UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`DECLARATION OF STEPHEN HOWARD CYPES
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`
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`
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`
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`Merck Exhibit 2124, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`DECLARATION OF STEPHEN HOWARD CYPES
`
`
`
`
`
`
`
`
`
`
`
`
`Merck Exhibit 2124, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`
`
`DECLARATION OF STEPHEN HOWARD CYPES
`
`I, Stephen Howard Cypes, hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
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`I am a named inventor of subject matter claimed in U.S. Patent No.
`
`7,326,708 (“the ’708 patent”). I understand that Merck Sharp & Dohme Corp.
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`(“Merck”) is the owner and assignee of the ’708 patent.
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`2.
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`I understand that claim 1 of the ’708 patent recites a
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`dihydrogenphosphate (“DHP”) salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-
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`dihydro[1,2,4] triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-
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`amine, a compound also known as sitagliptin, in which the DHP counterion and the
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`sitagliptin freebase are present in a 1:1 stoichiometric ratio. I further understand
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`that claim 4 patent recites a crystalline monohydrate of the 1:1 DHP salt.
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`3.
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`In this declaration, I provide facts based on my personal, first-hand
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`knowledge regarding the creation and identification of the crystalline monohydrate
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`of the 1:1 DHP salt of sitagliptin.
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`II. BACKGROUND
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`4.
`
`I received my B.S. in chemical engineering in 2002 from Cornell
`
`University, where I also received my M.Eng. in chemical engineering and an MBA
`
`in 2003 and 2012, respectively.
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`2
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`Merck Exhibit 2124, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`5.
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`From January 2003 to January 2004, I was a Staff Chemical Engineer
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`in the Chemical Engineering Research & Development (“CERD”) group of Merck
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`Research Laboratories (“MRL”).
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`6.
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`I left Merck in January 2004 to join Symyx Technologies where I
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`served as a Director in the Life Science Research and Business Development
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`groups. I currently serve as Vice President, Global Workflow Sales at Unchained
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`Labs, Symyx’s corporate successor.
`
`7.
`
`In this declaration, I have cited to several documents from Merck’s
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`archives related to the research and development of sitagliptin, including a
`
`laboratory notebook that I maintained as a Merck employee. I am familiar with
`
`Merck’s practices with respect to lab notebooks at the time. In the usual and
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`ordinary course of its business, Merck issued numbered lab notebooks to scientists
`
`for the purpose of recording their daily research activity. Each lab notebook page
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`was numbered and individual entries typically included information regarding the
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`project or compound for which the experiment was run. Entries in my lab
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`notebooks were made by me at or near the time that I conducted each experiment.
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`It was also my customary practice (and one generally shared by my colleagues) to
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`refer to particular lab notebook numbers and pages to track samples and/or
`
`experimental procedures (e.g., “NB 66839-113”). A true and correct copy of my
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`laboratory notebook (LNB 66839) may be found in EX2125.
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`3
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`Merck Exhibit 2124, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`8.
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`In addition to my laboratory notebook, I have cited to several of my
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`weekly reports. These weekly reports were generated as part my duties as a
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`scientist in CERD; at the time, scientists in CERD were required to submit weekly
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`reports in the usual and ordinary course of Merck’s business to track their research
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`progress and experimental observations. These weekly reports were composed at
`
`or near the time of the experiments in question. True and correct copies of my
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`weekly reports may be found in EX2126.
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`III. CREATION OF THE CRYSTALLINE MONOHYDRATE OF THE 1:1
`DHP SALT OF SITAGLIPTIN
`
`9.
`
`Immediately after joining Merck, I was assigned to the project team
`
`responsible for developing an inhibitor of dipeptidyl-peptidase-IV (“DPP-IV”) into
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`an oral treatment for type 2 diabetes. At this point in the DPP-IV project, the team
`
`had selected sitagliptin as the lead compound and had spent over a year developing
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`it, including selection of a salt form, the 1:1 DHP salt. Characterization of the 1:1
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`DHP salt had identified a number of anhydrous polymorphs of the compound,
`
`along with several organic solvates. However, no hydrates of the 1:1 DHP salt—
`
`much less a crystalline monohydrate—had been identified.
`
`10.
`
`In January 2003, scientists in the DPP-IV project, including myself
`
`and others from CERD and Physical Measurements, initiated a series of
`
`experiments to identify a non-solvating solvent to crystallize the 1:1 DHP salt.
`
`The goal of our experiments was to directly crystallize a pure anhydrous crystal
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`4
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`Merck Exhibit 2124, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`form without having to desolvate an intermediate solvated crystal. See EX2126
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`(Jan. 23, 2003 Weekly Report) at 2.
`
`11. By the end of January, the team had run several solvent experiments,
`
`with mixed results. The following table summarizes our findings as of January 30,
`
`2003, based on the criteria I had identified as important for an appropriate solvent
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`system. See EX2126 (Jan. 30, 2003 Weekly Report) at 5.
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`12. On February 7, 2003, I ran a crystallization experiment using isoamyl
`
`alcohol (“IAA”) and found that the resulting crystal was mixture of anhydrous
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`Forms I and III, with some amorphous material. See EX2125 (LNB 66839-051) at
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`
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`5
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`Merck Exhibit 2124, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`13.1 Additional experiments performed by myself and Russell Ferlita—a colleague
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`from the Physical Measurements group and a named co-inventor of the ’708
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`patent—confirmed that IAA would likely be a good candidate for further direct
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`crystallization studies. See EX2126 (Feb. 14, 2003 Weekly Report) at 11.
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`13. The crystals formed from IAA were small and had unfavorable needle
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`morphology. See, e.g., EX2125 (LNB 66839-67) at 29 (“Mainly fines
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`crystallized.”). I therefore investigated whether larger crystals could be obtained
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`by adding a small amount of water and found resulting crystals had improved size
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`and morphology. See EX2125 (LNB 66839-73) at 35–36; see also EX2126 (Feb.
`
`27, 2003 Weekly Report) at 19–20 (“[D]oping the system with water to promote
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`crystal growth will be attempted”). At this time, the form of the crystal was
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`determined to be a mixture of Form I and Form III by x-ray powder diffraction
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`(“XRPD”). See EX2125 (LNB 66839-74) at 36 (“XRD revealed mix of Form I
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`and III in final wetcake.”). I performed several experiments using a mixture of
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`95/5% mixture of IAA/water at different temperatures to see if further
`
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`1 An updated version of the table shown above reflecting solvent screening
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`experiments with IAA, as well as diethoxymethane and methyl benzoate, may be
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`found in my February 6, 2003 weekly report, which I incorporate herein by
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`reference. See EX2126 at 8.
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`6
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`Merck Exhibit 2124, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`improvements could be made to improve the purity of the crystal form and its
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`morphology. See EX2126 (Mar. 6, 2003 Weekly Report) at 23–25; id. (Mar. 20,
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`2003 Weekly Report) at 26–28.
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`14. On March 26, 2003, I continued a series of a “heel cycling”
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`experiments using the 95/5% IAA/water system in an attempt to grow pure
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`anhydrous form crystals with favorable morphology. Quite unexpectedly, the
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`crystals resulting from this experiment displayed an anomalous XRPD pattern and
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`a 3.3% weight loss on drying (“LOD”). See EX2125 (LNB 66839-113) at 75.
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`(“XRD: Anomalous pattern on wetcake and 3.3 wt% LOD”). This anomalous
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`pattern was subsequently confirmed through thermogravimetric analysis (“TGA”)
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`and differential scanning calorimetry (“DSC”) to correspond to a new crystal form
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`of the 1:1 DHP salt: a crystalline monohydrate.2
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`15. The appearance of the crystalline monohydrate was a surprising and
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`unexpected development. The DPP-IV project team had spent over a year
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`developing the 1:1 DHP salt of sitagliptin without identifying a crystalline
`
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`2 Both prior to and at the time that I created the crystalline monohydrate of the 1:1
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`DHP salt of sitagliptin, I understood that in accordance with Merck’s policies and
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`procedures and as a condition of my employment, I was under an obligation to
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`assign (and did assign) this subject matter to Merck.
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`7
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`Merck Exhibit 2124, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF STEPHEN HOWARD CYPES
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`monohydrate. I further understood the team had run extensive searches for other
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`polymorphs both internally and using the Symyx polymorphic screening platform,
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`without identifying a monohydrate, which made the creation of the monohydrate
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`even more surprising. Moreover, I had personally performed numerous
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`experiments with the 1:1 DHP salt in IAA and water using different temperatures,
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`crystallization conditions, and reaction scales, without obtaining the monohydrate
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`in my initial experiments. The creation of the monohydrate under these
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`circumstances was therefore surprising and unexpected.
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`*
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`*
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`*
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`I hereby declare that all statements made herein of my own knowledge are
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`true and that all statements made on information and belief are believed to be true;
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
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`
`Dated: August 20, 2020
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`
`
`
`Stephen Howard Cypes
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`
`
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`8
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`Merck Exhibit 2124, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`
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