`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`AMNEAL PHARMACEUTICALS, LLC
`Petitioner
`v.
`
`PURDUE PHARMA L.P.,
`THE P.F. LABORATORIES, INC., and
`PURDUE PHARMACEUTICALS L.P.
`Patent Owners
`____________________
`Cases IPR2016-01027 and IPR2016-010281
`U.S. Patent No. 9,060,976
`_____________________
`(Exhibit 2097)
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`DECLARATION OF BENJAMIN OSHLACK
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`1 The word-for-word identical paper is filed in each proceeding identified in the
`heading.
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`KASHIV1019
`IPR of Patent No. 9,492,393
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`Declaration of Benjamin Oshlack
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`TABLE OF CONTENTS
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`Cases IPR2016-01027, -01028 for
`U.S. Patent No. 9,060,976
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`Introduction ...................................................................................................... 1
`I.
`The Discovery of the ’976 Patent Invention .................................................... 4
`II.
`III. Conclusion ..................................................................................................... 14
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`KASHIV1019
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`Declaration of Benjamin Oshlack
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`I, Benjamin Oshlack, hereby declare:
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`I.
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`INTRODUCTION
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`Cases IPR2016-01027, -01028 for
`U.S. Patent No. 9,060,976
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`1.
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`I make this declaration in support of Patent Owners Purdue Pharma
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`L.P., The P.F. Laboratories, Inc., and Purdue Pharmaceuticals L.P.’s Response, and
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`specifically, to attest to facts relating to the conception and reduction to practice of
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`the invention claimed in U.S. Patent No. 9,060,976 (the “’976 patent”).
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`2.
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`I received a Bachelor of Pharmacy degree from Victorian College of
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`Pharmacy in Melbourne, Australia, in 1972. For several years thereafter, I worked
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`in retail pharmacy, including some time in Great Britain.
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`3.
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`In 1976, I joined Dagra, N.V., a small pharmaceutical company in the
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`Netherlands that was associated with Purdue Frederick Company. At Dagra, I was
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`the head of the Pharmaceutical Research and Development department and was
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`responsible for the development, scale-up, and manufacturing of new formulations.
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`My work at Dagra primarily focused on immediate-release solid oral dosage forms,
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`although it also included development of suspensions, creams, and extended-
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`release products.
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`4.
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`In 1980, I was transferred to the company now known as Purdue
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`Pharma L.P. (“Purdue”), at its Yonkers, New York site, which later moved to
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`Ardsley, New York. For my first several years at Purdue, I was a scientist
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`responsible for the development of solid dosage forms in the Pharmaceutical
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`Development department. This involved many of the same development, scale-up,
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`and manufacturing activities I was involved with at Dagra. At Purdue, however, I
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`began to develop a specialization in extended-release delivery systems, particularly
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`for oral administration. Shortly after I arrived at Purdue, I was temporarily sent to
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`an associated company in Scotland, Napp Pharmaceuticals, to train with them in
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`the development of extended-release dosage forms. When I returned to the United
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`States, I brought this expertise back to Purdue’s formulation development team and
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`began to focus on extended-release dosage forms.
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`5.
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`In 1984, I was promoted to Director of the Pharmaceutical
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`Development Solid Dosage Forms group at Purdue. Between 1986 and 1998, I
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`was promoted several times, becoming the Director of the entire Pharmaceutical
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`Development group, and ultimately being named the Executive Director of the
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`group. During this time, I became responsible for all aspects of the development
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`of all of Purdue’s new pharmaceutical dosage forms.
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`6.
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`It was also during this time that I and my team developed the original
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`OxyContin® formulation. The original OxyContin® formulation was a 12-hour,
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`extended-release formulation, and is described in Examples 3 and 4 of U.S. Patent
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`No. 5,508,042. (Ex. 2100.) I am a named inventor on this patent and on other
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`patents covering the original OxyContin® product. (Id.; Ex. 2101; Ex. 2102; Ex.
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`2103.) The original formulation was prepared by the following procedure: (1)
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`Eudragit® RS 30D and Triacetin® are combined and mixed at low shear to prepare
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`a suspension; (2) oxycodone hydrochloride, lactose, and povidone are placed in a
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`fluid bed granulator, and the suspension prepared in (1) is sprayed onto the powder
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`in the fluid bed to prepare a granulation, which is then dried; (3) stearyl alcohol is
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`heated to approximately 70 °C and then mixed with the warm granulation to wax-
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`coat the granules; (4) after the waxed granulation is cooled, it is lubricated by
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`blending with talc and magnesium stearate for approximately 3 minutes; and (5)
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`the lubricated granulate is then compressed in a tableting machine. (Ex. 2100 at
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`Examples 3, 4; see also id. at Tables 5, 7.) According to this manufacturing
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`procedure, the oxycodone hydrochloride is contained inside the wax-coated
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`granules, whereas the magnesium stearate and talc are on the outside as lubricant.
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`7.
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`The original OxyContin® product was approved by the FDA in
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`December 1995 and entered the market in 1996. The original OxyContin®
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`formulation was considered a significant advance at the time. In contrast to other
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`oxycodone formulations that required administration every several hours to avoid
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`break-through pain, OxyContin®’s formulation permitted patients to take a tablet
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`only twice daily.
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`8.
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`It was also during this period, in 1991, that I received my Master of
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`Science degree in Industrial Pharmacy from Long Island University in Brooklyn,
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`New York. As part of my master’s program, I prepared a thesis based on research
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`I was conducting at Purdue. This thesis focused on the effect of surface area on
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`extended-release dosage forms.
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`9.
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`In 1998, I was promoted to Vice President of Pharmaceutics. In this
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`position, I continued to be responsible for all of the Pharmaceutical Development
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`activities. I also worked with the development of products for outside the United
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`States and coordinated research and development activities with Purdue’s
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`international associated companies. In this position, approximately fifty
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`employees reported to me, including approximately twenty formulators and the
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`employees responsible for preparation and packaging of clinical study supplies.
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`10.
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`I retired from Purdue in 2005. While at Purdue, I spent the majority
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`of my time on the development of extended-release opioid products. In my later
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`years at Purdue, we focused on the development of abuse-deterrent extended-
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`release opioid products.
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`II. THE DISCOVERY OF THE ’976 PATENT INVENTION
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`11. Purdue has a long history of work to develop abuse-deterrent opioid
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`formulations. Purdue’s efforts began in mid-1996, when Purdue initiated
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`development of an abuse-deterrent extended-release hydrocodone combination
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`with an opioid antagonist. (Ex. 2088 at 90, 92.) One year later, Purdue met with
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`the Food and Drug Administration, the Drug Enforcement Agency, and the
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`National Institute of Drug Abuse, and it was agreed to prioritize development of
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`this product. (Id.) Consequently, in mid-1998, Purdue filed an Investigational
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`New Drug application for extended-release hydrocodone with naltrexone. (Id.) At
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`the end of 1998, Purdue began a program to combine oxycodone with an opioid
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`antagonist to reduce oxycodone side effects. (Id.) Then, in the late 1990s and
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`early 2000, Curtis Wright and others at Purdue began a major initiative to identify
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`and develop abuse-deterrent opioid formulations, which would span many years.
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`(Id.) The official project team, which became known as the “Opioid X” project,
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`was formed on April 17, 2000. (Id.)
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`12. The abuse-deterrent oxycodone program fell under the Opioid X
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`program umbrella. As previously mentioned, I was responsible for the
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`development of the original OxyContin® formulation, which was launched in
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`1996. Before the development of OxyContin®, I had also been involved in the
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`development of the MS Contin® product, an extended-release formulation of
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`morphine sulfate. Following the launch of MS Contin®, Purdue received only
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`very infrequent and isolated reports of abuse of MS Contin®. Given the similar
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`dosage forms and strengths of original OxyContin® and MS Contin®, we did not
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`have any reason to believe that OxyContin® would be any different with respect to
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`abuse and misuse. Several years after the launch of original OxyContin®,
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`however, Purdue began to hear reports of OxyContin® abuse. I learned of these
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`reports from my colleagues in the medical department at Purdue, such as Curtis
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`Wright. These reports, along with the previously known abuse problems with
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`hydrocodone, were a major impetus for the Opioid X project.
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`13. As far as I was aware, Purdue was the first company to undertake a
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`wide-ranging and comprehensive program for the development of abuse-deterrent
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`opioid formulations. We were at the forefront of a nascent field. Moreover, the
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`Opioid X project was considered extremely important and urgent within Purdue.
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`OxyContin® was a very successful, breakthrough product, because it was able to
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`provide 12 hours of pain relief in those who suffered from chronic pain. It was
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`also critical to the success of the company. Purdue therefore invested an enormous
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`amount of resources into its reformulation. Under the Opioid X umbrella, we
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`evaluated every abuse-deterrent option that we could think of, including a
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`multitude of variations on those options. Knowing that it would be impossible to
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`predict in advance which option would ultimately be successful, we tried a number
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`of approaches in parallel, and later continued to go back and forth among these
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`options depending on the results of our experiments and clinical studies. Our focus
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`on the development of abuse-deterrent technologies continued throughout my time
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`at the company.
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`14. As the Vice President of Pharmaceutics, the formulation development
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`activities of the Opioid X project were my responsibility. My group and I
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`considered a great number of formulation options for achieving the abuse-deterrent
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`goal. Early on, we focused on so-called “chemical” approaches involving
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`combining the opioid with an opioid antagonist like naloxone or naltrexone. This
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`posed a number of formulation and pharmacological challenges and opportunities.
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`For example, in some formulations we included very small amounts of an
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`immediate-release portion of the antagonist, which we believed would have no
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`effect if taken as indicated but would block the opioid effect if misused or abused.
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`We believed that the addition of a small amount of naloxone to the original
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`OxyContin® formulation under this approach would render the formulation abuse
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`resistant and would be our fastest approach to the market with an abuse-deterrent
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`product. Our goal was to bring an effective abuse-deterrent formulation to market
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`as quickly as possible. We later learned, however, that even small amounts of
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`naloxone could pose withdrawal issues to patients who took high doses of
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`oxycodone. In a different “chemical” approach, we tried the opposite—to
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`completely sequester larger amounts of the antagonist, so that it would be
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`bioavailable only if the dosage form were tampered or misused. As we later
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`discovered, this approach also suffered from drawbacks, including unanticipated
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`leakage of the sequestered antagonist.
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`15. We looked at a wide variety of techniques to prepare various
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`“chemical”-approach formulations. As of April 2001, we had evaluated at least the
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`following formulation options with respect to oxycodone: incorporating small
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`amounts of naloxone into the original OxyContin® formulation (Ex. 2104 at 11-
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`21); combining original OxyContin® granules with extended-release naloxone
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`granules, prepared the same way, in tablets (id. at 22-29); combining original
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`OxyContin® granules with extended-release naloxone granules prepared with a
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`different extended-release agent (ethylcellulose), in tablets (id. at 30-37); preparing
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`the foregoing naloxone granules by extrusion rather than granulation (id. at 38-40);
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`combining extended-release (coated non-pareil) beads of oxycodone with non-
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`bioavailable (coated non-pareil) beads of naltrexone in capsules (id. at 46-47);
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`incorporating non-bioavailable naltrexone beads into the original OxyContin®
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`formulation (id. at 46, 48-50); combining the foregoing oxycodone and naltrexone
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`beads in tablets (id. at 46, 48, 51-52); combining extended-release pellets (melt-
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`extruded multiparticulates) of oxycodone with non-bioavailable pellets (melt-
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`extruded multiparticulates) of naltrexone in capsules (id. at 46, 67-83); and
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`partnering with a third party to use 3D-printing technology to print tablets with
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`controlled segregation of oxycodone and the antagonist and with specified wall
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`thickness, porosity, and geometry to control the release of both components (id. at
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`99-105).
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`16. We also evaluated a number of so-called “physical” approaches to
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`abuse deterrence. These included the inclusion of dyes that were released when
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`tampered or abused to “mark” the misuser, the inclusion of bittering or irritant
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`agents that made misuse and abuse very unpleasant, and the inclusion of gelling
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`agents to make syringing or snorting the tampered dosage form difficult or
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`impossible. (This latter approach is the subject of the ’976 Patent invention.)
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`17. Our main objective with the OxyContin® Opioid X project was to
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`create a formulation that had additional, effective abuse-deterrent features but that
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`also provided bioequivalence, including equivalent drug release and absorption
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`profiles, to the original OxyContin® formulation. In other words, we needed a
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`formulation that reduced, or eliminated, misuses but that was otherwise
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`indistinguishable to a patient who was not misusing it. We also wanted to bring
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`this product to market as soon as possible, to address the need for it.
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`18. Throughout the Opioid X project, I spent many hours meeting and
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`brainstorming with others at Purdue, and especially with Curtis Wright, about how
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`to address the abuse deterrence problem. At the time, Dr. Wright was in the
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`medical group and responsible for clinical research activities. As part of this
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`group, he received reports about how the original OxyContin® formulation was
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`being misused in the market. From his prior experience as a treating physician, he
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`also had a lot of experience with patients who had misused or abused other opioids,
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`and great insight into how opioids were abused. I provided the formulation
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`expertise to these discussions. Christopher Breder, a clinical project leader trained
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`as an anesthesiologist, reported to Dr. Wright in the medical group.
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`19. The gelling concept that is embodied in the ’976 Patent was the result
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`of conversations that I had with Dr. Wright. Dr. Wright had explained that two
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`common ways of abusing opioids, including the original OxyContin®, were
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`injecting and snorting it. The injection route involved crushing and dissolving the
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`tablet in a small amount of water, possibly heating the solution, and then pulling
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`the solution into a syringe through a cotton filter. Abusers could do this with
`
`common items (spoons, a cigarette lighter, insulin syringe, and a cotton ball) and in
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`a typical bathroom. The snorting route involved crushing or grinding up the tablet
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`and then inhaling the powder directly. During the course of one of our
`
`conversations, sometime in the late 1990s or early in 2000, we had the idea to add
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`an ingredient to the formulation that would cause the drug solution to form a gel,
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`so that it could not be easily syringed and it would form a gunky mass in the nasal
`
`cavity if snorted.
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`20. To achieve gelling of a tampered dosage form, based on my guidance,
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`we looked at adding pharmaceutically acceptable binders that could have gelling
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`properties to the formulation. There were a relatively large number of binders
`
`known at the time, and many of them had the potential to increase the viscosity of
`
`a solution. We were not aware of them having been used for the purpose of abuse
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`deterrence before, however, and we were concerned that using adequate quantities
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`of binders to provide gelling under abuse conditions could lead to other problems
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`with the formulation. Specifically, we were concerned that the same properties
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`that would prevent syringing or inhaling the solution would also ruin the release
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`profile of the formulation when administered as directed.
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`21. There were other unknowns associated with this approach. Even if
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`the addition of sufficient quantities of gelling agents did not prevent release of the
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`drug, they were still likely to have an effect on the release of the drug. This was
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`particularly undesirable because it suggested that we would have to completely
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`reformulate OxyContin® under this approach; developing a new formulation
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`would likely be a significant challenge in light of the extensive work we conducted
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`to develop the original formulation. We also did not know what quantity of gelling
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`agent would be required to achieve our goal, how the particular gelling agent
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`would interact with other components of the formulation in terms of stability or
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`drug release, what kind of manufacturing and processing steps would be required,
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`and whether the particular gelling agent would create any other problems, such as
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`dose dumping or toxicity when injected.
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`22.
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`In early 2001, we began conducting laboratory experiments to get a
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`sense of the viability of this approach. These experiments were conducted by
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`various members of my formulation development group and the pharmaceutical
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`analysis group. Beginning in January 2001, at my direction, Purdue laboratory
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`scientists tested the syringeability of various concentration solutions of pectin,
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`sodium alginate, and sodium acrylate, as well as combinations of pectin and
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`sodium alginate. (Ex. 2105.) The results of these experiments showed, among
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`other things, that certain samples did indeed become too thick and viscous to be
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`drawn into the syringe, establishing an initial proof-of-concept for this approach,
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`and that the abuse deterrence provided by the gelling agent was enhanced when
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`OxyContin® placebo tablets were added. (Id.) (Data from this experiment is
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`reported in Example 3 of the ’976 Patent.)
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`23. Following these initially promising results, between February and
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`May 2001, under my direction, Purdue scientists conducted additional
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`experiments, including quantifying (in cP) the viscosity of the tampered solutions
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`that corresponded to the syringeability test results. This experiment showed that
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`the tested gel solutions below about 60 cP could be filled into a syringe only with
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`difficulty, and that solutions above approximately 60 cP could preclude injection
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`from a typical insulin syringe. (Ex. 2106 at 12-19.) (The results of this
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`experiment are also reported in Example 3 of the ’976 Patent.) This testing helped
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`set a viscosity benchmark for further studies. Among the other experiments
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`conducted during this period were testing of the effect of pH and alcohol on gelling
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`(Ex. 2106 at 2-11); the evaluation of xanthan gum, carrageenan, and locust bean
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`gum (and combinations thereof) as gelling agents (Ex. 2108); and the testing of the
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`recovery of oxycodone from solutions containing original OxyContin® and
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`xanthan gum (Ex. 2107). (Xanthan gum examples are provided in Examples 1 and
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`2 of the ’976 Patent.)
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`24. While these experiments were ongoing, we worked with Purdue’s in-
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`house and outside counsel to prepare a patent application covering our invention.
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`The provisional patent application, No. 60/310,534, was filed on August 6, 2001,
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`and named Curtis Wright, Christopher Breder, and me as inventors.
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`25. Following the filing of the provisional patent application, we
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`continued to develop and test numerous methods of reformulating OxyContin® for
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`abuse deterrence. We continued to pursue many of the options that we had
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`identified early on, including trying new variations as well as turning back to ideas
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`that we had previously worked on. I continued to be responsible for overseeing
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`these activities. When I left in mid-2005, Purdue had not yet completed
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`development of reformulated OxyContin®.
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`Declaration ofBenjamin Oshlack
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`III. CONCLUSION
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`I hereby declare under penalty of perjury under the laws of the United States
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`of America that the foregoing is true and correct, and that all statements made of
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`my own knowledge are true and that all statements made on information and belief
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`are believed to be true by me. I understand that willful false statements and the
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`like are punishable by fine or imprisonment or both (18 U.S.C. § 1001).
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`Dated: February !_, 2017
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`Benjamin Oshlack
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