`__________________
`
`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 GARY HERMAN, M.D.
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`1
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`Merck Exhibit 2109, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF GARY HERMAN, M.D.
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`I, Gary Herman, M.D., hereby declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I understand that this proceeding involves issues related to U.S. Patent
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`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 17 of the ’708 patent claims a pharmaceutical
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`composition comprising a therapeutically effective amount of the 1:1
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`dihydrogenphosphate salt of sitagliptin (“1:1 sitagliptin DHP”) in association with
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`one or more pharmaceutically acceptable carriers.
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`3.
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`I understand that claim 19 of the ’708 patent claims a method for the
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`treatment of type 2 diabetes comprising administering to a patient in need of such
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`treatment a therapeutically effective amount of 1:1 sitagliptin DHP, or a hydrate
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`thereof.
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`4.
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`In this declaration, I provide facts about which I have first-hand
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`knowledge regarding the timing of the early clinical development of sitagliptin,
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`which led to various FDA approved drugs, including Januvia®. I did not invent
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`the subject matter claimed in the ’708 patent, but it is my understanding that I have
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`relevant knowledge about the dates by which certain of the inventions conceived of
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`by the inventors listed on the ’708 patent were actually reduced to practice.
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`2
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`Merck Exhibit 2109, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF GARY HERMAN, M.D.
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`II.
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`BACKGROUND
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`5.
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`In 1982, I received a Bachelor’s Degree in Biochemistry and Cell
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`Biology from the University of California, San Diego.
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`6.
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`After graduating from UCSD, I attended Harvard Medical School,
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`from which I received an M.D. in 1988.
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`7.
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`In 1988, I returned to California to train as a resident and postdoctoral
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`fellow at the University of California, San Francisco. In 1995, I became an
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`assistant professor at UCSF responsible for running a laboratory, taking care of
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`patients, and teaching.
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`8.
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`In 2001, I joined Merck as Associate Director, Clinical Pharmacology,
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`and was promoted in 2003 to Director, Clinical Pharmacology, and in 2006 I was
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`again promoted to Senior Director, Clinical Pharmacology.
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`9.
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`In my roles at Merck as Associate Director, Director, and Senior
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`Director, Clinical Pharmacology, I co-chaired the MK-0431 product development
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`team and, among other things, lead the entire early clinical and clinical
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`pharmacology program for Januvia®, from planning, first-in-human trials, and
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`regulatory filing.
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`10. Between 2006 and 2015, I held various other position at Merck,
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`including senior positions in Clinical Pharmacology, Experimental Medicine, and
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`Early Stage Development.
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`Merck Exhibit 2109, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF GARY HERMAN, M.D.
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`11.
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`In 2015, I left Merck to become Vice President, Early Clinical
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`Development at Regeneron Pharmaceuticals, Inc. I am now Senior Vice President,
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`Early Clinical Development & Experimental Sciences at Regeneron.
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`III. EARLY CLINICAL STUDIES INVOLVING MK-0431
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`12. During 2002, I was heavily involved in planning, executing, and
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`evaluating the results from the early clinical studies involving MK-0431, which I
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`understand to be 1:1 sitagliptin DHP. MK-0431 was first administered to
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`patients—that is, humans with type 2 diabetes—in October 2002, as part of a
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`clinical study that I will refer to as “Protocol 005.” EX2106 is a true and correct
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`copy of the Synopsis and Comprehensive Study Summary of the Clinical Study
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`Report for Protocol 005, as submitted to the FDA as part of the Januvia® NDA. I
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`am an author of Protocol 005. See EX2106 at 23.
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`13. A major objective of Protocol 005 was to evaluate whether
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`administering doses of MK-0431 to patients would have the desired therapeutic
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`effect in patients, i.e., lead to a dose-dependent decrease in glucose levels. If such
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`dose-dependent decreases in glucose levels were observed, it would establish
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`“proof-of-concept.”
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`14.
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`The Protocol 005 Clinical Study Report is dated November 2005;
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`however, the portion of the study that actually involved administering MK-0431 to
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`patients ended no later than March 16, 2003, see EX2106 at 17, and I and others on
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`Merck Exhibit 2109, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF GARY HERMAN, M.D.
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`the Merck team working to develop MK-0431 into an FDA-approved drug
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`received data showing partial but reliable results from Protocol 005 well before
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`then.
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`15. As part of Protocol 005, patients received treatments consisting of a
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`25 mg dose of MK-0431 and a 200 mg dose of MK-0431, formulated into simple
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`oral capsules. See EX2106 at 17-18, 39-40. These simple capsules were
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`formulated in three strengths: 5 mg, 20 mg, and 100 mg. Id.
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`16.
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`It was Merck’s ordinary and customary practice to assign a
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`formulation number to each formulation, and the 5 mg, 20 mg, and 100 mg
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`strengths were assigned formulation numbers 0431DFC001E001,
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`0431DFC001G001, and 0431DFCF002D001, respectively. Id.
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`17.
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`It was also Merck’s ordinary and customary practice to assign a
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`number to each batch of drug substance, and the MK-0431 in the capsules used as
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`part of Protocol 005 came from Drug Substance Batch No. L-000224,715-
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`006F017. See EX2108 at 4-5. I understand that EX2108 is a true and correct copy
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`of module 3.2.P.5.4 Batch Analysis submitted to the FDA as part of the Januvia®
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`NDA.
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`18.
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`In late November and early December 2002, I conducted an interim
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`analysis on the first 18 patients who had completed Protocol 005. My interim
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`analysis showed that administering MK-0431 to patients with type 2 diabetes led to
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`5
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`Merck Exhibit 2109, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF GARY HERMAN, M.D.
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`a treatment-related and dose-dependent reduction in glucose levels as measured by
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`an Oral Glucose Tolerance Test, which was a standard test at the time. In other
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`words, my analysis demonstrated proof-of-concept. I presented my analysis during
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`a December 6, 2002, meeting with consultants advising on the clinical
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`development of MK-0431, see, e.g., EX2110, and during a December 9, 2002,
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`meeting with the DP-IV Project Development Team, see EX2158. EX2158 is a
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`true and correct copy of my email dated December 7, 2002, attaching slides to be
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`presented by me at the December 9, 2002, meeting. I also prepared slides and a
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`memo summarizing my interim analysis to be presented to a Merck management
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`committee on January 8, 2003. See EX2111. EX2111 is a true and correct copy of
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`my email dated January 3, 2003, attaching a draft slide deck and draft memo I had
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`prepared as of January 3, 2003, to be presented at that January 8 management
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`committee meeting.
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`19.
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`The fact that proof-of-concept had been established for MK-0431 was
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`communicated within the Merck team working to develop MK-0431 into an FDA-
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`approved drug. See, e.g., EX2110.
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`20.
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`Thus, by early December 2002, Merck had administered a
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`pharmaceutical composition containing 1:1 sitagliptin DHP to patients in need of
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`treatment for type 2 diabetes, and had generated data showing that 25 mg and 200
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`mg doses of MK-0431 were effective at reducing glucose levels in those patients.
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`6
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`Merck Exhibit 2109, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF GARY HERMAN, M.D.
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`21.
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`In November 2002, as part of a clinical study that I will refer to as
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`“Protocol 006,” MK-0431 was first administered in tablet form. EX2107 is a true
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`and correct copy of the Synopsis and Comprehensive Study Summary of the
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`Clinical Study Report for Protocol 006, as submitted to the FDA as part of the
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`Januvia® NDA. I am an author of Protocol 006. See EX2107 at 12.
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`22.
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`The Protocol 006 Clinical Study Report is dated March 2005, but the
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`portion of the study that actually involved administering MK-0431 to patients
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`ended in December 2002. See EX2107 at 2, 10.
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`23. As part of Protocol 006, some doses of MK-0431 were formulated
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`into simple, oral, film-coated tablets. See EX2107 at 10, 24-26. These simple
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`tablets were formulated in a 50 mg strength. The other ingredients in the tablet
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`included microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium
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`stearate, and Opradry™ White. Id. at 26. The 50 mg oral tablet used in Protocol
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`006 was assigned formulation number 0431FCT001B001. The MK-0431 in the 50
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`mg tablets used in Protocol 006 came from Drug Substance Batch No. L-
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`000224,715-006F017. See EX2108 at 17.
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`24.
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`Thus, by early December 2002, Merck had created 50 mg tablets
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`containing 1:1 sitagliptin DHP and other pharmaceutically acceptable ingredients,
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`and based on Protocol 005, had generated data showing that doses between 25 mg
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`and 200 mg (i.e., 50 mg), had a therapeutic effect.
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`7
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`Merck Exhibit 2109, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF GARY HERMAN, M.D.
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`IV. DPP-IV INHIBITOR CANDIDATES AS OF JUNE 2003
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`25.
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`In my experience, candidate compounds in a drug discovery program
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`more often than not fail to demonstrate safe and effective profiles in preclinical and
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`clinical trials, if they advance even that far. A compound’s in vitro potency, for
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`example, frequently does not lead to therapeutic efficacy in the clinical context,
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`and many compounds with in vitro potency do not work in the clinical context.
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`26.
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`Thus, in my experience, the ideal candidate in a drug-development
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`program is a compound that has exhibited in vivo potency, and even better, one
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`that has already demonstrated safety and at least some efficacy in preclinical and
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`clinical trials. To the extent that only in vitro data are available, drug compounds
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`with stronger in vitro potencies (e.g., lower IC50 values) are typically preferable.
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`27. As part of my involvement in Merck’s DPP-IV project, I stayed
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`current with other companies’ attempts to develop DPP-IV inhibitors. I was aware
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`at the time, for example, that Novartis and Probiodrug were attempting to develop
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`DPP-IV inhibitors, and sought out publications describing the safety and efficacy
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`of the candidates in their drug development programs.
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`28. At the time Merck was developing MK-0431, there were other very
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`promising DPP-IV inhibitors in development by other companies. One such DPP-
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`IV inhibitor, known as P32/98, had demonstrated promising activity by June 2000.
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`For example, P32/98 had been reported to enhance the insulin response in human
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`Merck Exhibit 2109, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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`DECLARATION OF GARY HERMAN, M.D.
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`volunteers and improve glucose tolerance. EX2112 (Demuth 20001). By 2002,
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`experiments in rats had demonstrated that P32/98 could “cause sustained
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`improvements in glucose tolerance, insulinemia, β-cell glucose responsiveness, and
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`peripheral insulin sensitivity.” EX2113 (Pospisilik 20022) at 943.
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`29.
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`In fact, before developing MK-0431, Merck considered P32/98 to be a
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`promising “lead” compound and in-licensed it for further experimentation based on
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`its good, and established, clinical results. See EX2014 (Thornberry 20073) at 558
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`(discussing both P32/98 and NVP-DPP728 and noting that they “were already
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`advancing through human clinical trials”). Ultimately, Merck’s internal research
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`program revealed toxicity problems with P32/98, see id. at 558-60, and Merck’s
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`1 Demuth et al., Single Dose Treatment of Diabetic Patients by the DP IV Inhibitor
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`P32/98, 49 DIABETES A102 (2000).
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`2 Pospisilik et al., Long-Term Treatment with the Dipeptidyl Peptidase IV Inhibitor
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`P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity,
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`Hyperinsulinemia, and β-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats,
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`51 DIABETES 943 (2002).
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`3 Thornberry & Weber, Discovery of JANUVIA (Sitagliptin), a Selective Dipeptidyl
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`Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes, 7 CURRENT TOPICS IN
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`MEDICINAL CHEMISTRY 557 (2007).
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`Merck Exhibit 2109, Page 9
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`DECLARATION OF GARY HERMAN, M.D.
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`research ultimately culminated in the discovery of MK-0431, which was highly
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`potent and had a clean toxicological profile, see id. at 565. These superior qualities
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`of MK-0431 relative to P32/98 were not public until after June 2003.
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`30. Another example of a promising DPP-IV inhibitor was Novartis’s
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`compound NVP-DPP728, which had, as of June 2000, already shown positive
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`results in human clinical trials. See EX2015 (Rothenberg 20004) (“Prandial
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`glucose exercise above baseline were reduced by NVP-DPP728 relative to
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`placebo . . . . No clinically significant adverse events were observed. . . . [These
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`results] support the investigation of the glucose-lowering potential of NVP-
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`DPP728 for the treatment of type 2 diabetics.”).
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`31. As of June 2003, both P32/98 and NVP-DPP728 were viewed as
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`promising DPP-IV inhibitors, and there was more information publicly available
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`about their safety and efficacy profiles than about MK-0431.
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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 true
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`and that all statements made on information and belief are believed to be true; and
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`4 Rothenberg et al., Treatment with a DPP-IV Inhibitor, NVP-DPP728, Increases
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`Prandial Intact GLP-1 Leels and Reduces Glucose Exposure in Humans, 49
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`DIABETES 160-OR (2000).
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`Merck Exhibit 2109, Page 10
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`DECLARATION OF GARY HERMAN, M.D.
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`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 19, 2020
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`Gary Herman, M.D.
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`11
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`Merck Exhibit 2109, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
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