Declaration of Steven E. Patterson, Ph.D.
`
`Inter-Partes Review ______________
`
`Petitioner: Mylan Pharmaceuticals, Inc.
`
`Patent Owner: UCB Pharma GmbH
`
`Patent No.: 6,858,650
`
`
`
`1.
`
`Introduction and Background Qualifications
`
`I, Steven E. Patterson, Ph.D., have been retained by Kilpatrick Townsend &
`
`Stockton, LLP, counsel for Mylan Pharmaceuticals Inc. and Mylan Laboratories
`
`Limited (“Mylan”). My curriculum vitae is attached here and is labeled Ex. 1004.
`
`I understand that Mylan has petitioned for inter partes review of U.S. Patent No.
`
`6,858,650 (“’650 patent”) and requests that the United States Patent and
`
`Trademark Office cancel Claims 1-5 and 21-24 of the ’650 patent as unpatentable.
`
`The following discussion and analyses address the bases for Mylan’s Petition.
`
`2.
`
`I obtained my Ph.D. in Chemistry in 1995 and began a postdoctoral research
`
`position at the University of Notre Dame sponsored by Bayer in 1996. As part of
`
`my research there, I focused on combinatorial methods to develop selective sensors
`
`for carbohydrates and carbohydrate derivatives such as nucleic acid. This work, as
`
`could be expected given its sponsorship, was aimed at hopefully finding
`
`commercially viable compounds with pharmaceutical applications.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 1
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`

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`Currently, I am professor at the Center for Drug Design at The University of
`
`
`
`3.
`
`Minnesota. My research focuses on the efficient preparation of novel nucleosides
`
`and nucleotide analogs. Much focus in this space is in the prodrug context and is
`
`aimed at providing commercially viable pharmaceutical or therapeutic compounds
`
`that are either derived from existing, known effective treatments or the discovery
`
`of new compounds.
`
`4.
`
`As shown in my curriculum vitae, I am listed as author or co-author of over
`
`80 peer reviewed journal articles or publications focused on pharmaceutical and
`
`chemical analysis of compounds used in pharmaceutics. I have also served as the
`
`Director of the National Science Foundation’s Workshop in Medicinal Chemistry
`
`in 2012, 2013, 2014, and 2016 (scheduled). I am a member of the American
`
`Chemical Society in both the Medicinal and Organic Chemistry Divisions.
`
`5.
`
`Also as indicated in my curriculum vitae, I hold a U.S. patent for a novel
`
`compound and its preparation of an aklylamino compound – same class of
`
`compounds at issue in my analysis here. I have applied for at least four other
`
`patents, with at least two of those applications still pending.
`
`6. Much of my granted and focused research at the Center for Drug Design is
`
`in the area of structural analogs and improving the bioavailability of compounds
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 2
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`for use in pharmaceuticals or therapeutics. As will be discussed in great detail
`
`below, my understanding of how structural analogs are viewed by persons of skill
`
`in the art in terms of advancing the pharmaceutical arts is critical in determining
`
`which compounds are focused on by artisans in this field.
`
`7.
`
`As detailed below, I understand that the relevant period for my analysis is
`
`the first half 1998. In 1998 I had experience in drug design and development
`
`having specifically researched combinatorial synthesis of heterocyclic libraries as
`
`novel drug candidates. Specifically the libraries were focused on discovering
`
`potential leads for cancer drugs and pneumocystis carinii. This involved obtaining
`
`an understanding of what was known about compounds and drug candidates in the
`
`area of cancer therapeutics.
`
`8.
`
`At that time, I was very familiar with the design and development of prodrug
`
`compounds based on known active compounds through literature and my own
`
`work on discovery of and structure-activity relationship of a novel class of anti-
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`HIV compounds as a graduate student, some work with rifamycin derivatives,
`
`work with amidine-based prodrugs for pneumocystis carinii, and my work in
`
`discovery at Pharmasset where I was part of the team that discovered PSI-6130, a
`
`highly potent anti-HCV compound.
`
`
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 3
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`Materials Considered
`
`The following table shows the materials that I considered and relied upon in
`
`9.
`
`coming to my opinions. I also relied on the understanding that a skilled person in
`
`the field of drug design and development was not an automaton and instead
`
`possessed reasonable creativity in solving problems known to exist in the field.
`
`
`Exhibit No.
`1001
`1002
`1003
`1004
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`1010
`
`Title
`U.S.P.N. 6,858,650
`File History for Exhibit 1001
`Declaration of Dr. Steven Patterson, Ph.D.
`C.V. for Dr. Steven Patterson, Ph.D
`“Johansson” – WO 94/11337 Filed 6 November 1992 – “Novel
`3,3-Diphenylpropylamines, Their Use and Preparation”
`“Andersson Review” – BJU International (1999), 84, 923-947 –
`“The Pharmacological Treatment of Urinary Incontinence”; K-
`E Andersson, R. Appell, L.D. Cardozo, C. Chapple, H.P. Drutz,
`A.E. Finkbeiner, F. Haab, and R. Vela Navarrete.
`“Brynne 1997” – International Journal of Clinical
`Pharmacology and Therapeutics (1997), 35, 287-295 –
`“Pharmacokinetics and pharmacodynamics of tolterodine in
`man: a new drug for the treatment of urinary bladder
`overactivity”; N. Brynne, M.M.S. Stahl, B. Hallen, P.O.
`Edlund, L. Palmer, P. Hoglund, and J. Gabrielsson.
`“Thomas” – British Heart Journal (1995), 74, 53-56 –
`“Concentration dependent cardiotoxicity of terodine in patients
`treated for urinary incontinence”; S. Thomas, P. Higham, K
`Hartigan-Go, F. Kamali, P. Wood, R. Campbell, and G. Ford.
`“Detrol® Label” – Pharmacia & Upjohn.
`“Postlind” – Drug Metabolism and Disposition (1998), 26 (4),
`289-293 – “Tolterodine, A New Muscarinic Receptor
`Antagonist, Is Metabolized by Cytochromes P450 2D6 and 3A
`in Human Liver Microsomes”; H. Postlind, A. Danielson, A.
`Lindgren, and S. Andersson.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 4
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`

`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`1020
`
`1021
`
`1022
`
`1023
`
`“Brynne 1998” – Clinical Pharmacology & Therapeutics (May
`1998), 63(5), 529-539 – “Influence of CYP2D6 polymorphism
`on the pharmacokinetics and pharmacodynamics of
`tolterodine”; N. Brynne, P. Dalen, G. Alvan, L. Bertilsson, and
`J. Gabrielsson.
`“Bundgaard” – Elsevier Science Publishers (1985) – “Design of
`Prodrugs”; Hans Bundgaard.
`“Berge 1977” – Journal of Pharmaceutical Sciences (1977), 66
`(1), 1-19 – “Pharmaceutical Salts”; S. Berge, L., Bighley, and
`D. Monkhouse.
`“Andersson 1998” – Drug Metabolism and Disposition (1998),
`26(6), 528-535 – “Biotransformation of tolterodine, a new
`muscarinic receptor antagonist, in mice, rats, and dogs”; S.
`Andersson, A. Lindgren, and H. Postlind.
`“Nilvebrant” – Pharmacology and Toxicology (1997), 81, 169-
`172 – “Antimuscarinic Potency and Bladder Selectivity of
`PNU-200577, a Major Metabolite of Tolterodine”; L.
`Nilvebrant, P. Gillberg, and B. Sparf.
`“DeMaagd” – P&T (2012), 37(6), 345-361 – “Management of
`Urinary Incontinence”; G. DeMaagd and T. Davenport.
`“Appell” – Urology (1997), 50, 90-96 – “Clinical efficacy and
`safety of tolterodine in the treatment of overactive balder: a
`pooled analysis”; R. Appell.
`“Ashworth” – Home Care Provider (1997), 2(3), 117-120 – “Is
`My Antihistamine Safe?”; L. Ashworth.
`“Lipinski” – Advanced Drug Delivery Reviews
`“Bundgaard PCT” – WO 92/08459 Filed 11 November 1991 –
`“Topical Compositions for Transdermal Delivery of Prodrug
`Derivatives of Morphine”
`“AUA Guideline” – American Urological Association
`Eductatio and Research (2014) – “Diagnosis and Treatment of
`Overactive Bladder (Non-Neorogenic) in Adults: AUA/SUFU
`Guideline”; E. Gormley, et al.
`“Pfizer 2012 Press Release” – Aug. 2, 2012 “Study Shows
`Toviaz is Effective in Reducing Urge Urinary Incontinence in
`Patients with Overactive Bladder After Suboptimal Response to
`Detrol LA” – www.pfizer.com
`“PM360” – April 1, 2012 “Overactive Bladder Market:
`Managing the Future” – www. pm360online.com
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 5
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`

`
`“Toviaz® Label” – Pfizer Labs
`“FDA Approval Letter” –NDA20-771
`“FDA Guidance” – Applications Covered by Section 505(b)(2)
`– October 1999 – FDA (CDER)
`“Gould” – International Journal of Pharmaceutics (1986), 3,
`201-217 – “Salt Section for Basic Drugs”; P. Gould.
`“Alabaster” – Discovery & Development of Selective M3
`Antagonists for Clinical Use, 60 Life Science 1053 (1997)
`“Takeuchi” – 1,2,3,4-Tetrahydro-2-Isoquinolinecarboxylate
`Derivatives: A Novel Class of Selective Muscarinic
`Antagonists, III, in 213th ACS National Meeting, San
`Francisco, Abst. 046 (Apr. 13-17, 1997)
`“Goldberg” – Clinical Pharmacology & Therapeutics (1997)
`61(1), 59-69 – “DuP 532, an angiotensin II receptor antagonist:
`First Administration and comparison with losartan”; M.
`Goldberg, M. Lo, D. Christ, R. Chiou, C. Furtek, O. Amit, A.
`Carides, J. Biollaz, V. Piguet, J. Nussberger, H. Brunner.
`“Begley” – J. Pharm. Pharmacol. (1996), 48, 136-146 – “The
`Blood-brain Barrier: Principles for Targeting Peptides and
`Drugs to the Central Nervous System”; D. Begley.
`
`1024
`1025
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`
`
`The ’650 Patent and Prosecution History
`
`
`10. As part of my analysis, I began with a review of the ’650 patent and its
`
`prosecution file history to understand the field of the invention.
`
`11. The ’650 patent is generally related to a class of compounds and salts of 3,3-
`
`diphenylpropylamines. The inventor suggested that the prodrug described has
`
`improved pharmacokinetic properties over oxybutynin and tolterodine. Col.. 1, ll.
`
`23-25. The inventor also identified that the preferred compound was R-(+)-2-(3-
`
`diisopropylamino-1-phenylproyl)-4-hydroxymethyl-phenylisbutyrate ester
`
`hydrogen fumarate. Col. 16, l. 39-Col. 17, l. 67.
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 6
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`12. Claim 1 provides a generic structure for the covered molecule reproduced
`
`below
`
`
`According to the claim, “R denotes C1-C6 –alkyl, C3-C10-cycloaklyl, substituted
`
`or unsubstituted phenyl and X- is the acid residue of a physiological compatible
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`inorganic or organic acid.” Claim 1.
`
`13. Claims 2-5 specify the type of acid (claims 2 and 4), adding specific
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`chirality (claim 3), and two specific substitutions and salt forms (claim 5).
`
`Specifically, claim 5 lists R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-
`
`hydroxymethl-phenylisobutyrate ester hydrogen fumarate. This product is
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`commercially referred to as fesoterodine fumarate and is the active compound in
`
`Toviaz®. Claims 21-24 recite methods of use.
`
`14. Because the claims recite general formulas that contain, or at the most
`
`specify a compound with the structure of, R-(+)-2-(3-(diisopropylamino-1-
`
`phenylpropyl)-4-hydroxymethl-phenylisobutyrate ester hydrogen fumarate, my
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 7
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`analysis focused on that structure. This is commonly referred to as fesoterodine
`
`fumarate.
`
`15. During prosecution, Ex. 1002, the application leading to the ’650 patent was
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`rejected as anticipated by Johansson WO 94/11337, Ex. 1005, for teaching
`
`compounds with the same general structure. Applicant amended the claims to
`
`remove the identical overlapping genus in the November 5, 2003, response to an
`
`office action. The application was then allowed.
`
`
`16.
`
`In short, it is my opinion that a person of ordinary skill in the art of drug
`
`Summary of Opinions
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`design or development in 1998 considering treatment, or improving treatment, of
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`overactive bladder would have immediately recognized the desirability of making
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`a prodrug of the known active metabolite of tolterodine – 5-HMT (5-
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`hydroxymethyltolterodine). Given the well-documented drawbacks and unproven
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`efficacy of other compounds known at the time, coupled with the well documented
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`problems of dosing tolterodine and the clear ability to avoid most if not all of those
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`concerns by looking at 5-HMT, a skilled drug designer would have been motivated
`
`with a predictable likelihood of success in obtaining a bioavailable, readily
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`activated prodrug of 5-HMT.
`
`
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 8
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`
`17.
`
`I understand that a patent claim is unpatentable as obvious if the subject
`
`Understanding of the Law
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`matter of the claim as a whole would have been obvious to a person of ordinary
`
`skill in the art as of the time of the invention at issue. I understand that the
`
`following factors must be evaluated to determine whether the claimed subject
`
`matter is obvious: (1) the scope and content of the prior art; (2) the difference or
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`differences, if any, between the scope of the claim of the patent under
`
`consideration and the scope of the prior art; and (3) the level of ordinary skill in the
`
`art at the time the patent was filed.
`
`18.
`
`I understand that prior art references can be combined to make a claim
`
`obvious under 35 U.S.C. § 103 when there was an objective reason for a person of
`
`ordinary skill in the art, at the time of the invention, to combine the references or
`
`make obvious modifications, which includes, but is not limited to (A) identifying a
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`teaching, suggestion, or motivation to combine prior art references; (B) combining
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`prior art methods according to known methods to yield predictable results; (C)
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`substituting one known element for another to obtain predictable results; (D) using
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`a known technique to improve a similar device in the same way; (E) applying a
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`known technique to a known device ready for improvement to yield predictable
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`results; (F) trying a finite number of identified, predictable potential solutions, with
`
`a reasonable expectation of success; or (G) identifying that known work in one
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 9
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`field of endeavor may prompt variations of it for use in either the same field or a
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`different one based on design incentives or other market forces if the variations are
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`predictable to a person of ordinary skill in the art.
`
`19.
`
`I further understand that in the chemical arts the structural similarity
`
`between the claim compound or molecule and the prior art subject matter creates
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`what is known as a prima facie case of obviousness when the prior art gives a
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`reason to combine or modify the prior art structures. I understand that this prima
`
`facie case of obviousness is because established structural relationships can
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`indicate the motivation to combine or modify. I also understand that important to
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`this creation of a prima facie case of obviousness it the proper selection of a so-
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`called lead compound where the prior art available to the skilled person would
`
`have led a chemist to modify a known compound in a particular manner.
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`20.
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`I understand that the selection of a so-called lead compound cannot be made
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`simply because of structural similarity. It has been explained that in determining
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`and describing a prima facie case of obviousness I am to avoid using hindsight.
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`That means I must avoid using the patent of the claimed subject matter as a
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`“roadmap” to arrive at selecting a structurally similar compound and modifying it.
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`Accordingly, selecting a prior art compound requires that I look beyond simply
`
`structural similarity and take into consideration the known functional properties
`
`and limitations of the prior art compounds in the relevant field.
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 10
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`21. Moreover, I have been informed and I understand that so-called objective
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`indicia of non-obviousness, also known as “secondary considerations,” like the
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`following are also to be considered when assessing the strength of the prima facie
`
`case of obviousness: (1) commercial success; (2) long-felt but unresolved needs;
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`(3) copying of the invention by others in the field; (4) initial expressions of
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`disbelief by experts in the field; (5) failure of others to solve the problem that the
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`inventor solved; and (6) unexpected results. I also understand that evidence of
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`objective indicia of non-obviousness must be commensurate in scope with the
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`claimed subject matter.
`
`A Person of Ordinary Skill in the Art
`
`
`22.
`
`I understand that appreciating the knowledge, skill, and creativity of the
`
`person of ordinary skill in the art is necessary for my analysis so that the
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`motivations and rationales for selections and modifications are consistent with
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`what would have been known at the relevant time – May 1998 – which is
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`explained in more detail below.
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`23. After reviewing the ’650 patent and available materials concerning the prior
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`art to the ’650 patent, I believe that a person of ordinary skill in the art would have
`
`a Ph.D. in chemistry, medicinal chemistry, pharmacology, or a related field, and at
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`least one year of industrial exposure to drug discovery, drug design, and synthesis.
`
`In lieu of an advanced degree, the individual may have additional years of industry
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 11
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`experience, including, for example, in drug discovery, drug synthesis, and
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`structure-activity work. As described above in Paragraphs 2, 7, and 8, I was a
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`person of ordinary skill in the art in 1998 by virtue of my educational degrees and
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`work with industrial focus on drug design and development.
`
`
`
`Technical Background and State of the Art
`
`The ‘650 Patent Field and Its Timing
`
`24. The ’650 patent claims priority to a November 16, 1999, foreign patent
`
`application, which would make the critical date for prior art November 16, 1998.
`
`However, I understand there are other patents with at least one common inventor
`
`with earlier filing dates. I understand that the “so-called” critical date for all
`
`patents that relate to the claimed subject matter is at the earliest May 11, 1998.
`
`Thus, I considered the scope and content of the prior art before May 11, 1998.
`
`25. The relevant field for compounds of interest to a person of skill in the art at
`
`that time would have been those used for treatment, or might be used for treatment,
`
`of overactive bladder. It was well-known, as discussed below, that contraction of
`
`the bladder is mediated by muscarinic receptor stimulation. The treatment of
`
`urinary urge incontinence and other symptoms related to overactive bladder was
`
`thus centered, but not exclusive, to this area.
`
`
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 12
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`Prior art Compounds and Treatments for Overactive Bladder
`
`26. The following were compounds that prior to the May 1998 critical date
`
`would have been known a person of ordinary skill in the drug design and drug
`
`development field interested in overactive bladder. Numerous publications
`
`describe these compounds, their mechanisms of action, and their known uses in
`
`treatment of overactive bladder. This is where any skilled person would begin
`
`because regardless of whether a new compound or an improvement was the desired
`
`course because an understanding of what had already been done is crucial to drug
`
`design and development.
`
`27. Oxybutynin. Oxybutynin hydrochloride (Ditropan®) is an antimuscarinic
`
`antagonist that exerts direct antispasmodic effect on smooth muscles and inhibits
`
`the muscarinic action of acetylcholine on smooth muscles. Ex. 1006, 929-30.
`
`Oxybutynin relaxes bladder smooth muscle. Clinical studies found that this
`
`activity led to increased bladder capacity, decreased the frequency of uninhibited
`
`contractions of the detrusor muscle, and delayed the initial desire to void. Id.
`
`Oxybutynin was approved for treatment of overactive bladder in 1997 and its
`
`chemical structure is shown below.
`
`
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 13
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`
`28. Hyoscyamine. Hyoscyamine is a tropane alkaloid that has been marketed
`
`
`
`under several brand names, including Levsin®. Hyoscyamine was approved for
`
`use prior to 1997 and was used to treat a variety of stomach and intestinal
`
`problems, such as cramps and irritable bowel syndrome. Hyoscymamine is
`
`considered to exhibit anticholinergic activity which showed some benefit in
`
`decreasing bladder contractions; however, the treatment was associated with
`
`systemic side effects. Ex. 1006, 926. The structure of hyoscyamine is:
`
`
`29. Propantheline. Propantheline is a quaternary ammonium compound that was
`
`
`
`approved prior to 1982. Propantheline is indicated as adjunctive therapy in the
`
`treatment of peptic ulcer, but was commonly used to treat overactive bladder in
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 14
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`1997. Ex. 1007, 287. However, the treatment was understood to have limited
`
`utility in that it must be administered parenterally and was associated with adverse
`
`events such as dry mouth and tachycardia. Id. The structure of propantheline is:
`
`
`30. Terodiline. Terodiline was an antimuscarinic and calcium antagonist used to
`
`
`
`relax smooth muscles and reduce bladder tone in the treatment of urinary
`
`frequency. Ex. 1008, 53. Terodiline was not approved for use in the United
`
`States, and was withdrawn from European markets in 1991 due to concerns of
`
`prolonged QT interval, ventricular tachycardia and arrhythmia. Id. The structure
`
`of terodiline is:
`
`
`31. Trospium. Trospium (Sanctura®) is a muscarinic antagonist indicated for
`
`
`
`the treatment of overactive bladder. In 1998, trospium was not approved for use
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 15
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`and there was limited clinical data regarding its safety and efficacy. Ex. 1006, 928;
`
`Ex. 1016, 351-352. The chemical structure of trospium is:
`
`
`
`
`32. Solifenacin. Solifenacin (Vesicare®) is an antimuscarinic developed for the
`
`
`
`treatment of overactive bladder. Solifenacin was in early research stages in 1998,
`
`and was not approved for use until 2004. Ex. 1016, 351. The structure of
`
`solifenacin is:
`
`
`33. Darifenacin. Darifenacine (Enablex®) is another muscarinic antagonist that
`
`
`
`was in early research stages in 1998. The product was not approved for use for the
`
`treatment of overactive bladder until 2004. Id. Darifenacine is metabolized by
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 16
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`

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`CYP3A4 and CYP2D6 and requires dosage and treatment precautions in patients
`
`with impaired cytochrome P450 metabolism.
`
`
`
`
`34. Tolterodine. Tolterodine (Detrol®) is a muscarinic receptor antagonist
`
`approved in 1998 for the treatment of overactive bladder. Ex. 1009; Ex. 1025.
`
`Tolterodine is metabolized in the liver resulting in the formation of a 5-
`
`hydroxymethyl derivative. Ex. 1009, Metabolism. The label for tolterodine
`
`identifies that the 5-hydroxymethyl derivative as the “major pharmacologically
`
`active metabolite.” The primary metabolic pathway for the above active
`
`metabolite of tolterodine is mediated CYP2D6. Other key transformations that
`
`lead to inactive metabolites are mediated by CYP3A4. Tolterodine and the 5-
`
`hydroxymethyl metabolite both exhibited antimuscarinic activity in clinical trials.
`
`The chemical structure of tolterodine is:
`
`
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 17
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`
`
`
`
`
`
`
`Prior Art Publications and Materials Detailing Known Properties and
`Limitations of Compounds Used, or Potentially Used, for
`Treatment of Overactive Bladder
`
`
`35. The following publications or other publicly available materials provided
`
`further information to the skilled person in drug design or development in 1998 as
`
`to the functional properties and drawbacks of prior art compounds in overactive
`
`bladder treatment. It is important to consider these materials in determining where
`
`a person of skill in drug design or development would have focused their efforts if
`
`focused on treating conditions associated with overactive bladder.
`
`36. Detrol Label (Ex. 1009). Detrol® (tolterodine tartrate) was approved for use
`
`in March 1998. Ex. 1009, 7. Accordingly, the label was publicly available before
`
`May 1998. Tolterodine is described as a “competitive muscarinic receptor
`
`antagonist” and was approved for the treatment of overactive bladder with
`
`symptoms of urinary frequency, urgency or urge incontinence. Id., 2. The
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 18
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`oxidation of tolterodine by cytochrome P450 2D6 to 5-hydroxymethyltolterodine
`
`(or 5-HMT) is described as the major metabolic pathway in the elimination of
`
`tolterodine after oral administration. Id. Pharmacokinetic studies revealed that
`
`tolterodine is metabolized at a slower rate in poor metabolizers than in extensive
`
`metabolizers. Poor metabolism by the CYP2D6 pathway (about 7% of the
`
`population) results in significantly higher serum concentrations of tolterodine, and
`
`negligible concentrations of 5-HMT in poor metabolizers. Id.
`
`37. Tolterodine and 5-HMT have similar antimuscarinic effects. The label
`
`recites that “[a]fter oral administration, tolterodine is metabolized by the liver,
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`resulting in the formation of the 5-hydroxymethyl derivative, a major
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`pharmacologically active metabolite.” Id. “Both tolterodine and 5-HMT exhibit a
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`high selectivity for muscarinic receptors, since both show negligible activity or
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`affinity for other neurotransmitters . . . .” Id. The label taught that a total of 339
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`patients received Detrol 2 mg twice daily and 177 patients received placebo. The
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`endpoints of the study were number of micturitions per 24 hours, incontinence
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`episodes per 24 hours and volume voided per micturition. Statistically significant
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`improvement was seen in the number of micturitions per 24 hours and volume
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`voided per micturition.
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`38. The label also taught the dosing of Detrol® should be adjusted in patients
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`with reduced hepatic function or who are concurrently taking CYP3A4 inhibitors
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`due to the potential for adverse events. Id.
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`39. The Detrol® label identifies U.S. Patent No. 5,382,600 with respect to the
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`tolterodine compound. Id.
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`40. Postlind (Ex. 1010). The Postlind reference was published in April, 1998.
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`Because of its publication date, Postlind was publicly available before May 1998.
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`Postlind teaches tolterodine, a new potent muscarinic receptor antagonist, was
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`metabolized by two pathways: oxidation of the 5-methyl group; and dealkylation
`
`of the nitrogen. According to the Abstract (289):
`
`In an attempt to identify the specific cytochrome P450 enzymes
`involved in the metabolic pathway, tolterodine was incubated with
`microsomes from 10 different human liver samples where various
`cytochrome P450 activities had been rank ordered. Strong correlation
`was found between the formation of the 5-hydroxymethyl metabolite
`of tolterodine (5-HM) and CYP2D6 activity (r2, 0.87), as well as
`between the formation of N-dealkylated tolterodine and CYP3A
`activity (r2, 0.97). When tolterodine was incubated with human liver
`microsomes in the presence of compounds known to interact with
`different P450 isoforms, quinidine was found to be the strongest
`inhibitor of the formation of 5-HM. Ketoconazole and
`troleandomycin were found to be the strongest inhibitors of the
`formation of N-dealkylated tolterodine. A weak inhibitory effect on
`the formation of N-dealkylated tolterodine was found with
`sulfaphenazole, whereas tranylcypromine did not inhibit the formation
`of this metabolite. Microsomes from cells overexpressing CYP2D6
`formed 5-HM, whereas N-dealkylated tolterodine was formed by
`microsomes expressing CYP2C9, -2C19, and -3A4. The Km for
`formation of N-dealkylated tolterodine by CYP3A4 was similar to
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 20
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`that obtained in human liver microsomes and higher for CYP2C9 and
`-2C19.
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`41. The authors concluded from these studies that the formation of 5-HMT was
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`catalyzed by CYP2D6 and that the formation of N-dealkylated tolterodine is
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`predominantly catalyzed by CYP3A isoenzymes in human liver microsomes. Id.
`
`The metabolic pathway identified in Postlind is (289):
`
`
`42. Postlind also teaches that tolterodine metabolism is extensive and that less
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`than 1% of the drug is excreted in the urine unchanged and that 80% of tolterodine
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`is metabolized to 5-HMT. Ex. 1010, 292. Metabolism of tolterodine to 5-HMT
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`proceeds through the CYP2D6 enzyme in the liver. Id. Postlind further notes that
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 21
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`previous clinical studies of other compounds eliminated by CYP2D6 demonstrated
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`that the patients were in a high-risk group to develop adverse events. Id.
`
`43. Postlind recites (292 (internal citations omitted)):
`Clinical studies have demonstrated that individuals with reduced
`CYP2D6-mediated metabolism represent a high-risk group in the
`population with a propensity to develop adverse drug effects. The
`number of drugs identified as being affected by CYP2D6
`polymorphism has increased steadily over the years and includes
`diverse classes such as -adrenoreceptor antagonists, tricyclic
`antidepressants, neuroleptics, and other miscellaneous drugs like
`dextromethorphan and codeine. CYP3A is the major P450 subfamily
`in human liver and is involved in the metabolism of >50% of
`pharmaceutical drugs on the market. In addition, CYP3A enzymes
`have been reported to be involved in interactions with several drugs
`such as macrolides, ketoconazole, cyclosporin, and others. The
`possibility of clinical drug interaction at the enzyme level thus exists,
`especially if tolterodine is administered at the same time as a
`compound that is preferentially metabolized by CYP2D6 or to
`individuals associated with the CYP2D6 poor metabolizer phenotype.
`
`44. Brynne 1997 (Ex. 1007). Brynne 1997 was titled “Pharmacokinetics and
`
`Pharmacodynamics of Tolterodine in Man: a New Drug for the Treatment of
`
`Urinary Bladder Activity” and published in July 1997 and thus was publicly
`
`available before May 1998. According to the Abstract:
`
`The aim of this study was to determine the pharmacokinetics,
`pharmacodynamics, and safety of tolterodine following single oral
`and intravenous doses in healthy volunteers. A secondary aim was to
`identify major urinary metabolites and determine mass balance.
`Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of
`tolterodine (as the tartrate salt) were given to 17 healthy male
`volunteers. Two intravenous doses (0.64 and 1.28 mg) were
`administered to 8 of the volunteers and mass balance was studied after
`a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine
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`was rapidly absorbed following oral administration (time to peak
`serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was
`highly variable, ranging from 10 to 70%. The volume of distribution
`at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance
`ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life
`of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2
`hepatic metabolic pathways were identified: oxidation and
`dealkylation. Independent of route of administration, < 1% of the
`parent compound was excreted unchanged in urine. Five metabolites
`were structurally identified in urine. Following oral administration of
`(14C)-tolterodine, the excretion of radioactivity into urine and feces
`was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased
`stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg,
`and nearpoint of vision after 12.8 mg. Six of 8 subjects reported
`micturition difficulties after a dose of 12.8 mg. The lack of a direct
`relationship between tolterodine serum concentrations and effects on
`stimulated salivation suggested the presence of pharmacologically
`active metabolite(s).
`
`45. The two metabolic pathways identified in Brynne 1997 are:
`
`
`
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`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1003 - Page 23
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`46.
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`In review of the data, the authors concluded, “Overall, these data
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`suggested that tolterodine undergoes extensive and variable hepatic first-
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`pass metabolism, rather than incomplete absorption.” Ex. 1007, 291.