IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`COALITION FOR AFFORDABLE DRUGS X LLC,
`Petitioner,
`
`v.
`
`ANACOR PHARMACEUTICALS, INC.,
`Patent Owner.
`
`Case No. IPR2015-01776
`Patent No. 7,582,621
`
`
`
`DECLARATION OF PAUL J. REIDER, PH.D., IN SUPPORT OF
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 1/96
`
`

`
`TABLE OF CONTENTS
`
`IPR2015-01776
`
`Page
`
`I.
`
`INTRODUCTION .......................................................................................... 1
`
`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS ........................ 1
`
`III. SCOPE AND SUMMARY OF THE OPINION ............................................ 4
`
`IV. TECHNICAL BACKGROUND .................................................................... 6
`
`A. Organic Chemistry Tutorial ................................................................. 6
`
`1.
`
`2.
`
`3.
`
`Aliphatic and Aromatic Molecules ............................................ 7
`
`Heterocycles ............................................................................... 8
`
`Substituted Carbon Molecules ................................................. 11
`
`a)
`
`b)
`
`Halogens ........................................................................ 12
`
`Boron-Containing Substituents ..................................... 14
`
`(1) Boranes and Organoboranes ................................ 15
`
`(2) Borinic acids ........................................................ 17
`
`(3) Boronic Acids ...................................................... 17
`
`(4) Borate Esters and Borate Anion Complexes ....... 18
`
`B.
`
`The Multi-Dimensional Challenge of Drug Development ................ 20
`
`1.
`
`Selected Desirable Biochemical and Physical Properties
`For Pharmaceuticals ................................................................. 26
`
`a)
`
`b)
`
`c)
`
`d)
`
`Absence of Toxicity at Therapeutic Doses .................... 26
`
`Selectivity ...................................................................... 28
`
`Potency .......................................................................... 30
`
`Stability .......................................................................... 32
`
`
`
`i
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 2/96
`
`

`
`IPR2015-01776
`
`2.
`
`3.
`
`4.
`
`e)
`
`f)
`
`Hydrophilicity/Lipophilicity .......................................... 33
`
`Tavaborole Confirms These Principles ......................... 34
`
`Compound Identification ......................................................... 35
`
`Small Structural Changes Have Unpredictable and
`Dramatic Biological Effects ..................................................... 36
`
`A POSA in 2005 Rarely Would Have Considered Boron-
`Containing Compounds as Drug Candidates ........................... 38
`
`a)
`
`b)
`
`c)
`
`A POSA in 2005 Would Not Have Expected
`Boron-Containing Compounds To Be Non-Toxic ........ 39
`
`A POSA in 2005 Would Not Have Expected
`Boron-Containing Compounds To Be Selective ........... 42
`VELCADE® Was a Warning to POSAs in the
`Early 2000s About the Toxicity of Boron-
`Containing Compounds ................................................. 46
`
`V.
`
`THE ’621 PATENT ...................................................................................... 46
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART .......................................... 48
`
`VII. CLAIM CONSTRUCTION ......................................................................... 49
`
`VIII. OVERVIEW OF THE CITED REFERENCES ........................................... 50
`
`A. Austin ................................................................................................. 50
`
`B.
`
`C.
`
`Brehove............................................................................................... 55
`
`Freeman .............................................................................................. 57
`
`IX. RESPONSE TO PETITIONER’S GROUNDS 1 AND 2 ............................ 59
`
`A. Ground 1: Claims 1-12 Are Not Obvious Over Austin and
`Brehove............................................................................................... 59
`
`1.
`
`Austin ....................................................................................... 59
`
`ii
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 3/96
`
`

`
`IPR2015-01776
`
`a)
`
`b)
`
`c)
`
`A 2005 POSA Would Not Consider Austin to be
`Relevant ......................................................................... 59
`
`Austin Does Not Provide an Expectation of
`Success in Using Boron-Containing Compounds to
`Treat Onychomycosis .................................................... 63
`
`A POSA Would Not Have Selected Tavaborole
`from the Many “Preferred” Compounds of Austin ....... 63
`
`2.
`
`Brehove .................................................................................... 65
`
`a)
`
`Brehove Is Not Credible ................................................ 65
`
`3.
`
`A 2005 POSA Would Not Have Been Motivated to
`Combine Austin with Brehove................................................. 73
`
`a)
`
`b)
`
`c)
`
`The Proposed Combination Lacks Data that Would
`Have Provided a POSA with an Expectation of
`Success ........................................................................... 73
`
`The Benzoxaboroles of Austin and the
`Dioxaborinanes of Brehove Are Structurally
`Dissimilar ....................................................................... 74
`
`Brehove Would Not Have Supplied a Reasonable
`Expectation of Success and Does Not Make
`Tavaborole Obvious to Try ............................................ 77
`
`B. Ground 2: Claims 1-12 Are Not Obvious Over Austin and
`Freeman .............................................................................................. 78
`
`1.
`
`2.
`
`Austin ....................................................................................... 78
`
`Freeman .................................................................................... 78
`
`a)
`
`b)
`
`A 2005 POSA Would Not Have Considered
`Freeman’s Compounds To Be Effective Against
`Microorganisms ............................................................. 78
`
`A 2005 POSA Would Have Expected the Phenyl
`Boronic Acids of Freeman To Be Toxic to
`Mammals ....................................................................... 81
`
`iii
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 4/96
`
`

`
`IPR2015-01776
`
`3.
`
`4.
`
`5.
`
`A 2005 POSA Would Not Have Been Motivated to
`Combine Austin with Freeman ................................................ 83
`
`Freeman Would Not Have Supplied a Reasonable
`Expectation of Success and Does Not Make Tavaborole
`Obvious To Try ........................................................................ 86
`
`Dr. Murthy’s and Dr. Kahl’s Theory Would Have Led a
`2005 POSA To Expect Tavaborole To Be Inactive
`Against Microorganisms and Toxic to Mammals ................... 86
`
`X.
`
`IT WOULD HAVE BEEN UNEXPECTED IN 2005 AND
`REMAINS SO TODAY THAT TAVABOROLE IS BOTH SAFE
`AND EFFECTIVE FOR TREATING ONYCHOMYCOSIS IN
`HUMANS ..................................................................................................... 88
`
`XI. CONCLUSION ............................................................................................. 89
`
`iv
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 5/96
`
`

`
`IPR2015-01776
`
`I, PAUL J. REIDER, Ph.D., hereby state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been asked by Patent Owner Anacor Pharmaceuticals, Inc.
`
`(“Anacor”) to offer my expert opinions in the inter partes review (“IPR”) of U.S.
`
`Patent No. 7,582,621 (“the ’621 Patent”) filed by Petitioner Coalition for
`
`Affordable Drugs X LLC (“CFAD”).
`
`2.
`
`This Declaration contains my opinions relating to the validity of
`
`claims 1-12 of the ’621 Patent.
`
`3.
`
`This Declaration is based on information currently available to me. I
`
`reserve the right to continue my investigation and analysis, which may include a
`
`review of documents and information not yet provided. I further reserve the right
`
`to expand or otherwise modify my opinion and conclusions as my investigation
`
`and study continues, and to supplement my opinions and conclusions in response
`
`to any additional information that becomes available to me.
`
`II. ACADEMIC AND PROFESSIONAL QUALIFICATIONS
`
`4.
`
`I am a Lecturer at the rank of Professor of Chemistry at Princeton
`
`University. A copy of my curriculum vitae is attached as Exhibit 2030. My
`
`educational background and my professional experience are summarized below.
`
`5.
`
`I obtained an A.B. degrees in Psychology and Chemistry from the
`
`Washington Square College at New York University in 1972. I obtained my Ph.D.
`
`
`
`1
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 6/96
`
`

`
`IPR2015-01776
`
`in Organic Chemistry from the University of Vermont in 1978. My Ph.D. thesis
`
`concerned the total synthesis of the natural product ibogamine.
`
`6.
`
`After two years of post-doctoral work at Colorado State University
`
`from 1978-1980, I joined Merck Research Labs as a Senior Research Chemist in
`
`Process Research. For the next 22 years, I remained at Merck, eventually rising to
`
`the rank of Vice President. During that time, I participated in the discovery and
`
`development of more than a dozen FDA approved drugs, including CANCIDAS®,
`
`an intravenous antifungal medication.
`
`7.
`
`I left Merck in 2002 and joined Amgen as Vice President, Chemistry
`
`Research & Discovery, where I was responsible for chemistry and small molecule
`
`drug discovery, including medicinal chemistry, analytical chemistry, the sample
`
`collection and compound procurement, computational chemistry, molecular
`
`modeling, protein chemistry, automation and robotics, crystallography, process
`
`chemistry, peptide chemistry and high-throughput screening.
`
`8.
`
`In 2008, I left the pharmaceutical industry to join the faculty of
`
`Princeton. I currently serve as a Lecturer at the Rank of Professor in the Princeton
`
`University Department of Chemistry. In this position, I teach organic chemistry,
`
`medicinal chemistry and pharmaceutical sciences to Princeton undergraduate and
`
`graduate students based on my experiences at Merck and Amgen. My research at
`
`2
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 7/96
`
`

`
`IPR2015-01776
`
`Princeton focuses on treatments for neglected diseases (e.g., TB, malaria, dengue
`
`fever and Human African Trypanosomiasis).
`
`9.
`
`Over the course of my career, I have had extensive experience with
`
`the use of boron-containing catalysts and reactants in the synthesis of potential
`
`drug candidates, but I have never developed boron-containing compounds for use
`
`as drug candidates themselves because of their undesirable properties, discussed in
`
`detail below.
`
`10.
`
`I have presented numerous invited lectures and am the inventor of
`
`over 35 patents. I am the author or co-author of over 180 peer-reviewed scientific
`
`articles, including “Semisynthesis of an Antifungal Lipopeptide Echinocandin,” J.
`
`Org. Chem. (1999), 64(7), 2411-2417.
`
`11.
`
`I have won numerous awards for my research, including the 2000 Prix
`
`Galien Award (SINGULAIR®, montelukast), the 1998 Merck Scientific Director’s
`
`Award (CRIXIVAN®, indinavir) and the 2011 National Academy of Sciences
`
`Award for Chemistry in Service to Society.
`
`12.
`
`I currently sit on the Scientific Advisory Boards of the TB Alliance
`
`(New York) and the Medicines For Malaria Venture (Geneva).
`
`13.
`
`I consider myself to be an expert in organic chemistry, including in
`
`the field of medicinal chemistry.
`
`3
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 8/96
`
`

`
`IPR2015-01776
`
`III. SCOPE AND SUMMARY OF THE OPINION
`
`14.
`
`I have been asked to consider whether claims 1-12 of the ’621 Patent
`
`are non-obvious over the references cited by Petitioner in the IPR against Anacor.
`
`15. For my work in connection with this case, I am being compensated at
`
`my usual and customary hourly rate for my expert services in connection with this
`
`Inter Partes Review proceeding. My compensation does not depend in any way on
`
`the opinions or conclusions that I express in this report or the outcome of this
`
`litigation.
`
`16.
`
`I have reviewed the Petition for Inter Partes Review of U.S. Patent
`
`No. 7,582,621 filed by Coalition for Affordable Drugs, X LLC, including the
`
`Declarations of Dr. Kahl and Dr. Murthy, as well as the exhibits and articles cited
`
`in those documents. I have also reviewed the articles and documents cited in this
`
`declaration.
`
`17. This report sets forth my opinions formed in answering those
`
`questions. My opinions include the following, which will be discussed in detail
`
`below:
`
`• A POSA would not have been aware of references, such as Austin,
`
`that relate to an entirely different field than “the research,
`
`development, or production of pharmaceuticals.”
`
`4
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 9/96
`
`

`
`IPR2015-01776
`
`• Even if a POSA were aware of Austin, a POSA would not have
`
`considered a compound from Austin for development as a
`
`pharmaceutical because a POSA in 2005 would have been
`
`concerned about the toxicity of the compounds of Austin,
`
`including tavaborole.
`
`• A POSA would not have combined Austin with either Brehove or
`
`Freeman, because a POSA would consider biological data related
`
`to dioxaborinanes and phenyl boronic acids to be irrelevant to the
`
`biological properties of the structurally dissimilar benzoxaboroles.
`
`• Even if a POSA chose to select a compound from Austin, the
`
`POSA would not have selected tavaborole because it is not a
`
`“particularly preferred” compound.
`
`• A POSA in 2005 would not have had a reason to combine Austin
`
`with either Brehove or Freeman, and either combination would not
`
`have provided a 2005 POSA with a reasonable expectation of
`
`successfully achieving the invention of the ’621 Patent.
`
`• A POSA would have found the selective toxicity of tavaborole,
`
`that is, its activity against the target fungus without toxic effects to
`
`mammals including humans, to be unexpected.
`
`5
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 10/96
`
`

`
`IPR2015-01776
`
`IV. TECHNICAL BACKGROUND
`
`A. Organic Chemistry Tutorial
`
`18. Organic chemistry is the study of organic compounds, which usually
`
`contain carbon and hydrogen atoms. Organic compounds that contain only carbon
`
`and hydrogen atoms are called hydrocarbons, but these are a small fraction of
`
`organic compounds. Frequently, organic compounds contain other atoms, called
`
`“heteroatoms,” such as oxygen, nitrogen, phosphorous, sulfur, chlorine, and
`
`fluorine. An organic chemist is a scientist trained to understand and manipulate
`
`the chemistry of organic compounds.
`
`19. When drawing chemical structures, organic chemists generally omit
`
`the “C,” which denotes a carbon atom. Instead, organic chemists represent carbon
`
`linkages as straight-line drawings and frequently omit the hydrogen atoms bonded
`
`to those carbons. Because carbon forms four bonds, organic chemists understand
`
`that each unlabeled carbon contains the appropriate number of bonded hydrogens
`
`to satisfy each carbon’s four-bond requirement, unless otherwise noted.
`
`Figure 1
`
`6
`
`
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 11/96
`
`

`
`IPR2015-01776
`
`20. Organic chemists also depict single, double, and triple chemical bonds
`
`with single, double, and triple lines, respectively. These conventions have been
`
`adopted for representing the chemical structures discussed below, and for the
`
`chemical structures throughout this report.
`
`1.
`Aliphatic and Aromatic Molecules
`21. Carbon-containing molecules are roughly divided into aromatic and
`
`aliphatic molecules based on the nature of the carbon-carbon bonds they contain.
`
`See Figure 2 below. Aromatic molecules generally have a flat three-dimensional
`
`orientation and are unusually stable. In other words, aromatic carbon-carbon
`
`bonds are especially difficult to break. The stability of aromatic molecules results
`
`from the unique configuration of electrons in aromatic carbon-carbon bonds.
`
`22.
`
`In contrast, aliphatic molecules do not possess stabilizing electronic
`
`properties, as in aromatic molecules. The most common aliphatic molecules are
`
`straight and branched carbon chains, and unsaturated molecules. A compound is
`
`“unsaturated” when a carbon is doubly or triply bonded to another carbon or when
`
`a ring is present.
`
`7
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 12/96
`
`

`
`IPR2015-01776
`
`Figure 2
`
`
`
`23. An organic compound is said to be “unsubstituted” if the carbon
`
`atoms that comprise the backbone or ring of the compound are bound only to each
`
`other and hydrogen atoms. See Figure 2 above. If one or more carbons in the
`
`backbone or ring of the molecule are bound to atoms other than hydrogen, the
`
`organic compound is “substituted.”
`
`2. Heterocycles
`24. Organic compounds are not always built solely from carbon atoms.
`
`Heteroatoms may also contribute to an organic molecule’s basic skeleton.
`
`“Heterocycles” represent just such a case. A heterocycle is any ring system
`
`composed of two or more types of atoms. See Figure 3 below. In organic
`
`chemistry, a heterocycle is typically a cyclic structure containing carbon and at
`
`least one other atom type. Common heterocycles include pyridine, thiophene,
`
`furan, and 1,3-oxazole, shown below.
`
`8
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 13/96
`
`

`
`IPR2015-01776
`
`Figure 3
`
`
`
`25. Notably, a heterocycle does not necessarily contain carbon. As in the
`
`unusual example of borazine, shown above, any cyclic structure that contains more
`
`than one type of atom is a heterocycle.
`
`26. Heterocycles also are not necessarily planar. Non-aromatic
`
`heterocycles almost always deviate from planarity. For example, even though
`
`chemists frequently draw piperidine as a planar six-membered ring, piperidine
`
`actually adopts the non-planar conformation shown in the center of Figure 4,
`
`below. Even the carborane clusters frequently used by Dr. Kahl are heterocycles
`
`because they contain cyclic structures composed of both carbon and boron.
`
`9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 14/96
`
`

`
`IPR2015-01776
`
`Figure 4
`
`
`
`27.
`
`In this case, tavaborole contains a heterocycle—the five-membered
`
`boron-containing ring—that is nearly flat. The boron is constrained within the
`
`cyclic framework of the molecule. This structure is in contrast to phenyl boronic
`
`acids, where the boron is part of a substituent that is external from the structural
`
`core of the molecule and is free to rotate around its carbon-boron bond. See Figure
`
`5 below.
`
`10
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 15/96
`
`

`
`IPR2015-01776
`
`Figure 5
`
`
`
`Substituted Carbon Molecules
`
`3.
`“Substituents” are a frequent component of an organic compound’s
`
`28.
`
`structure. A “substituent” is an atom or group of atoms that is substituted in place
`
`of a hydrogen atom on the backbone or ring of an organic molecule. As described
`
`in Section IV.B.3 below, the structure of an organic compound determines how the
`
`compound behaves in a biological system. Substituents play a key role in
`
`determining an organic compound’s structure because they directly introduce new
`
`three-dimensional groups to the compound and may sometimes indirectly modify
`
`the orientation of the compound’s backbone or ring. Thus, an organic compound’s
`
`substituents are important to understanding the compound’s chemistry.
`
`29. Substituents can also alter an organic compound’s biological
`
`properties, for example, by modulating the steric environment of nearby carbon
`
`atoms. Atoms do not like to be crowded, and bonds will move to adopt the spatial
`
`relationship that provides the greatest stability.
`
`11
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 16/96
`
`

`
`IPR2015-01776
`
`30. Certain substituents also influence the electronic properties of
`
`compounds, and some substituents possess either electron-donating or electron-
`
`withdrawing effects. The specific electronic effect of a substituent depends on the
`
`nature of the substituent and the nature of the group to which the substituent is
`
`attached. For example, methoxy and other alkoxy substituents are electron-
`
`donating when they are attached to an aromatic group, but electron-withdrawing
`
`when attached to an aliphatic group. See, e.g., Michael B. Smith & Jerry March,
`
`“March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure,”
`
`John Wiley & Sons, New York, NY (5th ed., 2001) (Ex. 2114) at 17-18 & 369-70.
`
`The combination of a substituent’s structural and electronic effects can cause
`
`profound changes in the chemical and biological behavior of the parent organic
`
`compound.
`
`a) Halogens
`“Halogens” refer to those atoms in the second-to-last column of the
`
`31.
`
`periodic table, and they are common substituents in organic molecules. Organic
`
`chemists typically work with the first four halogens: fluorine, chlorine, bromine,
`
`and iodine. Even though these compounds all come from the halogen class of
`
`substituents, they exhibit a range of structural and electronic effects.
`
`32. At one end of the halogen spectrum is fluorine (“F”). F is the smallest
`
`halogen, with an atomic radius similar to a hydrogen atom. See S. S. Batsanov,
`
`12
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 17/96
`
`

`
`IPR2015-01776
`
`Van der Waals Radii of Elements, Inorg. Materials, vol. 37, pp. 871-885, at 881
`
`(2001) (Ex. 2115). As a result, F does not have a large steric effect due to its
`
`shape. However, the electronic effects of F are pronounced because the F atom is
`
`strongly electron-withdrawing. When bound to an aromatic ring, F pulls the
`
`electron density associated with the ring toward the F substituent. This
`
`modification can significantly affect the reactivity of other portions of the
`
`molecule.
`
`33. The carbon-fluorine bond is particularly strong. Consequently,
`
`medicinal chemists frequently replace hydrogen atoms with fluorine atoms at sites
`
`prone to metabolism; the stronger carbon-fluorine bond is often more resistant to
`
`metabolism. Yet, fluorine is similar to hydrogen in size.
`
`34. At the other end of the halogen spectrum is iodine (“I”), and to a
`
`lesser extent, bromine (“Br”). These halogens differ from fluorine both
`
`structurally and electronically. First, they are much larger. The atomic radius of a
`
`iodine atom is nearly twice as large as the radius of fluorine, and bromine’s atomic
`
`radius is similar. Batsanov (Ex. 2115) at 881. Second, iodine and bromine do not
`
`have the same electron-withdrawing effect as fluorine. Third, carbon-bromine and
`
`carbon-iodine bonds are weaker than carbon-fluorine bonds. As a result, bromine
`
`and iodine are common functional groups in reagents and other reactive molecules,
`
`but they are less common in pharmaceuticals, where metabolism is a concern.
`
`13
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 18/96
`
`

`
`IPR2015-01776
`
`b)
`Boron-Containing Substituents
`35. The chemistry of boron differs from the chemistry of atoms typically
`
`found in organic compounds, such as carbon, hydrogen, silicon, oxygen, sulfur,
`
`nitrogen, phosphorous, fluorine, and chlorine. This difference is apparent simply
`
`by looking at a periodic table, which shows boron at the top of the Group 13
`
`column of compounds. Notably, none of the atoms in Group 13 are common in
`
`organic molecules, so there are few, if any, atoms that demonstrate similar
`
`chemistry as boron.
`
`36. Boron’s unusual chemistry is due to boron’s unusual electronic
`
`arrangement. The atom features an empty p-orbital, which in essence makes it
`
`hungry for electrons. The empty p-orbital on boron can be thought of as an
`
`unfilled reservoir that drives the atom’s electron-deficient nature. This uncommon
`
`electronic arrangement of boron has two primary effects. First, boron typically
`
`binds to only three other atoms at a time and adopts a flat conformation, known as
`
`a trigonal planar conformation. Second, boron’s electron deficiency causes it to
`
`interact not only with the atoms it is covalently bound to, but also with nearby,
`
`electron-rich atoms. This results in boron’s tendency to be promiscuous, that is, it
`
`binds non-selectively with oxygen and nitrogen atoms found widely in nature.
`
`With this inherent electron-deficiency and promiscuous binding, a POSA would
`
`14
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 19/96
`
`

`
`IPR2015-01776
`
`have known that a boron-containing compound would have a propensity towards
`
`toxicity and a lack of selectivity. See Section IV.B.4 below.
`
`37. The boron-oxygen bond is nearly twice as strong as the boron-carbon
`
`bond. This means that an organic compound with boron-carbon bonds will have
`
`some tendency to decompose when exposed to oxygen or water, with the boron-
`
`carbon bonds breaking in favor of new boron-oxygen bonds. The very stable
`
`inorganic compound boric acid (B(OH)3) is the common decomposition product of
`
`boron-containing organic compounds. See Groziak (Ex. 1027) at 322.
`
`38. Numerous different classes of organic compounds were known in
`
`2005 that include boron. However, most medicinal chemists today, as well as in
`
`early 2005, are less familiar with the chemistry of boron-containing compounds
`
`than they are with organic compounds containing other heteroatoms. Below is a
`
`brief review of some common classes of boron compounds.
`
`(1) Boranes and Organoboranes
`39. Boranes are a class of inorganic compounds that contain boron and
`
`hydrogen. The simplest commercially available borane, called diborane (B2H6), is
`
`a highly reactive reductant that is commonly used as a reagent. It is so reactive
`
`that it ignites spontaneously in air, and thus, it is unsuitable for use in human
`
`applications.
`
`15
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 20/96
`
`

`
`IPR2015-01776
`
`40. More complex boranes do not have the same reactivity as diborane.
`
`For example, decaborane (B10H14) is a crystalline solid at room temperature, but it
`
`is highly toxic. F. D. Henman et al., Effects of Decaborane on Gastric Secretion in
`
`the Shay Rat, Br. J. Pharmacol., vol. 40, no. 1, p. 164P+ (1970) (Ex. 2116).
`
`Dodecaborate ([B12H12]–) is an ionic molecule that can be isolated as salts. Kahl
`
`Dep. (Ex. 2033) at 102:1-103:2.
`
`41. Organoboranes contain carbon atoms and/or hydrogen atoms around a
`
`boron atom. For example, trialkylboranes (BR3) are a specific class of
`
`organoborane compounds that are often highly reactive. As Dr. Kahl pointed out
`
`in his declaration, some of these compounds, such as triethylborane (Et3B), also
`
`spontaneously ignite in air. Ex. 1006 at ¶ 30. However, I agree with Dr. Kahl that
`
`the reactivity of trialkylborane is modulated by large R groups, and that
`
`sufficiently large R groups prevent trialkylboranes from spontaneously igniting.
`
`Kahl Dep. (Ex. 2033) at 36:17–37:18.
`
`42. Organoboranes are not limited to trialkylboranes. One particularly
`
`useful dialkylborane for chemical synthesis is 9-borabicyclo[3.3.1]nonane, or 9-
`
`BBN.
`
`16
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 21/96
`
`

`
`IPR2015-01776
`
`Figure 6
`
`
`
`(2) Borinic acids
`43. Borinic acids are a functional group where a boron atom is bound to
`
`two carbons and one oxygen. These compounds are frequently unstable in air due
`
`to oxidation. See Steiner et al., Diphenylborinic Acid Is a Strong Inhibitor of
`
`Serine Proteases, Bioorg. & Med. Chem. Lett., vol. 4, pp. 2417–20, at 2417 (1994)
`
`(Ex. 2117).
`
`Figure 7
`
`(3) Boronic Acids
`44. Boronic acids are a very common boron-containing substituent.
`
`Molecules containing boronic acids constitute a broad class of molecules of the
`
`
`
`17
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 22/96
`
`

`
`IPR2015-01776
`
`general formula R–B(OH)2. Most organic chemists are familiar with boronic acids
`
`because they are reactants in the Suzuki cross-coupling, a common reaction for
`
`forming carbon-carbon bonds in compounds that themselves are specifically
`
`designed not to contain boron. See Excerpt from Dennis G. Hall, “Boronic Acids,”
`
`pp. 123-31 (Wiley-VCH, 2005) (Ex. 2118) at p. 124.
`
`45. The stability and reactivity of a boronic acid is usually related to the R
`
`group in R–B(OH)2. Alkyl boronic acids, where R is an alkyl group, are generally
`
`unstable. See Excerpt from Dennis G. Hall, “Boronic Acids,” pp. 28-48 (Wiley-
`
`VCH, 2005) (Ex. 2119) at p. 48. On the other hand, aryl boronic acids, where R is
`
`an aryl group, are generally more stable. See id. at 28 & 48.
`
`46. For example, the compounds of Freeman are all phenyl boronic acids
`
`because they contain an acyclic boronic acid substituent attached to a phenyl ring.
`
`Figure 8
`
`(4) Borate Esters and Borate Anion Complexes
`47. Borate esters (or boric acid esters) are a class of boron-containing
`
`molecules related to boric acid (B(OH)3). Instead of three hydroxyl substituents on
`
`
`
`18
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 23/96
`
`

`
`IPR2015-01776
`
`a boron atom, as in boric acid, borate esters have alkoxy groups. Borate esters,
`
`such as triisopropyl borate (B(Oi-Pr)3) and trimethyl borate (B(OMe)3), are
`
`frequently used as reagents for the synthesis of boronic acids.
`
`48. Borate esters are generally stable in organic solutions at room
`
`temperature, but readily hydrolyze to boric acid in the presence of water.
`
`Figure 9
`
`
`
`49.
`
`In light of boron’s affinity for oxygen, it is understandable that boric
`
`acid, containing three boron-oxygen bonds, is the ultimate decomposition product
`
`for many, if not most, organic boron-containing compounds. See Groziak (Ex.
`
`1027) at 322. Boronic acids, on the other hand, have only two boron-oxygen
`
`bonds and are less stable.
`
`19
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 24/96
`
`

`
`IPR2015-01776
`
`B.
`The Multi-Dimensional Challenge of Drug Development
`50. Not all organic chemists design and develop drugs. Generally,
`
`organic chemistry is broadly divided into the fine chemical industry and the bulk
`
`chemical industry. Fine chemicals are single, complex, pure chemical substances.
`
`Organic chemists who specialize in fine chemicals include those who develop
`
`flavors, perfumes, compounds with electronic properties for technological
`
`applications, or pharmaceuticals.
`
`51. The other branch of organic chemistry is bulk chemicals, where the
`
`price of the chemical drives development considerations. With bulk chemicals,
`
`purity and complexity are uncommon.
`
`52. Thus, different organic chemists have different skill sets. Organic
`
`chemistry provides each of these fields with basic tools, i.e., the ability to create
`
`organic compounds using chemical reactions. However, scientists in each field are
`
`guided by different bodies of knowledge and requirements unique to their
`
`industries. For example, a pharmaceutical scientist may understand the organic
`
`chemistry that an oil scientist uses to synthesize an anti-knock fuel additive, but the
`
`pharmaceutical scientist will not understand how anti-knock agents work or why
`
`the oil scientist targeted that particular anti-knock additive in the first place. As
`
`another example, the primary concern of an organic chemist identifying and
`
`developing an industrial biocide is the power of a compound to kill living
`
`20
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2034 - 25/96
`
`

`
`IPR2015-01776
`
`organisms. In contrast, the primary concern of an organic chemist identifying and
`
`developing pharmaceuticals, that is, a medicinal chemist, is the balance of safety
`
`and efficacy of the compound in a human or animal.
`
`53. The pharmaceutical industry is one of the most sophisticated and
`
`complex industries that relies on organic chemistry. As such, it has developed its
`
`own internal body of literature about how to identify and develop drugs. This
`
`section of my declaration summarizes that process.
`
`54. The discovery and development of a new pharmaceutical is a
`
`lengthy, expensive, and challenging process. Today, it is estimated to cost more
`
`than $1 billion and often take more than 10 years for a pharmaceutical company to
`
`discover a new drug and bring it to market. Joseph A. DiMasi et al., Innovation in
`
`the Pharmaceutical Industry: New Estimates of R&D Costs, J. Health Econ., vol.
`
`47, pp. 20-33, at Abstract & 21 (2016) (Ex. 2121).
`
`55. The process of drug discovery and development is expensive and
`
`time-consuming, in part, because of its unpredictability coupled with overriding
`
`con