Dichloromethane was then distilled off under vacuum and the residue (4 g) was taken up in 2-butanone. After the addition of trimethylchlorosilane/water, 3.8 g of hydrochloride (+21) (98% theoretical) crystallized out. (Ex. 1006 at 32; Ex. XX. ¶ XX.) Based on the foregoing teachings, Dr. Expert2 commenced the synthetic procedure by mixing 300 mg tapentadol HCl (from the research sample) with 4.5 ml freshly prepared saturated aqueous sodium bicarbonate, and then this mixture three times with 3 ml dichloromethane. (Ex. XX. ¶ XX.) He then dried the combined dichloromethane extracts over sodium sulfate, filtered, and evaporated the solvent in vacuo to give the free base of tapentadol (257 mg, 100% yield) as a colorless oil which solidified after storage at 5 °C. (Ex. XX. ¶ XX.) Dr. Expert2 observed that these crystals melted at 86 – 88 °C. (Ex. XX. ¶ XX.) Then, Dr. Expert2 followed the EP 475 disclosure in an attempt to create tapentadol HCl (and particularly, Form B) from the tapentadol free base. Because Example 24 did not define the particular reagent:reagent ratio used during the crystallization step, Dr. Expert2 was able to look to other examples in the EP 475’s specification (e.g., Example 1) to obtain specific ratios of 2-butanone : TMSCl/water. (Ex. XX. ¶ XX.). Dr. Expert2’s Example 25 crystallization procedures are set forth below:
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
[EP 475] furthers this policy of allowing the public to practice expired patents.” SmithKline Beecham Corp., 403 F.3d at 1346. (See Ex. 1020 at 1.) As the XRPD patterns in Dr. Expert’s report demonstrate, following the Example 24/25 synthesis in EP 475 – and other general procedures described therein – at best produces a mixture of both Forms A and B of tapentadol HCl. (Ex. XX. ¶ XX.) The Form A and Form B overlays (generated from the Form A and Form B peaks listed in Table I of the ’364 Patent), when placed on the obtained XRPD patterns below, demonstrate the peaks resulting from the presence of Form A and Form B, respectively. (Ex. XX. ¶ XX.) Additionally, the obtained XRPD patterns contain each of the “unique peaks in the X-ray diffraction diagram, i.e. the [Form A] lines with sufficient intensity at 2-theta values, where Form B does not show lines with significant intensity.” (Ex. 1001 at 2:30-32; Ex. XX. ¶ XX.) As the ’364 Patent explains, “[s]uch characteristic X-ray lines (2-theta values) for Form A in a powder diffraction pattern when measured using Cu Kα radiation at ambient temperature are: 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2, 27.3±0.2, 29.3±0.2 and 30.4±0.2.” (Ex. 1001 at 2:32-36.) These characteristic Form A peaks are clearly present in the XRPD patterns obtained by Drs. Expert and Expert2. (Ex. XX. ¶ XX.) Because claim 1 of the ’364 Patent requires only “crystalline Form A” “exhibiting at least [the above] X-ray lines (2-theta values) in a powder diffraction
As shown above with respect to claim 1, EP 475 inherently discloses tapentadol HCl Form A. The ’364 Patent admits that the Form A polymorph has a monoclinic form, stating: “Crystal structure analysis of Form A of (-)-(1R,2R)-3-(3 dimethylamino-1-ethyl-2 -methylpropyl)-phenol hydrochloride showed monoclinic crystals.” (Ex. 1001 at 2:54-56.) Moreover, as confirmed by Dr. Expert, “the form – i.e. shape – of a polymorph’s crystals is an inherent characteristic of that particular polymorph. Said differently, the same polymorphs – as confirmed by XRPD patterns – will invariably exhibit the same crystalline shape.” (Ex. XX ¶ XX.) Consequently, because EP 475 inherently discloses tapentadol HCl Form A, and Form A is known to have a monoclinic form, EP 475 also inherently discloses tapentadol HCl Form A having a monoclinic form, anticipating claim 4. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.”). Additionally, in the ANDA litigations discussed above with respect to claim 3, the Patent Owner admitted: The phrase “monoclinic form” is a term of art in the field of crystallography. Its plain meaning is described in the scientific literature. See, e.g., J. Glusker & K. Trueblood, Crystal Structure
Analysis: A Primer 232 (Oxford University Press 1985) (“monoclinic form” means “a unit cell in which there is a two-fold rotation axis parallel to one cell axis (usually chosen as b).”) …. An example of a monoclinic unit cell is shown below: … Nothing in the specification (or elsewhere in the intrinsic evidence) suggested that the inventors wished to depart from the conventional meaning of “monoclinic form.” (Ex. 1019 at 41-42 (citation omitted).) In so stating, the Patent Owner argued that “monoclinic form,” as used in this claim, “could encompass unit cells of many different shapes and sizes,” and should not “limit that broad claim term to a single unit cell having the precise parameters described in column 2, lines 58 to 61 of the ’364 patent specification.” (Ex. 1019 at 42.) Petitioner agrees. Thus, any observed variations from the particular monoclinic form disclosed in the ’364 patent do not affect Petitioner’s anticipation analysis. EP 475 anticipates dependent claims 24 and 26. Claim 24 depends from claim 1 and adds the limitation that Form A is produced by the process of: dissolving (−) hydrochloride of Form B in acetonitrile together with active carbon, heating the solution to the boiling point, removing the active carbon by filtering, stirring the solution at a temperature below 40o C.,
Claim 25 of the ’364 Patent merely requires “A solid pharmaceutical composition comprising, as an active ingredient,” the crystalline Form A of claim 1, “and at least one suitable additive or auxiliary substance.” (Id. at 19:56-63.) As with respect to claim 1, Bartholomaeus inherently discloses tapentadol HCl Form A. Bartholomaeus further discloses in Example 1 “Matrix tablets” containing “Hydroxypropyl methylcellulose,” “Microcrystalline cellulose,” “Highly disperse silicon dioxide,” and “Magnesium stearate.” (Ex. 1009 at 18.) Thus, Bartholomaeus explicitly discloses a solid pharmaceutical composition comprising “at least one suitable additive or auxiliary substance” in addition to the inherently disclosed Form A, anticipating claim 25. (Ex. XX ¶ XX.) (Compare to Ex. 1001 at 4:24-30 (stating that suitable additives and auxiliary substances include “carrier materials, fillers, solvents, diluents, coloring agents and/or binders, and may be administered as liquid medicament preparations in the form of injectable solutions, drops or juices, as semi-solid medicament preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.”) Bartholomaeus anticipates dependent claims 2–4. Claim 2 depends from claim 1 and adds the limitation that Form A exhibits “at least X-ray lines (2-theta values) in a powder diffraction pattern when measured using Cu Kα radiation at 14.5±0.2, 18.2±0.2, 20.4±0.2, 21.7±0.2 and 22.5±0.2.” (Id. at 19:7-10.)