UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`BRECKENRIDGE PHARMACEUTICAL, INC.,
`Petitioner,
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01023 and IPR2016-01103
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01059
`
`
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01102
`
`Patent No. 5,665,772
`
`
`
`
`
`
`
`EXPERT DECLARATION OF PROFESSOR
`ALEXANDER M. KLIBANOV
`
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 1 of 15
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`BRECKENRIDGE PHARMACEUTICAL, INC.,
`Petitioner,
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01023 and IPR2016-01103
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01059
`
`
`
`ROXANE LABORATORIES, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`IPR2016-01102
`
`Patent No. 5,665,772
`
`
`
`
`
`
`
`EXPERT DECLARATION OF PROFESSOR
`ALEXANDER M. KLIBANOV
`
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 1 of 15
`
`
`
`I, Alexander M. Klibanov, Ph.D., declare as follows:
`
`1.
`
`I submit this expert declaration in response to certain arguments made
`
`in the following four petitions for inter partes review (“IPR”) and two expert
`
`declarations cited in those petitions:
`
`a. Breckenridge Pharmaceutical, Inc.’s Petition For Inter Partes Review
`
`Of U.S. Patent No. 5,665,772 (IPR2016-01023, Paper 4) (requesting
`
`IPR of claims 1-3 and 8-10) (“Breckenridge Pet. I”).
`
`b. Breckenridge Pharmaceutical, Inc.’s Petition For Inter Partes Review
`
`Of U.S. Patent No. 5,665,772 (IPR2016-01103, Paper 1) (requesting
`
`IPR of claim 7) (“Breckenridge Pet. II”).
`
`c. Par Pharmaceutical, Inc.’s Petition For Inter Partes Review Of U.S.
`
`Patent No. 5,665,772 (IPR2016-01059, Paper 1) (requesting IPR of
`
`claim 7) (“Par Pet.”).
`
`d. Roxane Laboratories, Inc.’s Petition For Inter Partes Review Of U.S.
`
`Patent No. 5,665,772 (IPR2016-01102, Paper 2) (requesting IPR of
`
`claims 1-3, 7-10) (“Roxane Pet.”).
`
`e. Declaration of William L. Jorgensen, Ph.D., in Support of Petition for
`
`Inter Partes Review of U.S. Patent No. 5,665,772, submitted in IPR
`
`Nos. 2016-01059 (Ex. 1003), 2016-01102 (Ex. 1003), and 2016-
`
`01103 (Ex. 1003), and also submitted, but not relied upon, in
`
`1
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 2 of 15
`
`
`
`IPR2016-01023 (Ex. 1003) (“Jorgensen Decl.”).
`
`f. Declaration of Steven W. Baldwin, Ph.D., in Support of Petition for
`
`Inter Partes Review of U.S. Patent No. 5,665,772, submitted in IPR
`
`No. 2016-01023 (Ex. 1030) (“Baldwin Decl.”).
`
`I.
`
`Qualifications
`
`2.
`
`I am a Novartis Endowed Chair Professor of Chemistry and
`
`Bioengineering at the Massachusetts Institute of Technology (“M.I.T.”), where I
`
`have been teaching and conducting research for over 37 years.1 In 2012-2013, I
`
`held the Roger and Georges Firmenich Endowed Chair Professorship in Chemistry
`
`and Bioengineering, and in 2007-2012, the same chaired professorship as I
`
`currently hold. Prior to that, I was a Professor of Chemistry and a Professor of
`
`Bioengineering at M.I.T., positions I held from 1988 and 2000, respectively. From
`
`1979 to 1988, I was an Assistant Professor, then Associate Professor, and
`
`thereafter a Full Professor of Applied Biochemistry in the Department of Applied
`
`Biological Sciences (formerly the Department of Nutrition and Food Science) at
`
`M.I.T.
`
`
`1 Novartis has no say in who receives this chair or my compensation at M.I.T., and
`
`my title at M.I.T. in no way affects the content of this declaration or my opinions
`
`in this matter.
`
`2
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 3 of 15
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`
`
`3.
`
`I obtained my M.S. in Chemistry from Moscow University in Russia
`
`in 1971 and Ph.D. in Chemical Enzymology from the same University in 1974.
`
`Thereafter, I was a Research Chemist at Moscow University’s Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
`
`University of California in San Diego.
`
`4.
`
`Over the last 40+ years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of chemistry, including
`
`biological, medicinal, physical, bioorganic, formulation, and polymer.
`
`5.
`
`During my research career, I have earned numerous prestigious
`
`professional awards and honors. For example, I was elected to the U.S. National
`
`Academy of Sciences (considered among the highest honors that can be given to an
`
`American scientist) and also to the U.S. National Academy of Engineering
`
`(considered among the highest honors that can be given to an American engineer).
`
`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 (for achievements in organic
`
`chemistry), the Marvin J. Johnson Award (for achievements in biochemical
`
`technology), the Ipatieff Prize (for achievements in physical chemistry, particularly
`
`3
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 4 of 15
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`
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`in catalysis), and the Leo Friend Award, all from the American Chemical Society,
`
`as well as the International Enzyme Engineering Prize.
`
`6.
`
`I have published over 310 scientific papers in various areas of
`
`chemistry and am also a named inventor of 21 issued United States patents and of
`
`many pending and foreign ones. I have given some 370 invited lectures (including
`
`a number of named lectures) at professional conferences, universities, and
`
`corporations all over the world, numerous of them dealing with formulation,
`
`solubility, stability, delivery, and biological evaluation of pharmaceutically active
`
`compounds.
`
`7.
`
`In addition to research and teaching at M.I.T., I have consulted widely
`
`for pharmaceutical, medical device, chemical, and biotechnology companies,
`
`including both innovator and generic pharmaceutical companies. I have also
`
`founded six pharmaceutical companies and have been on the scientific advisory
`
`boards and/or boards of directors of those companies and of many others. A
`
`number of these consulting, advisory, and directorship activities have dealt
`
`specifically with the formulation, solubility, stability, delivery, administration, and
`
`biological evaluation of pharmaceutically active compounds, as well as their
`
`discovery and development.
`
`8. My curriculum vitae, which lists my professional experience and
`
`academic qualifications in greater detail, is attached hereto as Exhibit 2402.
`
`4
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 5 of 15
`
`
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`9.
`
`The time I spend working on this matter is being compensated at my
`
`current customary consulting rate of $950 per hour. This compensation does not
`
`monetarily benefit me personally but instead is credited directly to M.I.T. in order
`
`to financially support graduate students, postdoctoral associates, and scholarly
`
`activities. This compensation does not depend on, and is not affected by, the
`
`content of this expert declaration.
`
`II.
`
`Petitioners’ Obviousness Case Concerning The ’772 Patent Claims Is
`Based On The Erroneous Allegation That One Claimed Compound,
`Everolimus, Is Obvious
`
`10. Petitioners challenge claims 1-3 and 7-10 of U.S. Patent No.
`
`5,665,772 (“the ’772 Patent”). To understand why their challenge should not be
`
`allowed to succeed, let us analyze Petitioners’ argument concerning the
`
`obviousness of the chemical compound everolimus, which is specifically taught by
`
`compound claim 10 and generically taught by compound claims 1-3 of the ’772
`
`Patent. Pharmaceutical-composition claim 7, as well as method-of-use claims 8
`
`and 9, of the ’772 Patent also encompass the chemical compound everolimus
`
`because of their dependency from claim 1. Thus, Petitioners must prove that
`
`everolimus itself would have been obvious before they can even begin to argue that
`
`a pharmaceutical composition containing, or a method of using, it would have been
`
`obvious. A brief summary of Petitioners’ case is provided below.
`
`11. Petitioners allege that one of ordinary skill in the art as of October 9,
`
`5
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 6 of 15
`
`
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`1992, would have selected rapamycin (chemical structure depicted below, left) as a
`
`lead compound and also would have been motivated to increase its water solubility
`
`(i.e., solubility in water).2 Petitioners further contend that a person of ordinary
`
`skill3 would have then relied on the combined teachings of four references, namely
`
`Van Duyne, Rossmann, Yalkowsky, and Lemke, to arrive at the compound
`
`everolimus (chemical structure also depicted below, right).4
`
`
`2 Breckenridge Pet. I at 6, 14-15, 24-25, 38, 40-41; Breckenridge Pet. II at 9, 19-20,
`
`40-41, 43-44; Par Pet. at 11, 19-20, 27-29, 39-40, 42-43; Roxane Pet. at 4, 7-8, 17-
`
`18, 26-28, 41, 43-45.
`
`3 For purposes of this declaration only, I accept the definitions of a person of
`
`ordinary skill as of October 9, 1992, provided by Petitioners and their declarants.
`
`See Jorgensen Decl. ¶¶ 45-46; Baldwin Decl. ¶¶ 44-46; Breckenridge Pet. I at 13-
`
`14; Breckenridge Pet. II at 19; Par Pet. at 19; Roxane Pet. at 16-17.
`
`4 Breckenridge Pet. I at 10, 39, 48, 50; Breckenridge Pet. II at 13-14, 42, 54; Par
`
`Pet. at 2, 12, 41, 53; Roxane Pet. at 13, 43, 51-52, 55-57.
`
`6
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 7 of 15
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`
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`12.
`
`In particular, Petitioners allege that a person of ordinary skill would
`
`have selected rapamycin’s C40 position as a site for chemical modification (based
`
`on the combined teachings of Van Duyne and Rossmann) and, moreover,
`
`specifically would have sought to replace rapamycin’s hydroxyl (HO-) group at
`
`C40 with a “flexible” substituent (based on the teachings of Yalkowsky) having an
`
`alcohol, amine, or carboxylic acid functional group (based on the teachings of
`
`Lemke).5 One of the three possible C40 substituents that Petitioners say a skilled
`
`artisan would have investigated is the 2-hydroxyethyl ether (also denoted as 2-
`
`
`5 Breckenridge Pet. I at 3-4, 17-22, 25-33, 41-48; Breckenridge Pet. II at 7, 22-27,
`
`29-37, 44-51; Par Pet. at 9-10, 22-27, 29-36, 43-49; Roxane Pet. at 5, 20-25, 28-35,
`
`45-51.
`
`7
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 8 of 15
`
`
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`hydroxyethoxy, HOCH2CH2O-).6 The rapamycin derivative with this substituent
`
`at the C40 position is commonly known as everolimus, and it is covered by claim 1
`
`of the ’772 Patent, from which claims 2-3 and 7-10 all depend.7
`
`III. A Summary Of This Declaration
`
`13. This expert declaration concerns one prior-art reference, namely
`
`Yalkowsky. Petitioners and their experts rely on Yalkowsky to support their key
`
`argument that one of ordinary skill would have been motivated to chemically
`
`modify rapamycin to improve its water solubility by specifically replacing its C40
`
`hydroxyl group with a “flexible” substituent to arrive at everolimus. Petitioners
`
`and their experts also rely on Yalkowsky to support their argument that one of
`
`ordinary skill would have reasonably expected everolimus to exhibit an improved
`
`water solubility compared to rapamycin. This declaration explains my opinion that
`
`there can be no factual dispute that Yalkowsky is not applicable to rapamycin’s
`
`solubility in water at least because Yalkowsky is expressly limited to ideal
`
`solubility, whereas the water solubility of rapamycin is not ideal.
`
`
`6 Breckenridge Pet. I at 32-33, 45-48; Breckenridge Pet. II at 36-37, 48-51; Par Pet.
`
`at 35-36, 47-49; Roxane Pet. at 34-35, 48-51.
`
`7 Breckenridge Pet. I at 1-2, 11-13; Breckenridge Pet. II at 4-6, 16-18; Par Pet. at 7-
`
`8, 13-15; Roxane Pet. at 2-4, 15-16.
`
`8
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 9 of 15
`
`
`
`IV. No Factual Dispute Exists That Yalkowsky Concerns Ideal Solubility;
`Because Water Is Not An Ideal Solvent For Rapamycin, Yalkowsky Is
`Not Applicable To Rapamycin’s Solubility In Water
`
`14. As even its Abstract makes clear, Yalkowsky is directed specifically
`
`to the “ideal solubility” of “rigid molecules” and their “long chain derivatives”
`
`(emphasis added). (Ex. 1007 at 108.)
`
`15. Below I discuss the concept of “ideal solubility,” explain why water is
`
`not an ideal solvent for rapamycin, and, consequently, why Yalkowsky is not
`
`applicable to the water solubility of rapamycin.
`
`16.
`
`In contrast to this discussion, neither the Petitioners nor Drs.
`
`Jorgensen and Baldwin even discuss what ideal solubility is, much less address
`
`whether water is an ideal solvent for rapamycin. The reason for that conspicuous
`
`omission, in my opinion, is quite simple: water is not at all an ideal solvent for
`
`rapamycin. If it were, rapamycin would not be considered to have “poor
`
`solubility” in water as both Drs. Jorgensen and Baldwin have opined.8
`
`17. Yalkowsky’s discussion of internal entropy of fusion (ΔSf) expressly
`
`relates specifically to ideal solubility. (See, e.g., Ex. 1007 at 111 (“The ideal
`
`solubility of many crystalline compounds can be estimated from the melting point
`
`
`8 Jorgensen Decl. ¶¶ 75-76, 138-140; see also Baldwin Decl. ¶¶ 78-79, 142-144;
`
`Breckenridge Pet. I at 15, 24-25, 40-41; Breckenridge Pet. II at 20, 28-29, 43-44;
`
`Par Pet. at 20, 27-29, 42-43; Roxane Pet. at 18, 26-28, 43-45.
`
`9
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 10 of 15
`
`
`
`and entropy of fusion as given by eq[uations] 5 and 6 . . . which provide a very
`
`simple means of obtaining a reasonable estimate of ideal solubility . . . .”
`
`(emphasis added)); see also Ex. 1007 at 108 (providing background information on
`
`means for calculating ideal solubility).) Yalkowsky does not ever mention water
`
`solubility. Nor does Yalkowsky state that its teachings about ideal solubility,
`
`including the formula that Drs. Jorgensen and Baldwin focus on (equation 6 on
`
`page 111), applies to the water solubility of compounds like rapamycin.
`
`18. To understand why Yalkowsky’s discussion and conclusions about
`
`ideal solubility are inapplicable to rapamycin’s water solubility, it is important to
`
`consider the concepts of solubility in general and ideal solubility in particular, as
`
`they would have been understood by a person of ordinary skill. Solubility is the
`
`property of one substance (e.g., a solid) called a solute to dissolve in another
`
`substance (e.g., a liquid) called a solvent to form a homogenous mixture called a
`
`solution. (Ex. 24039 at 957-958.) Ideal solubility concerns specifically the
`
`solubility of a given solute in an ideal solvent for that solute to form an ideal
`
`solution. For example, the 1981 Condensed Chemical Dictionary defines an ideal
`
`solution as “[a] solution which exhibits no change of internal energy on mixing and
`
`complete uniformity of cohesive forces.” (emphasis added). (Ex. 2403 at 556.) In
`
`other words, the attractive forces between the solvent molecules are equivalent to
`
`9 The Condensed Chemical Dictionary (10th ed., 1981).
`
`10
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 11 of 15
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`
`
`those between the solute molecules. As noted by Hildebrand, “[i]t has long been
`
`known that differences in the degree of polarity between two molecular species
`
`tend to produce, in their solutions, deviations from the ideal solution laws.” (Ex.
`
`240410 at 285.) Since there is a vast and indisputable difference “in the degree of
`
`polarity” between rapamycin (which is only slightly polar) and water (which is
`
`highly polar), it follows that a solution of rapamycin in water cannot be ideal or
`
`even close to it; hence Yalkowsky’s teachings do not apply.
`
`19. A classical principle of solubility of chemical compounds is “like
`
`dissolves like.” When two substances (such as a solute and a solvent) have nearly
`
`identical physicochemical properties (in particular polarity and hydrophobicity),
`
`then both the solubility of the solute in that solvent and the resultant solution are
`
`nearly ideal. Conversely, the more dissimilar the solute and the solvent molecules
`
`are in terms of their physicochemical properties, the more profoundly both the
`
`solubility and the solution deviate from ideal. And a person of ordinary skill, even
`
`by just comparing the chemical structures of rapamycin (see above) and water
`
`(H2O or H-OH) would have immediately recognized that their respective polarities
`
`and hydrophobicities are vastly dissimilar.
`
`10 J.H. Hildebrand and J.M. Carter, The Influence On The Ideal Solution Laws Of
`
`The Distribution Of Polarity Within The Molecule, Proceedings of the National
`
`Academy of Sciences of the U.S.A. 16:285-288 (1930).
`
`11
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`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 12 of 15
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`20. According to Drs. Jorgensen and Baldwin, rapamycin has “poor
`
`solubility in water” and is “a large molecule with relatively few hydrophilic
`
`moieties and with large hydrophobic [i.e., “water-hating”] regions.” (Jorgensen
`
`Decl. ¶¶ 75, 139; Baldwin Decl. ¶¶ 78,143.) Water, in stark contrast, is
`
`hydrophilic (i.e., “water-loving”) rather than hydrophobic, just the opposite of
`
`rapamycin.
`
`21. Because Yalkowsky’s ideal solubility relates to the solubility of
`
`solutes in “like” solvents, such as hydrophobic and nonpolar solutes in
`
`hydrophobic and nonpolar organic solvents (e.g., hydrocarbons in other
`
`hydrocarbons), or, alternatively, such hydrophilic and polar solutes as table sugar
`
`or salt in such hydrophilic and polar solvents as water, Yalkowsky is not
`
`applicable to the non-ideal solubility of unlike solutes and solvents, much less such
`
`strikingly dissimilar ones as the predominantly non-polar compound rapamycin
`
`with its “large hydrophobic regions” and the ultimate polar and hydrophilic solvent
`
`water.
`
`22.
`
`In fact, none of the papers Drs. Jorgensen and Baldwin cite as
`
`examples employing the use of flexible side chains to improve solubility (see
`
`Jorgensen Decl. ¶ 78; Baldwin Decl. ¶ 81) concerns water solubility. Rather, only
`
`hydrophobic solutes in organic solvents are discussed: Bell studied the properties
`
`of hydrophobic heptacyclic terpyridines “in many organic solvents” (Ex. 1021 at
`
`12
`
`
`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 13 of 15
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`765); Ballauff examined the solubility of such hydrophobic rigid-rod polymers as
`
`poly(γ-benzyl glutamate) in organic solvents (such as chloroform and DMF) (Ex.
`
`1022 at 1372-1373 (noting the extreme sensitivity of the [polymer/DMF] system
`
`“toward small amounts of water”)); and Stern addressed the solubility of certain
`
`hydrophobic rigid-rod aromatic polyesters in such hydrophobic organic solvents or
`
`mixtures thereof as dichlorobenzene, tetrachloroethane, phenol, toluene, and
`
`chloroform (Ex. 1023 at 2098). As a result, one of ordinary skill would not rely on
`
`any of these references for the same reasons (s)he would not rely on Yalkowsky.
`
`23. Water is undeniably not an ideal solvent for rapamycin (tellingly, Drs.
`
`Jorgensen and Baldwin do not claim that it is; they just ignore the term “ideal”
`
`modifying the term “solubility” throughout Yalkowsky). As explained above,
`
`ideal solutions exist only when the physicochemical properties of the solute and
`
`solvent are very similar. The fact that rapamycin, according to Drs. Jorgensen and
`
`Baldwin, exhibits “poor solubility in water” and has “large hydrophobic regions”
`
`(Jorgensen Decl. ¶¶ 75, 139; Baldwin Decl. ¶¶ 78, 143) evidences that a
`
`rapamycin-in-water solution is not ideal. Accordingly, Yalkowsky’s teachings
`
`about ideal solubility are not applicable to the solubility of rapamycin in water.
`
`For at least this reason, I believe that Petitioners’ challenge to the claims of the
`
`’772 Patent fails.
`
`
`
`I hereby declare that all statements made herein of my own knowledge are
`
`13
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`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 14 of 15
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`NOVARTIS EXHIBIT 2401
`Roxane v. Novartis, IPR 2016-01102
`Page 15 of 15
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