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 GARY HERMAN, M.D.
`
`1
`
`Merck Exhibit 2109, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`DECLARATION OF GARY HERMAN, M.D.
`
`1
`
`Merck Exhibit 2109, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`I, Gary Herman, M.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I understand that this proceeding involves issues related to 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.
`
`I understand that claim 17 of the ’708 patent claims a pharmaceutical
`
`composition comprising a therapeutically effective amount of the 1:1
`
`dihydrogenphosphate salt of sitagliptin (“1:1 sitagliptin DHP”) in association with
`
`one or more pharmaceutically acceptable carriers.
`
`3.
`
`I understand that claim 19 of the ’708 patent claims a method for the
`
`treatment of type 2 diabetes comprising administering to a patient in need of such
`
`treatment a therapeutically effective amount of 1:1 sitagliptin DHP, or a hydrate
`
`thereof.
`
`4.
`
`In this declaration, I provide facts about which I have first-hand
`
`knowledge regarding the timing of the early clinical development of sitagliptin,
`
`which led to various FDA approved drugs, including Januvia®. I did not invent
`
`the subject matter claimed in the ’708 patent, but it is my understanding that I have
`
`relevant knowledge about the dates by which certain of the inventions conceived of
`
`by the inventors listed on the ’708 patent were actually reduced to practice.
`
`2
`
`Merck Exhibit 2109, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`II.
`
`BACKGROUND
`
`5.
`
`In 1982, I received a Bachelor’s Degree in Biochemistry and Cell
`
`Biology from the University of California, San Diego.
`
`6.
`
`After graduating from UCSD, I attended Harvard Medical School,
`
`from which I received an M.D. in 1988.
`
`7.
`
`In 1988, I returned to California to train as a resident and postdoctoral
`
`fellow at the University of California, San Francisco. In 1995, I became an
`
`assistant professor at UCSF responsible for running a laboratory, taking care of
`
`patients, and teaching.
`
`8.
`
`In 2001, I joined Merck as Associate Director, Clinical Pharmacology,
`
`and was promoted in 2003 to Director, Clinical Pharmacology, and in 2006 I was
`
`again promoted to Senior Director, Clinical Pharmacology.
`
`9.
`
`In my roles at Merck as Associate Director, Director, and Senior
`
`Director, Clinical Pharmacology, I co-chaired the MK-0431 product development
`
`team and, among other things, lead the entire early clinical and clinical
`
`pharmacology program for Januvia®, from planning, first-in-human trials, and
`
`regulatory filing.
`
`10. Between 2006 and 2015, I held various other position at Merck,
`
`including senior positions in Clinical Pharmacology, Experimental Medicine, and
`
`Early Stage Development.
`
`3
`
`Merck Exhibit 2109, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`11.
`
`In 2015, I left Merck to become Vice President, Early Clinical
`
`Development at Regeneron Pharmaceuticals, Inc. I am now Senior Vice President,
`
`Early Clinical Development & Experimental Sciences at Regeneron.
`
`III. EARLY CLINICAL STUDIES INVOLVING MK-0431
`
`12. During 2002, I was heavily involved in planning, executing, and
`
`evaluating the results from the early clinical studies involving MK-0431, which I
`
`understand to be 1:1 sitagliptin DHP. MK-0431 was first administered to
`
`patients—that is, humans with type 2 diabetes—in October 2002, as part of a
`
`clinical study that I will refer to as “Protocol 005.” EX2106 is a true and correct
`
`copy of the Synopsis and Comprehensive Study Summary of the Clinical Study
`
`Report for Protocol 005, as submitted to the FDA as part of the Januvia® NDA. I
`
`am an author of Protocol 005. See EX2106 at 23.
`
`13. A major objective of Protocol 005 was to evaluate whether
`
`administering doses of MK-0431 to patients would have the desired therapeutic
`
`effect in patients, i.e., lead to a dose-dependent decrease in glucose levels. If such
`
`dose-dependent decreases in glucose levels were observed, it would establish
`
`“proof-of-concept.”
`
`14.
`
`The Protocol 005 Clinical Study Report is dated November 2005;
`
`however, the portion of the study that actually involved administering MK-0431 to
`
`patients ended no later than March 16, 2003, see EX2106 at 17, and I and others on
`
`4
`
`Merck Exhibit 2109, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`the Merck team working to develop MK-0431 into an FDA-approved drug
`
`received data showing partial but reliable results from Protocol 005 well before
`
`then.
`
`15. As part of Protocol 005, patients received treatments consisting of a
`
`25 mg dose of MK-0431 and a 200 mg dose of MK-0431, formulated into simple
`
`oral capsules. See EX2106 at 17-18, 39-40. These simple capsules were
`
`formulated in three strengths: 5 mg, 20 mg, and 100 mg. Id.
`
`16.
`
`It was Merck’s ordinary and customary practice to assign a
`
`formulation number to each formulation, and the 5 mg, 20 mg, and 100 mg
`
`strengths were assigned formulation numbers 0431DFC001E001,
`
`0431DFC001G001, and 0431DFCF002D001, respectively. Id.
`
`17.
`
`It was also Merck’s ordinary and customary practice to assign a
`
`number to each batch of drug substance, and the MK-0431 in the capsules used as
`
`part of Protocol 005 came from Drug Substance Batch No. L-000224,715-
`
`006F017. See EX2108 at 4-5. I understand that EX2108 is a true and correct copy
`
`of module 3.2.P.5.4 Batch Analysis submitted to the FDA as part of the Januvia®
`
`NDA.
`
`18.
`
`In late November and early December 2002, I conducted an interim
`
`analysis on the first 18 patients who had completed Protocol 005. My interim
`
`analysis showed that administering MK-0431 to patients with type 2 diabetes led to
`
`5
`
`Merck Exhibit 2109, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`a treatment-related and dose-dependent reduction in glucose levels as measured by
`
`an Oral Glucose Tolerance Test, which was a standard test at the time. In other
`
`words, my analysis demonstrated proof-of-concept. I presented my analysis during
`
`a December 6, 2002, meeting with consultants advising on the clinical
`
`development of MK-0431, see, e.g., EX2110, and during a December 9, 2002,
`
`meeting with the DP-IV Project Development Team, see EX2158. EX2158 is a
`
`true and correct copy of my email dated December 7, 2002, attaching slides to be
`
`presented by me at the December 9, 2002, meeting. I also prepared slides and a
`
`memo summarizing my interim analysis to be presented to a Merck management
`
`committee on January 8, 2003. See EX2111. EX2111 is a true and correct copy of
`
`my email dated January 3, 2003, attaching a draft slide deck and draft memo I had
`
`prepared as of January 3, 2003, to be presented at that January 8 management
`
`committee meeting.
`
`19.
`
`The fact that proof-of-concept had been established for MK-0431 was
`
`communicated within the Merck team working to develop MK-0431 into an FDA-
`
`approved drug. See, e.g., EX2110.
`
`20.
`
`Thus, by early December 2002, Merck had administered a
`
`pharmaceutical composition containing 1:1 sitagliptin DHP to patients in need of
`
`treatment for type 2 diabetes, and had generated data showing that 25 mg and 200
`
`mg doses of MK-0431 were effective at reducing glucose levels in those patients.
`
`6
`
`Merck Exhibit 2109, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`21.
`
`In November 2002, as part of a clinical study that I will refer to as
`
`“Protocol 006,” MK-0431 was first administered in tablet form. EX2107 is a true
`
`and correct copy of the Synopsis and Comprehensive Study Summary of the
`
`Clinical Study Report for Protocol 006, as submitted to the FDA as part of the
`
`Januvia® NDA. I am an author of Protocol 006. See EX2107 at 12.
`
`22.
`
`The Protocol 006 Clinical Study Report is dated March 2005, but the
`
`portion of the study that actually involved administering MK-0431 to patients
`
`ended in December 2002. See EX2107 at 2, 10.
`
`23. As part of Protocol 006, some doses of MK-0431 were formulated
`
`into simple, oral, film-coated tablets. See EX2107 at 10, 24-26. These simple
`
`tablets were formulated in a 50 mg strength. The other ingredients in the tablet
`
`included microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium
`
`stearate, and Opradry™ White. Id. at 26. The 50 mg oral tablet used in Protocol
`
`006 was assigned formulation number 0431FCT001B001. The MK-0431 in the 50
`
`mg tablets used in Protocol 006 came from Drug Substance Batch No. L-
`
`000224,715-006F017. See EX2108 at 17.
`
`24.
`
`Thus, by early December 2002, Merck had created 50 mg tablets
`
`containing 1:1 sitagliptin DHP and other pharmaceutically acceptable ingredients,
`
`and based on Protocol 005, had generated data showing that doses between 25 mg
`
`and 200 mg (i.e., 50 mg), had a therapeutic effect.
`
`7
`
`Merck Exhibit 2109, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`IV. DPP-IV INHIBITOR CANDIDATES AS OF JUNE 2003
`
`25.
`
`In my experience, candidate compounds in a drug discovery program
`
`more often than not fail to demonstrate safe and effective profiles in preclinical and
`
`clinical trials, if they advance even that far. A compound’s in vitro potency, for
`
`example, frequently does not lead to therapeutic efficacy in the clinical context,
`
`and many compounds with in vitro potency do not work in the clinical context.
`
`26.
`
`Thus, in my experience, the ideal candidate in a drug-development
`
`program is a compound that has exhibited in vivo potency, and even better, one
`
`that has already demonstrated safety and at least some efficacy in preclinical and
`
`clinical trials. To the extent that only in vitro data are available, drug compounds
`
`with stronger in vitro potencies (e.g., lower IC50 values) are typically preferable.
`
`27. As part of my involvement in Merck’s DPP-IV project, I stayed
`
`current with other companies’ attempts to develop DPP-IV inhibitors. I was aware
`
`at the time, for example, that Novartis and Probiodrug were attempting to develop
`
`DPP-IV inhibitors, and sought out publications describing the safety and efficacy
`
`of the candidates in their drug development programs.
`
`28. At the time Merck was developing MK-0431, there were other very
`
`promising DPP-IV inhibitors in development by other companies. One such DPP-
`
`IV inhibitor, known as P32/98, had demonstrated promising activity by June 2000.
`
`For example, P32/98 had been reported to enhance the insulin response in human
`
`8
`
`Merck Exhibit 2109, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`volunteers and improve glucose tolerance. EX2112 (Demuth 20001). By 2002,
`
`experiments in rats had demonstrated that P32/98 could “cause sustained
`
`improvements in glucose tolerance, insulinemia, β-cell glucose responsiveness, and
`
`peripheral insulin sensitivity.” EX2113 (Pospisilik 20022) at 943.
`
`29.
`
`In fact, before developing MK-0431, Merck considered P32/98 to be a
`
`promising “lead” compound and in-licensed it for further experimentation based on
`
`its good, and established, clinical results. See EX2014 (Thornberry 20073) at 558
`
`(discussing both P32/98 and NVP-DPP728 and noting that they “were already
`
`advancing through human clinical trials”). Ultimately, Merck’s internal research
`
`program revealed toxicity problems with P32/98, see id. at 558-60, and Merck’s
`
`
`1 Demuth et al., Single Dose Treatment of Diabetic Patients by the DP IV Inhibitor
`
`P32/98, 49 DIABETES A102 (2000).
`
`2 Pospisilik et al., Long-Term Treatment with the Dipeptidyl Peptidase IV Inhibitor
`
`P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity,
`
`Hyperinsulinemia, and β-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats,
`
`51 DIABETES 943 (2002).
`
`3 Thornberry & Weber, Discovery of JANUVIA (Sitagliptin), a Selective Dipeptidyl
`
`Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes, 7 CURRENT TOPICS IN
`
`MEDICINAL CHEMISTRY 557 (2007).
`
`9
`
`Merck Exhibit 2109, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`
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`DECLARATION OF GARY HERMAN, M.D.
`
`research ultimately culminated in the discovery of MK-0431, which was highly
`
`potent and had a clean toxicological profile, see id. at 565. These superior qualities
`
`of MK-0431 relative to P32/98 were not public until after June 2003.
`
`30. Another example of a promising DPP-IV inhibitor was Novartis’s
`
`compound NVP-DPP728, which had, as of June 2000, already shown positive
`
`results in human clinical trials. See EX2015 (Rothenberg 20004) (“Prandial
`
`glucose exercise above baseline were reduced by NVP-DPP728 relative to
`
`placebo . . . . No clinically significant adverse events were observed. . . . [These
`
`results] support the investigation of the glucose-lowering potential of NVP-
`
`DPP728 for the treatment of type 2 diabetics.”).
`
`31. As of June 2003, both P32/98 and NVP-DPP728 were viewed as
`
`promising DPP-IV inhibitors, and there was more information publicly available
`
`about their safety and efficacy profiles than about MK-0431.
`
`*
`
`*
`
`*
`
`I hereby declare that all statements made herein of my own knowledge true
`
`and that all statements made on information and belief are believed to be true; and
`
`
`4 Rothenberg et al., Treatment with a DPP-IV Inhibitor, NVP-DPP728, Increases
`
`Prandial Intact GLP-1 Leels and Reduces Glucose Exposure in Humans, 49
`
`DIABETES 160-OR (2000).
`
`10
`
`Merck Exhibit 2109, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
`
`DECLARATION OF GARY HERMAN, M.D.
`
`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 19, 2020
`
`Gary Herman, M.D.
`
`11
`
`Merck Exhibit 2109, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`
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