Case 1:05-cv-12237-WGY Document 610-3
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`Filed 06/29/2007 Pagel of 75
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`EXHIBIT 5
`WIT. /Kti haaaJ
`DATE 3-.fl-aa-
`
`KR4MM COURTREPORTING
`
`UNITED STATES DISTRICT COURT
`DISTRICT OF MASSACHUSETTS
`
`AMGEN, INC.,
`
`Plaintiff,
`
`V.
`
`Civil Action No. 05-CV-I2237 WGY
`
`F. HOFFMANN-LA ROCHE, LTD.,
`ROCHE DIAGNOSTICS GMBH, and
`HOFFMANN-LA ROCHE, INC.
`
`Defendants.
`
`DECLARATION OF ALEXANDER M. KLIBANOV, Ph.D. IN SUPPORT
`OF DEFENDANTS' OPPOSITION TO AMGEN'S MOTION FOR SUMMARY
`JUDGMENT OF INFRINGEMENT OF '422 CLAIM 1,'933 CLAIM 3, AND '698
`CLAIM 6
`
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`1.
`
`I, Alexander M. Klibanov, Ph.D., submit this Declaration in support of Roche's
`
`Opposition to Amgen's Motion for Summary Judgment of Infringement of '422 Claim 1, '933
`
`Claim 3, and '698 Claim 6. My opinions and analysis submitted in this Declaration were
`
`previously disclosed in expert reports submitted in this litigation.
`
`2.
`
`1 am a Professor of Chemistry and of Bioengineering at the Massachusetts
`
`Institute of Technology ("M.I.T.").
`
`3.
`
`In 1971, 1 earned a Masters of Science degree in Chemistry from Moscow
`
`University in Russia and continued there to earn a Ph.D. in Chemical Enzymology in 1974.
`
`4.
`
`Between 1974 and 1977, Following my immigration to the United States, I was
`
`employed as a Research Chemist in the Chemistry Department of Moscow University. I was a
`
`Postdoctoral Associate at the Chemistry Department of the University of California, San Diego
`
`from 1977 to 1979. In 1979, I accepted a position as Assistant Professor of Applied
`
`Biochemistry at M.I.T. I was promoted to Associate Professor in 1983, and then to full Professor
`
`in the Department of Applied Biological Sciences in 1987. In 1988, I moved to the Department
`
`of Chemistry at M.I.T., where I assumed a full professorship, a position I still hold today. Since
`
`2000,1 also hold ajoint appointment as Professor of Bioengineering in the Department of
`
`Biological Engineering at M.I.T.
`
`5.
`
`My research is multi-faceted. Over the course of my career, I have had extensive
`
`experience studying, working with, and publishing about, enzymes, hormones, and other
`
`proteins, including their chemistry, biochemistry, purification, characterization, chemical
`
`modification (including chemical reactions with poly(ethylene glycol) ("PEG") reagents to make
`
`new chemical substances, henceforth referred to as pegylation), biological effects, and synthesis.
`
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`In particular, for the last 30 years or so, I have been active in developing and studying protein
`
`formulations, including their stability, administration, delivery, and biological evaluation.
`
`6.
`
`During over 30 years of scholarly work, I have earned numerous prestigious
`
`professional awards and honors. For example, I was elected to the United States National
`
`Academy of Sciences (considered among the highest professional honors that can be bestowed
`
`on an American scientist) and to the United States National Academy of Engineering (considered
`
`among the highest professional honors that can be bestowed on an American engineer or applied
`
`scientist). I am also a Founding Fellow of the American Institute for Medical and Biological
`
`Engineering and a Corresponding Fellow of the Royal Society of Edinburgh (Scotland's National
`
`Academy of Science and Letters). In addition, I have received the Arthur C. Cope Scholar
`
`Award, the Marvin J. Johnson Award, the Ipatieff Prize, and the Leo Friend Award, all from the
`
`American Chemical Society, as well as the International Enzyme Engineering Prize. 1 also have
`
`given 17 distinguished named lectureships all over the world.
`
`7.
`
`I currently serve on the Editorial Boards of eight scientific journals: Applied
`
`Biochemistry and Biotechnology, Biocatalysis and Biotransformation, Biotechnology Progress,
`
`Journal of Molecular Catalysis - Enzymatic, Microbial Biotechnology, Central European Journal
`
`of Chemistry, Biotechnology & Bioengineering, and Patents in Biotechnology. In the past, I was
`
`also an Editorial Board member for other scientific journals, e.g., Proceedings of the National
`
`Academy of Sciences of the U.S.A. (1999-2005), and Biochimica et Biophysica Acta - Protein
`
`Structure & Molecular Enzymology (1994- 1996).
`
`8.
`
`I have published over 260 scientific papers, many dealing with chemical reactions
`
`of proteins, purification, stability, formulation, and delivery. I am also a named inventor of 16
`
`issued United States patents, including several dealing with pharmaceutical formulations and the
`
`2
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`delivery of proteins. Finally, I have given over 350 invited lectures at professional conferences,
`
`universities, and corporations (including both Aingen and Roche) all over the world, many
`
`dealing with formulation, stability, delivery, and biological evaluation of proteins.
`
`9.
`
`Over my 27 years at M.I.T., I have taught numerous undergraduate and graduate
`
`courses in general (freshman) chemistry, organic chemistry, biological chemistry, enzyme and
`
`protein chemistry, biotechnology, and analytical biochemistry. I have also been a lecturer in
`
`summer courses at M.I.T. directed to industrial scientists, including "Controlled Release of
`
`Pharmaceuticals" and "Analytical Biochemistry in Process Monitoring and Validations." I have
`
`co-authored and co-edited several books including the "Handbook of Pharmaceutical Controlled
`
`Release Technology," published by Marcel Dekker in 2000.
`
`10.
`
`In addition to my research and teaching duties at M.I.T.,! have consulted widely
`
`for pharmaceutical, chemical, and biotechnology companies. I have also founded four
`
`biotechnology companies and have been on the scientific advisory boards and/or boards of
`
`directors of those companies and many others.
`
`II.
`
`Many of these consulting, advisory, and directorship activities have dealt
`
`specifically with formulation, stability, delivery, and biological evaluation of therapeutic
`
`proteins.
`
`12. A copy of my Curriculum Vitae detailing my awards, appointments, publications,
`
`and patents is attached as Exhibit A.
`
`I.
`
`FUNDAMENTALS OF ORGANIC CHEMISTRY AND BIOCHEMISTRY
`
`A.
`
`Atoms, Molecules, and Chemical Bonds
`
`13.
`
`Atoms are the basic building blocks of all molecules, which, in turn, comprise all
`
`chemical compounds. An atom is composed of a nucleus, which includes protons and neutrons,
`
`surrounded by electrons. The identity of an atom is defined by the number of protons in the
`
`3
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`nucleus (which necessarily equals the number of electrons). This is also called the atomic
`
`number. A chemical element is a substance made up of only one type of atoms, those having the
`
`same atomic number. For example, the simplest chemical element hydrogen is composed of
`
`atoms having one proton and one electron. Thus, hydrogen has an atomic number of I. Carbon
`
`atoms have six protons, hence atomic number 6; nitrogen atoms have seven protons, hence
`
`atomic number 7; oxygen atoms have eight protons, hence atomic number 8; etc.
`
`14.
`
`Protons are positively charged particles, and electrons are equally but negatively
`
`charged. When the number of electrons equals the number of protons (as in an atom), there is no
`
`net charge. Conversely, when the number of electrons is less or greater than the number of
`
`protons, the substance, called an ion, has a net positive or negative charge, respectively.
`
`15.
`
`If the charge of an ion is positive it is called a cation; if the charge is negative it is
`
`called an anion. The net charge of an ion is an important physical attribute which influences its
`
`physical, chemical, and biological properties.
`
`16.
`
`The atomic mass of an atom is the sum of the number of protons plus the number
`
`of neutrons (yet another, electrically neutral subatomic particle; the mass of electrons can be
`
`neglected because an electron is roughly 2,000 times lighter than a proton or a neutron). For
`
`example, a carbon atom that has 6 protons and 6 neutrons possesses an atomic mass of 12.
`
`17. A different arrangement of atoms within a molecule corresponds to a different
`
`compound with its own unique set of chemical and physical properties. (Ex. 242, Morrison &
`
`Boyd (1983) at 79)! Molecules are the smallest individual particles of chemical compound.
`
`They typically are groups of atoms held together by chemical bonds. When one atom of element
`
`All Exhibits cited herein are attached to the Declaration of Keith E. Toms in Support of Defendants' Opposition to
`Amgen's Motion for Summary Judgment of Infringement of'422 Claim 1,933 Claim 3, and '698 Claim 6.
`
`4
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`A bonds with one atom of element B, a molecule AB, or A-B results. It is important to note that
`
`molecule A-B is neither A nor B. In other words, A-B is substantially different from either A or
`
`B with its own physical and chemical properties. The molecule A-B does not "contain" or
`
`comprise either A or B, because both A and B significantly change upon their bonding, leading
`
`to the formation of A-B.
`
`18.
`
`Molecular weight is the total weights of all the individual atoms that make up the
`
`molecule. Molecular weight is a fundamental property of a chemical compound. Two
`
`substances having different molecular weights are by definition different chemical entities.
`
`Large differences in molecular weight typically are an indication that the substances are
`
`substantially different. This is because additional atoms that lead to higher molecular weights
`
`necessarily affect the properties of the substance.
`
`19.
`
`Depending on the types of atoms inn molecule, each molecule possesses a
`
`specific charge distribution within it. Charges, negative and positive, are typically localized in
`
`certain regions of a molecule.
`
`20.
`
`The field of organic chemistry involves the study of structure, properties, and
`
`synthesis of chemical compounds consisting of at least carbon and hydrogen atoms. "Carbon
`
`atoms can attach themselves to one another to an extent not possible for atoms of any other
`
`element. Carbon atoms can form chains thousands of atoms long, or rings of all sizes; the chains
`
`and rings can have branches and cross-links." (Ex. 242 at 2). Morrison and Boyd also state in
`
`their classic organic chemistry textbook:
`
`Each different arrangement of atoms corresponds to a different
`compound, and each compound has its own characteristic set of
`chemical and physical properties. It is not surprising that more
`than a million compounds of carbon are known today and that
`thousands of new ones are being made each year. It is not
`surprising that the study of their chemistry is a special field.
`
`5
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`Organic chemistry is a field of immense importance to technology:
`it is the chemistry of dyes and drugs, paper and ink, paints and
`plastics, gasoline and rubber tires; it is the chemistry of the food
`we eat and the clothing we wear.
`
`Organic chemistry is fundamental to biology and medicine. Aside
`from water, living organisms are made up chiefly of organic
`compounds; the molecules of "molecular biology" are organic
`molecules. Biology, on the molecular level, is organic chemistry.
`(Ex. 242 at 2-3).
`
`21.
`
`Chemists use various pictures, letters, symbols, and words to represent molecules.
`
`These representations are typically shorthand notations used for convenience in a particular
`
`situation. Undergraduate students taking their first course in organic chemistry are taught that
`
`the pictures need to be interpreted to understand what is meant: "These crude pictures and
`
`models are useful to us only if we understand what they are intended to mean." (Ex. 242 at 3).
`
`22.
`
`Organic chemists have devised a standard system for representing the structure of
`
`molecules. In general, atoms are represented by their one- or two-letter symbols in the periodic
`
`table of the elements. For example, hydrogen is H, carbon is C, nitrogen is N, and oxygen is 0.
`
`23.
`
`Organic molecules are formed by the joining of atoms through covalent bonds.
`
`Covalent bonding occurs when two atoms share electrons. The sharing of electrons creates a
`
`force that holds the atoms together. Covalent bonds are considered strong chemical bonds
`
`compared to other chemical bonds that can hold atoms or molecules together.
`
`24.
`
`Molecules made up exclusively of groups of carbon and hydrogen atoms are
`
`called hydrocarbons. These molecules can have different orientations in space. The carbon and
`
`hydrogen atoms in molecules can be connected in chains that can be linear, branched, or cyclic.
`
`Carbon in organic molecules always has four and only four covalent bonds. These bonds can be
`
`single bonds, double bonds, or triple bonds. A carbon atom covalently bonded to 4 hydrogen
`
`atoms constitutes one of the simplest organic substances called "methane". Methane (the main
`
`6
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`component of natural gas) is a flammable gas. Its properties are dramatically different from
`
`elemental carbon (which occurs in nature as either diamonds or graphite) and elemental
`
`hydrogen. Methane can be represented by the following equivalent formulas:
`
`H
`
`H-C--H
`
`CH4
`
`H
`
`25.
`
`Covalent bonds between atoms are represented by single straight lines (or dashes).
`
`Each line represents one bond or one pair of shared electrons. Thus, a single bond is represented
`
`by a single line, a double bond is represented by two parallel lines, and a triple bond by three
`
`parallel lines. Chemists have refined the system for visual simplicity so that carbons are
`
`represented by an intersection of lines or simply by the end of a line, and hydrogen atoms bonded
`
`to carbon atoms and the lines representing C-i-I bonds are often not drawn at all. Thus, for all
`
`carbon atoms, if only two bonds are actually depicted, it is understood that there are also two
`
`bonds to hydrogen atoms implied, but not drawn. mother words, because chemists understand
`
`that in organic molecules, carbon always has four bonds, chemists do not always write out the
`
`carbon and hydrogen atoms on a molecule. Chemists understand a notation where every straight
`
`line represents a carbon-to-carbon bond and any carbon atom with fewer than four bonds
`
`depicted by implication includes enough single bonds to hydrogen atoms to make four bonds.
`
`This is illustrated below for the hydrocarbon compound called propane:
`
`7
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`H H H
`
`H—c—c—c—H
`
`C3H8
`
`H H H
`
`H2
`
`H3C
`
`cH 3
`
`26.
`
`Each of these equivalent representations of propane is understood to refer to a
`
`molecule having three carbon atoms and eight hydrogen atoms. As molecules become larger,
`
`these shorthand notations are used more frequently. However, the mere fact that a shorthand
`
`representation is used does not mean that any atom or bond is insignificant. To the contrary, to
`
`understand the nature of a chemical substance, every atom and every bond within its molecules
`
`should be considered important.
`
`27.
`
`There are three distinct two-carbon hydrocarbon molecules: ethane (C2H6),
`
`ethylene (C2H4), and acetylene (C21-1 2).
`
`H H
`
`H—c—c—H
`
`C2H6
`
`H H
`
`H\ _c/H
`
`H/c
`
`NH
`
`C7H4
`
`H - c c—H
`
`c2n2
`
`28.
`
`In ethane, the two carbon atoms are attached to each other by a single bond. To
`
`fill out the required number of four bonds, each carbon atom is also bonded to three hydrogen
`
`8
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`atoms. In ethylene, the two carbon atoms are bonded to each other by a double bond. To fill out
`
`the required number of four bonds, each carbon atom is also bonded to two hydrogen atoms. In
`
`acetylene, the two carbon atoms are bonded to each other by a triple bond. To fill out the
`
`required number of four bonds, each carbon atom is also bonded to only one hydrogen atom.
`
`Although these three molecules structurally differ only by the type of covalent bond and the
`
`number of hydrogens attached to the carbons, they have very different chemical and physical
`
`properties.
`
`29.
`
`Organic molecules often have structures in the form of rings. In particular, six-
`
`membered ring structures are common. Consider two simple 6-membered ring hydrocarbon
`
`substances that differ in the type of covalent bonds and the number of hydrogen atoms attached
`
`to the ring: cyclohexane (C6H12) and benzene (C51-I6). Despite what might appear as only a small
`
`difference in structure, benzene and cyclohexane have markedly different chemical and physical
`
`properties. Thus it can be misleading to superficially look at such ring structures to
`
`simplistically derive any inference about the properties of molecules.
`
`cyclohexane C6H12 benzene C61-1 5
`
`30.
`
`The molecular structure of the common household drug aspirin is shown below.
`
`One can discern in it the presence of a six-membered ring that resembles benzene. However, no
`
`scientist would say that aspirin has benzene in it. The two compounds are strikingly distinct in
`
`their properties: aspirin is a white, odorless, pain-relieving, crystalline solid, while benzene is a
`
`sweet-smelling, volatile, cancer-causing liquid. It is my opinion that if a patent claim were
`
`directed to benzene, aspirin would not infringe.
`
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`aspirin
`
`31.
`
`Organic molecules often have oxygen and/or nitrogen atoms in addition to
`
`carbons and hydrogens. A nitrogen typically forms three covalent bonds but can accommodate a
`
`fourth bond, resulting in a nitrogen that is positively charged. Oxygen usually forms only two
`
`covalent bonds.
`
`32.
`
`Certain groups of atoms, sometimes referred to as functional groups or residues,
`
`are designated by a specific name. For instance, a primary amine is a chemical group composed
`
`of a nitrogen atom attached to a carbon and two hydrogen atoms by three single covalent bonds.
`
`An alcohol group is —OH or a hydroxyl group typically attached to a carbon atom.
`
`H
`/
`
`primary amine
`
`primary alcohol
`
`33.
`
`An acid is a chemical compound that can donate a proton or positively charged
`
`hydrogen ion (H+) to another molecule. A carboxylic acid is an example of an organic acid
`
`having a group which has the formula -C(=O)OH, usually written -COOl-I or -0O2F1.
`
`10
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`0
`
`P 112— C
`'OH
`
`carboxylic acid
`
`34.
`
`An amide forms when a carboxylic acid reacts with a primary amine. It has the
`
`following general structure:
`
`0
`
`amide
`
`35.
`
`Ethanol, also called ethyl alcohol, is the intoxicating substance known as alcohol
`
`in drinks like vodka, whiskey, beer, and wine. The molecular structure of ethanol (CU3CH2OH),
`
`shown below, may seem structurally similar to ethane (1127 above). In fact, the molecular
`
`structures differ by a single atom: ethanol has an additional oxygen atom that is not present in
`
`ethane. The physical and chemical properties of the substances are nonetheless strikingly
`
`different. At room temperature and pressure, for example, ethanol is a colorless liquid, while
`
`ethane is a gas.
`
`H H
`
`H H
`
`H-C--C-OH
`
`H-C-c--H
`
`H H
`ethanol
`
`H H
`
`ethane
`
`36.
`
`This is just one example of the fundamental principle of organic chemistry that
`
`even seemingly small differences in molecular structure can and usually do have a profound
`
`impact on chemical, physical, and biological properties of substance. The presence of the
`
`oxygen atom in ethanol, with all the other atoms being the same in kind and number, makes it a
`
`II
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`markedly distinct compound from ethane. The properties of compound thus are a result of the
`
`entire structure of the molecule. It is my opinion that if patent claim were directed to ethane,
`
`ethanol would not infringe. There is no ethane in ethanol.
`
`37.
`
`Organic synthesis involves the development of chemical reactions that transform
`
`organic compounds into new ones through the formation of covalent bonds. It is the process of
`
`making, breaking, and rearranging covalent bonds. The flow of electrons in the course of a
`
`reaction can be depicted by curved arrows, a method of representation called "arrow pushing,"
`
`where each arrow represents an electron pair. (See, e.g., Ex. 242 at 157).
`
`38.
`
`The second of the two starting materials in the scheme below is called
`
`formaldehyde (belonging to a large class of organic molecules called aldehydes). In this scheme,
`
`it reacts with the simplest amine (ammonia, NH3). This type of a reaction is relevant to some of
`
`the discussions below.
`
`H
`
`H-7
`H
`
`H5H
`
`H
`
`0
`
`H-7 — C H
`H
`
`39.
`
`The following pharmaceutical example might be instructive. In the early 1950s,
`
`Dr. Jonas Salk of the University of Pittsburgh developed the first effective polio vaccine. This
`
`medical breakthrough essentially eradicated polio in the United States and saved millions of
`
`children from this debilitating disease. From the chemical standpoint, Dr. Salk's discovery
`
`involved reacting a mixture of three active polio virus strains with formaldehyde.
`
`40.
`
`Formaldehyde predominantly forms covalent bonds with amino groups of the
`
`protein subunits of polio virus, thereby rendering the latter non-virulent but still able to cause the
`
`protective immune reaction in the human body. This type of nucleophilic substitution reaction
`
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`involving an amine, exemplified above, is conceptually similar to the chemical reaction of
`
`epoetin beta's amino groups with m-PEG-SBA employed by Roche to produce CERA (see
`
`below). In my opinion, the active ingredient in Dr. Salk's life-saving polio vaccine is materially
`
`changed compared to the starting material, the disease-causing polio virus (otherwise, the FDA
`
`presumably would have never approved its use to vaccinate children). If so, then CERA is
`
`likewise materially changed compared to epoetin beta.
`
`41.
`
`Once a chemical reaction occurs, the original substances cease to exist and a new
`
`and different substance (or substances) is (are) created. New covalent bonds are formed (and old
`
`ones broken) producing new compounds with new properties that are distinct from those of the
`
`starting materials or reagents. Pegylation is an example of an organic synthesis that transforms
`
`starting materials into new chemical compounds through the formation of covalent bonds (see
`
`explanation of pegylation technology below).
`
`42.
`
`For example, ethanol can be formed by the chemical addition of water across the
`
`double bond of ethylene as described below:
`
`/ H
`
`H
`
`H
`
`
`
`ethylene
`
`water (H2O)
`
`H
`
`H—C--H
`
`H—c—OH
`
`H
`
`ethanol
`
`43.
`
`This type of chemical reaction, called hydration, has been known for over a
`
`century. However, the fact that this reaction seems relatively straightforward and is old does not
`
`mean that changes that occur to the starting materials are not substantial. To the contrary.
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`ethylene and water are both vastly different from ethanol in physical, chemical, and biological
`
`properties.
`
`44.
`
`One can inspect the structure of ethanol and mentally discern the elements of
`
`water (HO) in it (H and OH). This certainly does not mean that water is the same as ethanol
`
`and/or that the biological properties of ethanol are the same as, or even similar to, the biological
`
`properties of water. A healthy person can readily drink an eight ounce glass of pure water and
`
`feel perfectly fine. However, drinking an eight ounce glass of pure ethanol would cause
`
`significant biological effects (e.g., intoxication). Thus newly formed molecules cannot be
`
`viewed as physical assemblies of "parts" or "components", or of the starting materials. Nor are
`
`the properties of these newly formed molecules predictably derived from the properties of the
`
`starting materials.
`
`H-
`
`H-
`
`OH
`
`elements
`of water
`
`ethanol
`
`45.
`
`There are many other examples in which seemingly small structural differences
`
`between two molecules result in large differences in the properties of the substances. For
`
`example, the difference between water, H2O, and hydrogen sulfide, H2S, is only one atom, but
`
`the two substances have drastically different properties. At room temperature and pressure,
`
`water is a liquid that supports life, while hydrogen sulfide is a poisonous gas. Similarly,
`
`hydrogen peroxide, H202, differs from water by only one extra oxygen atom. However, that one
`
`atom difference makes hydrogen peroxide highly reactive, toxic, and explosive.
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`46.
`
`With respect to the hydrogen peroxide 1-1202, a superficial inspection may suggest
`
`that it consists of H2 and 02 molecules. Nothing can be further from the truth, however, as
`
`revealed even by the fact that H2 and 02 are both gases (the latter constitutes about 20% of the
`
`air we breathe) at room temperature and pressure, while H202 is a thick liquid.
`
`47.
`
`The chemical name for the active agent in household vinegar is acetic acid. This
`
`simple carboxylic acid has the formula:
`
`0
`
`H3c—c\
`
`" OH
`
`acetic acid (vinegar)
`
`48.
`
`The replacement of a single carbon-bonded hydrogen atom of acetic acid with a
`
`fluorine atom means the difference between a relatively harmless substance used in cooking and
`
`a severely toxic substance, mono-fluoroacetic acid. Although the chemical name mono-
`
`fluoroacetic acid includes the words acetic acid, this does not mean that mono-fluoroacetic acid
`
`contains or comprises acetic acid. It is my opinion that if a patent claim were directed to acetic
`
`acid, mono-fluoroacetic acid would not infringe.
`
`49.
`
`Besides covalent bonds, there are other types of chemical interactions between
`
`molecules. For example, a hydrogen bond is a ubiquitous chemical interaction in molecules
`
`between a hydrogen and another atom that is electronegative, particularly oxygen or nitrogen.
`
`An electronegative atom in a covalent bond draws electron density toward itself. In a hydrogen
`
`bond between hydrogen and oxygen, the slight negative charge on the electronegative oxygen is
`
`attracted to the slight positive charge on the relatively less electronegative hydrogen. A
`
`hydrogen bond is much weaker than a covalent bond. The existence of hydrogen bonds within a
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`molecule or among molecules can have a significant influence on the physical, chemical and
`
`biological properties of the substance.
`
`50.
`
`Nucleophilic substitutions or additions are a type of organic chemical reaction in
`
`which a nucleophile (usually an electron-rich group that is therefore attracted to atoms having a
`
`localized positive charge) typically forms a new covalent bond to a carbon atom while displacing
`
`a leaving group from it.
`
`B.
`
`Amino Acids and Protein Chemistry
`
`51.
`
`Biochemistry is a subset of organic chemistry dealing with the chemistry of living
`
`organisms and the molecular basis of life. The fundamental principles of organic chemistry,
`
`such as the structure of molecules and chemical bonding, also apply to large biochemical
`
`molecules (also called biomacromolecules), such as proteins, nucleic acids (DNA and RNA), and
`
`carbohydrates. Furthermore, like in simpler organic molecules, the structure of
`
`biomacromolecules dictates their function: as is often stated, "structure begets function." A
`
`standard undergraduate textbook of Biochemistry states that "[t]he interplay between the three-
`
`dimensional structure of biomolecules and their biological function is the unifying motif of this
`
`book." (Ex. 285 at 4).
`
`52.
`
`The strongest bonds that are present in biochemicals, as in simpler organic
`
`chemicals, are covalent bonds. Indeed, covalent bonds can "withstand the thermal motions that
`
`tend to pull molecules apart." (Ex. 57, Alberts (1983) at 92). As stated above, covalent bonds
`
`are broken and formed when chemical reactions occur between atoms and/or molecules. In
`
`general, when covalent bonds are broken and new ones formed, large amounts of energy are
`
`involved. On the other hand, "noncovalent bonds are about 100 times weaker." (Ex. 57 at 92).
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`These noncovalent bonds are nevertheless vital for maintaining cellular functions that require
`
`molecules to associate and dissociate.
`
`53.
`
`Because bioinacromolecules typically contain thousands of atoms, scientists will
`
`not usually draw detailed pictures of the structure. Rather, certain abbreviations or letter codes
`
`are often used to represent structure, as explained below.
`
`54.
`
`Genes are nucleic acids that contain the information necessary for a cell to
`
`produce proteins. Genes and proteins are examples of chemical compounds that are
`
`biomacromolecules. It is noteworthy that my review of the Federal Circuit opinion in Anzgen,
`
`Inc. v. Chugai Pharmaceutical Co., a case involving an earlier patent granted to Amgen's Dr.
`
`Lin based on the same work and same patent application as the asserted Lin patents, indicates
`
`that the Court treats genes as chemical compounds: "A gene is a chemical compound, albeit a
`
`complex one, and it is well established in our law that conception of chemical compound
`
`requires that the inventor be able to define it so as to distinguish it from other materials, and to
`
`describe how to obtain it." 927 F.2d 1200, 1206 (Fed. Cit. 1991).
`
`55.
`
`Proteins are formed through the chemical reactions of certain natural amino acids
`
`in the cells through the biochemical process of translation. Amino acids are organic compounds
`
`containing an amino group and a carboxyl group. Although there is a potentially infinite number
`
`of various amino acids, there are only twenty (20) different, so-called standard amino acids that
`
`make up virtually all naturally occurring proteins.
`
`56.
`
`Each such standard amino acid is composed of a central alpha carbon bonded to a
`
`hydrogen, to a carboxyl group, to an amino group, and to a unique side chain or R-group. In
`
`other words, the central alpha carbon bonded to a hydrogen, a carboxyl group and an amino
`
`group constitute a "core" structure that is common to each standard amino acid (except Pro). It
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`is the unique side chain that determines the individual chemical structure and properties of each
`
`standard amino acid. One standard amino acid is only distinguished from another by the unique
`
`side chain, which dictates the distinctive physicochemical properties of each amino acid.
`
`57.
`
`The side chains of the twenty standard amino acids (along with their I-letter and
`
`3-letter codes) in alphabetical order are:
`
`Amino Acid
`
`Abbreviation
`
`Side Chain's Structural Formula
`
`I.
`
`Alanine
`
`A, Ala
`
`H
`
`—H
`
`H
`
`2.
`
`Arginine
`
`R, Ara
`
`NH
`
`H2
`
`H2
`
`H2
`
`H
`
`3.
`
`Asparagine
`
`N,