`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case No. IPR2020-00040
`U.S. Patent No. 7,326,708
`__________________
`
`DECLARATION OF VICKY K. VYDRA
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF VICKY K. VYDRA
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`I, Vicky K. Vydra, hereby declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I am a named inventor of subject matter claimed in U.S. Patent No.
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`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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`In this declaration, I attest to certain facts related to the discovery of
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`the 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 (also known as “sitagliptin”) claimed in the ’708 patent. The structural
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`formula of the DHP salt of sitagliptin in a 1:1 stoichiometric ratio as claimed in the
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`’708 patent as shown below:
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`II.
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`BACKGROUND
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`3.
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`I received a Bachelor of Arts degree in chemistry from Rutgers, The
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`State University of New Jersey, in 2001.
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`4.
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`From June 2001 to June 2006, I was employed by Merck as a Staff
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`Chemist in the Process Research Department of Merck Research Laboratories. My
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`2
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`DECLARATION OF VICKY K. VYDRA
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`work involved attempting to identify candidate salts and polymorphic forms of
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`active pharmaceutical ingredients and other compounds of interest for further solid
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`form and formulation development.
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`5.
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`Since departing Merck in June 2006, I have held several positions at
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`Bristol-Myers Squibb (“BMS”), where I am currently employed. My present title
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`at BMS is Specialty Laboratories Category Manager, Clinical Laboratory Services,
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`Global Procurement.
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`III.
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`SYNTHESIS AND CHARARACTERIZATION OF THE
`DIHYDROGENPHOSPHATE SALT OF SITAGLIPTIN
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`6.
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`In or around December 2001, I began collaborating with the project
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`team developing L-224715, the internal Merck designation for sitagliptin. I
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`understood that sitagliptin had been identified by Merck as an inhibitor of the
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`enzyme dipeptidyl peptidase IV (“DPP-IV”) and that Merck was attempting to
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`develop L-224715 into a dosage form for the treatment of type 2 diabetes.
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`7.
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`As part of the project, I was asked to perform experiments in an
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`attempt to synthesize one or more crystalline salts of L-224715. The intended
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`purpose of my experiments was to attempt to identify crystalline salts of sitagliptin
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`suitable for further development into a final formulated dosage form.
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`8.
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`In accordance with Merck’s policies and my own recordkeeping
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`practices, I recorded the experiments I conducted in my lab notebook. Over the
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`course of my career at Merck, I maintained many lab notebooks; my lab notebooks
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`DECLARATION OF VICKY K. VYDRA
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`are contemporaneous records based on my personal knowledge and kept in the
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`course of my regularly conducted research activities on behalf of Merck. A true
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`and correct copy of the relevant pages of the lab notebook where I recorded my
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`experiments with L-224715 discussed herein is attached as Appendix A.
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`9.
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`On December 12, 2001, I began conducting a set of experiments with
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`L-224715 in an attempt to form one or more salts of the compound. As described
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`on page 59 of my lab notebook, I conducted these experiments in a 96-well plate.
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`10.
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`In column 4 of the 96-well plate, I dispensed solutions containing
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`equimolar amounts of L-224715 freebase and phosphoric acid. I allowed the
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`solvent in the wells to evaporate before proceeding further.
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`11.
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`I then dispensed eight different recrystallization solvents, ethanol, 2-
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`propanol, toluene, nitromethane, acetonitrile, 1,2-dimethoxyethane (or “1,2-
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`DME”), isopropyl acetate, or methyl tert-butyl ether (or “MTBE”), one per row in
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`rows 1 through 8 (or A through H), respectively, across the 96-well plate.
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`12. After adding the recrystallization solvents, I capped the 96-well plate,
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`heated it to 70°C for one hour to dissolve any solids, and then lowered the
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`temperature from 70°C to 10°C over the course of 8 hours.
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`13. On December 14, 2001, I analyzed the results of my experiments
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`visually under a cross-polarized light microscope. I determined that solid material
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`had precipitated in the wells of column 4 in which I had reacted L-224715 freebase
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`4
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`DECLARATION OF VICKY K. VYDRA
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`and phosphoric acid. I proceeded to isolate and prepare the solids for X-Ray
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`Powder Diffraction (“XRPD”) analysis.
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`14. On December 18, 2001, I obtained 2-theta patterns from XRPD
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`(reflectance) analysis of the solid material I had been able to isolate and prepare in
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`sufficient quantities on December 14. To analyze my results, I compared the
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`patterns to a reference pattern for the crystalline freebase of L-224715, as well as a
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`reference pattern for Teflon. The XRPD diffraction patterns that I compared are
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`shown on page 62 of my lab notebook in Appendix A and below:
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`DECLARATION OF VICKY K. VYDRA
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`15. Based on my analysis, I concluded that I had a successfully
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`synthesized a crystalline phosphoric acid salt of L-224715 from recrystallization in
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`ethanol (well A4), acetonitrile (well E4), and 1,2-DME (well F4). The
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`experiments in 2-propanol and isopropyl acetate (wells B4 and G4) produced
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`mostly amorphous matter, albeit with some amount of crystalline solids.
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`16.
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`I understood that additional testing would take place to determine the
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`specific properties of the crystalline phosphoric acid salt I had synthesized,
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`including to confirm the stoichiometric ratio between the phosphoric acid
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`counterion and the ionized sitagliptin freebase.
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`17. At the time that I synthesized the crystalline phosphoric acid salt
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`under the conditions set forth above and in my lab notebook, I understood that one
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`possible stoichiometric ratio was a 1:1 salt of sitagliptin and phosphoric acid,
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`corresponding to the DHP salt of sitagliptin shown in claim 1 of the ’708 patent.
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`18. At the time, I believed that based on the reaction conditions I had
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`used, including the relative amounts of L-224715 freebase and phosphoric acid, as
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`well as my analysis of the XRPD diffraction patterns I had obtained, it was likely
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`that I had produced a DHP salt of sitagliptin with a 1:1 stoichiometric ratio of the
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`ionized sitagliptin freebase to the phosphoric acid counterion.
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`6
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`DECLARATION OF VICKY K. VYDRA
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`19.
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`Specifically, it was my belief at the time, assuming that I had
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`successfully formed a crystalline phosphoric acid salt of sitagliptin, the following
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`reaction had likely taken place:
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`20.
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`I believed that the crystalline salt that I had synthesized would be
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`useful for further development and formulation as part of the L-224715 project.
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`Accordingly, I summarized my results in a memorandum to Michael Palucki, the
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`L-224715 project team member who had requested that I perform the experiments
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`I have described above.
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`21.
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`I emailed my memorandum to Dr. Palucki on December 18, 2001. A
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`true and correct copy of my email, which Dr. Palucki forwarded to Karl Hansen on
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`January 3, 2002, is attached as Appendix B. I understand that Dr. Hansen is also a
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`named inventor on the ’708 patent.
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`7
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`(cid:36)(cid:83)(cid:83)(cid:72)(cid:81)(cid:71)(cid:76)(cid:91)(cid:3)(cid:36)
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`Mer
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`A(cid:83)(cid:83)(cid:72)(cid:81)di(cid:91) B
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`Acid Salt Screen of L-224715 Free Base
`Created By: V.Vydra x-0307
`Notebook #: 72190-059
`Created for: M. Palucki
`Date: 18 Dec 2001
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`F
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`F
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`F
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`O
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`NH2
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`N
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`N
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`N
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`N
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`CF3
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`L-224715
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`Procedure:
`A 23 mg/ml stock solution of the substrate (L-224715 Free Base) was prepared by
`dissolving 525 mg of the L-224715 Free Base in 25ml of 1,2-Dichloroethane. Using the
`Cavro Liquid Handling Robot, 200 ul of this substrate stock solution was dispensed into
`each of the 96 wells (resulting in 4.6mg of substrate per well). Following the substrate
`dispense a 1:1 mole ratio of the acid stock solutions (0.03M) was then dispensed, by
`columns, to each of the 96 wells. The 96 well plate was placed in the Genevac to
`evaporate off the solvents. The plate was Genevaced at 1300rpm, at 35(cid:1)C for 6 hours
`(8mbar pressure). Once dry, the crystallization solvents were dispensed (by row) to the
`96 well plate. (200ul of crystallization solvent per well.) The Plate was capped and
`placed into a 70(cid:1)C oven for 1 hour to dissolve any solids. A temperature ramp from 70
`–10 (cid:1)C over 8 hours was applied to the plate as crystallization conditions.
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`Merk Sharp & Dohme Corp. Exhibit 2002
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`IPR2020-00040
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`
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`Results: X-Ray Powder Diffraction Results
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`12--None
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`FB
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`11--p-Toluenesulfonic Acid
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`10--Benzenesulfonic Acid
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`9--Methanesulfonic Acid
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`3
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`3
`3 A
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`8--Lactic Acid
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`7--Succinic Acid
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`6--L-Tartaric Acid
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`5--Sulfuric Acid
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`4--Phosphoric Acid
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`3--HCl
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`2--Citric Acid
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`1--Acetic Acid
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`1
`
`1
`1
`
`A
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`2
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`2
`2
`
`A
`
`A
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`4
`4
`
`4
`4
`
`4
`4
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`Columns--Bases:
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`Solvents:
`Ethanol
`2-Propanol
`Toluene
`Nitromethane
`Acetonitrile
`1,2-DME
`Isopropyl Acetate
`MTBE
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`FB =Free Base
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`A = Amorphous
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`Tf = Teflon
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`# = New crystalline form
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`Merk Sharp & Dohme Corp. Exhibit 2002
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