced when a solution of HCl gas in 2-butanone was added
`to tapentadol in 2-butanone (10-195-4). This method is distinct from those
`described in the ’364 or ’475 examples. I also attempted to convert Form A to
`Form B by heating according to Examples 8, 9, and 16 of the ’364 patent. When I
`heated Form A which was not cryomilled to 50, 130, or 215 °C, little or no Form B
`was produced. When I heated Form A which had been previously cryomilled to 65
`°C for 24 hours, a 52:48 ratio of Form A to Form B was produced. Heating
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`cryomilled Form A to 130 °C for 80 minutes gave a similar result, and heating to
`214 oc for 5 minutes gave a 75:25 ratio of Form A to Form B. It is my opinion
`that a POSA, by following the '364 and '475 Examples for obtaining Form B,
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`would necessarily obtain tapentadol hydrochloride containing exclusively or
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`predominantly Form A.
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`Executed this 15th day of January, 2016, in Wynnewood, Pennsylvania.
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