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
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`
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`DECLARATION OF LORIN JOHNSON, Ph.D.
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`PAGE 1 of 11
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`Dr. Falk Ex. 2036
`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 LORIN JOHNSON, Ph.D.
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`PAGE 1 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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`I, Lorin Johnson, under penalty of perjury, declare as follows:
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`1.
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`I am over 18 years of age. I have personal knowledge of the facts
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`stated in this Declaration and could testify competently to them if asked to do so.
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`A.
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`2.
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`Personal Background
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`I am the Founder and Chief Scientist of Glycyx PharmaVentures,
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`which was formed in April 2015. I also currently serve on the Board of Directors
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`of Atlantic Healthcare, plc, a specialty pharmaceutical company targeting
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`treatments for gastrointestinal disorders based in Cambridge, UK, and have since
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`April 10, 2015.
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`3.
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`I received my Ph.D. in molecular biology from the University of
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`Southern California in 1976 and conducted four-years of postdoctoral work at the
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`University of California San Francisco. I was then on the faculty at Stanford
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`University School of Medicine and worked for California Biotechnology.
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`4.
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`I formed Salix on November 1, 1989 with my co-worker at California
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`Biotechnology, Randy Hamilton. We formed Salix based on the idea of in-
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`licensing technology and developing products to market in my area of expertise,
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`the control of inflammation. In the early days, I was responsible for all of the
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`science that went into evaluating opportunities and developing products and
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`running the clinical trials, while Randy Hamilton handled the business aspects.
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`Over time, as we acquired more technology, we hired additional people to perform
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`PAGE 2 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
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`some of my duties, and I focused on acquisition of new products, the scientific
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`evaluation of potential products, and the lifecycle management of our products.
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`5.
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`Our first product was Colazal® (balsalazide disodium), which was
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`indicated for the treatment of ulcerative colitis with mesalamine as the active
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`ingredient. Our second product was Xifaxin® (rifaxamin), recently approved to
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`treat irritable bowel syndrome. Our third product was Apriso®, approved by the
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`FDA on October 31, 2008 as a once-daily, 1.5 gram dose of a granulated
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`mesalamine formulation for the maintenance of remission of ulcerative colitis. By
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`the time I left in 2015, Salix had developed or acquired a line of 22 products for
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`treatment of gastrointestinal disease, including Apriso®.
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`B.
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`6.
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`The ’688 Patent
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`Dr. Falk Pharma GmbH (“Falk”) is the owner by assignment of
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`United States Patent No. 8,865,688 (“the ’688 patent”), and Salix is Falk’s
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`exclusive licensee.
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`7. William Forbes and I are the inventors of the subject matter claimed
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`in the ’688 patent. A Petition to Correct Inventorship adding me as an inventor
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`was filed on July 31, 2015 and is currently pending before the U.S. Patent and
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`Trademark Office. (Ex. 2041, Petition to Correct Inventorship.) The ’688 patent is
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`generally directed to a method of maintaining the remission of ulcerative colitis
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`(“UC”) by administering 1.5g of a granulated mesalamine formulation once a day
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`PAGE 3 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
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`(“OD”) without food. It describes the extensive clinical studies conducted by Salix
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`(which I describe below) supporting the claimed method.
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`C.
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`8.
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`Salix’s In-License of Falk’s Granulated Mesalamine Technology
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`Salix in-licensed Falk’s granulated mesalamine technology in 2002
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`with the goal of developing a formulation for the U.S. market to treat active UC
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`administered three times a day (“TID”). At the time of the in-license, Falk had
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`been marketing its Granu-Stix® formulation in Germany under a dosing regimen
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`for treatment of acute episodes of UC and for maintenance therapy at 0.5 g to 1g
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`three times a day (“TID”). (Ex. 2008, Falk Brochure at 52.)
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`9.
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`Although it was known at the time of the in-license and even up to the
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`time the ’688 patent application was filed in October 2008 that a simplified dosing
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`regimen could facilitate greater compliance in patients, there were no mesalamine
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`formulations approved in the US for OD dosing for maintenance of remission of
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`UC, much less at a low, OD dose. At the time of the in-license from Falk, it was
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`my vision and hope to reduce the dosing frequency of a granulated mesalamine
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`formulation to twice or possibly even once a day as a follow-on indication.
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`Indeed, in Salix’s November 2002 pre-IND meeting request to the FDA, we
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`proposed evaluating the mesalamine pellets at 1.5 g administered twice a day
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`(“BID”) or 3 g administered OD versus placebo in active UC. (Ex. 2042, Pre-IND
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`Meeting Request at 3.)
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`PAGE 4 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
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`D.
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`Salix’s Development of its Granulated Mesalamine Formulation
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`10. By the time Salix submitted its pre-IND package to the FDA in July
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`2003, our focus had shifted to maintenance of remission rather than treatment of
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`active UC. We had determined that it might be more difficult to achieve OD
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`dosing in active UC patients because patients with active disease can have 10 to 12
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`bowel movements a day, so a once a day dose might not be resident in the colon
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`long enough. We therefore proposed pharmacokinetic studies with our granulated
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`mesalamine formulation to examine OD versus BID dosing and to examine the
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`impact of food on the absorption of mesalamine. (Ex. 2043, July 2003 Pre-IND
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`Package at 2.) Subsequently we conducted several clinical studies to establish the
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`safety and efficacy of a OD dose of a 1.5g dose of granulated mesalamine without
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`food for the maintenance of remission of ulcerative colitis over a 6 month period.
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`11. MPPK 1001. Salix first conducted a safety pharmacokinetic study in
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`healthy patients to determine whether OD dose of 1600 mg was within the safety
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`margin for the plasma level of mesalamine. (Ex. 2045, MPPK 1001 Report.) Salix
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`discovered the systemic absorption of mesalamine was comparable whether taken
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`OD or BID, thereby supporting the pursuit of a OD dosing regime in Phase III
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`clinical trials. (Ex. 2045, MPPK 1001 Report at 7, 58; Ex. 2046, Poster P682.)
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`12. MPPK 1002. Salix also conducted a food effect study in early 2004 to
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`understand the effect of food on the absorption of its granulated mesalamine
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`PAGE 5 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
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`formulation. (Ex. 2029, MPPK 1002 Report.) In my experience, there is no way to
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`predict for a particular mesalamine pharmaceutical formulation the effect of food
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`on absorption. In some cases the systemic absorption increases with food, in some
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`cases it decreases, and in some cases there is no impact. So for a particular
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`mesalamine formulation, one has to determine through a clinical study what the
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`effect of food will be, commonly referred to as a “food effect” study.
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`13. With mesalamine, it is desirable to maximize the delivery to the colon
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`while minimizing the absorption in the systemic circulation. Absorption of
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`mesalamine in the upper intestinal tract reduces the amount of mesalamine to be
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`delivered to inflamed areas of the colon, thereby reducing therapeutic efficacy.
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`14. When Salix designed its food effect study, it was aware that Falk’s
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`prior food effect study, SAG-19, conducted with Falk’s Granu-Stix® formulation,
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`had demonstrated a marked food effect. Namely, Falk’s study demonstrated that
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`administering granulated mesalamine with food resulted in less mesalamine being
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`absorbed systemically and more being available to act topically, indicating that
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`mesalamine should be administered with food, not without food. (Ex. 2026, SAG
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`19 Report at 3-12 and 97.)
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`15. Based on Falk’s results in SAG-19 with Granu-Stix®, we expected
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`that there would be a food effect with our granulated mesalamine formulation. (Ex.
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`2029, MPPK 1002 Report at 2-3, 19.) This is reflected in our study protocol where
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`PAGE 6 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
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`we stated, we “test[ed] the hypothesis that the maximum observed plasma
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`concentration (Cmax) and the area under the plasma concentration-time curve
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`(AUC) for 5-ASA [mesalamine] plus N-Ac-5-ASA [its metabolite] following MP
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`[granulated mesalamine] 1600-mg orally administered with a meal is significantly
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`less than when administered during fasting.” (Id. at 2 & 19.)
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`16.
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`In Salix’s study, healthy subjects were given 1.6 g of Apriso®
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`following either an overnight fast or a high fat meal, and pharmacokinetic
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`parameters were assessed. (Id. at 19.) Contrary to Falk’s results and our own
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`hypothesis that food would have an impact on absorption, our expectations turned
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`out to be wrong. We surprisingly discovered that for our granulated mesalamine
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`formulation, the absorption of mesalamine and its metabolite were not significantly
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`affected by a high fat meal. (Ex. 2029, MPPK 1002 Report at 2-6 & 53-54.)
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`17. This study demonstrated that Apriso® could be given without food.
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`This was a significant advantage for a drug used to maintain remission of a chronic
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`condition like ulcerative colitis—where patients are generally asymptomatic and
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`may be more likely to forget to take medication—because it permitted a simplistic
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`dosing regime that did not require administration with food. Complex and
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`inconvenient dosing regimes such as dosing several times a day or requiring
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`administration with a meal can have a negative impact on adherence to treatment
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`PAGE 7 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
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`and can lead to relapse. For example, many people skip meals, and therefore may
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`skip their medication if it is required to be administered with food.
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`18. Further to the Falk study using Granu-Stix®, if I were to look to other
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`mesalamine formulations, there would be no way to predict the outcome of a food
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`effect study with oral OD mesalamine. For example, the bioavailability of
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`balsalazide administered in a capsule (Colazal®) or a tablet was known to increase
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`with food, while the bioavailability of olsalazine (Dipentum®) was known to
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`decrease with food. Meanwhile, for mesalamine drugs, the bioavailability of pH-
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`dependent delayed release tablets (Claversal®, Asacol®) was known to decrease
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`with food, while the food effect on extended release granules (Pentasa®) was not
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`available, and the once daily, delayed and extended release formulation (Lialda®)
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`was indicated for administration with a meal for induction of remission.
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`19. MPUC 3003 and MPUC 3004. After Salix had the results of MPPK
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`1001 and 1002, Salix conducted two multi-center, randomized Phase III placebo-
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`controlled clinical trials to assess the safety and efficacy of a once daily dose of 1.5
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`g of its granule mesalamine formulation (Apriso®) versus placebo for the
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`maintenance of remission of UC over a 6 month period. (Ex. 2048, MPUC 3003
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`Protocol.)
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`20. We discovered through these clinical trials that the proportion of
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`patients who remained relapse free at the end of 6 months was greater for the
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`PAGE 8 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
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`granulated mesalamine than for placebo. (Ex. 2049, MPUC 3003 Report at 6-7 &
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`117; Ex. 2050, MPUC 3004 Report at 6-7 & 121.) “Relapse” (classified as a
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`“treatment failure”) had been defined in the protocol under the primary efficacy
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`endpoint as a rectal bleeding score of 1 or more and a mucosal appearance score of
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`2 or more using the revised Sutherland DAI. The study demonstrated that
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`approximately 79%-80% of the patients maintained remission of UC over 6
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`months under this primary endpoint. (Ex. 2049, MPUC 3003 Report at 4, 6, & 79;
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`Ex. 2050, MPUC 3004 Report at 4, 6 & 83.)
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`21. Prior to these studies, it was not known whether a OD, low dose
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`granulated mesalamine formulation administered without food could effectively
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`maintain the remission of UC for 6 months. The conventional thinking at the time
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`was that mesalamine formulations be administered in divided doses, and with
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`higher doses such that the dosing levels that achieved induction should be
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`continued for maintenance therapy. In addition, Salix and Falk believed, in view of
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`Falk’s SAG-19 clinical study results, that administration of mesalamine with food
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`led to lower systemic absorption of mesalamine, and therefore administration
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`without food negatively impacted the amount of mesalamine available to act
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`topically. Salix’s clinical studies, which are described in the ’688 patent
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`specification, surprisingly demonstrated the safety and efficacy of a low OD dose
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`of mesalamine administered without food for the maintenance of remission of UC.
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`PAGE 9 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
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`E.
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`Salix’s Press Release
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`22. Salix issued a press release on September 5, 2007 announcing
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`statistically significant top-line results of a unique granulated mesalamine product
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`registration study in UC. The purpose of the press release was to update the
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`shareholders, investors, and financial analysts on the business of the company and
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`included as required a safe harbor statement underscoring the fact that the
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`“forward-looking statements” are “just predictions and are subject to risks and
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`uncertainties that could cause the actual events or results to differ materially.” (Ex.
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`1012, Sept. 2007 Press Release at 3.) Salix did not intend its press releases to be
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`used as a source of technical or scientific information and certainly not to educate
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`clinicians how to treat patients.
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`PAGE 10 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
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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 12, 2016 by:
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`Lorin Johnson, Ph.D.
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`PAGE 11 of 11
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`Dr. Falk Ex. 2036
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
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