Helsinn Healthcare Exhibit 2028
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
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`Page 1 of 46
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`TABLE OF CONTENTS
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`II.
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`BACKGROUND ............................................................................................................... ..1
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`PROFESSIONAL QUALIFICATIONS ............................................................................ ..2
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`HI.
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`SUMMARY OF OPINIONS ............................................................................................. ..3
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`IV. METHODOLOGY APPLIED AND MATERIALS REVIEWED .................................... ..4
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`VI.
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`THE PATENTS-IN—SUIT ................................................................................................. ..7
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`BACKGROUND ON DRUG FORMULATION AND
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`FORMULATION OPTIMIZATION ............................................................................... ..11
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`A. Typical Components of an Intravenous Solution..................................................... ..11
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`B.
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`Prefonnulation Study and Formulation Development ............................................. .. 15
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`VII.
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`THE PERSON OF ORDINARY SKILL IN THE ART .................................................. ..17
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`VIII. THE MEANING OF “PHARMACEUTICALLY STABLE” ......................................... .. 18
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`IX.
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`THE RELEVANT PRIOR ART ...................................................................................... ..20
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`X.
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`THE DIFFERENCES BETWEEN THE CLAIMED FORMULATION
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`AND THE PRIOR ART WOULD HAVE BEEN OBVIOUS ........................................ ..24
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`A. A Person of Ordinary Skill in the Art Would Have Made an
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`Intravenous Solution of Palonosetron Containing a pH Buffer, a
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`Tonicifying Agent and a Stabilizing Agent ............................................................. ..24
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`B. A Person of Ordinary Skill in the Art Would Have Selected a
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`Low Concentration of Palonosetron for an Intravenous Solution............................ ..26
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`C. A Person of Ordinary Skill in the Art Would Have Selected a
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`Slightly Acidic pH of About 3 to 6 for an Intravenous Solution of
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`Palonosetron ............................................................................................................. ..27
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`D. A Person of Ordinary Skill in the Art Would Have Used a
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`Tonicifying Agent in an Intravenous Solution of Palonosetron .............................. ..29
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`E. A Person of Ordinary Skill in the Art Would Have Used EDTA as
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`a Chelating Agent to Stabilize an Intravenous Solution of
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`Palonosetron ............................................................................................................. . . 3 1
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`Page 2 of 46
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`Page 2 of 46
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`F. A Person of Ordinary Skill in the Art Would Have Expected An
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`Intravenous Solution of Palonosetron to Be Phannaceutically
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`Stable ........................................................................................................................ ..33
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`XI.
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`ALL OF THE ASSERTED CLAIMS ARE OBVIOUS .................................................. ..35
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`A. Claim 2 of the ‘725 Patent Is Obvious ..................................................................... ..35
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`B. Claims 2 and 9 of the ‘724 Patent Are Obvious ..................................................... ..39
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`C. Claims 2, 5 and 6 of the ‘424 Patent Are Obvious .................................................. ..40
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`XII.
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`ROUTINE DEVELOPMENT WORK LED TO THE CLAIMED
`INVENTION.................................................................................................................... ..4l
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`I, Patrick P. DeLuca, have been retained by Defendants Dr. Reddy’s Laboratories Ltd.
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`and Dr. Reddy’s Laboratories Inc. (“DRL”) in the above-captioned matter. If I am called at trial,
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`I expect to testify with regard to the opinions, and the bases and reasons therefore, expressed
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`below:
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`BACKGROUND
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`1.
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`I understand that this is a “Hatch-Waxman” patent infringement action arising
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`from defendants’ filing of ANDAs seeking approval from FDA to market generic versions of
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`Helsirm Healthcare’s ALOXI® (palonosetron hydrochloride) intravenous product.
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`2.
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`I understand that ALOXI® is indicated for the prevention of chemotherapy-
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`induced nausea and vomiting (CINV) and postoperative nausea and vomiting O’ONV). I also
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`understand that ALOXIQ is available as an aqueous solution for intravenous administration
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`containing 0.05 mg/ml palonosetron in two dosage strengths: 0.25 mg/5 mL and 0.075 mg/1.5
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`3.
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`I understand that the patents at issue in this case are United States Patent Nos.
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`7,947,724 (“the ‘724 patent”), 7,947,725 (“the‘725 patent”), and 7,960,424 (“the ‘424 patent”)
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`(collectively, “the patents-in-suit”), and that plaintiffs have asserted claims 2 and 9 of the ‘724
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`patent; claim 2 of the ‘725 patent; and claims 2, 5 and 6 of the ‘424 patent against DRL. The
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`asserted claims relate to pharmaceutical formulations of palonosetron.
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`I have been asked by counsel for DRL to opine, based on my knowledge, skill,
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`education, training and experience in the field of pharmaceutical formulation on the obviousness
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`of the asserted claims. I understand that DRL retained another expert, Dr. David Frame, to opine
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`on certain aspects of the asserted claims.
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`I have reviewed Dr. Frame’s expert report and relied
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`on his expert opinions in providing my opinions.
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`5.
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`I am being compensated for my work in connection with this matter at the rate of
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`' per hour plus expenses. No part of my compensation is dependent in any way on the
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`6.
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`I have not testified as an expert witness at trial or by deposition within the
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`7.
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`I expect to rely on various exhibits at trial, including demonstratives, b11t I have
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`not yet prepared any such exhibits.
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`II.
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`PROFESSIONAL UALIFICATIONS
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`I am a Professor Emeritus in the Department of Pharmaceutical Sciences, College
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`of Pharmacy, University of Kentucky. I received a B.S. and M.S. in Pharmacy from Temple
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`University in 1957 and 1960, respectively. I received my Ph.D. in Pharmaceutical Sciences from
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`Temple University in 1963.
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`During my career of over 50 years, my research and teaching interests in
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`pharmaceutical science and technology have been in various areas including parenteral and
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`intravenous pharmaceutical formulations and drug product stability. I have published over 200
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`research articles and authored or co-authored chapters in several textbooks in the field. I have
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`received numerous awards and honors for my research and teaching achievements.
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`I am a founding member and Fellow of the American Association of Pharmaceutical
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`Scientists (AAPS) and served as its President between 2008 and 2009. I was the first Editor—in-
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`Chief of the international journal Pllamzaceutical Development and Teclmologv between 1995 and
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`1999, the first Editor—in-Chief of flie AAPS online journal PI1armSciTech between 2000 and 2007,
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`and also served on the editorial boards of several other scientific journals in the broad field of
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`pharmaceutical sciences with special focus on pharmaceutical technology and drug product
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`development.
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`In addition to my research and teaching, I have consulted over the years for both
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`brand and generic pharmaceutical companies on matters related to pharmaceutical formulation
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`Additional details of my education, experience and credentials are set forth in my
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`curriculum vitae, a copy of which is attached as Ex. 1.1
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`IH.
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`SUMMARY OF OPINIONS
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`Prior to the invention of the patents-in-suit, it was well understood by a person of
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`ordinary skill in the art of pharmaceutical formulation development that an intravenous solution
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`contained an active ingredient and typically the following inactive components: (i) a pH buffer
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`to control and maintain the solution at a desired pH; (ii) a tonicifying agent to reduce the pain
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`and irritation of injection; and, to the extent necessary, (iii) a stabilizing agent to prevent or
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`control degradation of the active ingredient and/or to maintain the overall quality of the solution.
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`Indeed, a formulation with these components would have been the typical starting point for the
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`development of an intravenous solution formulation.
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`It was common practice to select the appropriate amount of the active ingredient
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`to use in an intravenous solution, the appropriate pH for the intravenous solution, and the
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`inactive ingredients (e.g., the tonicifying or the stabilizing agents) in appropriate amounts for the
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`intravenous solution through screening and optimization experiments, carried out in
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`preformulation studies and as part of formulation development.
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`1 Exhibits hereto are referred to as “Ex. _.”
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`The prior art suggested using a low dose and a low concentration of palonosetron
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`for the treatment of emesis. The prior art also suggested that a low concentration of palonosetron
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`was preferable to maintain the stability of an intravenous formulation.
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`The prior art included intravenous solution formulations of palonosetron and
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`several other “setron” drugs or agents that were fimctionally and structurally similar to
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`palonosetron. In particular, these prior art solutions all included the same basic inactive
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`components: (i) pH buffers to maintain the intravenous solutions within an acidic range, (ii)
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`tonicifying agents, including mannitol, and (iii) stabilizing agents including EDTA.
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`17.
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`It would have been obvious for a person of ordinary skill in the art to make an
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`intravenous solution ofpalonosetron containing a low concentration of palonosetron (e.g, “about
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`”), that was buffered at a pH of “from 4.0 to 6.0,” and that included “mannitol” and
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`“EDTA” as components of the fonnulation, as in the asserted claims. Indeed, such a fonnulation
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`would have been nothing more than the result of the ordinary formulation development process.
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`Based on the prior art, a person of ordinary skill in the art would have expected that such an
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`18.
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`Because the asserted claims of the patent-in-s11it merely claim intravenous
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`solutions of palonosetron suggested by the prior art, it is my opinion that the claimed intravenous
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`solutions of palonosetron would have been obvious to a person of ordinary skill in the art.
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`IV. METHODOLOGY APPLIED AND MATERIALS REVIEWED
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`19.
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`I understand that a patent is to be understood from the perspective of a person of
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`ordinary skill in the art to which it pertains. I also understand that the earliest patent application
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`that ultimately led to the patents-in-suit was originally filed on January 30, 2003. Unless stated
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`otherwise, I provide my opinions in this Report with respect to the time period preceding January
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`30, 2003, which I understand to be the relevant time frame for evaluating the obviousness of the
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`patents-in-suit. I understand that the “prior art” in this matter includes references and other
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`printed publications published prior to January 30, 2002.
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`20.
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`I also understand that in determining whether a claimed invention is obvious, the
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`scope and content of the prior art must be determined, and the differences between the prior art
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`and the claimed invention must be ascertained. The obviousness of the claimed invention must
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`be judged from the viewpoint of a person of ordinary skill in the art at the time the claimed
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`invention was made, including the knowledge such a person could have gleaned from the
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`references available at that time. I imderstand that the analysis should not be done using
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`hindsight, but that the determination of whether a claimed invention would have been obvious
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`must be based on a consideration of the prior art, and without knowledge of the teachings of the
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`patents.
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`21.
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`I provide my opinions based on my review of the following materials:
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`0 U.S. Patent No. 7,947,724 (“the ‘724 patent,” Ex. 2)
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`0 U.S. Patent No. 7,947,725 (“the ‘725 patent,” Ex. 3)
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`0 U.S. Patent No. 7,960,424 (“the ‘424 patent,” Ex. 4)
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`0 U.S. Patent No. 5,202,333 (“the ‘333 patent,” Ex. 5)
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`0 Kenneth E. Avis et al., PHARMACEUTICAL DOSAGE FoRMs: PARENTERAL
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`MEDICATIONS, vol. 1 (Marcel Dekker Inc. 1992) (“Avis”), Chapters 2, 4 & 5
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`(excerpts in Ex. 6)
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`0 Leon Lachman et al., THE THEORY AND PRACTICE or INDUSTRIAL PHARMACY
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`Urea & Febiger 1986) (“Lachman”), Chapters 8, 22 & 26 (excerpts in Ex. 7)
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`PHARMACEUTICAL PREFORIVIULATION AND FORMULATION: A PRACTICAL GUIDE
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`FROM CAND]DA'I'E DRUG SELECTION TO COMMERCIAL DOSAGE FoRM (Gibson ed.,
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`CRC Press 1“ ed. 2001) (“Gibson”), Chapters 6, 8 & 9 (excerpts in Ex. 8)
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`0 L.A. Trissel, “Drug Stability and Compatibility Issues,” in HANDBOOK ON
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`INJECTABLE DRUGS (ASHIP 7"‘ ed. 1992) (“Trissel”) (Ex. 9)
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`5
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`L.G. Wade Jr., ORGANIC CHEMISTRY (Prentice Hall 3"‘ ed. 1995) (“Wade”),
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`Chapter 19 (excerpts in Ex. 10)
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`K. A. Connors, et al., CHEMICAL STABILITY or PHARMACEUTICALS: A HANDBOOK
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`FOR PHARMACISTS (John Wiley & Sons 2"” ed. 1986) (“Connors”), Chapter 5
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`(excerpts in Ex. 1 1)
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`THE UNITED STATES PHARMACOPEIA (USP) 25 (2002) (“USP 2002”), <1 15 l>
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`Pharmaceutical Dosage Forms (Ex. 12)
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`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (20"' ed. 2000)
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`(“Remington”), Chapter 52 (EX. 13)
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`Helsinn News Releases dated April 10, 2001, October 3, 2001 and January 16,
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`2002, HELSN03767l9-24 (Ex. 14)
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`J. Tang et al., The Eflicacv ofRS-25259, A Long-Acting Selective 5-HT3 Receptor
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`Antagonist, for Preventing Postoperative Nausea And Vomiting After
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`Hvsterectomy Procedures, Anesth. Analg., 1998; 87: 462-7 (Tang”) 03x. 15)
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`R. M. Eglen et al., Pharmacological characterization ofRS 25259-I97, a novel
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`and selective 5-HT3 receptor antagonist, in vivo, Br. J. Pharmacology, (1995)
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`114, 860-866 (“Eglen”) (Ex. 16)
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`C.M. Won et al., Photolytic and Oxidative Degradation ofan Antiemetic Agent,
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`RGI29I5, Int’l J. Pharmaceutics, 121 (1995), 95-105 (“Won”) (Ex. 17)
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`THE PHYSICIANS’ DESK REFERENCE, 1503-07 (5"‘ ed. 2001) (“PDR 2001”) for
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`ZOFRAN9,
`and “ANZEMET9.” (Ex. 18)
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`Syntex Prefonnulation Book for RS-25259, PD Letter No. 63,086,
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`ROCHE0010222-338 (“Syntex Formulation Book”)
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`Syntex RS-25259-197 Formulation Book for Intravenous Dosage Forms,
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`ROCHE0008749-876 (“Syntex Preformulation Book”)
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`Oread Memorandum Letter #D7799-003 dated April 26, 1999, I-IELSNOI 16379-
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`86 (“Oread Memo”)
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`Stability Statement for RS-25259-197 Solution (F25259-002, -005 and -006)
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`dated May 26, 1992, I-IELSN0128734-39 (“Syntex 1992 Stability Statement”)
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`Stability Statement for RS-25259-197 IV Solutions (F25259-002, -005 and -006)
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`dated April 11, 1995, ROCHE0013199-201 (“Syntex 1995 Stability Statement”)
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`Excerpts of Helsinn IND 39,797 Amendment #64, HELSN0l75550-59 (“Helsinn
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`IND Amendment #64”)
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`0
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`Statutory Declaration of Daniele Bonadeo dated February 13, 2007,
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`HELSN0000123-28 (“Bonadeo Declaration 2007”)
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`0 Declaration of Daniele Bonadeo dated February 9, 2009, HELSN000l639-47
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`(“Bonadeo Declaration 2009”)
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`0
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`Supplemental Declaration of Daniele Bonadeo dated June 8, 2009,
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`HELSN000l683-87 (“Bonadeo Supplemental Declaration 2009”)
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`0 Expert Report of David G. Frame, Pharm.D. (“Frame Report”).
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`22.
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`I reserve the right to supplement my opinions and may rely on additional
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`information to support my opinions as it is made available.
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`V.
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`THE PATENTS-IN-SUIT
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`23.
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`The patents-in-suit concern the field of pharmaceutical fonnulation for injection
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`via the intravenous (IV) route, and are directed to pharmaceutically stable intravenous solutions
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`of palonosetron for treating emesis. These solutions have specific concentrations of
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`palonosetron, specific pH ranges and specific concentrations of certain inactive ingredients.
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`(Exs. 2-4.)
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`24.
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`More specifically, the asserted claims of the patents—in-suit are directed to
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`phannaceutically stable solutions containing either “0.05 mg/ml” or “about 0.05 mg/ml” of
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`palonosetron or a pharmaceutically acceptable salt thereof (e.g., palonosetron hydrochloride).
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`(Id.) Further, the palonosetron solutions are buffered at a pH of “from 4.0 to 6.0” or more
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`narrowly “from 4.5 to 5.5.” (Id.) The solutions also contain “from 0.005 mg/mL to 1.0 mg/mL”
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`EDTA and mannitol in an amount to render the solutions isotonic. (Id.)
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`25.
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`Claim 2 of the ‘725 patent is representative:
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`A pharmaceutically stable solution for reducing emesis or reducing the likelihood
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`of emesis comprising:
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`a) 0.05 mg/mL palonosetron hydrochloride, based on the weight of the free
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`base, in a sterile injectable aqueous carrier at a Ifl of from 4.5 to 5.5;
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`from 0.005 mg/mL to 1.0 mg/mL EDTA; and
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`b)
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`c) mannitol in an amount sufficient to tonicify said solution, in a
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`concentration of from about 10 mg/ml to about 80 mg/ml.
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`(Ex. 3, underlining added.) The other asserted claims (i.e., claims 2 and 9 of the ‘724 patent and
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`claims 2, 5 and 6 of the ‘424 patent) are essentially the same, only differing in the claimed
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`palonosetron concentration (“about 0.05 mg/
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`”) or pH range (“from 4.0 to 6.0”). (Exs. 2 & 4.)
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`26.
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`The specifications of the patents-in-suitl assert that “formulating palonosetron in
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`liquid formulations has not proven an easy task, typically due to shelf-stability issues,” citing as
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`support for this statement an intravenous formulation disclosed in Example 13 of U.S. Patent No.
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`5,202,333.3 (Ex. 2, ‘724 patent, col. 1, lines 52-67.) According to the specification, the
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`formulation in Example 13 “has a pH of 3.7 and a shelf stability of less than the 1-2 year time
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`period required by health authorities in various countries.”4 03x. 2, ‘724 patent, col. 2, lines 1-3.)
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`The specification concludes that “there exists a need for a palonosetron formulation with
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`increased stability and thereby increased shelf life. There also exists a need for an appropriate
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`range of concentrations for both the 5-HT; receptor antagonist and its pharmaceutically
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`acceptable carriers that would facilitate making a formulation with this increased stability.” (Ex.
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`2, ‘724 patent, col. 2, lines 36-41.)
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`27.
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`In the Summary of the Invention, the inventors state that they “have made a series
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`of discoveries that support a surprisingly effective and versatile formulation for the treatment and
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`prevention of emesis using palonosetron. These formulations are shelf stable for periods greater
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`2 In this Report, unless otherwise stated, I refer to the specifications of the three patents-in-suit
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`by citing only to the ‘724 patent because I understand that the three patents-in-suit contain
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`identical specifications.
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`3 I note that the patents-in-suit list “Palonosetron HCI” as the active ingredient in the
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`formulation, whereas Example 13 of the ‘333 patent does not, and instead recites “Compound of
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`Formula I,” which includes palonosetron and numerous other compounds within the generic
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`fonnula. (See Ex. 5, ‘333 patent, Example 13.)
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`4 I note that no stability data are described in the patents-in-suit or were submitted to the Patent
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`Office to support the asserted “shelf stability of less than [] 1-2 year” for this hypothetical
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`formulation of palonosetron.
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`than 24 months at room temperature, and thus can be stored without refrigeration, and
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`manufactured using non—aseptic, terminal sterilization processes.” (Ex. 2, ‘724 patent, col. 2,
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`line 56-col. 3, line 30.)
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`28.
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`In addition to the above disclosures, the specification also includes several
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`examples. Examples 1-3 are particularly relevant to the discussion herein as they relate to the
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`selection of an optimal pH range, a tonicifying agent and the concentrations of palonosetron and
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`excipients in the claimed formulations. (Ex. 2, ‘724 patent, col. 7, lines 6-45.) Moreover,
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`Example 4 discloses a representative intravenous formulation of palonosetron. (Ex. 2, ‘724
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`patent, col. 7, lines 46-67.)
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`29.
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`Specificafly, Example 1, entitled “Stabilizing pH,” describes a study “conducted
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`to determine the effect of pH on formulations containing palonosetron hydrochloride, measuring
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`the stability at 80°C. at pH 2.0, 5.0, 7.4, and 10.0.” (Ex. 2, ‘724 patent, col. 7, lines 6-15.) The
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`inventors concluded based on this study that “[t]he results indicated that palonosetron
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`hydrochloride is most stable at pH 5.0.” (Id.)
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`30.
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`Example 2, entitled “Stabilizing Concentration Ranges,” describes “a formulation
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`optimization study [] performed using an experimental design software.” (Ex. 2, ’724 patent,
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`col. 7, lines 16-34.) According to the example, “[t]we11ty-four lots of drug product were
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`analyzed to investigate the appropriate concentration ranges for palonosetron hydrochloride
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`(0.05 mg/mL to 5.0 mg/mL), citrate buffer (0 to 80 mM) and EDTA (0 to 0.l0%).” (Id.) Based
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`on this analysis an optimal formulation was identified and “[t]he level of EDTA and citrate
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`buffer were selected based on [this] optimal formulation, which was shown to be formulated
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`with EDTA 0.05% and 20 mM citrate buffer at pH 5.0.” (Id.) In addition, “the results of [the]
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`study indicated that palonosetron concentration was also a critical factor ir1 chemical stability,
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`with greatest stability seen at the lowest palonosetron concentrations.” (Id.)
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`31.
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`Example 3, entitled “Tonicifying Agent,” describes a study in which
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`“[f]ormulations of palonosetron hydrochloride in citrate buffer were prepared including either a)
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`sodium chloride or b) mannitol.” (Ex. 2, ‘724 patent, col. 7, lines 35-45.) Based on this study, it
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`was detemlined that “[t]he palonosetron hydrochloride formulation including mannitol showed
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`superior stability. The optimum level of mannitol required for an isotonic solution was folmd to
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`32.
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`Example 4 of the patents-in—suit describes “a representative pharmaceutical
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`formulation containing palonosetron that is useful for intravenous formulations, or other liquid
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`formulations of the drug.” (Ex. 2, ‘724 patent, col. 7, lines 46-67.) The composition of the
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`representative fonnulation set forth in Example 4 is as follows:
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`mg/mL
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`0.05.
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`q.s. to 1 ml
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`pH 5.0 i 0.5
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`Ingredient
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`Mannitol
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`Sodium hydroxide solution and/or
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`hydrochloric acid solution
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`‘calculated as a free base
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`(Ex. 2, ‘724 patent, col. 7, lines 56-66.) In this Report, I will refer to this formulation as “the
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`Example 4 Formulation.” I understand that the Example 4 Formulation is representative of the
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`formulations claimed in the patents-in-suit.
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`33.
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`Notably, the patents-in—suit are silent as to how the inventors arrived at the 0.05
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`mg/ml palonosetron concentration used in the Example 4 Formulation or specified in the claims.
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`10
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`Page 13 of 46
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`Indeed, aside from the fact that 0.05 mg/ml is the lowest concentration (and “with the greatest
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`stability seen”) in the range that was investigated in the optimization study described in Example
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`2, there is no discussion hr the specification concerning why 0.05 mg/ml was selected by the
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`inventors. (See Ex. 2, ‘724 patent, col. 7, lines 22-34.)
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`VI.
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`BACKGROUND ON DRUG FORMULATION AND FORMULATION
`OPTINIIZATION
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`34.
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`Drug products are “formulated” in dosage forms to be administered to patients
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`through various routes (e.g., oral, injectable and transde1maletc.). An intravenous solution is a
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`parenteral liquid solution dosage form that is administered through injection into a “vein” of the
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`human body. (See generally Ex. 6, Avis at 22-25; Ex. 7, Lachman at 639-44.)5
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`A.
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`Typical Components of an Intravenous Solution
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`35.
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`An intravenous solution contains a number of typical components. First, every
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`intravenous solution drug product contains an appropriate unit amount or concentration of the
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`active drug substance (also referred to as the “active pharmaceutical ingredient” or “API”). The
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`concentration is primarily determined by the therapeutic dosage and the injection volume
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`selected for treating a particular disease or condition, as well as other considerations such as
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`solubility and stability. (See e.g. , Ex. 8, Gibson at 332.)
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`36.
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`In addition to the active drug substance, an intravenous solution drug product
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`contains a “carrier” or Wehicle,” which typically is a sterile aqueous carrier (i.e., sterile water as
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`the solvent of the solution). (Ex. 6, Avis at 174, 175, 190; Ex. 7, Lachman at 640.)
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`37.
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`An intravenous solution drug product also contains inactive ingredients
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`(excipients) for various purposes, e.g., to facilitate administration or to maintain the quality of
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`5 Many textbooks, treatises, standards, guidelines and other authoritative references teach the
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`general concepts and practices in the field of pharmaceutical formulation that I discuss here as
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`background and I cite only a few such references as examples.
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`11
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`the drug product. (See, e.g., Ex. 6, Avis at 173-74, 192; Ex. 7, Lachman at 639-44.) Typical
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`inactive components include: 1) a pH buffer; 2) a tonicifying agent; and 3) when necessary, one
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`or more stabilizing agents, such as an antioxidant, a chelating agent and/or a preservative. The
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`selection of the specific excipients and their appropriate amounts for these components is a
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`primary task of formulation development.
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`38.
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`A pH buffer will be included to control and maintain an a