UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`
`LIMITED,
`
`Petitioners,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case Nos. lPR20l6—005 10; lPR20l6—005 12; lPR2016—005l4; lPR2016—005l6;
`lPR20l6—00517
`
`Patent Nos. 6,858,650; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF CLAUS O. MEESE, Ph.D.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC. and MYLAN LABORATORIES
`
`LIMITED,
`
`Petitioners,
`
`V.
`
`UCB PHARMA GMBH,
`Patent Owner.
`
`Case Nos. lPR20l6—005 10; lPR20l6—005 12; lPR2016—005l4; lPR2016—005l6;
`lPR20l6—00517
`
`Patent Nos. 6,858,650; 7,384,980; 7,855,230; 8,338,478; 7,985,772
`
`DECLARATION OF CLAUS O. MEESE, Ph.D.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0001
`
`
`
`.
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`I, Dr. Claus Meese, submit this Declaration on behalf of UCB Pharma
`
`GMBH (“UCB”), in support of its Patent Owner Response in the above-
`
`rcfcrcnced Inter Parres Reviews.
`
`.
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`I am the named inventor of the inventions claimed in United States Patent
`
`No. 6,858,650 (the ‘“650 patent”).
`
`I am a named co-inventor of
`
`inventions claimed in United States Patent Nos. 7,384,980; 7,855,230;
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`7,985,772; and 8,338,478.
`
`.
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`I testified at trial in Pfizerlnc. v. Scmdoz Inc, CA. No. 13-1110 (GMS)
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`(D. Del.). My testimony from the transcript of the proceedings in that
`
`trial is of record in this interparres review. (E Ex. 2006 at 43:8 —
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`10021.)
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`.
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`.
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`I am a German national and have always resided in Germany. Presently,
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`I reside in Monheim, Germany.
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`I am an organic chemist, having earned both a diploma and Ph.D. from
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`the University of Hamburg, where I studied pharmaceutical chemistry
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`and pharmacy.
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`.
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`I was employed as a chemist and head of the Chemistry Department at
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`the UCB predecessor, Schwarz Pharma AG (“Schwarz”), in Monheim,
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`Germany, from 1993 until 2008, when I retired from the company.
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`. Beginning in 1997, I was involved in a research and development project
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`at Schwarz that resulted in the invention of the compound, fesoterodine
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0002
`
`
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`fumarate (the “Project”) that today is the active ingredient in a drug
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`marketed around the world for the treatment of overactive bladder.
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`8. My role in the Project was as leader of chemical development, and my
`
`responsibilities included the design, synthesis, and testing of candidate
`
`prodrugs of (R)-2-(3-(diisopropy1amino)-1-pheny1propy1-4-
`
`(hydroxymethyl)phenol (“S-HMT”) and later, the design, synthesis, and
`
`testing of salt forms of these candidate prodrugs, including the fumarate
`
`salt of fesoterodine. All such synthesis and testing was performed either
`
`by me or by others involved in the Project working at my direction.
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`9. Cited in this Declaration are certain Schwarz records reflecting the state
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`of the Project as of the date of the respective documents. These records
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`are in the form of internal reports from my chemistry department or
`
`meeting minutes from meetings of the Project Team. These records are
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`representative of records ordinarily made and kept for all research and
`
`development projects undertaken at Schwarz during my time with the
`
`company. To the best of my knowledge, such documents referred to and
`
`cited to in this Declaration are true and correct copies of such Schwarz
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`company records.
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`l0.By February 1998, I had synthesized or directed the synthesis of at least
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`22 racemic 5-HMT prodrug candidates, including fesoterodine. (E
`
`Chemical Development Plan of 2/20/98 (Ex. 2094).) These candidates
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`were identified in laboratory records by their benzyl-side/phenyl-side
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`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0003
`
`
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`substitution from the 5-1-lMT chemical structure, as well as by an “SPM”
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`laboratory code number. (See id.; see also Timetable (Exhibit 2095) at
`
`5.) For example, raccmic fesotcrodine was identified in Project records
`
`both as “HO/OiBut” and as “SPM 7504.” (E Exhibits 2094 and
`
`2095.)
`
`l l.By August 1998, I, or those at my direction, had synthesized racemic
`
`fesoterodine in the form of a hydrochloride salt, which is referred to in
`
`the Project records as “SPM 7527.” (E Minutes of 9/10/98 Mtg. (Ex.
`
`2096) at 9; Ex.2095 at 5.)
`
`l2.By February 1999, l, or those at my direction, had synthesized chiral (R-
`
`(+)) 5-HMT prodrug candidates, including the R-enantiomer of
`
`fesoterodine. (E Chem. Dev. Plan of 2/24/99 (Ex. 2097).) The free
`
`base form of R-enantiomer of fesoterodine is referred to in Project
`
`records as “SPM 8224.” (E Lab. Jnl. of 8/19/99 (Ex. 2098).) At that
`
`time, my colleagues and I had already observed the difficulty in preparing
`
`stable, crystalline, and non—hygroscopic salts of these chiral 5—HMT
`
`prodrug candidates. (E Ex. 2097.)
`
`13.By May 1999, our Project Team at Schwarz has identified the R-
`
`enantiomer of fesoterodine as a “selected candidate” compound to be a
`
`particular focus of development, going forward. (E Minutes of 5/28/99
`
`Mtg. (Ex. 2099).) By that time, I, or those at my direction, had
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0004
`
`
`
`synthesized the first salt form of R—fesoterodine, a hydrochloride salt,
`
`which is referred to in the Project records as “SPM 8228.” (l_cl.)
`
`l4.At the Project Team meeting of28 May 1999, it was noted that a stable
`
`and crystalline salt form of fesoterodine had been requested of my
`
`department, (Q), which is consistent with the necessity that the salt form
`
`of an active pharmaceutical ingredient exhibit the properties of purity,
`
`stability, and crystallinity in order for it to be viable oral pharmaceutical.
`
`At that time, I communicated to the Project Team that efforts to prepare a
`
`fesoterodine salt having those properties had been unsuccessful, resulting
`
`in oily masses not useful as pharmaceuticals. Specifically, I
`
`communicated that the fesoterodine hydrochloride, SPM 8228, “is
`
`amorphous and hygroscopic. We shall look now for [approximately] 20
`
`other salts to improve the physiochemical properties.” (I_d.) The
`
`handwriting which appears on the face of Ex. 2099 is mine.
`
`l5.ln fact, following the May 1999 Project Team meeting, 1, or those at my
`
`direction, would need to synthesize and evaluate not 20, but more than 70
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`fesoterodine salts, Ex. 2006 at 58, made with more than 40 different
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`organic acids, inorganic acids, and metal complexes. (E “Information
`
`about SPM 8224 & SPM 8272” (Ex. 2100) at 1.)
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`l6.0fthe over 70 fesoterodine salts that were prepared at my direction and
`
`observed over months as each was suspended in its solvent system, all but
`
`one yielded salts that were oils, not useful as oral pharmaceutical
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0005
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`
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`ingredients. (E Ex. 2006 at 58-59.) The one exception finally yielded a
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`stable, pure, and crystalline salt form, which was fesoterodine fuinarate.
`
`(See id.; 8/31/99 email from Arth to Mccsc (Ex. 2101).) These
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`properties were confirmed in November 1999. and the synthesis ofthis
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`pure, stable, crystalline fumarate salt of fesoterodine was described in a
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`German patent application filed that month, which would result in the
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`U.S. ‘650 patent. (E Ex. 2006 at 58-63.)
`
`l7.After the discovery of fesoterodine fumarate as a stable, pure, and
`
`crystalline salt — characterized by X—ray structure analysis — I discovered
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`a further salt of fesoterodine which also exhibited these solid state
`
`properties (stable and crystalline form), i.e. fesoterodine hydrochloride
`
`hi. (L at 63-64.) This discovery was totally serendipitous and
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`unexpected.
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`l8.As previously mentioned, I had previously prepared fesoterodine
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`hydrochloride(SPM 8228), which crystallized initially, but then converted
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`into an undesirable oily, sticky (amorphous and hygroscopic) mass. (E
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`Q at 63; Ex. 2099.) One day, such preparation was left on the shelf in a
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`flask for some time as an oily mass. (E Ex. 2006, 64.) A lab technician
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`alerted me that this oily liquid had suddenly begun to crystalize again.
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`(L) In trying to understand why this transformation was occurring, I
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`suspected that the moisture level in the laboratory that day was elevated
`
`over normal levels. Suspecting that this change in the environment was
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0006
`
`
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`driving the crystallization of this hydrochloride preparation, I had the idea
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`to improve the process by using aqueous solvent in the crystallization
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`process of fesoterodine hydrochloride. (E Q) As a result, I prepared
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`and characterized a new form of fesoterodine and a hydrochloride
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`13%, which I subsequently confirmed to be a second stable, pure, and
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`highly crystalline compound.
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`(_S_e_§ Q) Very importantly. the fesoterodine
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`hydrochloride lyclrifeis distinct from the previously obtained
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`fesoterodine hydrochloride in terms of solid state properties.
`
`19.The synthesis of fesoterodine hydrochloride hydrate was also described in
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`the German patent application filed in November 1999, which would
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`result in the U.S. ‘650 patent. (_SLe Q, p. 65)
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`20.1 declare under the penalty of perjury that the foregoing Declaration is to
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`the best of my knowledge true and correct.
`
`Dated: 19. October 2016
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`Io... Mm 0 my,»
`
`
`
`Dr. Claus O. Meese
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0007
`
`
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`List of Exhibits Cited
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`EX"‘b“N°-
`2006
`
`2094
`
`2095
`
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
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`Trial Transcript, July 13, 2015, Pfizer Inc. et al. v. Sandoz, Inc. et
`al, 13—ev—O1l10 (D. Del.).
`
`“Chemical Development Plan,
`February 20, 1998.
`
`Incontinence Project,”
`
`dated
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`“Timetable ofthe development ofFesoterodine.”
`
`“Minutes: Team Meeting, N CE Incontinence” [sic]_,” dated August
`10, 1998.
`
`“Chemical Development Plan,
`February 24, 1999.
`
`Incontinence Project,”
`
`dated
`
`“Laborjoumal: A. Cawello,” dated August 19, 1999.
`
`“NCE—lneontinenee Meeting,” dated May 28 1999.
`
`“Some information about SPM 8224” & “Some information about
`
`SPM 8272.”
`
`Email from Dr. Christoph Arth to Dr. Claus Meese, dated August
`31, 1999.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2025 - 0008
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