UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`GENERICO, LLC
`FLATLINE CAPITAL, LLC
`Petitioners,
`
`v.
`
`DR. FALK PHARMA GmbH,
`Patent Owner
`
`Case IPR2016-00297
`Patent No. 8,865,866
`
`
`
`DECLARATION OF ROLAND H. GREINWALD, Ph.D.
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`PAGE 1 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`GENERICO, LLC
`FLATLINE CAPITAL, LLC
`Petitioners,
`
`v.
`
`DR. FALK PHARMA GmbH,
`Patent Owner
`
`Case IPR2016-00297
`Patent No. 8,865,866
`
`
`
`DECLARATION OF ROLAND H. GREINWALD, Ph.D.
`
`
`
`
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`
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`
`
`PAGE 1 of 8
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`
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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`
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`I, Roland H. Greinwald, under penalty of perjury, declare as follows:
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`1.
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`I am over 18 years of age and otherwise competent to make this
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`declaration. I have personal knowledge of the facts stated in this declaration.
`
`A.
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`2.
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`Personal Background
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`I currently work for Dr. Falk Pharma GmbH in Freiburg, Germany as
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`head of research and development. I have held that position since 2000.
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`3.
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`As part of my roles and responsibilities of head of research and
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`development, I oversee all the development teams including the pharmaceutical
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`development, preclinical development, clinical development, and regulatory teams.
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`4.
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`I first joined Dr. Falk Pharma GmbH in April 1993 as a clinical
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`project manager and stayed in that role until I became head of research and
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`development in 2000.
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`5.
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`I obtained my doctoral degree in natural sciences in 1988 from the
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`University of Wurzburg after three years of study. I focused on four subjects:
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`pharmaceutical biology, which was my main focus, as well as microbiology,
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`biochemistry, and plant science. Before that I obtained my masters degree in
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`biology at University of Wurzburg.
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`PAGE 2 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
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`B.
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`6.
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`Background of Dr. Falk Pharma GmbH
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`Dr. Falk Pharma GmbH is an independent family business based in
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`Freiburg, Germany that was first established by Dr. Herbert Falk in 1960 and has
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`grown to a small company of 130 employees.
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`7.
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`Dr. Falk Pharma GmbH specializes in the development and sale of
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`specialty pharmaceuticals to treat inflammatory bowel diseases and liver diseases.
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`Dr. Falk Pharma GmbH’s research and development department has many years of
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`experience in product formulation and pre-clinical and clinical development.
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`8.
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`Dr. Falk Pharma GmbH’s products include a variety of
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`pharmaceutical products for the treatment of gastrointestinal disorders including
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`mesalamine formulations (tablets, granules, enemas, suppositories, and rectal
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`foam) sold under the trade name Salofalk®.
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`C.
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`9.
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`Salofalk® Granu-Stix®
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`Dr. Falk Pharma GmbH markets and sells a granulated mesalamine
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`formulation in Europe under the trade name Salofalk® Granu-Stix®. In October
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`2008, Salofalk® Granu-Stix® was available in two dosage strengths, 500 mg and
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`1000 mg, in a sachet. (Ex. 2008, Falk Brochure at 52.) Salofalk® Granu-Stix® was
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`indicated for the treatment of active ulcerative colitis and the maintenance of
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`remission of ulcerative colitis. (Id.)
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`PAGE 3 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
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`10. For the maintenance of remission of ulcerative colitis, the Summary
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`of Product Characteristics1 instructed that one sachet Salofalk® 500 mg Granu-
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`Stix® should be taken three times daily in the morning, at lunchtime, and in the
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`evening (id.), which corresponds to mealtimes for breakfast, lunch, and dinner.
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`The Summary of Product Characteristics further states that “[t]he granules should
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`be taken on the tongue and swallowed, without chewing, with plenty of liquid.”
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`(Id.)
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`11. To this day, Salofalk® Granu-Stix® has never been approved in the
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`European Union for a maintenance of remission indication at a 1.5 g once daily
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`dose. (Ex. 2009, 2014 Granu-Stix® SPC at 2.) Rather, the formulation is approved
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`at a standard 0.5 g three times a day dose or, for patients known to be at increased
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`risk for relapse for medical reasons or adherence issues, 3.0 g once daily. (Id. at 2.)
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`D.
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`SAG-27: Dr. Falk Pharma GmbH’s Once Daily Dosing Study of
`Its Granulated Mesalamine Formulation
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`12. Dr. Falk Pharma GmbH conducted an efficacy and tolerability study
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`on the once daily dosing of Salofalk® Granu-Stix® for the maintenance of
`
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`1 A Summary of Product Characteristics (“SPC”) is a document required by the
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`European Medicines Agency before a medicinal product is authorized for
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`marketing in Europe. It contains a definitive description of the product both in
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`terms of its properties and its clinical use(s).
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`PAGE 4 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
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`remission of ulcerative colitis which failed to demonstrate the therapeutic
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`equivalence of once daily dosing versus three times daily dosing of a total 1.5 g of
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`mesalamine for maintenance of remission of ulcerative colitis. The study is
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`referred to as SAG-27, where “SAG” refers to Salofalk® granules.
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`13. The primary objective of the SAG-27 study was to prove the
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`therapeutic equivalence of once daily dosing versus three times daily dosing of a
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`total 1.5 g of mesalamine for maintenance of remission and to evaluate whether a
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`3 g once daily dose was superior to a 0.5 g three times daily dose for the
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`maintenance of remission of ulcerative colitis over a 12 month period. (Ex. 2025,
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`SAG-27 at 32.)
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`14. As explained in the “Selection of Doses in the Study” section of the
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`final report, a 0.5 g three times daily dose was selected as the comparator because
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`it was the standard dose for maintenance of remission and was the registered dose
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`for Salofalk® Granu-Stix®. (Id. at 42.) The 1.5 g once daily dose was chosen
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`because it was the same daily mesalamine dose as the comparator. (Id.) The higher
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`dose of 3 g was chosen because, although only a small number of dose finding
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`studies had been done with mesalamine, many gastroenterologists believed that
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`patients coming into remission on higher doses would benefit from maintenance
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`doses higher than 1.5 g per day. (Id.) 3.0 g per day was chosen as a higher dose,
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`PAGE 5 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
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`therefore, because this dosage had been shown to be an optimal dose for induction
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`of remission. (Id.)
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`15.
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`In the final report, Dr. Falk Pharma GmbH concluded that the study
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`failed to show therapeutic equivalence of 1.5 g of mesalamine once daily compared
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`to 0.5 g of mesalamine three times a day. (Id. at 102.)The study showed that the
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`optimal dose for maintenance of remission was 3 g of mesalamine once daily. (Id.)
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`3 g once daily of mesalamine was most efficacious in maintaining remission of
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`ulcerative colitis followed by 0.5 g of mesalamine three times daily and then 1.5 g
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`of mesalamine once daily.
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`16. Thus, Dr. Falk Pharma GmbH’s goal of proving the therapeutic
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`equivalence of once daily dosing versus three times daily dosing of a total 1.5 g of
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`mesalamine for maintenance of remission of ulcerative colitis unfortunately failed.
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`E.
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`SAG-19: Dr. Falk Pharma GmbH’s Food Effect Study on Its
`Granulated Mesalamine Formulation
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`17. Dr. Falk Pharma GmbH conducted a food effect study with Salofalk®
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`Granu-Stix® which demonstrated that administering granulated mesalamine with
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`food resulted in less mesalamine being absorbed systemically.
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`18. Dr. Falk Pharma GmbH’s study, with its granulated mesalamine
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`formulation Granu-Stix®, demonstrated a marked food effect: administering
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`granulated mesalamine with food resulted in less mesalamine being absorbed
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`systemically. The study is referred to as SAG-19.
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`PAGE 6 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
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`19. The objective of SAG-19 in part was to compare the systemic
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`availability, the plasma pharmacokinetics, and the urinary and fecal excretion of 5-
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`ASA and N-Ac-5-ASA after a single oral dose of 500 mg of mesalamine granules
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`administered during fasting and after a high fat breakfast in healthy human
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`subjects. (Ex. 2026, SAG-19 at 3.)
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`20. As shown in Table 11.3.1.2: 1: Descriptive statistics of the main
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`pharmacokinetic parameters of 5-ASA in the final report, the geometric mean of
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`the area under the curve (AUC 0-∞) was 410.47 ng·h/mL for the fed state and
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`877.99 ng·h/mL for the fasted state. (Id. at 60.) Thus, there was substantially less
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`mesalamine in plasma under fed conditions.
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`21. SAG-19 demonstrated a marked food effect with respect to systemic
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`bioavailability as demonstrated by the lack of bioequivalence of the granule
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`formulation administered with food as compared to under fasted conditions. Dr.
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`Falk Pharma GmbH’s study showed that administering granulated mesalamine
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`with food resulted in less mesalamine being absorbed systemically. (Id. at 3-12 &
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`97.)
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`PAGE 7 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
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`I declare under penalty of perjury that the all statements made herein are of
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`my own knowledge and are true and that all statements made upon information and
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`belief are believed to be true; and further that these statements were made with the
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`knowledge that willful false statements and the like so made are punishable by fine
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`or imprisonment, or both, under Section 1001 of Title 18 of the United States
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`Code.
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`Executed on September it, 2016 by:
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`Roland H. Greinwa d, Ph.D.
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`PAGE 8 of 8
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`Dr. Falk Ex. 2037
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
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