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 No. IPR2020-00040
`U.S. Patent No. 7,326,708
`__________________
`
`DECLARATION OF VICKY K. VYDRA
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 1
`
`
`__________________
`
`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
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 1
`
`
`
`DECLARATION OF VICKY K. VYDRA
`
`I, Vicky K. Vydra, hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`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.
`
`(“Merck”) is the owner and assignee of the ’708 patent.
`
`2.
`
`In this declaration, I attest to certain facts related to the discovery of
`
`the dihydrogenphosphate (“DHP”) salt of 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 (also known as “sitagliptin”) claimed in the ’708 patent. The structural
`
`formula of the DHP salt of sitagliptin in a 1:1 stoichiometric ratio as claimed in the
`
`’708 patent as shown below:
`
`II.
`
`BACKGROUND
`
`3.
`
`I received a Bachelor of Arts degree in chemistry from Rutgers, The
`
`State University of New Jersey, in 2001.
`
`4.
`
`From June 2001 to June 2006, I was employed by Merck as a Staff
`
`Chemist in the Process Research Department of Merck Research Laboratories. My
`
`2
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 2
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`
`
`DECLARATION OF VICKY K. VYDRA
`
`work involved attempting to identify candidate salts and polymorphic forms of
`
`active pharmaceutical ingredients and other compounds of interest for further solid
`
`form and formulation development.
`
`5.
`
`Since departing Merck in June 2006, I have held several positions at
`
`Bristol-Myers Squibb (“BMS”), where I am currently employed. My present title
`
`at BMS is Specialty Laboratories Category Manager, Clinical Laboratory Services,
`
`Global Procurement.
`
`III.
`
`SYNTHESIS AND CHARARACTERIZATION OF THE
`DIHYDROGENPHOSPHATE SALT OF SITAGLIPTIN
`
`6.
`
`In or around December 2001, I began collaborating with the project
`
`team developing L-224715, the internal Merck designation for sitagliptin. I
`
`understood that sitagliptin had been identified by Merck as an inhibitor of the
`
`enzyme dipeptidyl peptidase IV (“DPP-IV”) and that Merck was attempting to
`
`develop L-224715 into a dosage form for the treatment of type 2 diabetes.
`
`7.
`
`As part of the project, I was asked to perform experiments in an
`
`attempt to synthesize one or more crystalline salts of L-224715. The intended
`
`purpose of my experiments was to attempt to identify crystalline salts of sitagliptin
`
`suitable for further development into a final formulated dosage form.
`
`8.
`
`In accordance with Merck’s policies and my own recordkeeping
`
`practices, I recorded the experiments I conducted in my lab notebook. Over the
`
`course of my career at Merck, I maintained many lab notebooks; my lab notebooks
`
`3
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 3
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`
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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
`
`course of my regularly conducted research activities on behalf of Merck. A true
`
`and correct copy of the relevant pages of the lab notebook where I recorded my
`
`experiments with L-224715 discussed herein is attached as Appendix A.
`
`9.
`
`On December 12, 2001, I began conducting a set of experiments with
`
`L-224715 in an attempt to form one or more salts of the compound. As described
`
`on page 59 of my lab notebook, I conducted these experiments in a 96-well plate.
`
`10.
`
`In column 4 of the 96-well plate, I dispensed solutions containing
`
`equimolar amounts of L-224715 freebase and phosphoric acid. I allowed the
`
`solvent in the wells to evaporate before proceeding further.
`
`11.
`
`I then dispensed eight different recrystallization solvents, ethanol, 2-
`
`propanol, toluene, nitromethane, acetonitrile, 1,2-dimethoxyethane (or “1,2-
`
`DME”), isopropyl acetate, or methyl tert-butyl ether (or “MTBE”), one per row in
`
`rows 1 through 8 (or A through H), respectively, across the 96-well plate.
`
`12. After adding the recrystallization solvents, I capped the 96-well plate,
`
`heated it to 70°C for one hour to dissolve any solids, and then lowered the
`
`temperature from 70°C to 10°C over the course of 8 hours.
`
`13. On December 14, 2001, I analyzed the results of my experiments
`
`visually under a cross-polarized light microscope. I determined that solid material
`
`had precipitated in the wells of column 4 in which I had reacted L-224715 freebase
`
`4
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 4
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`
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`DECLARATION OF VICKY K. VYDRA
`
`and phosphoric acid. I proceeded to isolate and prepare the solids for X-Ray
`
`Powder Diffraction (“XRPD”) analysis.
`
`14. On December 18, 2001, I obtained 2-theta patterns from XRPD
`
`(reflectance) analysis of the solid material I had been able to isolate and prepare in
`
`sufficient quantities on December 14. To analyze my results, I compared the
`
`patterns to a reference pattern for the crystalline freebase of L-224715, as well as a
`
`reference pattern for Teflon. The XRPD diffraction patterns that I compared are
`
`shown on page 62 of my lab notebook in Appendix A and below:
`
`5
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 5
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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
`
`synthesized a crystalline phosphoric acid salt of L-224715 from recrystallization in
`
`ethanol (well A4), acetonitrile (well E4), and 1,2-DME (well F4). The
`
`experiments in 2-propanol and isopropyl acetate (wells B4 and G4) produced
`
`mostly amorphous matter, albeit with some amount of crystalline solids.
`
`16.
`
`I understood that additional testing would take place to determine the
`
`specific properties of the crystalline phosphoric acid salt I had synthesized,
`
`including to confirm the stoichiometric ratio between the phosphoric acid
`
`counterion and the ionized sitagliptin freebase.
`
`17. At the time that I synthesized the crystalline phosphoric acid salt
`
`under the conditions set forth above and in my lab notebook, I understood that one
`
`possible stoichiometric ratio was a 1:1 salt of sitagliptin and phosphoric acid,
`
`corresponding to the DHP salt of sitagliptin shown in claim 1 of the ’708 patent.
`
`18. At the time, I believed that based on the reaction conditions I had
`
`used, including the relative amounts of L-224715 freebase and phosphoric acid, as
`
`well as my analysis of the XRPD diffraction patterns I had obtained, it was likely
`
`that I had produced a DHP salt of sitagliptin with a 1:1 stoichiometric ratio of the
`
`ionized sitagliptin freebase to the phosphoric acid counterion.
`
`6
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 6
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`
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`DECLARATION OF VICKY K. VYDRA
`
`19.
`
`Specifically, it was my belief at the time, assuming that I had
`
`successfully formed a crystalline phosphoric acid salt of sitagliptin, the following
`
`reaction had likely taken place:
`
`20.
`
`I believed that the crystalline salt that I had synthesized would be
`
`useful for further development and formulation as part of the L-224715 project.
`
`Accordingly, I summarized my results in a memorandum to Michael Palucki, the
`
`L-224715 project team member who had requested that I perform the experiments
`
`I have described above.
`
`21.
`
`I emailed my memorandum to Dr. Palucki on December 18, 2001. A
`
`true and correct copy of my email, which Dr. Palucki forwarded to Karl Hansen on
`
`January 3, 2002, is attached as Appendix B. I understand that Dr. Hansen is also a
`
`named inventor on the ’708 patent.
`
`7
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 7
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 8
`
`
`
`(cid:36)(cid:83)(cid:83)(cid:72)(cid:81)(cid:71)(cid:76)(cid:91)(cid:3)(cid:36)
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 9
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`
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 10
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 11
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`
`
`Mer
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 12
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 13
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 14
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 15
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 16
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 17
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 18
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 19
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 20
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`
`
`A(cid:83)(cid:83)(cid:72)(cid:81)di(cid:91) B
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 21
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`
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`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 22
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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
`
`F
`
`F
`
`F
`
`O
`
`NH2
`
`N
`
`N
`
`N
`
`N
`
`CF3
`
`L-224715
`
`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.
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 23
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`
`
`Results: X-Ray Powder Diffraction Results
`
`12--None
`
`FB
`
`11--p-Toluenesulfonic Acid
`
`10--Benzenesulfonic Acid
`
`9--Methanesulfonic Acid
`
`3
`
`3
`3 A
`
`8--Lactic Acid
`
`7--Succinic Acid
`
`6--L-Tartaric Acid
`
`5--Sulfuric Acid
`
`4--Phosphoric Acid
`
`3--HCl
`
`2--Citric Acid
`
`1--Acetic Acid
`
`1
`
`1
`1
`
`A
`
`2
`
`2
`2
`
`A
`
`A
`
`4
`4
`
`4
`4
`
`4
`4
`
`Columns--Bases:
`
`Solvents:
`Ethanol
`2-Propanol
`Toluene
`Nitromethane
`Acetonitrile
`1,2-DME
`Isopropyl Acetate
`MTBE
`
`FB =Free Base
`
`A = Amorphous
`
`Tf = Teflon
`
`# = New crystalline form
`
`Merk Sharp & Dohme Corp. Exhibit 2002
`Mylan Pharmaceuticals Inc. v. Merk Sharp & Dohme Corp.
`IPR2020-00040
`Page 24
`
`
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