`
`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 KARL B. HANSEN, PH.D.
`
`
`
`
`
`
`Merck Exhibit 2127, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`
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`DECLARATION OF KARL B. HANSEN, PH.D.
`
`I, Karl B. Hansen, Ph.D., hereby declare as follows:
`
`I.
`
`
`
`1.
`
`I am a named inventor of subject matter claimed in U.S. Patent No.
`
`2.
`
`
`
`4-oxo-4-[3-(trifluoromethyl)-5,6-
`
`dihydro[1,2,4] triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-
`
`amine, a compound also known as sitagliptin, in which the DHP counterion and the
`
`sitagliptin freebase are present in 1:1 stoichiometric ratio.
`
`
`
`3.
`
`In this declaration, I provide facts about which I have first-hand
`
`knowledge regarding
`
` research and development of sitagliptin into the
`
`FDA-approved drug, Januvia®. In particular, I provide information related to my
`
`role in synthesizing and characterizing the claimed 1:1 DHP salt of sitagliptin, the
`
`timing of that synthesis and characterization, and my efforts to form and
`
`characterize its crystal polymorphs.
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`2
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`Merck Exhibit 2127, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
`
`II.
`
`
`
`4.
`
`I received my doctorate in organic chemistry from Harvard University
`
`in 1998 and my B.S. in chemistry from the University of Delaware in 1993.
`
`5.
`
`After receiving my Ph.D., I joined the Process Research department of
`
`Merck Research Laboratories
`
`as a Senior Research Chemist. My
`
`responsibilities principally focused on the development of robust chemical
`
`syntheses suitable for commercial scale-up of drug candidates under development
`
`by Merck. A significant portion of my work was devoted to the synthesis and
`
`identification of new salt forms, as well as their selection and optimization in terms
`
`of pharmaceutical properties, an area in which I have substantial experience.
`
`6.
`
`archives related to the research and development of sitagliptin and Januvia®,
`
`including several lab notebooks and weekly reports. I maintained several lab
`
`notebooks over the course of my career at Merck and am generally familiar with
`
`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
`
`was numbered and individual entries typically included information regarding the
`
`project or compound for which the experiment was run. Entries in my lab
`
`notebooks were made by me at or near the time that I conducted each experiment.
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`3
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`Merck Exhibit 2127, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`It was also my customary practice (and one generally shared by my colleagues) to
`
`refer to particular lab notebook numbers and pages to track samples and/or
`
`experimental procedures (e.g.
`
`-
`
`sitagliptin in several lab notebooks, true and correct excerpts of which may be
`
`found in EX2128
`
`EX2130 (LNB 72471).
`
`29 (LNB 70316), and
`
`7.
`
`During my time at Merck, scientists in the Process Research
`
`department submitted weekly reports summarizing their activities at or near the
`
`time they submitted the report. These reports were generated in the usual and
`
`ordinary course of business to track the work of individual scientists. True and
`
`correct copies of weekly reports submitted by me in January, February, March,
`
`April and November of 2002 may be found in EX2131.
`
`8.
`
`In 2006, I left Merck to join Amgen, where I was eventually promoted
`
`to Scientific Director for Process Development. While at Amgen, I led,
`
`participated, and was accountable for multi-disciplinary teams that discovered,
`
`developed and selected optimal salt forms and polymorph of drug candidates. In
`
`2018, I joined Boston Pharmaceuticals where I became the Vice President for
`
`am currently employed as
`
`the Senior Vice President for CMC at Praxis Precision Medicines.
`
`
`
`
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`4
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`Merck Exhibit 2127, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`III.
`
`
`
`9.
`
`In or around January 2002, I joined the Merck team developing L-
`
`224715, the internal Merck designation for sitagliptin. I understood that L-224715
`
`overall project to develop an inhibitor of the enzyme dipeptidyl-peptidase IV
`
`-
`
`DPP-IV
`
`project team, I joined the effort to develop sitagliptin into a dosage form suitable
`
`for administration to humans as part of clinical trials designed to investigate
`
` at inhibiting DPP-IV in patients, and eventually,
`
`for approval by the FDA for the treatment of type 2 diabetes.
`
`10.
`
`In January 2002, a primary focus of the DPP-IV project team was to
`
`identify crystalline salts of L-224715 suitable for further research and
`
`development. The salt selection process for sitagliptin required both the synthesis
`
`and identification of candidate salts, as well as the development and scale-up of the
`
`synthesis reactions to produce quantities of the candidate salts sufficient to
`
`characterize their physical properties.
`
`
`
`
`
`11. The initial synthesis and identification of sitagliptin salts was assigned
`
`to Vicky Vydra
`
`a colleague of mine at Merck and a named co-inventor of the
`
`t. In December 2001, Ms. Vydra conducted a series of salt formation
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`5
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`Merck Exhibit 2127, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`experiments in an attempt to synthesize different salts of sitagliptin. I received the
`
`results of
`
`salt formation experiments, which she summarized in a
`
`memorandum dated December 18, 2001, in an email forwarded by another Merck
`
`colleague, Michael Palucki, on January 3, 2002. A true and correct copy of Dr.
`
`12. My understanding at the time
`
` EX2132.
`
`, which
`
`is consistent with my understanding today, is that she used stock solutions to
`
`dispense a 1:1 mole ratio of the sitagliptin freebase and the following acids into a
`
`96-well plate: acetic acid, citric acid, hydrochloric acid, phosphoric acid, sulfuric
`
`acid, tartaric acid, succinic acid, lactic acid, methanesulfonic acid, benzenesulfonic
`
`acid, and toluenesulfonic acid. See EX2132 at 2. After allowing the stock-solution
`
`solvents to evaporate, she added one of the following recrystallization solvents:
`
`ethanol, 2-
`
`1,2-
`
`-
`
`and methyl tert-butyl ether
`
`She then heated the 96-well plate to 70°C for 1 hour and then cooled
`
`acetonitrile,
`
`the plate slowly to 10°C over 8 hours. See id. She then isolated the solids she had
`
`obtained for x-
`
`
`
`13. The layout of the acid counterions and solvents that Ms. Vydra used,
`
`as well as the XRPD results she reported to the DPP-IV project team, are shown in
`
`the table excerpted from her memorandum below:
`
`6
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`Merck Exhibit 2127, Page 6
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`14. Based on this table, I understood at the time that Ms. Vydra had
`
`successfully synthesized crystalline phosphoric acid, sulfuric acid, tartaric acid,
`
`and benzenesulfonic acid salts of sitagliptin. See EX2132 at 3. She had also
`
`synthesized amorphous solid materials using phosphoric acid, sulfuric acid, and
`
`toluenesulfonic acid under certain solvent conditions. See id. In this experiment,
`
`Ms. Vydra did not report XRPD results for acetic acid, citric acid, hydrochloric
`
`acid, succinic acid, lactic acid, and methanesulfonic acid
`
`in any recrystallization
`
`solvent which indicated to me that these experiments had failed to produce
`
`appreciable quantities of the salt for XRPD analysis or had not simply not
`
`produced any salt using these counter acids at all.
`
`15.
`
`In my experience as of January 2002 which is consistent with my
`
`experience today the formation of a particular pharmaceutically acceptable salt of
`
`a given compound is an unpredictable reaction that depends on numerous factors,
`
`including temperature, the concentration of the counterion, the concentration of the
`
`7
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`Merck Exhibit 2127, Page 7
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`free form of the drug compound, the solvents being used, seeding, and time. The
`
`selection of a counterion is no guarantee that the counterion will form a salt with
`
`the free form. And even if a salt successfully forms, the properties of the salt
`
`including its thermal properties, stability, morphology, crystallinity, and other
`
`properties may not be desirable for use in a drug product. The results that Ms.
`
`Vydra obtained
`
`in which she was able to obtain only certain salts under certain
`
`experimental conditions were thus consistent with my experience that salt
`
`formation is unpredictable. And, as I discuss in further detail below, my own
`
`extensive experiments to form sitagliptin salts similarly confirmed that forming
`
`salts with sitagliptin was an unpredictable, trial-and-error process.
`
`16.
`
`In January 2002,
`
`experiments as a starting point, I set out to develop robust and reproducible
`
`synthetic processes to produce salts of sitagliptin in sufficient quantities for further
`
`characterization and with the goal of obtaining a salt with properties suitable for
`
`further development. In all, I ran over four dozen salt formation experiments using
`
`phosphoric acid, hydrochloric acid, tartaric acid, benzensulfonic acid, hydrobromic
`
`acid, succinic acid, citric acid, and sulfuric acid, before the selection by the DPP-
`
`IV project team of the 1:1 DHP salt for further development. These experiments
`
`are discussed in further detail in the following sections.
`
`8
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`Merck Exhibit 2127, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`17. Over the course of January and February 2002, I recorded over a
`
`dozen salt formation experiments in which I attempted to form phosphoric acid
`
`salts of sitagliptin. The following table identifies the dates on which I performed
`
`these experiments and the lab notebook entries where they were recorded:
`
`Date(s)
`Jan. 9, 2002
`Jan. 10, 2002
`Jan. 24, 2002
`Jan. 25, 2002
`Jan. 30, 2002
`
`Jan. 30, 2002
`
`Jan. 30, 2002
`
`Jan. 31, 2002
`Feb. 1, 2002
`Jan. 31, 2002
`Feb. 4, 2002
`Feb. 1, 2002
`
`Feb. 4, 2002
`Feb. 5, 2002
`Feb. 6, 2002
`Feb. 7, 2002
`Feb. 8, 2002
`Feb. 13, 2002
`Feb. 8, 2002
`Feb. 12, 2002
`Feb. 13, 2002
`Feb. 18, 2002
`Feb. 18, 2002
`Feb. 21, 2002
`
`Counter Acid
`Phosphoric
`
`LNB #
`70130-323
`
`Exhibit
`EX2128 at 24
`
`Phosphoric
`
`70130-393
`
`EX2128 at 146
`
`Phosphoric
`
`70316-011
`
`EX2129 at 81
`
`Phosphoric
`
`70316-013
`
`EX2129 at 83
`
`Phosphoric
`
`70316-015
`
`EX2129 at 85
`
`Phosphoric
`
`70316-017
`
`EX2129 at 87
`
`Phosphoric
`
`70316-019
`
`EX2129 at 90 91
`
`Phosphoric
`
`70316-021
`
`EX2129 at 92
`
`Phosphoric
`
`70316-025
`
`EX2129 at 104 05
`
`Phosphoric
`
`70316-031
`
`EX2129 at 116 17
`
`Phosphoric
`
`70316-035
`
`EX2129 at 124 26
`
`Phosphoric
`
`70316-037
`
`EX2129 at 152
`
`Phosphoric
`
`70316-039
`
`EX2129 at 160
`
`Phosphoric
`
`70316-041
`
`EX2129 at 176
`
`9
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`Merck Exhibit 2127, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`Counter Acid
`Phosphoric
`
`LNB #
`70316-043
`
`Exhibit
`EX2129 at 196
`
`Phosphoric
`
`70316-049
`
`EX2129 at 233
`
`Date(s)
`Feb. 22, 2002
`Feb. 25, 2002
`Feb. 26, 2002
`Feb. 28, 2002
`
`
`
`18.
`
`In general, my experiments entailed contacting the sitaglipin freebase
`
`4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazine-7(8H)-
`
`yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
`
`ic acid in a solvent or a
`
`mixture of solvents (such as ethanol and water). Illustratively, as described in
`
`EX2129 (LNB 70316-025) at 104, on February 4, 2002, I combined equimolar
`
`amounts of the freebase and phosphoric acid in an aqueous ethanol solution at a
`
`temperature of 63°C. This resulted in a white solid, which I proceeded to
`
`recrystallize by adding additional solvent and further heating and cooling of the
`
`solution. On February 5, 2002, I isolated 199 mg of the crystals that had formed as
`
`a white, highly crystalline solid. Through HPLC, I determined that 83.6% by
`
`weight of this material corresponded to the sitagliptin freebase, which confirmed
`
`my understanding that I had synthesized the 1:1 DHP salt based on theoretical
`
`freebase content by HPLC of 80.5%.
`
`19. Consistent with my general experience with salt formation
`
`and my
`
`experience as of January 2002 my experiments with phosphoric acid were
`
`unpredictable. Although I was able through persistence to obtain the 1:1 DHP salt
`
`in each of the experiments above, the phosphoric acid salt did not immediately
`
`10
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`Merck Exhibit 2127, Page 10
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`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`appear under my initial reaction conditions, which required me to consider whether
`
`additional steps
`
`such as heating or cooling; adding additional solvent, a different
`
`solvent, or switching solvents
`
`could be taken to generate the salt.1 For at least
`
`one experimental arm, I did not obtain a phosphoric salt despite dissolving and
`
`bringing the freebase and phosphoric acid into contact in solution. See EX2129
`
`(LNB 70316-019) at 90 91 (Vial E).
`
`
`1 See EX2128 (LNB 70130-393) at 146 (solution of the freebase and H3PO4
`
`remained clear even after heating; salt formed only after 0.5 mL of IPA); EX2129
`
`(LNB 70316-011) at 81 (solution of freebase and H3PO4 in tetrahydrofuran
`
`0 minutes after more THF); id;
`
`(LNB 70316-013) at 83 (solution of freebase and H3PO4 in acetonitrile remained
`
`clear for 1 hour and then formed a salt after adding 0.5 mL MTBE); id. (LNB
`
`70316-019) at 90 (ethanol solutions containing between 10 and 40% water took up
`
`to 6 hours to form salts (Vials A, B, C, D); 50% solution (Vial E) remained clear
`
`even after 6 hours; after heating to 70°C and cooling to room temperature, salt did
`
`not reform in 30 and 40% solutions (Vials C & D) and only formed salts 1 hour
`
`after stirring); id. (LNB 70316-021) at 92 (solution of freebase and H3PO4 in
`
`methanol did not form solids after heating to 70°C).
`
`11
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`Merck Exhibit 2127, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`20. Additionally, the solid materials I was able to obtain varied greatly in
`
`their quality and suitability for further pharmaceutical development. My first
`
`experiment with phosphoric acid (LNB 70130-323) on January 9, 2002, formed
`
`what I understood to be the 1:1 DHP salt, but the resulting solids consisted of very
`
`small particles with little or no crystallinity
`
`completely unsuitable for
`
`development. See EX2128 at 24. This was despite the fact that I had used large
`
`amount of the freebase and multiple solvents and temperature cycles to improve
`
`the quality of the salt. Id. These poor initial results with phosphoric acid led me to
`
`deprioritize further work on the phosphate salt until later that month. The results
`
`of my subsequent experiments were equally unpredictable, as the solids I obtained
`
`ranged from amorphous to crystalline and often changed their crystallinity and
`
`morphology due to changes in certain conditions or simply the passage of time.2
`
`
`2 See EX2128 (LNB 70130-
`
`s with little or no
`
`id. (LNB 70130-393) at 146 (initially amorphous solids that later
`
`see also EX2129 (LNB 70316-013) at 83
`
`id. (LNB 70316-015) at 85
`
`id. (LNB 70316-017) at
`
`became crystalline plates); id. (LNB 70316-
`
`12
`
`Merck Exhibit 2127, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`This was consistent with my overall experience that the properties of a given salt
`
`are unpredictable until it is created and characterized.
`
`21.
`
`In each of the experiments above, I used an equimolar or slightly
`
`more than equimolar amount of phosphoric acid as compared to the sitagliptin
`
`freebase. Although I believed that the 1:1 DHP salt was one possible
`
`stoichiometry that could result from this proportion of starting materials (as well
`
`my reaction conditions), other stoichiometries were possible due (at least) to the
`
`polyprotic nature of phosphoric acid. I was aware of this possibility, and in several
`
`experiments, I confirmed the 1:1 stoichiometry of the phosphoric acid salts using
`
`HPLC. See EX2129 (LNB 70316-025) at 104 (83.6% freebase by weight
`
`compared to a theoretical amount of 80.5%); id. (LNB 70316-035) at 124 (80.6%
`
`freebase by weight compared to theoretical 80.6%); id. (LNB 70316-043) at 196
`
`(80.0% freebase by weight compared to 80.6%). The 1:1 stoichiometry was later
`
`confirmed by Dr. Leigh Shultz
`
`another member of the DPP-IV project team from
`
`the Pharmaceutical Research & Development group
`
`also using HPLC.
`
`
`that turned over to crystalline plates after heating and cooling); EX2131 (Jan. 28,
`
`2002 Weekly Report) at 8 (discussing 70130-393); id. (Feb. 4, 2020 Weekly
`
`Report) at 9-10 (discussing 70316-015 and -017); id. (Feb. 11, 2002 Weekly
`
`Report) at 12 (discussing 70316-011, -013, and -015).
`
`13
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`Merck Exhibit 2127, Page 13
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`22. As indicated in my lab notebooks, I provided several samples of the
`
`phosphoric acid salts I synthesized to other members of the DPP-IV project team.
`
`I provided these samples for the purpose of further characterizing
`
`physical properties and to use in the DPP-IV project
`
`an
`
`oral dosage form to treat patients with type 2 diabetes. Aside from Dr. Shultz, who
`
`was responsible for assessing the salt for various properties including stability and
`
`suitability for formulation, I provided samples to Dr. Christopher Lindemann from
`
`Physical Measurements for further solid-state characterization, as well as to
`
`various other members of the DPP-IV project team responsible for formulation
`
`development and clinical research, including clinical trials in humans. See, e.g.,
`
`EX2129 (LNB 70316-026) at 105
`
`to
`
`id. (LNB 70316-036) at 124
`
`-U-
`
`id. (LNB 70316-035) at 130
`
`for Safety Assessment
`
`3
`
`
`3 At the time of my experiments with phosphoric acid and my formation of the 1:1
`
`DHP salt of sitagliptin, I understood that I was under an obligation to assign (and
`
`did assign) this subject matter to Merck, in accordance with Me
`
`procedures at the time and as a condition of my employment.
`
`14
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`Merck Exhibit 2127, Page 14
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`
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`
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`23. Although I understood that Ms. Vydra had not reported forming a
`
`crystalline hydrochloric acid salt of sitagliptin as part of her initial salt formation
`
`experiments in December 2001, I attempted to form an HCl salt in light of the
`
`widespread use of this counterion, which was (and is) one of the most common
`
`if
`
`not the most common
`
`counterion in pharmaceutical development. The following
`
`table identifies the dates on which I performed my experiments to form an HCl salt
`
`of sitagliptin and the lab notebook entries where they were recorded:
`
`Date(s)
`Jan. 17, 2002
`Jan. 18, 2002
`Jan. 17, 2002
`
`Jan. 17, 2002
`
`Jan. 18, 2002
`Jan. 21, 2002
`Jan. 21, 2002
`Jan. 22, 2002
`
`
`
`Counter Acid
`Hydrochloric
`
`LNB #
`70130-361
`
`Exhibit
`EX2128 at 92
`
`Hydrochloric
`
`70130-363
`
`EX2128 at 96
`
`Hydrochloric
`
`70130-365
`
`EX2128 at 98
`
`Hydrochloric
`
`70130-369
`
`EX2128 at 102
`
`Hydrochloric
`
`70130-371
`
`EX2128 at 105
`
`24.
`
`In my first experiment with hydrochloric acid, EX2128 (LNB 70130-
`
`361) at 92, I combined a 25 µL solution of hydrochloric acid in diethyl ether
`
`2
`
`solids
`
`a hydrochloric acid salt of sitagliptin
`
`formed, which appeared
`
`birefringent under polarized light. I proceeded to recrystallize the salt by adding
`
`additional solvents (methanol and IPA) and heating and cooling the solution. After
`
`15
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`Merck Exhibit 2127, Page 15
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`aging the solution overnight at room temperature, small crystals had developed
`
`which appeared as needles under microscope, as shown in Figure 1.
`
`
`
`Figure 1. Microscope image of sitagliptin HCl crystals.
`
`25. Despite my initial success, the results of my other experiments with
`
`hydrochloric acid were inconsistent and confirmed my overall experience and
`
`understanding at the time that salt formation is unpredictable. An experiment on
`
`January 21, 2002 used similar solvents (IPA, Et2O, methanol) but failed to produce
`
`an HCl salt, while another on January 18, 2002, did. Compare EX2128 (LNB
`
`70130-371) at 105
`
`with EX2128 (LNB 70130-369) at 102
`
`and IPA also did not produce a salt. See EX2128 (LNB 70130-363) at 96
`
`id. (LNB 70130-365) at 98
`
`
`
`16
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`Merck Exhibit 2127, Page 16
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`DECLARATION OF KARL B. HANSEN, PH.D.
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`
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`26.
`
`In parallel with my experiments with phosphoric acid and
`
`hydrochloric acid, I performed extensive work to synthesize sitagliptin salts using
`
`tartaric acid and benzenesulfonic acid. These experiments were motivated by my
`
`t formation experiments, which suggested to me
`
`that the tartrate and besylate salts were the most promising candidates. See
`
`EX2131 (Jan. 7, 2002 Weekly Report) at 1. Dr. Shultz had also requested that I
`
`produce tartrate salts of sitagliptin first, based on the fact that a tartrate salt of L-
`
`221869, a compound closely related to sitagliptin that was also under development
`
`by Merck as a potential DPP-IV inhibitor at the time, had been identified as the
`
`best salt form candidate for that compound. See EX2133 (Jan. 11, 2002 email
`
`from L. Shultz to K. Hansen) at 1. Despite these initial assessments from myself
`
`and Dr. Shultz, neither the tartrate nor besylate salts were ultimately selected for
`
`further development.
`
`
`
`
`
`27. As part of my salt formation experiments, I also attempted to form a
`
`number of other salts of sitagliptin, including from hydrobromic acid, succinic
`
`acid, citric acid, and sulfuric acid. The following table identifies the lab notebook
`
`entries where I recorded my experiments for these other acids.
`
`17
`
`Merck Exhibit 2127, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`Counter Acid
`Hydrobromic
`
`LNB #
`70130-325
`
`Exhibit
`EX2128 at 26
`
`Succinic
`
`70130-351
`
`EX2128 at 80
`
`Succinic
`
`70130-355
`
`EX2128 at 85
`
`Succinic
`
`70130-357
`
`EX2128 at 87
`
`Citric
`
`Citric
`
`Succinic
`
`70130-383
`
`Sulfuric
`
`70130-395
`
`EX2128 at 149
`
`70130-367
`
`EX2128 at 100
`
`70130-383
`
`EX2128 at 128
`
`EX2128 at 128
`
`Date
`Jan. 10, 2002
`
`Jan. 15, 2002
`
`Jan. 16, 2002
`
`Jan. 16, 2002
`Jan. 17, 2002
`Jan. 17, 2002
`
`Jan. 22, 2002
`Jan. 24, 2002
`Jan. 22, 2002
`Jan. 24, 2002
`Jan. 24, 2002
`Jan. 25, 2002
`
`
`
`28.
`
`In the case of hydrobromic acid, I was only able to form a transient
`
`foam or oily precipitate from which I was not able to isolate solid material. The
`
`remaining counter acids formed salts inconsistently, sometimes not at all, or
`
`formed amorphous material or sticky solids not suitable for further development.
`
`See also EX2131 (Jan. 14, 2002 Weekly Report) at 3; id. (Jan. 21, 2002 Weekly
`
`Report) at 5 6; id. (Jan. 28, 2002 Weekly Report) at 7 8. This was particularly
`
`surprising for succinic acid due its close structural similarity to tartaric acid, which
`
`had consistently formed salts in both my experiments and the initial salt formation
`
`experiments performed by Ms. Vydra.
`
`18
`
`Merck Exhibit 2127, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`IV.
`
`
`
`29. Following the selection of the 1:1 DHP salt of sitagliptin for further
`
`development, I synthesized several large-scale batches of the salt for use in
`
`formulation development and clinical research by other members of the DPP-IV
`
`project team. I recorded the syntheses for two of these batches in EX2130 (LNB
`
`72471-11, -17, -49) at 4 10, 46.
`
`30. These two batches (72471-017 and 72471-049) were subsequently
`
`designated for further clinical research and development as lots 006F007 and
`
`224715, and variations thereof). This information was
`
`-
`
`-
`
`respect to D-Sheets. In the usual and ordinary course of its business
`
`and as part
`
`of
`
`Merck
`
`required clinical batches to be accompanied by a D-Sheet identifying the batch and
`
`summarizing the analytical tests that had been performed to ensure the identity and
`
`purity of the drug substance. The information that appears on a D-Sheet was
`
`communicated by the Merck scientists responsible for determining or running the
`
`particular test or experiment in question. True and correct copies of the D-Sheets
`
`for the two batches discussed above may be found in EX2135 and EX2136.
`
`19
`
`Merck Exhibit 2127, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`31. The purpose of batches 006F007 and 006F017 was to provide clinical
`
`supplies of the 1:1 DHP salt of sitagliptin for Phase I and Phase II studies in
`
`humans as well as formulation development and toxicity studies. These purposes
`
`were reflected on the respective D-Sheets for these batches. See EX2135
`
`32. Based on the goals of the DPP-IV project and the previous studies
`
`36
`
`
`
`had been shown to have relevant biological activity (inhibition of the DPP-IV
`
`enzyme) to treat type 2 diabetes in humans. My belief (and the goal of the DPP-IV
`
`project) was that a pharmaceutical composition comprising sitagliptin would prove
`
`to be have efficacy against type 2 diabetes. This expectation was confirmed in
`
`November 2002 when I and the rest of the DPP-IV project team learned that
`
`sitagliptin had achieved pharmacological proof of concept using a therapeutically
`
`effective dose in a Phase IB study in humans. This information was communicated
`
`to me in an email from Cindy Starbuck on November 22, 2002, a true and correct
`
`copy of which may be found in EX2139.
`
`
`
`20
`
`Merck Exhibit 2127, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`V.
`
`33.
`
`In late March 2003, Stephen Cypes
`
`a colleague of mine at Merck
`
`and a co-
`
`t
`
`synthesized a new crystal form of the 1:1
`
`DHP salt of sitagliptin. This new form was subsequently characterized and
`
`determined to be a crystalline monohydrate.
`
`34.
`
`I was personally surprised by the discovery of the crystalline
`
`monohydrate because members of the DPP-IV project team including myself had
`
`spent over a year experimenting with and developing anhydrous forms of the 1:1
`
`DHP salt of sitagliptin without synthesizing a crystalline monohydrate. Indeed,
`
`many of my attempts to crystallize a phosphoric acid salt of sitagliptin in January
`
`and February 2002 took place in aqueous solutions. See supra Section III.B.4 In or
`
`around November 2002, I deliberately set out to synthesize a hydrate form of the
`
`1:1 DHP salt in the hopes that the hydrate would provide a pathway to a pure
`
`
`4 See also EX2131 (Apr. 22, 2002 Weekly Report) at 17 (reporting my
`
`development of an unseeded process for obtaining the 1:1 DHP salt using mixture
`
`of ethanol and water); id. (Nov. 11, 2002 Weekly Report) at 18 (summarizing
`
`experiments I conducted in November 2002 to crystallize the phosphoric acid salt
`
`from a series of solvent/water mixtures, without obtaining a crystalline
`
`monohydrate).
`
`21
`
`Merck Exhibit 2127, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`anhydrous form, rather the mixtures of Form I and the Form III anhydrate. These
`
`experiments involved experiments in pure water and mixtures of water with tert-
`
`-
`
` and other solvents including methanol, ethanol, and IPA. See
`
`EX2131 (Nov. 11, 2002 Weekly Report) at 18 (reporting recrystallizations in
`
`aqueous mixtures of t-BuOH, methanol, acetone, IPA, n-propa
`
`-
`
`ethanol containing 24%, 32%, 16%, 24%, 24%, and 28% water, respectively, as
`
`well as pure water). Despite this, I did not obtain a hydrate of the 1:1 DHP salt,
`
`much less the crystalline monohydrate.
`
`35. Additionally, Merck had made concerted efforts in 2002 (in parallel
`
`with salt selection) to identify all polymorphs of the 1:1 DHP salt of sitagliptin.
`
`This endeavor was taken very seriously by the DPP-IV project team as the
`
`appearance of a new polymorph during pilot-plant-scale production (necessary to
`
`produce large quantities of the sitagliptin drug substance) could potentially have
`
`delayed the project by several months, if not years.
`
`36.
`
`sitagliptin was conducted both internally and using the Symyx polymorph
`
`screening platform. See EX2134 at 1 (a February 7, 2002 email from me noting
`
`that Dr. Lindemann would continue to look for other polymorphs of the phosphoric
`
`acid salt). True and correct copies of the results from a November 2001 internal
`
`polymorph screen and a Symyx polymorph screen may be found in EX2137 and
`
`22
`
`Merck Exhibit 2127, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF KARL B. HANSEN, PH.D.
`
`EX2138. None of these efforts yielded a crystalline monohydrate despite using
`
`different crystallization techniques (heating, cooling, evaporation), and solvents
`
`including water. It was not until Mr.
`
`in
`
`March 2003 that the DPP-IV project team identified the new monohydrate crystal
`
`of the 1:1 DHP salt of sitagliptin.
`
`*
`
`*
`
`*
`
`I hereby declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and belief are believed to be true;
`
`and further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Dated: August 20, 2020
`
`Karl B. Hansen, Ph.D.
`
`23
`
`Merck Exhibit 2127, Page 23
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
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