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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`___________________
`
`
`Inter Partes Review No.: IPR2014-00550
`
`U.S. Patent No. 6,335,031
`
`
`
`
`
`DECLARATION OF CHRISTIAN SCHÖNEICH, PH.D.
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`Page 1 of 34
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`Noven Ex. 1011
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`I, Christian Schöneich, Ph.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`1.
`
`I am currently the Chair of the Department of Pharmaceutical
`
`Chemistry at the University of Kansas. I have been Chair of that department since
`
`2005. I have been a professor in that department since 2003.
`
`2.
`
`In addition, I currently hold the position of Takeru Higuchi
`
`Distinguished Professor for Bioanalytical Chemistry. I also have an appointment
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`as Courtesy Professor in the Department of Chemistry at the University of Kansas.
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`3.
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`From 1998 to 2003, I was an associate professor and from 1992 to
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`1998, I was an assistant professor in the Department of Pharmaceutical Chemistry
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`at the University of Kansas.
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`4.
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`Prior to those appointments, I was a Postdoctoral Fellow in the same
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`department from 1991 to 1992. I earned my Ph.D. in chemistry with honors from
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`the Technical University Berlin in 1990.
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`5.
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`I have been fortunate to receive a number of distinctions for my
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`research on free radical and oxidation chemistry including: “Young Investigator
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`Award” of the Society For Free Radical Research (SFRR) in 1990 and 1994; the
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`Pfizer Research Scholar Award in 2001, 2002, 2003, and 2004; and Dolph Simons
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`Award in Biomedical Sciences. For a full list of my awards and honors, please see
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`my curriculum vitae, which is included as Exhibit 1023.
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`Noven Ex. 1011
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`6.
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`I serve on the Editorial Board of the journals Experimental
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`Gerontology and Free Radical Biology and Medicine, and on the Editorial
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`Advisory Board for the Journal of Pharmaceutical Sciences and Chemical
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`Research in Toxicology. I am also a review editor for the journal Free Radical
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`Research. As an editor, I routinely review scientific manuscripts concerning free
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`radical reactions, oxidation reactions, and the degradation of small and large
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`molecule pharmaceuticals.
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`7.
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`My research interests include mechanisms of free radical reactions.
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`This includes, for example, the oxidative post-translational modifications of
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`proteins, which are generally carried out by reactive oxygen species and/or reactive
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`nitrogen species. Such oxidative modifications accompany physiological disorders
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`associated with biological aging or disease. My research spans the behavior of
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`proteins in solutions and the solid state, including stability of proteins in
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`pharmaceutical formulations, mechanisms for protein instability in these
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`formulations, and methods to stabilize proteins in these formulations.
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`8.
`
`I am being compensated for my time in this proceeding at a rate of
`
`$550 per hour. My compensation is not dependent upon the conclusions I reach or
`
`the outcome of this proceeding. In the last four years I testified in Graceway
`
`Pharmaceuticals, LLC et al. v. Perrigo Company (C.A. No. 10-937-WJM-MF
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`(D.N.J.)).
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`Page 3 of 34
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`II.
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`
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`INFORMATION CONSIDERED
`9.
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`In forming the opinions I have also considered the documents
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`discussed herein, which include the following:
`
` U.S. Patent No. 6, 335,031 (“the ʼ031 patent,” Ex. 1001)
`
` UK Patent Application GB 2,203,040 (Ex. 1002).
`
` Connors, Amidon, & Stella, Oxidation and Photolysis in Chemical
`
`Stability of Pharmaceuticals – A Handbook for Pharmacists (2nd
`
`Edition), John Wiley & Sons, NY (1986), pp. 82-114 (Ex. 1015);
`
` Howard C. Ansel, Introduction to Pharmaceutical Dosage Forms, 4th
`
`Edition, Lea & Febiger, Philadelphia (1985), pp. 83-116 (Ex. 1016);
`
` Ho-Leung Fung, Chapter 7 – Chemical Kinetics and Drug Stability in
`
`MODERN PHARMACEUTICS (G.S. Banker and C.T. Rhodes, eds.),
`
`Marcel Dekker, NY (1978), pp. 227-62 (Ex. 1017).
`
` Carey & Sundberg, ADVANCED ORGANIC CHEMISTRY, 2nd ed.
`
`Part A: Structure and Mechanism, Plenum Press, New York, 1984, pp.
`
`652 (Ex. 1007).
`
` Boccardi G. et al. Photochemical Iron(III)-Mediated Autoxidation of
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`Dextromethorphan. Chemical & Pharmaceutical Bulletin. Vol. 37, 308–
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`310 (1989) (“Boccardi,” Ex. 1019).
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` Linnell, R.H., The Oxidation of Nicotine. I. Kinetics of the Liquid Phase
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`Reaction Near Room Temperature. Tobacco Science, Vol. 4, pp. 89–90
`
`(1960) (“Linnell,” Ex. 1021).
`
` Bateman, L., Olefin Oxidation, Quarterly Review (1954) Vol. 8, pp. 147–
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`167 (Ex. 1020).
`
`
`III. SUMMARY OF OPINIONS
`10.
`I understand that Noven Pharmaceuticals, Inc. (“Noven”) is
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`submitting a petition to the United States Patent and Trademark Office’s Patent
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`Trial and Appeal Board requesting Inter Partes Review (“IPR”) of claims 1-3, 7,
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`15, 16, and 18 of the ’031 patent (Ex. 1001).
`
`11.
`
`I have been asked to provide my analysis and expert opinions on
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`what a person of ordinary skill in the art1, in 1998, would have expected about the
`
`1 I have been advised that a person of ordinary skill in the art would have been a
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`collaborative team of individuals in which each person would have been able to
`
`draw upon the experiences and knowledge of the others. In particular, the person
`
`of ordinary skill in the art at the time of the alleged invention would have been a
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`chemist, chemical engineer, polymer chemist or pharmaceutical chemist working
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`to develop pharmaceutical formulations, including transdermal drug delivery
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`systems. The person of ordinary skill would have been familiar with testing that
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`
`
`
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`Continued. . .
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`chemical reactivity of rivastigmine, based on his or her own understanding of
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`organic chemistry and the disclosures in the prior art.
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`12.
`
`A person of ordinary skill in the art in 1998 would have expected
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`that the compound rivastigmine was susceptible to oxidation. The person of
`
`ordinary skill would have arrived at this expectation based on the chemical
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`structure of rivastigmine. In particular, the person ordinary skill would have
`
`appreciated that the tertiary C–H bond in rivastigmine, which is adjacent to both an
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`aromatic ring and a tertiary amino group, was prone to oxidation. The ordinarily-
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`skilled artisan would have expected that rivastigmine would be susceptible to
`
`oxidation in many different chemical environments including in liquid
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`formulations, and dispersed or dissolved in polymeric matrices. The person of
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`ordinary skill would have further understood that the relative rate of rivastigmine
`
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`accompanies the development of any pharmaceutical formulation, including testing
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`for efficacy and stability. The person of ordinary skill would have been familiar
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`with excipients typically employed in pharmaceutical formulations, including
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`transdermal devices. The person of ordinary skill would have had knowledge of
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`organic chemistry, or would have collaborated with a person having knowledge of
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`organic chemistry, and would have been able to predict the physical properties of a
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`compound based upon its chemical structure.
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`oxidation would be influenced by the chemical environment in which the
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`rivastigmine was placed.
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`13.
`
`A person of ordinary skill in the art would have expected that the
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`oxidative degradation of drugs like rivastigmine could be inhibited by the addition
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`of an antioxidant. Therefore, it is my opinion that the person of ordinary skill,
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`desirous of making a pharmaceutical formulation of rivastigmine, would have been
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`motivated to combine rivastigmine with an antioxidant, with the reasonable
`
`expectation that the antioxidant would inhibit the oxidative degradation of the
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`rivastigmine.
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`
`IV. BACKGROUND
`14.
`All of the teachings discussed in this section would have been
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`known to a person of ordinary skill in the art prior to 1998, and are basic principles
`
`of organic chemistry that were typically taught in textbooks used in chemistry or
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`pharmaceutical chemistry courses at that time. A general discussion of radicals,
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`their reactions, and stability can be found in any undergraduate organic chemistry
`
`textbook. A discussion of the several different oxidation pathways, their relevance
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`in drug degradation, and the use of antioxidants to prevent oxidation may be found,
`
`for example, in Connors, Amidon, & Stella, Oxidation and Photolysis in Chemical
`
`Stability of Pharmaceuticals – A Handbook for Pharmacists (2nd Edition), John
`
`Wiley & Sons, NY (1986), pp. 82-114 (Ex. 1015); Howard C. Ansel, Introduction
`
`
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`to Pharmaceutical Dosage Forms, 4th Edition, Lea & Febiger, Philadelphia (1985),
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`pp. 83-116 (Ex. 1016); Ho-Leung Fung, Chapter 7 – Chemical Kinetics and Drug
`
`Stability in MODERN PHARMACEUTICS (G.S. Banker and C.T. Rhodes, eds.),
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`Marcel Dekker, NY (1978), pp. 227-62 (Ex. 1017).
`
`A. Radicals
`15.
`Radicals (often called “free radicals”) are atoms, molecules, or ions
`
`that have an unpaired electron. An unpaired electron is an energetically unstable
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`configuration, and thus many radicals are highly chemically-reactive. For this
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`reason, radicals are reactive intermediates in many chemical reactions, including
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`some oxidation reactions.
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`16.
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`Radicals may be formed by breaking a covalent bond in half, so that
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`one of the shared electrons becomes resident on each of the newly formed and
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`separate species. This process, called homolytic cleavage or homolysis, typically
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`requires significant energy. The bond energy (i.e., bond strength) of a hydrogen
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`molecule (H2 or H–H) is about 104 kilocalories/mole (435 kiloJoules/mole).2
`
`Breaking the bond in half therefore requires this amount of energy to be expended.
`
`The equation below shows the splitting of an H–H bond into two equivalent
`
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`2 For reference, it takes one kilocalorie to raise the temperature of one kilogram
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`of water one degree Celsius.
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`Page 8 of 34
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`hydrogen radicals, each of which possesses one of the two electrons originally
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`shared in the H–H bond.
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`H H
`
`H
`
`+
`Figure 1. Homolysis of an H–H bond.
`
`H
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`
`
`
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`17.
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`In chemical structures, a radical is generally denoted by a dot placed
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`immediately adjacent to the atomic symbol for the atom having the unpaired
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`electron. The curved half-arrows denote the movement of a single electron (as
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`opposed to a curved arrow having a full arrowhead, which shows the movement of
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`two electrons).
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`18.
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`The process shown in Figure 1 involves breaking a chemical bond.
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`Radicals may also be formed by removing a single electron from an electron lone
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`pair on an atom such as oxygen or nitrogen.
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`B. Radical Stability and the Formation of Radicals
`19.
`The amount of energy required to split a chemical bond and form
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`radicals depends, in large part, upon the stability of the resulting radicals. The
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`more stable the radical, the lower the amount of energy required to form that
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`radical and the easier that radical is to form.
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`20.
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`The stability of a carbon radical depends on the chemical context of
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`the carbon radical in the molecule. One factor that influences the stability of a
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`carbon radical is the type of atoms bonded to the carbon radical. Carbon radicals
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`are more stable when the carbon radical is bonded to other non-hydrogen atoms.
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`The order of relative stability of carbon free radicals (in order of increasing
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`stability) is:
`
`H C H
`
`H
`methyl
`radical
`(least stable)
`
`R C H
`
`H
`primary
`radical
`
`R C H
`
`R
`secondary
`radical
`
`R C R
`
`R
`tertiary
`radical
`
` (most stable)
`
`Figure 2. Carbon radical stability. R denotes a
`hydrocarbon (alkyl) group.
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`21.
`
`As depicted in Figure 2, the tertiary carbon radical is more stable
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`
`
`
`
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`than the secondary, primary, or methyl radical. It therefore takes less energy to
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`extract a hydrogen atom from a tertiary carbon to form a tertiary radical. In other
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`words, a reaction pathway that takes place via a tertiary radical intermediate will
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`often require less energy than a reaction pathway that proceeds via a primary or
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`secondary radical intermediate.
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`22.
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`For example, the stability of butyl radicals of butane depends upon
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`which carbon atom in the molecule bears the unpaired electron. Two butyl radicals
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`derived from butane are drawn below:
`
`H H H
`
`H H
`
`H
`
`H C C C C H
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`H C C C C H
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`H H H H
`H H H H
`Figure 3. Free radicals of butane.
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`23.
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`The butyl radical on the left in Figure 3 is a primary radical because
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`the carbon bearing the unpaired electron is bonded to one other carbon. The butyl
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`radical on the right is a secondary radical (bonded to two other carbons). The
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`primary radical of butane is less stable (and requires more energy to form) than the
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`secondary radical.
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`24.
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`Other structural elements in a molecule will also significantly affect
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`the stability, and thus ease of formation, of a radical species. For example, radicals
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`in which the unpaired electron can be distributed over a system of connected π
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`bonds (i.e., double and triple bonds) are more stable, and thus easier to form, than a
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`corresponding radical in which such a distribution is not possible. The sharing of a
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`single electron among multiple atoms is referred to as delocalization or resonance,
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`and is discussed in greater detail below.
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`25.
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`Heteroatoms (i.e., atoms other than carbon or hydrogen) can also
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`stabilize an adjacent radical. For example, an adjacent nitrogen (N) bonded to the
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`carbon radical can stabilize the radical and lower the energy required to form the
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`radical. An adjacent heteroatom can serve to stabilize the unpaired electron by
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`resonance or delocalization.
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`26.
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`Delocalization of an unpaired electron can also occur in molecules
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`that contain double or triple bonds. An example of such a comparatively stable
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`radical of this type is the benzyl radical discussed in more detail below.
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`C. Benzylic Position/Radical Stability
`27.
`The term “benzylic position” refers to a carbon atom that is directly
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`adjacent to a benzene (phenyl) ring:
`
`H
`C H
`
`H
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`a benzylic carbon
`
`
`Figure 4. Chemical structure showing the location of a
`benzylic carbon.
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`28.
`
`The benzylic C–H bond is especially weak. As discussed above, the
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`
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`more stable the free radical, the weaker the C–H bond and the lower the bond
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`dissociation energy. The homolysis of a benzylic C–H bond leading to the
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`formation of a benzylic radical is illustrated below:
`
`CH
`
`H
`
`H
`
`H
`
`C H
`
`Figure 5. Homolysis of a benzylic C–H bond.
`
`
`
`+
`
`H
`
`29.
`
`The benzyl radical is quite stable and thus is readily formed. It is
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`
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`stabilized by the adjacent phenyl ring. The unpaired electron of the radical is
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`delocalized between the benzylic carbon and carbons on the adjacent phenyl ring
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`as follows:
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`Page 12 of 34
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`CH
`
`H
`
`CH
`
`H
`
`CH
`
`H
`
`CH
`
`H
`
`Figure 6. Delocalization of the unpaired electron
`of a benzyl radical.
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`30.
`
`The delocalization of the unpaired electron over four separate carbon
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`
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`
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`
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`
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`atoms is more energetically stable than an unpaired electron restricted to a single
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`carbon atom. For this reason, the energy that it takes to break the C–H bond when
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`the carbon is a benzylic carbon is typically much lower than the C–H bonds at
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`other positions in a chemical compound.
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`31.
`
`The bond dissociation energy for the primary C–H bond of a methyl
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`group in hydrocarbons like butane is typically about 100 kcal/mol (418 kJ/mol). In
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`contrast, the dissociation energy for a benzyl C–H bond is only 85 kcal/mol (356
`
`kJ/mol). Thus, even though both radicals are primary (in that they are connected to
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`a single non-hydrogen substituent), the benzylic radical is substantially more stable
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`because the unpaired electron is delocalized over multiple atoms. The stabilization
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`by delocalization is not available to the butyl radical, because it does not contain
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`any double or triple bonds. These bond dissociation energies would have been
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`known to a person of ordinary skill in the art in 1998 and were provided in organic
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`chemistry textbooks, for example, Carey & Sundberg, ADVANCED ORGANIC
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`CHEMISTRY, 2nd ed. Part A: Structure and Mechanism, Plenum Press, New York,
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`1984, pp. 652 (Ex. 1007).
`
`D. Degradation of Drugs by the Formation of Free Radicals
`32.
`The principles discussed in the preceding sections describing the
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`susceptibility of particular bonds in a molecule to homolysis leading to radical
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`formation were known to ordinarily skilled artisans in 1998. These principles
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`would have been readily applied to drug molecules.
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`33.
`
`The bond in a drug molecule that can be most easily broken by
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`homolysis is the one that is weakest. In a drug molecule, this is often a covalent
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`bond between hydrogen and another atom, often carbon. The more easily a
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`particular bond in a compound can be broken, the more susceptible the drug will be
`
`to radical formation and degradative processes resulting therefrom, such as
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`oxidation.
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`34.
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`Thus, if a drug had a benzylic C–H bond, a person of ordinary skill
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`in the art in 1998 would have recognized that this bond was usually more
`
`susceptible to oxidative degradation by homolysis than other carbon-hydrogen
`
`bonds in the drug molecule. In other words, an ordinarily-skilled artisan would
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`have known that the presence of a benzylic C–H bond in a drug molecule would
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`likely dispose the drug to hydrogen abstraction and radical formation at that
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`position.
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`Page 14 of 34
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`35.
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`Once formed, a free radical-containing drug compound is highly
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`unstable and will react by a variety of pathways in order to reach an energetically
`
`more stable configuration. The specific pathway adopted by the free radical
`
`depends on the environment surrounding the compound. Regardless of which
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`pathway(s) are followed, it is important to note that in each case, the end result is
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`decomposition of the original drug compound.
`
`E. Mechanism of Free Radical Degradation of Drugs
`36.
`Free radical oxidation is a mechanism by which radicals participate,
`
`potentially in a chain reaction, in which a radical is reduced (gains an electron) by
`
`oxidizing (removing an electron from) another molecule. This type of degradation
`
`is a common mechanism for drug degradation in aqueous (water-containing)
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`pharmaceutical formulations. Often molecular oxygen participates in this
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`degradation. When oxidation is initiated by the reaction of molecular oxygen with
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`a drug substance, this process is called auto-oxidation (or “autoxidation”).
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`37.
`
`The oxidation of drugs can occur, as for many organic chemicals, by
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`a free radical chain reaction. Generally, a chain oxidation reaction can be
`
`described as occurring in the following sequence:
`
`In• + R–H → In–H + R•
`
`Initiation:
`
`Propagation: R• + O2 → R–O–O•
`
`R–O–O• + R–H → R–O–O–H + R•
`
`Termination: R–O–O• + R–O–O• → R–O–O–R + O2
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`Page 15 of 34
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`R• + R–O–O• → R–O–O–R
`R• + R• → R–R
`
`Figure 7. The general steps in a chain oxidation of a
`drug or organic molecule. In• is a free radical that
`initiates the reaction. R–H is the drug/organic molecule
`that has a bond to hydrogen (H) susceptible to homolytic
`cleavage.
`
`Initiation
`
`(1.)
`The first step in a free radical reaction is called “initiation.”
`
`38.
`
`Initiation is the chemical step that produces the radical species. Initiation may
`
`involve the breaking of a bond (homolysis, see paragraphs 16–17 above) with one
`
`electron accompanying each of the previously bonded partners.
`
`39.
`
`Pharmaceutical compositions often contain a number of known
`
`sources of free radicals that can act as the initiator in a free radical chain reaction.
`
`Some excipients may contain precursors for free radicals that can initiate the free
`
`radical chain reaction in the pharmaceutical composition. For example, some
`
`commonly-used polymers such as acrylates are made by a free radical
`
`polymerization. Such polymerization is often initiated by a compound which
`
`homolytically cleaves into radicals at elevated temperature. Trace amounts of such
`
`compounds remaining from the polymerization process can provide radicals which
`
`act as initiators in a free radical chain reaction leading to degradation of oxidation-
`
`sensitive drugs.
`
`40. Metal ions can also initiate a free radical reaction by donating or
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`accepting an electron. Trace amounts of metal ions such as iron (Fe+++) or copper
`
`(Cu++) ions can accept an electron from the drug or another formulation component
`
`to form an initiating free radical.
`
`41.
`
`Drug compounds that are susceptible to oxidative degradation may
`
`also face stability issues during storage of the drug and during manufacturing of
`
`the pharmaceutical product. Exposure of the drug to trace amounts of metals,
`
`which are often present during manufacture due to the use of metal equipment and
`
`containers, and oxygen in the air, can cause oxidation of the drug. Typically,
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`oxidation reactions occur faster in the liquid state; however, elevated temperatures
`
`and other conditions during manufacturing can promote the oxidation of the drug
`
`even in relatively dry conditions.
`
`(2.) Propagation
`In the “propagation” steps of a free radical reaction, the radicals
`
`42.
`
`react with various chemicals that are present in the same mixture to produce new
`
`or additional radical species. The radical that is formed in the initiation step (R•)
`
`contains an unpaired electron, which reacts rapidly with oxygen (O2) to form
`
`peroxyl radicals R–O–O•. Molecular oxygen, O2, exists in its normal state as a
`
`biradical, that is, each oxygen atom contains an unpaired electron. The oxygen
`
`molecule, with its two unpaired electrons, is reactive towards other radical species.
`
`The rate of reaction of oxygen with an organic radical is typically very fast.
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`Page 17 of 34
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`43.
`
`In the propagation step, the peroxyl radical (R–O–O•) can remove a
`
`hydrogen from another chemical species (R–H) to form a hydroperoxide (R–O–O–
`
`H) and an additional radical species R• leading to degradation of additional drug
`
`molecules. Hydroperoxides may undergo further chemical reactions
`
`(decomposition) to produce alcohols (compounds having –O–H groups) and/or
`
`ketones (compounds having C=O groups), in addition to other oxidized products.
`
`44.
`
`During the propagation steps, free radicals formed during initiation
`
`create additional free radicals that can, in turn, participate in the degradation of the
`
`drug. Such chain reaction can lead to substantial degradation of the drug over
`
`time.
`
`(3.) Termination
`The “termination” steps of a free radical chain reaction involve the
`
`45.
`
`formation of non-radical products. These non-radical products no longer propagate
`
`and therefore terminate the radical chain reaction.
`
`46.
`
`Termination may occur when two radicals combine as shown in the
`
`termination steps in Figure 9. A free radical chain reaction can also be stopped
`
`when an antioxidant is present, for example α-tocopherol, which can donate a
`
`hydrogen atom to a radical (such as the radical formed during initiation or during
`
`propagation), thus providing the radical with an electron so that it no longer has an
`
`unpaired electron. When the antioxidant donates the hydrogen, a radical is formed
`
`
`
`
`
`Page 18 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`on the antioxidant. However, this radical is much more stable and does not
`
`continue the propagation chain cycle. Therefore, certain antioxidants have “chain-
`
`breaking” properties, as they break the free radical chain reaction.
`
`F.
`
`Examples of Drugs Known to Undergo Oxidative Degradation at
`a Benzylic Carbon
`47. Many drugs are susceptible to oxidative degradation due to the
`
`presence of a benzylic C–H bond. For example, morphine derivatives such as
`
`dextromethorphan have a benzylic C–H bond and are susceptible to oxidative
`
`degradation at that position. See, e.g., Boccardi G. et al. Photochemical Iron(III)-
`
`Mediated Autoxidation of Dextromethorphan. Chemical & Pharmaceutical
`
`Bulletin. Vol. 37, 308–310 (1989) (“Boccardi,” Ex. 1020).
`
`O
`
`CH3
`
`H
`
`N CH3
`
`dextromethorphan
`with arrow at
`benzylic position
`
`Figure 8. The chemical structure of dextromethorphan.
`
`
`
`48.
`
`Nicotine is another drug that is susceptible to oxidative degradation.
`
`
`
`See, e.g., Linnell, R.H., The Oxidation of Nicotine. I. Kinetics of the Liquid Phase
`
`Reaction Near Room Temperature. Tobacco Science, Vol. 4, pp. 89–90 (1960)
`
`
`
`
`Page 19 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`(Ex. 1021). Linnell described the oxidative degradation of nicotine by a free
`
`radical mechanism that involves molecular oxygen and could be prevented by the
`
`addition of the antioxidant BHT. Linnell recognized that this oxidation would
`
`occur according to the well-known mechanisms for olefin oxidation, more
`
`specifically the oxidation at allylic and benzylic carbons. Linnell (Ex. 1021 at 2–3)
`
`(citing Bateman, L., Olefin Oxidation, Quarterly Review 1954, Vol. 8, pp. 147–
`
`167, (Ex. 1020)). The structure of nicotine is illustrated below with the benzylic
`
`position identified:
`
`
`
`
`
`
`
`H
`
`N
`
`N
`CH3
`
`a "benzylic" carbon
`
`
`
`Figure 9. The chemical structure of nicotine.
`
`49.
`
`Here, “benzylic” is in quotes because the aromatic ring adjacent to
`
`the carbon identified with the arrow is a pyridine ring rather than a benzene ring.
`
`However, the pyridine ring is aromatic and stabilizes the free radical at the
`
`indicated carbon through resonance in the same manner described above for an
`
`adjacent benzyl ring (see paragraph 29). The delocalization of the benzylic carbon
`
`radical of nicotine is illustrated below:
`
`
`
`
`
`Page 20 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`N C
`
`H3
`
`CH
`
`N
`
`N C
`
`H3
`
`CH
`
`N
`
`N C
`
`H3
`
`CH
`
`N
`
`N C
`
`H3
`
`C
`
`N
`
`
`
`
`
`Figure 10. Delocalization of the unpaired electron of
`the benzyl radical of nicotine.
`
`
`For this reason, chemists will often refer to the carbon indicated by the arrow in
`
`Figure 9 as a benzylic carbon.
`
`G. Antioxidants
`50.
`Antioxidants are substances that can be added to drug products to
`
`reduce or prevent the oxidative decomposition of other compound(s). They are
`
`(and were in 1998) commonly used in pharmaceutical products to protect the drug
`
`and/or excipients from oxidative degradation.
`
`51.
`
`Some antioxidants used in pharmaceutical preparations function as
`
`reducing agents. These antioxidants are more readily oxidized than the drug or
`
`excipient they are added to protect, and thus scavenge oxygen (by reacting with it)
`
`before it can participate in oxidation of the drug. Ascorbic acid, ascorbityl
`
`palmitate, and sodium metabisulfite were known to act as antioxidants.
`
`52.
`
`Some antioxidants used in pharmaceutical preparations function as
`
`chain breaking antioxidants. These compounds can donate a hydrogen atom to a
`
`radical intermediate in a free radical chain reaction, but the resulting radical
`
`formed on the antioxidant is more stable and does not continue the propagation
`
`
`
`
`
`Page 21 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`chain cycle. To apply this phenomenon to the general reaction scheme provided
`
`above in Figure 7, a chain breaking antioxidant can donate a hydrogen atom to the
`
`initiating radical (during the initiation step) or propagating radical (in the
`
`propagation step), but the chain breaking antioxidants will not participate in any
`
`subsequent propagation step. When the chain breaking antioxidant donates a
`
`hydrogen atom to the initiator or other radical, the initiator or radical no longer has
`
`an unpaired electron and is thus not available as an initiator or as part of the
`
`propagation chain cycle. Examples of chain breaking antioxidants commonly used
`
`in pharmaceutical preparations are α-tocopherol, ascorbityl palmitate, propyl
`
`gallate, butylated hydroxyasnisole (BHA), and butylated hydroxyl toluene (BHT).
`
`
`V. RIVASTIGMINE
`53.
`In 1998, rivastigmine was a known drug substance. The chemical
`
`structure of rivastigmine was known, having been published in, for example UK
`
`Patent Application GB 2,203,040 (Ex. 1002). The chemical structure is drawn
`
`below:
`
`54.
`
`CH3
`N
`
`O
`
`H3C
`
`H CH3
`
`CH3
`
`N
`CH3
`O
`
`Figure 11. The chemical structure of rivastigmine.
`
`A person of ordinary skill in the art would have immediately
`
`recognized certain characteristics of rivastigmine based on its chemical structure.
`
`
`
`
`Page 22 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`In particular, rivastigmine has a benzylic carbon identified in Figure 12:
`
`H3C
`
`CH3
`N
`
`O
`
`O
`
`H CH3
`
`CH3
`
`N
`CH3
`
`
`Figure 12. Rivastigmine has a benzylic carbon.
`
`a benzylic carbon
`
`
`
`55.
`
`As explained above, a person of ordinary skill in the art would have
`
`
`
`understood that the benzylic C–H bond would be especially weak because the
`
`resulting radical would be stabilized by the neighboring phenyl ring, methyl group,
`
`and nitrogen atom (see paragraphs 19–31). Therefore, the person of ordinary skill
`
`would have expected the molecule to be susceptible to homolysis of this C–H
`
`bond. In other words, a person of ordinary skill would have expected that
`
`rivastigmine would be susceptible to oxidative degradation because it contains a
`
`weak, readily-cleaved C–H bond.
`
`56.
`
`A person of ordinary skill in the art would have recognized the
`
`similarities in the structure of rivastigmine with other drugs like nicotine that were
`
`known to be susceptible to oxidative degradation. Nicotine in particular has a
`
`number of similarities to rivastigmine.
`
`
`
`
`
`Page 23 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`
`
`H3C
`
`CH3
`N
`
`O
`
`O
`
`H CH3
`
`CH3
`
`N
`CH3
`
`a tertiary nitrogen
`
`a benzylic carbon
`
`H2
`C
`
`H
`
`CH2
`
`N
`CH3
`
`N
`
`a tertiary nitrogen
`
`a "benzylic" carbon
`
`Figure 13. Comparison of the structures of rivastigmine and nicotine.
`
`
`
`57.
`
`Nicotine and rivastigmine both have a carbon adjacent to an
`
`aromatic ring, indicated in Figure 13 as a benzylic carbon. Additionally, in both
`
`molecules, the benzylic carbon is bonded to an adjacent carbon and a nitrogen (N).
`
`Further, in both molecules the nitrogen bonded to the benzylic carbon is a tertiary
`
`nitrogen (a tertiary amine); that is, the nitrogen is bonded to three carbon atoms.
`
`58.
`
`A person of ordinary skill in the art would have recognized that for
`
`nicotine and rivastigmine, the presence of a C–H bond on the carbon adjacent to
`
`the aromatic ring would stabilize a radical at this carbon and thus make that radical
`
`easier to form. For these reasons, a person of ordinary skill in the art would have
`
`expected that rivastigmine would be susceptible to oxidative degradation at the
`
`benzylic position via a similar mechanism as nicotine.
`
`
`
`
`
`Page 24 of 34
`
`Noven Ex. 1011
`
`
`
`
`
`59.
`
`The similarity in structure between nicotine and rivastigmine, and
`
`the known susceptibility of nicotine to oxidative degradation, would further
`
`support the expectation of the ordinarily-skilled artisan that rivastigmine would be
`
`susceptible to free radical mediated oxidative degradation. Nicotine was known to
`
`undergo free radical oxidation that could be prevented by the additional of an
`
`antioxidant. Linnell (Ex. 1021 at 2). A person of ordinary skill in the art would
`
`have expected that rivastigmine would undergo similar free radical oxidation
`
`reactions due to the presence of the benzylic C–H bond and the adjacent tertiary
`
`amine and to roughly the same extent as nicotine.
`
`60.
`
`A person of ordinary skill would understand that oxidative
`
`degradation of a drug like rivastigmine would proceed through a series of steps
`
`similar to the general propagation chain cycle described above (see paragraphs 37–
`
`46). Due to the reactive nature of the intermediates, however, there would be a
`
`number of paths that rivastigmine could take when it is degraded by free
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