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`Grunenthal GmbH Exhibit 2011
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
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`Contains Highly Confidential Information of Griinenthal - Subject to Protective Order
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`Dr. Struck’s Rule 30(b)(6) Responses to Topics for Deposition of Griinenthal, May 8, 2015
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`‘ I have been asked to investigate and provide general deposition testimony regarding topic
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`nos. 1, 2, 3, 5, 6, 7, 9,10,11,12,14,15,16, 20, 21,22, 23, 25,26, 27, 28, 29,30, 31, 32, 34, 35,
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`36, 37, 38, 39, and 45, as amended in Griinenthal’s Responses to Defendants’ Notice of Deposition.
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`In providing the following answers to the topics I have been asked to investigate, I relied upon my
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`own recollections, knowledge, and experience, my review of thousands of pages of documents, and
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`the information I obtained from interviews with the following people:
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`0 Helmut Buschmalm (inventor on tapentadol and related compound patent and polymorph
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`patent): Topics 1, 2, 5, 6, 9, 10,11, 12,14, 15, 16, 20, 21, 22, 25, 26, 27, 28, 29 23, 30, 34,
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`36, 37, 38, and 45.
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`Thomas Christoph (inventor on polyneuropathic pain patent): Topics 3, 7, 10, ll, 12, 14,
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`15, 16, and 45
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`Andreas Fischer (inventor on polyrnorph patent): Topics 2, 6, 20, 21, 25, 26, 27, 28, 29, 30,
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`34, 35, 36, 37, 38, and 39.
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`Carsten Griebel (Process Development Department): Topics 31 and 32
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`Michael Gruss (inventor on polyrnorph patent): Topics 2, 6, 20, 21, 23, 25, 26, 27, 28, 29,
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`30, 34, 35, 36, 37, 38, and 39.
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`Edmund I-Ieidenthal: Topic 23
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`Kurt Hel1fe1dt(Griinenthal in-house attorney): Topics 5, 6, and 7
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`Babette Koegel(inventor on polyneuropathic pain patent) Topics 3, 7, 10, ll, 12, 14, 15,
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`and 16
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`Alexander Kraus: Topics 22, 23, and 45
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`Regina Kleinert: Topics 3, 10, 12, 14, 15, 16, 22, and 23
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`Dagmar Lischke (inventor on polymorph patent): Topics 2, 6, 20, 21, 25, 26, 27, 28, 29, 30,
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`32, 34, and 35
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`Murielle Méen (inventor on polyneuropathic pain patent): Topic 3, 7, 10, 12, 14, 15, and 16
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`Marita Mueller (chemist who repeated Ex. 25 of tapentadol and related compounds patent):
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`Topics 20, 2.1, 29, 30, 31, and 32
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`Ralf Stowasser (Griinenthal in-house attorney): Topics 5, 6, and 7
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`Oswald Zimmer (Process Development Department): Topics 31 and 32
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`Based on the information reasonably available to and appreciated by me from these sources,
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`I provide the answers below.
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`Page 2 of 17
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`Amended Topic
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`Conception and/or reduction to practice of the inventions of the asserted claims of the
`RE593 Patent
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`Conception and/or reduction to practice of the inventions of the asserted claims of the
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`Conception and/or reduction to practice of the inventions of the asserted claims of the
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`’13O patent
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`Prosecution of the ’593 and ’737 patents (tapentadol and related structures)
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`Prosecution of the ’364 patent (polymorph Form A)
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`Prosecution of the ’130 patent (polyneuropathic pain)
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`Preparation of tapentadol hydrochloride that was the basis for Example 25 of the ’593 and
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`’737 patents and related analytical analyses
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`Practice of Example 25 ofU.S. Patent No. 6,248,737, U.S. Patent No. 6,344,558, and
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`European Patent No. EP 0 693 475 B1 produces Form B of tapentadol hydrochloride
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`Identity of the crystalline form of tapentadol hydrochloride produced by the procedure
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`described in example 25 ofU.S. Patent No. 6,248,737 and EP 693 475 B1
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`Procedure described in example 25 of U.S. Patent No. 6,248,737 and EP 693 475 B1 and
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`Marita Mueller’s replication of that procedure
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`Griinentha1’s decision to pursue tapentadol hydrochloride as a drug candidate
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`(1) Griinenthal‘s decision to grant an exclusive license regarding pharmaceutical
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`formulations containing tapentadol for human use in the field of pain within the United
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`States and (2) payments received pursuant to that license agreement
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`(1) Griinenthal’s decision to grant an exclusive license regarding pharmaceutical
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`formulations containing tapentadol for human use in the field of pain within the United
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`States; (2) payments received pursuant to that license agreement; and (3) Griinenthal’s
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`practice of requiring confidentiality provisions in contracts with third parties performing
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`work for Griinenthal andfor consulting with Griinenthal
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`Identity of crystalline forms of tapentadol hydrochloride known to Grfinenthal
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`Page 3 of 17
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`34
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`Contains Highly Confidential Information of Griinentha1— Subject to Protective Order
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`Examples of conditions under which crystalline Form A and/or Form B of tapcntadol
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`hydrochloride may convert into another crystalline or non-crystalline form of
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`tapcntadol hydrochloride
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`Examples of properties of crystalline Fonn A
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`Examples ofproperties of crystalline Fonn B
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`Whether samples of GB-Bu322—l-1, GB-Bu3 22-1-2, GB-Bu322-1-3, GB—Bu322—2-1, and
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`PGl026-001-l-l can be presently located at Griinenthal
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`(1) Griinenthal’s process development depart1nent’s implementation in 2010 of
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`regulations in Germany that deemed tapcntadol to be a controlled substance with respect
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`to the storage of samples of tapentadol hydrochloride previously kept in the process
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`development department and (2) the relevant Griinenthal protocol governing the expiration
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`of the reference standard for Form B of tapcntadol hydrochloride
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`Communication process between Griinenthal and SSCI on SSCI’s work for Griinenthal on
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`the polymorph screen of tapcntadol hydrochloride
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`single crystal structure analysis of CG5503, the solubility study of CG5503 Forms A and
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`B, and the moisture sorption/desorption analysis of CG5503 Form B performed for
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`FinalreportsreceivedfromSSCIonthepolymorphscreenoftapentadolhydrochloride,the
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`Communication process between Griinenthal and F&E Analytik regarding F&E
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`Analytik’s work for Griinenthal on the single crystal structure determination of tapcntadol
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`hydrochloride and the powder diffraction determination of BN200
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`Grfinenthal Report No. FE-AC 513 - Crystal Structure of BN200 and Griinenthal Report
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`No. FE-AC 514 - Powder Diffraction Determination of BN200
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`Communication process between Grfinenthal and Crystallics BV regarding Crystallics
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`BV’s work for Griinenthal on the crystallization optimization of tapentadol hydrochloride
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`Crystallics BV’s final report for Griinenthal on the crystallization optimization for
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`tapcntadol hydrochloride
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`(1) unexpected
`The following for the RE593 patent, ’364 patent, and/or ’ 130 patent:
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`results; (2) failure of others; (3) commercial success; and (4) praise for the invention
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`Page 4 of 17
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`Page 5 of 17
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`AMENDED TOPIC NO. 2
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`Relevant, non-privileged, general information regarding the conception and/or
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`reduction to practice of the inventions of the asserted claims of the ’364 patent.
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`I understand that the ’364 Patent is the patent claiming polymorph crystalline Form A of
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`tapentadol hydrochloride. As stated in Griinenthal‘s responses to Interrogatory No. 8, Andreas
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`Fischer, Helmut Buschmann, Michael Gruss, and Dagmar Lischke each contributed to the
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`conception and development of the inventions claimed in the '3 64 patent.
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`Dr. Buschmann, who was responsible for the initial synthesis of tapentadol, served as the
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`Head of Department of Synthetic Chemistry from July 1996 until December 2000 and the Head of
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`Chemical Research fi'om January 2001 until January 2002. Dr. Buschmann collaborated with Dr.
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`Fischer, Dr. Gruss and Ms. Lischke on the polymorphic investigation of tapentadol and oversaw
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`that investigation until he lefl: Griinenthal in January 2002.
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`Ms. Lischke was an analytical technician, who conducted early differential scanning
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`calorimetry (DSC) experiments on various batches of tapentadol hydro chloride prepared by the
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`chemical process department. As part of her job responsibilities, Ms. Lischke conducted DSC
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`analyses and tested XRPD samples together with Dr. Fischer to the extent those analyses were
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`conducted at Griinenthal, rather than a third-party contractor.
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`While owner of F&E Analytik from 1998 to 2001, Dr. Fischer was retained by Grfinenthal
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`to conduct a single crystal analysis of tapentadol hydrochloride and XRPD analyses of additional
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`tapentadol samples. See, e.g., GRT-NUC00020690-20718; GRT-NUC00020658—20690. Dr.
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`Fischer joined Griinenthal in summer of 2001 as the Head of Griinenthal’s solid state analytics
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`laboratory and served as the head of that laboratory until 2010. In this role, Dr. Fischer supervised
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`Ms. Lischke and other technicians and was responsible for conducting solid state analytical
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`analyses (including DSC and XRPD) done at Griinenthal.
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`Page 6 of 17
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`Dr. Gruss was hired to manage Grt'1nenthal’s solid state characterization in May 2000.
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`Since January 2002, he supervised Magda Kraszewski, a chemical laboratory technician, who
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`worked under his direction on certain investigations of tapentadol polymorphism. Dr. Gruss also
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`was responsible for directing and managing the work of the third-party contractors Griinenthal
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`hired to do solid state work including F&E Analytik, RWTH, University of Bonn, SSCI,
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`Crystallics, and Solvias. The named inventors of the ‘364 patent also directed and contributed to
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`the design and/or execution of specific experiments carried out by the third party contractors,
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`including, for example, by participating in teleconferences with SSCI while SSCI’s work was
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`ongoing.
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`In addition, documents supporting the patent examples have been previously identified in
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`Plaintiffs’ original and supplemental Responses to Interrogatory Numbers 17, 18, 21, 29, and 30.
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`In investigating this topic, I spoke with Helmut Buschmann, Andreas Fischer, Michael
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`Gruss, and Dagmar Lischke. Additional information regarding Dr. Buschmann’s, Dr. Fischer’s,
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`Dr. Gruss’s and Ms. Lischke’s personal knowledge can be found in their respective deposition
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`transcripts, including exhibits.
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`Page 7 of 17
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`Page 8 of 17
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`Contains Highly Confidential Information of Griinenthal m Subject to Protective Order
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`AMENDED TOPIC NO. 21
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`Relevant, non-privileged, general information regarding the factual bases for
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`Plaintiffs’ contention that the practice of Example 25 of U.S. Patent No. 6,248,737, U.S. Patent
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`No. 6,344,558, and European Patent No. EP 0 693 475 B1 produces Form B of tapentadol
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`hydrochloride.
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`I understand that the reference to Example 25 above is a reference to Example 25 of the
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`U.S. and European patents for tapentadol hydro chloride and structurally related compounds.
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`Support for the fact that the synthesis according to Example 25 of the compound patent yields
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`crystalline Form B can be found at Plaintiffs’ original and supplemental Response to Defendants’
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`Joint Interrogatories Numbers 17-18.
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`Each of the inventors of the ’364 patent (Fischer, Gruss, Lischke and Buschmann) has the
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`understanding that Example 25 produces Form B, not Form A. Each inventor had this
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`understanding prior to the filing of the polymorph patent and the results were discussed between
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`As stated in Plaintiffs’ original and supplemental responses to interrogatories numbers 17
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`and 18, in experiments set forth on the notebook pages identified below conducted from August 15,
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`2002 through September 5, 2002, Marita Mueller, a chemist at Griinenthal, prepared (—)—(1R,2R)-3-
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`(3-di1nethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to example 25 of
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`European Patent EP 693 475 B1. See, e.g., GRT-NUC00021278—2l280; GRT-NUC00021282;
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`GRT-NUC00021285—21286; GRT-NUC00021291; GRT-NUC001 10737-1 10844 at 110756,
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`110758, 110760, l10762—l 10765, l10767—l 10768. A sample ofthe resulting product of the
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`synthesis, identified as GB-BN200-Patent (Bu322-l-1-2), was sent for x-ray powder diffraction
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`(XRPD) testing by Dr. V. Kaiser of the Institute for Crystallography at RWTH-Aachen. See GRT-
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`NUC0002l291; GRT~NUC00056667. The 2002 samples were tested at RWTH Aachen because
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`Analysis of the XRPD pattern received for “BNZOOHCL (GB-BN200/Patent),” which is
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`stamped “22 Okt. 2002” and located at GRT—NUC00056667, shows that crystalline Form B of (F-)-
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`(1R,2R)-3-(3-dimethylamino-s1-ethyl-2-methylpropyl)-phenol hydrochloride was generated. GRT-
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`NUC00056667; see also GRT~NUC00021291. Additional XRPD patterns for GB-BN200/Patent
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`may be found at GRT-NUC00056669—56671 and GRT-NUCOOOS6674. The October 10, 2006 date
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`in the upper right hand comer of these documents is a date the documents were printed, and does
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`not reflect the date the data was obtained. Each of the identified pattems shows that crystalline
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`Form B of (—)-(1R,2R)—3—(3-dimethylarnino—1-ethyl-2-methylpropyl)-phenol hydrochloride was
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`generated. Additionally, associated data files dated September 13, 2002 can be found at GRT-
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`NUC00117038—117197.
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`In additional experiments set forth on the notebook pages identified below conducted
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`beginning on October 29, 2002 through November 29, 2002, Ms. Mueller prepared (—)—(1R,2R)-3-
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`(3-diniethylarnino-1-ethyl-2-methylpropyl)-phenol hydrochloride according to example 25 of
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`European Patent EP 693 475 B1 a second time. See GRT-NUC00021284; GRT-NUC00021289—
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`21290; GRT-NUCO0021293; GRT-NUC00110737—110844 at 1 10786-110791, 1lO793—110794,
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`110796, 110803—110804. A sample of the resulting product of the synthesis, identified as Bu322-
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`1-3-2 (BN200-Patent), was sent for XRPD testing on December 2, 2002. See GRT-NUC00021293;
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`GRT-NUC001 10804. Analysis of the XRPD pattems received for “GB-Bu322-1-3HCl,” located at
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`GRT-NUC00056668 and GRT-NUC0005667l—56674, shows that crystalline Form B of (—)-
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`(1R,2R)-3-(3-dimethylamino-1-ethyl-2-rnethylpropyl)-phenol hydrochloride was generated. The
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`October 10, 2006 date in the upper right hand comer of these documents is a date the documents
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`were printed, and does not reflect the date the data was obtained. Additionally, associated data files
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`33
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`Page 10 of 17
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`Contains Highly Confidential Information of Griinenthal —— Subject to Protective Order
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`can be found at GRT-NUC00122566—122679 (dated February 18, 2003). When Dr. Gruss sent
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`samples to Professor Heger’s attention at RWTH Aachen, he included standard instructions to
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`avoid mechanical or thermal stress on the samples. See GRT—NUC00l08727-108728.
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`Even though it was not Ms. Lischke’s responsibility to make final decisions on what XRPD
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`patterns showed in 2002, she saw the results before the ’364 patent application was filed and agreed
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`with Dr. Gruss and Fischer that the pattems showed Form B with no Form A. The inventors
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`would not always review XRPD patterns in hard-copy, paper format. Often, their review would
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`occur on the computer, as using a computer makes it more convenient to do comparisons.
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`In an additional experiment conducted in 2009, Ms. Mueller again prepared (—)—(lR,2R)-3-
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`(3-dimethylamino-l-ethyl-2-methylpropyl)-phenol hydrochloride according to example 25 of
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`European Patent EP 693 475 B1, beginning with the step corresponding to example 24, step 3,
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`using Bu35l as the starting material. See GRT-NUC00056648—56658; GRT-NUC00074243~—
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`74250. A sample of the resulting product of the synthesis, identified as PG1026-001-1-1, was sent
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`to the Analytical Department at Griinenthal for XRPD testing. See GRT-NUC00056650; GRT-
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`NUC00074250. Analysis of the XRPD patterns for “PG1026-001-1-1,” which were taken in
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`December 2009 and are located at GRT-NUC00056659—5666l, GRT-NUC00l4999l, and GRT-
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`NUC001639l5—l639l7, shows that crystalline Form B of (—)—(lR,2R)-3-(3-dimethylamino-L
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`ethyl-2-methylpropyl)-phenol hydrochloride was generated.
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`The proton NMR obtained for “GB BU 322-l-1-1” may be found at GRT—NUC00205078-
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`205079. The proton NMR obtained for “GB BU 322-l-3-1” may be found at GRT«NUC00205082-
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`205083.
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`Certified translations of the relevant notebook pages from Marita Mueller’s notebooks can
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`be found at GRT-NUC0002 l 278_T—2 l 29 l_T, GRT-NUC00021293_T; GRT-NUC001 10737_T—
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`l l0744_T, GRT-NUCOOI l 0756_T, GRT-NUC001 l0758_T, GRT-NUCOOI l0760_T, GRT-
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`NUC001 10'/'62_T—1 1 O765_~T, GRT-NUC00l10767_T—1 l076S_T, GRT-NUC001 10772_T—
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`1 10'/'75_T, GRT-NUC1 l0779wT, GRT-NUC001 10781_T, GRT—NUC00l l0786_T—1 l0791_T,
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`GRT-NUC001 10793_T—l lO794__T, GRT-NUC001 10796_T, GRT-NUC001 l0803_T—-1l0804_T;
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`GRT-NUCOO056648_T-56658_T; GRT-NUC00074243_T—74250_T.
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`In investigating this topic, I spoke with I-Ie1mutBuschmann, Michael Gruss, Andreas
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`Fischer, Dagmar Lischke, and Marita Mueller. Additional information regarding Dr. Buschmann’s,
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`Dr. Gruss’s, Dr. Fischer’s, Ms. Lischke’s and Ms. Mueller’s personal knowledge can be found in
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`their respective deposition transcripts, including exhibits.
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`Page 12 of 17
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`Page 13 of 17
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`Contains Highly Confidential Information of Griinenthal H Subject to Protective Order
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`AMENDED TOPIC N0. 26
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`Relevant, non-privileged, general information concerning examples of conditions
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`under which crystalline Form A and/or Form B of tapentadol hydrochloride may convert into
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`another crystalline or non-crystalline form of tapentadol hydrochloride.
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`Griinenthal has investigated the interconversions between tapentadol hydrochloride
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`polymorphic forms A and B and has certain data that suggests when interconversion does and does
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`not occur. However, polymorphism is unpredictable and Grfinenthal does not claim to know all or
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`every condition that might (or might not) cause conversion to occur between forms A and B of
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`tapentadol hydrochloride. Although other forms might be possible, the people with whom I spoke
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`have not characterized any Forms other than Form A and Form B of tapentadol hydrochloride.
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`Grfinenthal has various reports that touch upon conversions of crystalline form A and/or B
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`to another crystalline or non-crystalline fonn of tapentadol hydrochloride. Some of these reports
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`include: an SSCI polymorph screen (available at GRT-NUC00021090-21277) and a Griinenthal
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`internal report on pressure-induced transition of polyrnorphs A and B (GRT-NUC00074504-
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`The inventors each explained that one way to convert a crystalline polymorphic form to a
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`non-crystalline form of tapentadol hydrochloride is to dissolve solid crystals of tapentadol
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`hydrochloride in solution. No matter what solid crystalline polymorphic form you start with, after
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`it is dissolved in solution, the crystal lattice is destroyed. Solid state information (meaning the
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`crystal structure) is lost as soon as the solid is dissolved. So Fonns A and B do not exist after
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`tapentadol hydrochloride is dissolved in a solvent. In a solution, the molecules of tapentadol
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`hydrochloride are separated from each other and are not in crystals anymore. Each inventor has
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`had this understanding of the word “dissolved” for decades as a matter of basic chemistry.
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`Temperature also can have an effect on polymorphic conversion of Forms A and B of
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`tapentadol hydrochloride. Certain samples of tapentadol hydrochloride were tested by XRPD at
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`various temperatures. For example, samples of batch numbers CEPMI a and CEPM2a were tested
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`at both room temperature and at -10°C. An XRPD of these samples conducted at room temperature
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`showed they were Form B. But an XRPD of samples of CEPM1a and CEPM2a taken at -10°C,
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`showed peaks of Form A. See GRT-NUC00110099 (produced metadata shows file name
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`“CG5503_CEPMla_-10°C.emf”); GRT-NUC00110100 (produced metadata shows file name
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`“CG5503_CEPM2a_-10°C.emf”). Ms. Lischke confirmed that information about what temperature
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`an XRPD was taken is sometimes given in the file name or in the associated data file. The
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`associated data files can be found at GRT-NUC001 15789-115851 and GRT-NUC00115892-
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`115954. This conversion of Form B to Form A at subzero temperatures is consistent with the
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`information disclosed in the polymorph patent. For example, as disclosed in the ’3 64 patent,
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`Example 5, Form B converts to Form A when stored for 72 h at -40°C. See also ‘364 patent, col.
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`3, 11. 53-64. The XRPD patterns of CEPM1a and CEPM2a taken at -10°C give no information
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`about what polymorphic form was present in the sample at room temperature, before cooling.
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`As disclosed in the ’3 64 patent, Example 16, Form A converts to Form B from 40—50°C and
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`the result is reversible at a lower temperature. Example 16, however, specifies neither a time frame
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`for any conversion of Form B (made from heating form A) back to Form A nor the precise
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`temperature at which such a conversion may occur.
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`Form A can be converted to Fonn B by, for example, the application of mechanical stress,
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`like milling. As disclosed in the ’364 patent, Examples 8 and 9, Fonn A converts to Form B in the
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`presence of mechanical stress and/or heat, such as milling for 20 minutes and heating in an oven or
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`cryogrinding for at least 15 minutes and heating in a TGA.
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`Page 15 of 17
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`Contains Highly Confidential Information of Griinenthal -H Subject to Protective Order
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`Griinenthal is aware of pressure testing that showed a stability advantage of Form A over
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`Form B of tapentadol hydrochloride. For example, a November 2001 SSCI report to Griinenthal
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`indicates that in the presence of 5000 pounds of pressure for three days, Form A (in the absence of
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`excipients) did not convert to Form B. GRT~NUCOO021090—-21277 at 21 108 at Table 12. Under
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`10,000 pounds of pressure for eight days, Fonn B (in the absence of excipients) did convert to
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`Form A. GRT-NUC00O21 090-21277 at 21 108 at Table 12. And under 5000 pounds of pressure
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`for “several days," Form B (in the absence of excipients) converted to a mixture of Form B and
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`Form A. GRT-NUCOO021 090-21277 at 21 108 at Table 12.
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`In a different experiment conducted in 2008, the stability of Forms A and B of tapentadol
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`was evaluated under the application of pressure for the much shorter time period of only 60
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`seconds. Specifically, when 2 tons of pressure was applied for 60 seconds to samples of Form A of
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`tapentadol hydrochloride taken from a broad variety of batch types, in the absence of any other
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`tablet ingredients, Form A remained unchanged within the limit of quantification. But samples of
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`Form B of tapentadol hydrochloride taken from a broad variety of batch types, in the absence of
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`any other tablet ingredients, and under 2 tons of pressure applied for 60 seconds, converted into
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`mixtures ofFor1n B and Form A that varied from: 95% Form B to 5% Form A, 4% Form B to 96%
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`Form A, and 70% Form A to 30% Form B. Thus, these extreme stress tests of crystalline Form B
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`alone for extended durations of 60 seconds yielded mixtures of crystalline Forms B and A.
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`Pressure occurs in the drug manufacturing process. But anyone having basic knowledge of
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`pharmaceutical manufacturing would recognize that the application of 2 tons of pressure for 60
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`seconds was a significantly extended duration of time as compared to the typical time period of a
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`second or less that tablets are compressed during normal manufacturing processes for drug tablets.
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`Nevertheless, because active ingredients are exposed to pressure during the manufacturing process
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`Page 16 of 17
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`Contains Highly Confidential Information of Griinenthal — Subject to Protective Order
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`for drug tablets, Fonn A’s performance in this experiment demonstrates an advantage of Form A
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`over Form B with respect to stability under the application of high pressure.
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`In a different, later experiment conducted in 2009, however, Griinenthal found that when
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`crystalline form B of tapentadol hydrochloride (produced as disclosed in example 25 of the ‘737
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`patent) underwent normal tableting conditions in the presence of other tablet excipients, no
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`conversion to crystalline form A could be detected. GRT-NUC00056648-56666.
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`In investigating this topic, I spoke with He1mutBuschrnann, Michael Gruss, Andreas
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`Fischer, and Dagmar Lischke. Additional information regarding Dr. Buschmann’s, Dr. Gruss’s,
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`Dr. Fischer’s, and Ms. Lischke’s personal knowledge can be found in their respective deposition
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`transcripts, including exhibits.
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`Page 17 of 17