Helsinn Healthcare Exhibit 2027
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00008
`
`Page 1 of 71
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`

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`TABLE OF CONTENTS
`
`Page
`
`I.
`
`II.
`
`III.
`
`IV.
`
`QUALIFICATIONS. ...........................................................................................................1
`
`SUMMARY OF OPINIONS. ..............................................................................................3
`
`A.
`
`B.
`
`Legal Standards. .......................................................................................................3
`
`Summary Of Opinions. ............................................................................................4
`
`PERSON OF ORDINARY SKILL IN THE ART. ..............................................................5
`
`THE ASSERTED PATENTS. .............................................................................................7
`
`A.
`
`B.
`
`C.
`
`The ‘724 Patent. .......................................................................................................7
`
`The ‘725 Patent. .......................................................................................................8
`
`The ‘424 Patent. .......................................................................................................8
`
`V.
`
`BACKGROUND OF THE TECHNOLOGY. .....................................................................9
`
`A.
`
`B.
`
`C.
`
`5-HT3 Compounds As Therapeutic Agents For The Treatment Of Emesis. ...........9
`
`Selected Prior Art Relevant to Intravenous Palonosetron Formulations. ..............10
`
`1.
`
`The ‘333 Patent. .........................................................................................10
`
`The Approach of a POSA In Preparing Formulations For Intravenous
`Administration. ......................................................................................................22
`
`1.
`
`2.
`
`3.
`
`Formulation Principles. ..............................................................................22
`
`Strategies for Preformulation Studies. .......................................................23
`
`Strategies for Formulation Screening and Optimization Studies. ..............29
`
`VI.
`
`PLAIN AND ORDINARY MEANING OF “PHARMACEUTICALLY
`STABLE”. ..........................................................................................................................30
`
`VII. THE CLAIMS OF THE ASSERTED PATENTS ARE INVALID. .................................33
`
`A.
`
`Claims 2 And 9 Of The ‘724 Patent Are Obvious. ................................................34
`
`1.
`
`Claim 2 is Obvious in View of the ‘333 Patent and the Knowledge
`of One of Ordinary Skill in the Art. ...........................................................34
`
`i
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`Page 2 of 71
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`

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`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`g.
`
`h.
`
`A POSA would have been motivated to make an
`intravenous palonosetron formulation at the time of the
`alleged invention. ...........................................................................35
`
`A POSA would have been motivated to improve stability of
`an intravenous palonosetron formulation. ......................................39
`
`“Palonosetron or a pharmaceutically acceptable salt
`thereof is in a concentration of about 0.05 mg/ml” would
`have been obvious. .........................................................................40
`
`“Buffered at a pH from 4.0 to 6.0” would have been
`obvious. ..........................................................................................44
`
`“A pharmaceutically acceptable sterile aqueous carrier
`including a tonicifying effective amount of mannitol” would
`have been obvious. .........................................................................46
`
`“From 0.005 mg/ml to 1.0 mg/ml of EDTA” would have
`been obvious. .................................................................................47
`
`“Pharmaceutically stable” would have been obvious. .................50
`
`“For reducing emesis or reducing the likelihood of emesis”
`would have been obvious. ..............................................................51
`
`B.
`
`C.
`
`2.
`
`3.
`
`Claim 2 is Obvious in View of the ‘333 Patent and the Knowledge
`of One of Ordinary Skill in the Art, and Further in View of Won
`1995............................................................................................................51
`
`Claim 9 is Obvious in View of the Prior Art, Including the ‘333
`Patent and Won 1995. ................................................................................54
`
`Claim 2 Of The ‘725 Patent Is Obvious In View Of The Prior Art,
`Including The ‘333 Patent And Won 1995. ...........................................................55
`
`Claims 2, 5, And 6 Of The ‘424 Patent Are Obvious. ...........................................57
`
`1.
`
`2.
`
`3.
`
`Claim 2 is Obvious in View of the Prior Art, Including the ‘333
`Patent and Won 1995. ................................................................................57
`
`Claim 5 is Obvious in View of the Prior Art, Including the ‘333
`Patent and Won 1995. ................................................................................58
`
`Claim 6 is Obvious in View of the Prior Art, Including the ‘333
`Patent and Won 1995. ................................................................................59
`
`VIII. CONCLUSION. .................................................................................................................59
`
`
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`Page 3 of 71
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`
`
`I, Lee Kirsch, Ph.D., submit my expert report in the above-referenced case on behalf of
`
`Defendants Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries, Ltd.
`
`(collectively “Teva”) and Sandoz Inc. (“Sandoz”). I reserve the right to amend or supplement
`
`my opinions in light of evidence presented by Helsinn Healthcare S.A. and Roche Palo Alto LLC
`
`(collectively “Helsinn” or “Plaintiffs”), or additional information that may be made available to
`
`me in the future. I have not yet created the exhibits or demonstratives that I expect to use to
`
`summarize or explain my opinions at trial, but they will likely include formulation summaries
`
`and presentations showing the formulation development background described in this report.
`
`I. QUALIFICATIONS.
`
`1.
`
`I am currently a Professor at the University of Iowa, College of Pharmacy,
`
`Division of Pharmaceutics. A complete list of my publications, presentations, professional
`
`activities, and honors that I have received are fully set forth in my curriculum vitae, attached
`
`hereto at Exhibit A.
`
`2.
`
` I received a B.S. degree in Pharmacy in 1975 from Purdue University and
`
`received a Ph.D. in Pharmaceutical Chemistry in 1982 from the Ohio State University. From
`
`1982 to 1994, I was a research scientist at Lilly Research Laboratories in the Pharmaceutical
`
`Product Development Division. During my time at Lilly, my responsibility was to develop drug
`
`formulations for new drug substances and to address formulation issues associated with marketed
`
`drug products. My particular area of focus was injectable drug product design and development,
`
`including drugs intended for intravenous and extravascular administration. During my industrial
`
`tenure, my research focus was on drug stability issues as evidenced by my publication and
`
`presentation history during this time period. In 1994, I took a position at the University of Iowa
`
`College of Pharmacy, first as an Associate Professor and then in 2010 as a full Professor. During
`
`my time at Iowa, my research has continued to focus on issues of drug product design and
`
`
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`development, and especially drug product stability. In addition to conducting fundamental
`
`research on drug stability phenomena, I also have had the opportunity to work on numerous
`
`industrially-supported projects, addressing various drug product performance and design issues
`
`for injectable, solid oral, topical and various other types of drug formulations. I also have had
`
`the opportunity to teach courses at Iowa, including drug degradation kinetics and mechanisms,
`
`drug stability, pharmaceutical proteins, advanced compounding, solid dosage forms,
`
`lyophilization, pharmaceutical product development, pharmacokinetics and biopharmaceutics,
`
`pharmaceutical package design and integrity, and pharmaceutical technology.
`
`3.
`
`I have received numerous awards and honors, including the Distinguished Service
`
`Award from the Parenteral Drug Association, Jack L. Beal Post Baccalaureate Award from The
`
`Ohio State University, Fred Simon Award for the best paper in the PDA Journal of
`
`Pharmaceutical Science and Technology, Editor-in-chief for the AAPS PharmSciTech Journal,
`
`and Editor of the PDA Journal of Pharmaceutical Science and Technology.
`
`4.
`
`I have authored or co-authored over 50 published scientific articles in the areas of
`
`pharmaceutical chemistry, drug stability, drug delivery, pharmacokinetics, pharmaceutical
`
`package integrity, and analytical chemistry. I have served as a peer-reviewer on various well-
`
`respected pharmaceutical science and technology journals, including Journal of Pharmaceutical
`
`Science, Drug Development and Industrial Pharmacy, Pharmaceutical Research, International
`
`Journal of Pharmaceutics, PDA Journal of Pharmaceutical Science and Technology, Journal of
`
`Pharmaceutical Innovation, Pharmaceutical Development and Technology, AAPS
`
`PharmSciTech, and International Journal of Chemical Kinetics.
`
`5.
`
`In the last four years, I have testified at trial or by deposition in AstraZeneca v.
`
`Mylan, (10-cv-05519) (D.N.J. 2012).
`
`2
`
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`6.
`
`I am being compensated for my work at $
`
` per hour. No part of this
`
`compensation due or received is contingent upon the outcome of this litigation.
`
`7.
`
`In addition to those materials attached to this report as exhibits, a list of the other
`
`materials that I reviewed in connection with this report is attached hereto at Exhibit B.
`
`II. SUMMARY OF OPINIONS.
`
`A.
`
`8.
`
`Legal Standards.
`
`In order to form my opinions in the context of this litigation, counsel has
`
`explained to me certain legal standards that are not in my area of expertise. I therefore include
`
`below my understanding of these relevant legal standards.
`
`9.
`
`I have been informed that a patent claim is invalid as obvious if the differences
`
`between the subject matter sought to be patented and the prior art are such that the subject matter
`
`as a whole would have been obvious at the time that the invention was made to a person of
`
`ordinary skill in the art (a “POSA”).1 That is, a patent claim is obvious if the combined
`
`teachings of prior art references and the general knowledge of a POSA would be sufficient to
`
`teach all the parts of a claim, and that the combination of references and knowledge would be
`
`reasonable. For my analysis of obviousness, I have considered and applied the following factors:
`
`(a) the scope and content of the prior art; (b) differences between the prior art and the asserted
`
`claims; (c) the level of ordinary skill in the field of the invention; and (d) certain other objective
`
`factors, including whether a motivation existed to create the invention before the invention was made
`
`and whether the claimed invention applies known techniques that already had been used to improve a
`
`similar product in a similar way such that a POSA would have had a reasonable expectation of
`
`success in combining prior art to arrive at the claimed invention.
`
`1 I have also been informed that as the patentee, Helsinn can present evidence to show non-
`obviousness of the claimed invention, and I reserve the right to respond to Helsinn’s evidence
`and/or expert opinions on this issue.
`
`3
`
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`10.
`
`I also have been informed and understand that some ways to look at the question
`
`of obviousness include: (1) whether there existed at the time of the invention a known problem
`
`for which there was an obvious solution encompassed by the patent claims, (2) whether there is a
`
`combination of familiar elements according to known methods that yield predictable results, and
`
`(3) the inferences and creative steps that a person of ordinary skill in the art would employ, such
`
`a POSA being a person of ordinary creativity, not an automaton. I further understand that
`
`hindsight cannot be used when determining whether a claimed invention is obvious. While there
`
`must be motivation for a POSA to combine the claim elements in the manner claimed and with a
`
`reasonable expectation of success in doing so, such motivation to combine is demonstrated by
`
`applying common sense analysis rather than rigid rules. That is, any need or problem known in
`
`the field of endeavor at the time of the invention and addressed by the patent can provide a
`
`reason for combining the claim elements.
`
`B.
`
`11.
`
`Summary Of Opinions.
`
`I have been asked to provide my opinions regarding whether the asserted claims 2
`
`and 9 of U.S. Patent No. 7,947,724 (“the ‘724 patent”), the asserted claim 2 of U.S. Patent No.
`
`7,947,725 (“the ‘725 patent”), and the asserted claims 2, 5, and 6 of U.S. Patent No. 7,960,424
`
`(“the ‘424 patent”) (collectively, “the asserted claims” or “asserted patents”) would have been
`
`obvious to a POSA in view of the prior art. It is my opinion that each of the asserted claims
`
`would have been obvious to a POSA as of the earliest priority date of the asserted patents, which
`
`I understand is January 30, 2003.2 As described in more detail below, this is because the
`
`formulations of palonosetron that are described and claimed in the asserted patents include
`
`2 This priority date is based on the filing of the first patent application no. 60/444,351 to which
`the asserted patents claim priority. To the extent the asserted claims are assigned a priority date
`or invention date earlier than January 30, 2003 (for example in the mid to late 1990s), it is still
`my opinion that each of the asserted claims would have been obvious to a POSA based on the
`same prior art disclosures and/or knowledge and ordinary skill of a POSA as of this earlier date.
`
`4
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`nothing more than a combination of familiar excipients, concentration ranges, and other common
`
`formulation conditions that were already taught or suggested in the prior art at the time of the
`
`alleged invention. At the time, palonosetron had also already been shown to be more potent than
`
`other setron drugs in terms of treating emesis. Thus, a POSA would have been motivated to
`
`formulate palonosetron and would have had a reasonable expectation of success of formulating
`
`the compound as claimed by employing basic formulation development methods that were
`
`routinely practiced by formulators, in view of the teachings of the prior art and knowledge that
`
`were available at the time of the alleged invention.
`
`12.
`
`I may testify at trial about background scientific concepts and the development of
`
`intravenous formulations to better explain the context of the technology at issue, including an
`
`explanation of basic formulation techniques and common methods used to formulate unstable
`
`drugs in liquid formulations. I may also describe the chemistry of different formulation methods,
`
`such as the use of various excipients, to show what a POSA would have known about how they
`
`worked and how they could be used to make otherwise unstable compounds stable in intravenous
`
`formulations. The basis for my opinions include the documents, prior art, and standard
`
`textbooks and references cited in this report; my education; and my years of experience in
`
`industry and academia, including working on and teaching courses about the development of
`
`formulations for pharmaceutical products.
`
`III. PERSON OF ORDINARY SKILL IN THE ART.
`
`13.
`
`The subject matter of the asserted patents is generally directed to the field of
`
`intravenous formulations of antiemetic compounds (i.e. compounds used to treat nausea and
`
`vomiting). The field of formulation development, and the specific body of knowledge and
`
`research associated with formulating antiemetic compounds, was well-established and well-
`
`practiced by January 30, 2003, such that it had become a mature field of technology. The same
`
`5
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`formulation principles, strategies, and methods that were developed and effectively implemented
`
`in the 1980s and 1990s were routinely used in 2003, and indeed continue to be followed with
`
`success by formulators today.
`
`14.
`
`In my opinion, a POSA in the subject matter of the asserted patents would have a
`
`Ph.D. in pharmaceutics, pharmaceutical chemistry, or a similar field involving pharmaceutical
`
`formulations, and would have several years of experience in pharmaceutical formulation
`
`development, including development of intravenous solution formulations. Alternatively, a
`
`POSA would have a Bachelor’s or Master’s degree in pharmacy, pharmaceutical chemistry, or a
`
`similar field involving pharmaceutical formulations, and would have many years of experience
`
`developing and testing pharmaceutical formulations. In developing formulations, the POSA also
`
`would routinely collaborate as part of a project team with others having ordinary skill in various
`
`fields, for example, in clinical sciences to discuss issues regarding safety and efficacy profiles
`
`and requirements.
`
`15.
`
`A POSA would find particularly relevant prior art formulations for compounds
`
`with similar chemical structures and therapeutic uses as palonosetron, as well as other
`
`parenterally administered (e.g. intravenous) drug products in general. A POSA’s knowledge also
`
`would include routine preformulation studies, formulation screening studies, and formulation
`
`optimization or experimental design studies. These fields of art were routinely practiced by
`
`POSAs well prior to 2003 and continuing to today. Indeed, there were already numerous
`
`examples and data in prior art textbooks and other standard references to teach, or otherwise
`
`provide guidance for, a POSA on how best to formulate compounds in intravenous solutions.
`
`6
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`IV. THE ASSERTED PATENTS.
`
`A.
`
`16.
`
`The ‘724 Patent.
`
`I have reviewed U.S. Patent No. 7,947,724, Liquid Pharmaceutical Formulations
`
`of Palonosetron (the “‘724 patent”).3 The earliest United States priority application relating to
`
`the ‘724 patent was filed on January 30, 2003. The ‘724 patent discloses and claims stable
`
`palonosetron formulations. For example, the ‘724 patent discloses a representative intravenous
`
`formulation in Example 4, as follows:4
`
`Ingredient
`Palonosetron hydrochloride (free base)
`Mannitol
`EDTA
`Trisodium citrate
`Citric acid
`Water for injection
`Sodium hydroxide
`
`
`17.
`
`mg/ml
`0.05
`41.5
`0.5
`3.7
`1.56
`q.s. to 1 ml
`pH 5.0 ± 0.5
`
`The ‘724 patent purports to address “a need for a palonosetron formulation with
`
`increased stability and thereby increased shelf life.”5 At the time of the alleged invention, it was
`
`already known in the art that existing palonosetron formulations had “a pH of 3.7 and a shelf
`
`stability of less than the 1-2 year time period required by health authorities in various
`
`countries.”6 As a result and as discussed in detail below, the solution to this problem would have
`
`been obvious to a POSA. In light of the expected higher efficacy of a palonosetron intravenous
`
`drug product compared to other 5-HT3-receptor-antagonist drug products, a POSA would have
`
`been motivated to improve the stability of prior art intravenous formulations of palonosetron.
`
`
`3 Calderari et al., U.S. Patent No. 7,947,724, (May 24, 2011) (attached hereto at Exhibit C). I
`also have reviewed excerpts from the prosecution history of the ‘724 patent pertaining to the
`claimed formulations.
`4 Id. at col. 7, ll. 47-67.
`5 Id. at col. 2, ll. 36-41.
`6 Id. at col. 1, l. 46 – col. 2, l. 3.
`
`7
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`Moreover, a POSA would have had a reasonable expectation of success in this endeavor by
`
`reviewing the teachings of the prior art and conducting the routine formulation development
`
`studies that were commonly practiced at the time of the alleged invention. There was a limited
`
`set of readily-available formulation options that a POSA would have used to formulate a stable
`
`intravenous palonosetron formulation, and the claimed formulations of the ‘724 patent include
`
`nothing more than a predictable use of prior art elements according to their established functions.
`
`B.
`
`18.
`
`The ‘725 Patent.
`
`I have reviewed U.S. Patent No. 7,947,725, Liquid Pharmaceutical Formulations
`
`of Palonosetron (the “‘725 patent”).7 The earliest United States priority application relating to
`
`the ‘725 patent was also filed on January 30, 2003. The ‘725 patent has the same specification as
`
`the ‘724 patent, and also discloses and claims stable palonosetron formulations, which are
`
`similar in scope to the formulations claimed in the ‘724 patent. As with the ‘724 patent, the
`
`claimed formulations of the ‘725 patent include nothing more than a predictable use of prior art
`
`elements according to their established functions. Therefore, the asserted claims of the ‘725
`
`patent would also have been obvious to a POSA.
`
`C.
`
`19.
`
`The ‘424 Patent.
`
`I have reviewed U.S. Patent No. 7,960,424, Liquid Pharmaceutical Formulations
`
`of Palonosetron (the “‘424 patent”).8 The earliest United States priority application relating to
`
`the ‘424 patent was also filed on January 30, 2003. The ‘424 patent has the same specification as
`
`the ‘724 and ‘725 patents, and also discloses and claims stable palonosetron formulations, which
`
`
`7 Calderari et al., U.S. Patent No. 7,947,725, (May 24, 2011) (attached hereto at Exhibit D). I
`have also reviewed excerpts from the prosecution history of the ‘725 patent pertaining to the
`claimed formulations.
`8 Calderari et al., U.S. Patent No. 7,960,424, (June 14, 2011) (attached hereto at Exhibit E). I
`have also reviewed excerpts from the prosecution history of the ‘424 patent pertaining to the
`claimed formulations.
`
`8
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`are again similar in scope to the formulations claimed in the other two asserted patents. As with
`
`the ‘724 and ‘725 patents, the claimed formulations of the ‘424 patent include nothing more than
`
`a predictable use of prior art elements according to their established functions. Therefore, the
`
`asserted claims of the ‘424 patent would also have been obvious to a POSA.
`
`V. BACKGROUND OF THE TECHNOLOGY.
`
`A.
`
`20.
`
`5-HT3 Compounds As Therapeutic Agents For The Treatment Of Emesis.
`
`5-Hydroxytriptamine (“5-HT3”) receptor antagonist compounds have historically
`
`been shown to be effective for the treatment of emesis, i.e. nausea and vomiting. Well-known
`
`since the 1980s and 1990s, 5-HT3 compounds were “the focus of extensive research efforts …
`
`because of the clinical efficacy of selective antagonists in the treatment of emesis associated with
`
`cancer chemotherapy.”9 The asserted patents also acknowledge that stable intravenous
`
`formulations of 5-HT3 receptor antagonists were available in the prior art, including
`
`commercially-approved products such as Zofran® (ondansetron), Kytril® (granisetron),
`
`Navoban® (tropisetron), and Anzemet® (dolasetron).10
`
`21.
`
`The earliest 5-HT3 compounds that were developed and commercially marketed
`
`included ondansetron. Ondansetron was first reported in the literature in the 1980s, and was
`
`approved in the United States in 1991 for the prevention of nausea and vomiting.11 Ondansetron
`
`was marketed by GlaxoSmithKline as Zofran®, and was available as prior art in an intravenous
`
`formulation (2 ml single-dose vial) that included ondansetron hydrochloride dihydrate (2 mg/ml),
`
`
`9 Eglen and Bonhaus, 5-Hydroxytryptamine (5-HT3) Receptors: Molecular Biology,
`Pharmacology, and Therapeutic Importance, Current Pharmaceutical Design, 2, 367-374 (1996)
`(attached hereto at Exhibit J).
`10 ‘724 patent at col. 2, ll. 4-35.
`11 Butler et al., Pharmacological Properties of GR38032F, a Novel Antagonists at 5-HT3
`Receptors, Br. J. Pharmacol., 94, 397 (1988).
`
`9
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`sodium chloride (9 mg/ml), citric acid monohydrate (0.5 mg/ml), and sodium citrate dihydrate
`
`(0.25 mg/ml) to buffer the aqueous solution at a pH of 3.3 to 4.0.12
`
`22.
`
`Granisetron was another 5-HT3 compound that was successfully developed and
`
`marketed. Granisetron was first reported in the literature in the late 1980s, and was approved in
`
`the United States in 1993 for the prevention of nausea and vomiting.13 Granisetron was
`
`marketed by Roche Laboratories as Kytril®, and was available as prior art in a single-dose
`
`intravenous formulation (1 ml) that included granisetron hydrochloride (1.12 mg/ml) and sodium
`
`chloride (9 mg/ml) in an aqueous solution at a pH of 4.7 to 7.3.14
`
`23.
`
`Dolasetron was reported in the literature in the late 1980s, and was approved and
`
`marketed in the United States for the prevention of nausea and vomiting. Dolasetron was
`
`marketed as Anzemet® by Sanofi-Aventis in 1997.15 Dolasetron was available as prior art and
`
`formulated for intravenous administration, including dolasetron mesylate (20 mg/ml), mannitol
`
`(38.2 mg/ml), and an acetate buffer to maintain aqueous solution at a pH between 3.2 to 3.8.16
`
`B.
`
`Selected Prior Art Relevant to Intravenous Palonosetron Formulations.17
`
`1.
`
`The ‘333 Patent.
`
`24.
`
`U.S. Patent No. 5,202,333 (the “‘333 patent”) issued on April 13, 1993, and thus
`
`would have been available as prior art to a POSA.18 The inventors named on the ‘333 patent
`
`
`12 Physician’s Desk Reference, 55th ed., 1503-1507 (2001).
`13 Bermudez et al., 5-Hydroxytriptamine (5HT3) Receptor Antagonists, 1. Indazole and
`Indolizine-3-carboxylic Acid Derivatives, J. Med. Chem., 33, 1924 (1990).
`14 Physician’s Desk Reference, 55th ed., 3104-3106 (2001).
`15 Sorensen et al., Effect of Acute and Chronic MDL 73,147EF, a 5-HT3 Receptor Antagonist, on
`A9 and A10 Dopamine Neurons, Eur. J. Pharmacol., 163(1), 115-118 (1989).
`16 Physician’s Desk Reference, 55th ed., 680-683 (2001).
`17 The prior art discussed in this section would have been particularly relevant to a POSA who
`was trying to make intravenous formulations of palonosetron. A POSA would also have
`substantial background knowledge and experience in formulation techniques and practice, as
`illustrated by formulation textbooks and standard references, discussed in further detail below.
`18 Berger et al., U.S. Patent No. 5,202,333, (April 13, 1993) (attached hereto at Exhibit F).
`
`10
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`included Jacob Berger, Robin Clark, Richard Eglen, William Smith, and Klaus Weinhardt, and
`
`the patent was assigned to Syntex (U.S.A.), Inc. (“Syntex”). The ‘333 patent disclosed and
`
`claimed tricyclic 5-HT3 receptor antagonists, including specifically the palonosetron
`
`compound.19 The ‘333 patent also disclosed and claimed formulations including such
`
`compounds, as well as methods for treating emesis using such compounds.20 Specifically, the
`
`‘333 patent disclosed the tricyclic compound of Formula I, depicted as:
`
`25.
`
`The ‘333 patent disclosed that a compound “of particular interest” and “of most
`
`interest” is where R3 is 1-azabicyclo[2.2.2]oct-3-yl,21 depicted as:
`
`
`
`
`With R3 in this configuration, the compound of Formula 1 is the chemical structure of
`
`palonosetron, which is as follows:
`
`
`19 Id. at col. 2, l. 17 – col. 3, l. 24; col. 6, ll. 44-56; claims 1, 4, 40, 41.
`20 Id.
`21 Id. at col. 9, ll. 12-26.
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`26.
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`The ‘333 patent reported that these tricyclic compounds “are useful in the
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`prevention and treatment of emesis.”22 More specifically, the ‘333 patent disclosed:
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`Compounds of Formula I are of particular value in treating
`(especially preventing) the emesis induced by radiation poisoning,
`treatment for cancer with radiotherapy or chemotherapy with
`cytotoxic agents or drug therapy in general wherein a significant
`side effect is emesis…23
`
`The ‘333 patent further discussed the administration of compounds including
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`27.
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`palonosetron, and formulations that can be used for such administrations. In this regard, the ‘333
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`patent taught how a POSA would go about determining the therapeutically effective amounts of
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`the compounds that could be used:
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`One of ordinary skill in the art of treating such diseases will be
`able, without undue experimentation and in reliance upon personal
`knowledge and the disclosure of this application, to ascertain a
`therapeutically effective amount of a compound of Formula I for a
`given disease.24
`
`As to formulating the tricyclic compounds such as palonosetron, the ‘333 patent
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`28.
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`disclosed that the compounds could be administered via parenteral routes (e.g. intravenous), and
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`could be formulated in combination with pharmaceutically acceptable excipients that are “non-
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`toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound.”25
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`The ‘333 patent disclosed that the formulations “will comprise from 0.000001% w to 10.0% w of
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`the compound of Formula I, preferably 0.00001% w to 1.0% w, with the remainder being the
`
`
`22 Id. at col. 9, ll. 50-57; see also ‘724 patent at col. 1, l. 46 – col. 2, l. 3 (reporting that the results
`of clinical investigations of palonosetron showed that palonosetron “is an order of magnitude
`more potent than most existing 5-HT3 receptor antagonists, has a surprising half-life of about 40
`hours, and is effective to reduce delayed-onset nausea induced by chemotherapeutic agents.”)
`23 Id. at col. 10, ll. 6-13.
`24 Id. at col. 12, ll. 1-24.
`25 Id. at col. 12, ll. 25-41.
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`excipient or excipients.”26 The ‘333 patent also taught that the formulations could be preferably
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`administered “in a single unit dosage form for continuous treatment or in a single unit dosage
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`form ad libitum when relief of symptoms is specifically required,” and provided an exemplary
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`intravenous formulation in Example 13.27
`
`2.
`
`The Clark 1993 Article.
`
`29.
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`In 1993, Robin Clark along with many of the same Syntex scientists and inventors
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`of the ‘333 patent published an article (“Clark 1993”) reporting the structure-activity relationship
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`of various 5-HT3 receptor antagonists, including palonosetron.28 Of the compounds disclosed,
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`Clark 1993 reported that the compound “(S,S)-37, the highest affinity 5-HT3 receptor ligand of
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`this study, was also the most potent compound at inhibiting the [von Bezold-Jarisch] reflex (ID50
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`0.02 µg/kg iv). This compound was also highly effective in the inhibition of cisplatin-induced
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`emesis in both the ferret and dog by either iv or po administration (Table V).”29 The (S,S)-37
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`compound is palonosetron:30
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`
`
`30.
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`Clark 1993 also compared the crystal structure of palonosetron to other 5-HT3
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`antagonists, including an antiemetic compound known as RG 12915 that was being developed by
`
`26 Id. at col. 12, ll. 60-68.
`27 Id. at col. 13, ll. 1-8; Example 13.
`28 Clark et al., 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and Isoquinolin-1-ones. Potent
`Conformationally Restricted 5-HT3 Receptor Antagonists, J. Med. Chem., 36, 2645-2657 (1993)
`(attached hereto at Exhibit G).
`29 Id. at 2649.
`30 Id. at 2648.
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`Rhone-Poulenc Rorer. In particular, Clark 1993 noted that RG 12915 “has the conformation of
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`the quinuclidine ring system in a similar conformation to the ‘overlap’ conformation of (S,S)-
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`37.”31
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`
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`Clark 1993 further demonstrated the similarities in the chemical structure of palonosetron (in
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`white) with other 5-HT3 antagonists, including again RG 12915 (in yellow), by superimposing
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`the structures of each on top of one another:32
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`
`
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`31 Id. at 2649.
`32 Id. at 2651-52; Figures 2 and 3.
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`
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`3.
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`The Won 1995 Article.
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`31.
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`At the same time Syntex was developing palonosetron as a new 5-HT3 receptor
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`antagonist for the treatment of emesis, Rhone-Poulenc Rorer (“RPR”) was developing its own
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`antiemetic compound, RG 12915. As noted above, RG 12915 is structurally similar to
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`palono