Paper No. ____
`Date Filed: July 29, 2016
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01059
`
`Patent No. 5,665,772
`
`
`
`
`
`PATENT OWNER’S PRELIMINARY
`RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Summary Of The Asserted Grounds ............................................................... 3
`
`III.
`
`Petitioners Fail To Explain Why A Person Of Ordinary Skill
`Would Rely On Yalkowsky If The Goal Was To Increase
`Rapamycin’s Water Solubility ......................................................................... 8
`
`A.
`
`B.
`
`Petitioners’ Assumption That Yalkowsky Applies To
`Rapamycin’s Water Solubility Is Unsupported And
`Incorrect ................................................................................................. 8
`
`Petitioners’ Conclusory And Unsupported Assertions
`Cannot Remedy The Deficiencies In Their Analysis Or
`Give Rise To A Genuine Issue Of Material Fact ................................ 14
`
`IV. Petitioners Fail To Explain Why Lemke Would Have
`Motivated One Of Ordinary Skill To Synthesize Everolimus Or
`To Have Reasonably Expected Everolimus To Be More Water
`Soluble Than Rapamycin ............................................................................... 17
`
`A.
`
`B.
`
`Petitioners Ignore And Mischaracterize The Differences
`Between Rapamycin’s And Everolimus’ C40 Groups ....................... 17
`
`Petitioners Offer No Argument Or Evidence To Explain
`Why One Of Ordinary Skill Would Have Added An
`Ether And Two Carbons To Rapamycin To Increase Its
`Water Solubility .................................................................................. 18
`
`V.
`
`Petitioners’ Attorney Argument Against Pharmaceutical
`Composition Claim 7 In Ground B Contradicts Petitioners’
`Own Arguments And Expert Testimony Against The Claimed
`Compounds .................................................................................................... 21
`
`A. Overview ............................................................................................. 21
`
`B.
`
`Petitioners Advance Contradictory Arguments Regarding
`The Ability To Formulate Rapamycin Into
`Pharmaceutical Compositions ............................................................. 22
`
`
`
`i
`
`

`
`
`
`C.
`
`Petitioners’ Own Arguments Establish That Their Legal
`Authorities Are Inapplicable To The Present Case ............................. 26
`
`VI. Conclusion ..................................................................................................... 30
`
`
`
`
`
`
`
`ii
`
`

`
`TABLE OF AUTHORITIES
`
`
`
`Cases
`
`Apotex Inc. v. Wyeth LLC,
`IPR2015-00873, Paper 8 (September 16, 2015) ........................................9, 15
`
`Aventis Pharma Deutschland GmbH v. Lupin Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) .............................................................. 27, 28
`
`Geneva Pharm. Inc. v. Glaxosmithkline PLC,
`189 F. Supp. 2d 377 (E.D. Va. 2002) ..................................................... 27, 28
`
`In re Magnum Oil Tools Int’l, Ltd.,
`No. 2015-1300, slip op. (Fed. Cir. July 25, 2016) .......................... 8, 9, 20, 26
`
`Kimberly-Clark Worldwide, Inc. v. First Quality Baby Prods.,
`LLC.,
`900 F. Supp.2d 903 (E.D. Wis. 2012) ...........................................................15
`
`Kimberly-Clark Worldwide, Inc. v. First Quality Baby Prods.,
`LLC.,
`579 Fed. Appx. 996 (Fed. Cir. 2014) ............................................................15
`
`Kinetic Techs., Inc. v. Skyworks Solns., Inc.,
`IPR2014-00529, Paper 8 (September 23, 2014) ............................................14
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007).......................................................................................27
`
`Palo Alto Networks, Inc. v. Finjan, Inc.,
`IPR2015-02000, Paper 7 (March 23, 2016) ..................................................21
`
`Phillips Petroleum Co. v. Huntsman Polymers Corp.,
`157 F.3d 866 (Fed. Cir. 1998) .......................................................................16
`
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) .....................................................................28
`
`Sandt Tech., Ltd. v. Resco Metal and Plastics Corp.,
`264 F.3d 1344 (Fed. Cir. 2001) .....................................................................28
`
`Shopkick Inc. v. Novitaz, Inc.,
`IPR2015-00279, Paper 7 (May 29, 2015) .................................................9, 20
`
`
`
`iii
`
`

`
`
`
`Sinskey v. Pharmacia Ophthalmics, Inc.,
`982 F.2d 494 (Fed. Cir. 1992) .......................................................................22
`
`Wowza Media Sys., LLC v. Adobe Sys., Inc.,
`IPR2013-00054, Paper 16 (July 13, 2013) ....................................................14
`
`Statutes
`
`35 U.S.C. § 282 ........................................................................................................28
`
`Other Authorities
`
`81 Fed. Reg. 18750 (April 1, 2016) .................................................................. 16, 17
`
`Rules
`
`37 C.F.R. § 42.104 ..................................................................................................... 8
`
`37 C.F.R. § 42.108 ...................................................................................................16
`
`37 C.F.R. § 42.65 .....................................................................................................14
`
`
`
`
`
`
`
`iv
`
`

`
`LIST OF EXHIBITS
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2401 Declaration of Professor Alexander M. Klibanov
`
`2402 Curriculum vitae of Professor Alexander M. Klibanov
`
`2403
`
`The Condensed Chemical Dictionary (10th ed., 1981)
`
`2404
`
`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 16:285-288 (1930)
`
`Klibanov
`Decl.
`
`
`
`
`
`Hildebrand
`
`
`
`v
`
`
`
`
`
`

`
`Introduction
`
`Novartis AG (“Patent Owner”) respectfully submits this Preliminary
`
`
`
`I.
`
`
`
`Response to four Petitions seeking inter partes review of various claims of U.S.
`
`Patent No. 5,665,772 (“the ’772 patent”):
`
`(1) Breckenridge Pharmaceutical, Inc.’s (“Breckenridge”) Petition For
`
`Inter Partes Review Of U.S. Patent No. 5,665,772 (IPR2016-01023,
`
`Paper 4) challenging claims 1-3 and 8-10 of the ’772 patent
`
`(“Breckenridge Pet. I”);
`
`(2) Breckenridge’s Petition For Inter Partes Review Of U.S. Patent No.
`
`5,665,772 (IPR2016-01103, Paper 1) challenging claim 7 of the ’772
`
`patent (“Breckenridge Pet. II”);
`
`(3) Par Pharmaceutical, Inc.’s (“Par”) Petition For Inter Partes Review
`
`Of U.S. Patent No. 5,665,772 (IPR2016-01059, Paper 1) challenging
`
`claim 7 of the ’772 patent (“Par Pet.”); and
`
`(4) Roxane Laboratories, Inc.’s (“Roxane”) Petition For Inter Partes
`
`Review Of U.S. Patent No. 5,665,772 (IPR2016-01102, Paper 2)
`
`challenging claims 1-3 and 7-10 of the ’772 patent (“Roxane Pet.”).
`
`For the purposes of this preliminary response, Breckenridge, Par and Roxane are
`
`collectively referred to as “Petitioners.” For the Board’s convenience, the same
`
`preliminary response (with different cover pages) has been filed in all four cases.
`
`1
`
`
`
`

`
`The ’772 patent claims novel immunosuppressive 40-O-alkylated rapamycin
`
`
`
`
`
`derivatives including 40-O-(2-hydroxyethyl)-rapamycin, also known by the name
`
`“everolimus.” Everolimus is covered by compound claims 1-3 and 10 of the ’772
`
`patent. It is also covered by claim 7, which recites a pharmaceutical composition
`
`comprising a compound of claim 1, and claims 8 and 9, which recite methods of
`
`using the compounds of claim 1.
`
`Petitioners are not reasonably likely to show the unpatentability of any
`
`challenged claim under any of the alleged grounds for at least three independent
`
`reasons. First, Yalkowsky is a primary reference in each ground; however,
`
`Petitioners never explain why one of ordinary skill would have considered
`
`Yalkowsky’s teachings about ideal solubility relevant to rapamycin’s water
`
`solubility—particularly as a rapamycin-water solution is not an ideal solution. As
`
`a result, Petitioners have failed to establish a motivation to combine the references
`
`in their asserted grounds. Second, Petitioners’ arguments regarding Lemke, which
`
`is also a primary reference in each ground, ignore the indisputable similarities and
`
`differences between the substituents at rapamycin’s and everolimus’ carbon 40
`
`(“C40”). As a result, Petitioners rely on inapposite teachings in Lemke and offer
`
`no evidence or argument to explain how those teachings would lead one of
`
`ordinary skill to synthesize everolimus or reasonably expect it to have increased
`
`water solubility as compared to rapamycin. Third, Petitioners contradict their
`
`2
`
`
`
`

`
`
`
`arguments regarding the obviousness of pharmaceutical composition claim 7 with
`
`their own statements that rapamycin was difficult to formulate and had limited
`
`therapeutic utility. These blatant contradictions evidence Petitioners’ hindsight-
`
`based reasoning and failure to meet their burden at the institution phase.
`
`For any one of these three reasons, Patent Owner respectfully requests that
`
`the Board decline to institute review on all challenged claims.
`
`II.
`
`Summary Of The Asserted Grounds
`
`In their four petitions, Petitioners raise three grounds, which are summarized
`
`below.1 For convenience, these grounds have been labeled A, B and C.
`
`
`
`
`
`
`
` Petitioners rely on two expert declarations: the Declaration of William L.
`
` 1
`
`Jorgensen, Ph.D., cited in the Par Petition, Roxane Petition and Breckenridge
`
`Petition II (Ex. 1003 in all cases) (“Jorgensen Decl.”); and the Declaration of
`
`Steven W. Baldwin, Ph.D., cited in the Breckenridge Petition I (Ex. 1030 in
`
`IPR2016-01023) (“Baldwin Decl.”).
`
`3
`
`
`
`

`
`Cited Art
`
`IPR (Petitioner) Ground
`
`
`
`Ground
`
`Challenged
`Claims
`
`Morris, Van Duyne,
`
`A
`
`1-3, 10
`
`Rossmann, Lemke,
`
`Yalkowsky
`
`2016-1023 (Breckenridge) Ground 1
`
`2016-1102 (Roxane) Ground 1
`
`Morris, Van Duyne,
`
`2016-1059 (Par) Ground 1
`
`B
`
`7
`
`Rossmann, Lemke,
`
`2016-1103 (Breckenridge) Ground 1
`
`Yalkowsky, Hughes
`
`2016-1102 (Roxane) Ground 2
`
`Morris, Van Duyne,
`
`C
`
`8, 9
`
`Rossmann, Lemke,
`
`Yalkowsky, Hughes
`
`2016-1023 (Breckenridge) Ground 2
`
`2016-1102 (Roxane) Ground 2
`
`
`
`Each of Grounds A, B and C requires the combined teachings of five
`
`references: Morris (Ex. 1005), Van Duyne (Ex. 1006), Rossmann (Ex. 1024),
`
`Yalkowsky (Ex. 1007) and Lemke (Ex. 1008).2 Grounds B and C, directed to
`
`dependent claims 7, 8 and 9, require the additional teachings of a sixth reference,
`
`Hughes (Ex. 1009). Id.
`
`
`
`
`
` Breckenridge Pet. I at 10, 39, 48, 50; Breckenridge Pet. II at 13-14, 42, 54; Par
`
` 2
`
`Pet. at 2, 12, 41, 53; Roxane Pet. at 13, 43, 51-52, 55-57.
`
`4
`
`
`
`

`
`
`
`In Ground A, Petitioners allege that Morris would have led one of ordinary
`
`skill in the art,3 as of the October 9, 1992 priority date of the ’772 patent, to select
`
`rapamycin (structure below, left; Jorgensen Decl. ¶ 19; Baldwin Decl. ¶ 18) as a
`
`lead compound and would have provided a motivation to increase rapamycin’s
`
`water solubility.4 Petitioners further contend that Van Duyne and Rossmann taught
`
`one of ordinary skill to select rapamycin’s C40 position for chemical
`
`modification.5
`
`
`
` Patent Owner disagrees with Petitioners’ proposed definitions of a person of
`
` 3
`
`ordinary skill (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), but does not believe this disagreement affects the reasons the Board
`
`should deny institution.
`
`4 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.
`
`5 Breckenridge Pet. I at 3-4, 17-20, 25-31, 41-43; Breckenridge Pet. II at 7, 22-25,
`
`29-35, 44-46; Par Pet. at 9, 22-25, 29-34, 43-45; Roxane Pet. at 5, 20-23, 28-33,
`
`45-47; Ex. 2401 (Klibanov Decl.) at ¶ 12.
`
`5
`
`
`
`

`
`
`
`
`
`Having decided to modify rapamycin at its C40 position with the goal of
`
`increasing water solubility, Petitioners next allege the person of ordinary skill
`
`would have been motivated to introduce at C40 a “flexible” substituent (based on
`
`the teachings of Yalkowsky), having an alcohol, amine or carboxylic acid
`
`functional group (based on the teachings of Lemke).6 One of the three possible
`
`C40 substituents that Petitioners say a skilled artisan would have investigated is the
`
`2-hydroxyethyl ether (or 2-hydroxyethoxy, HOCH2CH2O-) group. 7 The
`
`
`
` Breckenridge Pet. I at 4, 20-22, 31-33, 44-48; Breckenridge Pet. II at 7, 25-27,
`
` 6
`
`35-37, 47-51; Par Pet. at 9-10, 25-27, 34-36, 45-49; Roxane Pet. at 5, 23-25, 33-35,
`
`47-51; Ex. 2401 (Klibanov Decl.) at ¶ 12.
`
`7 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; Ex. 2401 (Klibanov Decl.) at ¶ 12.
`
`6
`
`
`
`

`
`
`
`rapamycin derivative with this substituent at C40 is commonly known as
`
`everolimus (structure above; right) 8, and is covered by independent claim 1 of the
`
`’772 patent from which claims 2-3 and 7-10 depend. Ex. 2401 (Klibanov Decl.) at
`
`¶ 12.
`
`In Grounds B and C, Petitioners repeat their Ground A arguments. They
`
`further rely on Hughes and additional teachings in Morris to allege that
`
`pharmaceutical compositions of everolimus (Ground B) and methods of using
`
`everolimus (Ground C) would have been obvious.9
`
`This preliminary response focuses on critical deficiencies in Petitioners’
`
`arguments and evidence with respect to the Yalkowsky and Lemke references
`
`which are primary references in each of Grounds A, B and C. This response also
`
`explains the contradictions in Petitioners’ arguments which preclude Petitioners
`
`from meeting their burden on any of the challenged grounds.
`
`
`
` Breckenridge Pet. I at 1-2, 11-13; Breckenridge Pet. II at 4-6, 16-18; Par Pet. at 7-
`
` 8
`
`8, 13-15; Roxane Pet. at 2-4, 15-16.
`
`9 Breckenridge Pet. I at 49-50; Breckenridge Pet. II at 9, 38-39, 51-54; Par Pet. at
`
`11, 37-38, 50-53; Roxane Pet. at 8, 36-37, 52-57.
`
`7
`
`
`
`

`
`
`
`III. Petitioners Fail To Explain Why A Person Of
`Ordinary Skill Would Rely On Yalkowsky If The
`Goal Was To Increase Rapamycin’s Water Solubility
`
`A.
`
`Petitioners’ Assumption That Yalkowsky Applies To
`Rapamycin’s Water Solubility Is Unsupported And Incorrect
`
`Petitioners rely on Yalkowsky in each of Grounds A, B and C to allege that
`
`a person of ordinary skill would have replaced rapamycin’s C40 hydroxyl group
`
`with a “flexible” group with a reasonable expectation that such a group would
`
`increase rapamycin’s water solubility.10 This argument is fatally flawed because
`
`Petitioners have not and cannot explain why one of ordinary skill would be
`
`motivated to consider, let alone combine, Yalkowsky with the other references in
`
`the Grounds. As discussed below, Petitioners fail to explain how or why
`
`Yalkowsky’s teachings about ideal solubility are relevant to rapamycin’s water
`
`solubility, and, Yalkowsky itself does not provide that explanation. 37 C.F.R.
`
`§ 42.104(b)(5) (“The Board may exclude or give no weight to the evidence where a
`
`party has failed to state its relevance [to the challenge raised]….”); see also In re
`
`Magnum Oil Tools Int’l, Ltd., No. 2015-1300, slip op. at 24-25 (Fed. Cir. July 25,
`
`
`
`
`
`10 Breckenridge Pet. I at 4, 20-22, 31-32, 44-48; Breckenridge Pet. II at 7, 25-27,
`
`35-36, 47-51; Par Pet. at 9-10, 25-27, 34-35, 45-49; Roxane Pet. at 5, 23-25, 33-34,
`
`47-51; Ex. 2401 (Klibanov Decl.) at ¶ 13.
`
`8
`
`
`
`

`
`
`
`2016) (“In light of [petitioner’s] failure to explain why a skilled artisan would have
`
`sought to combine the prior art references to achieve the claimed invention, the
`
`Board had no basis for its conclusion that [petitioner] had met its burden of
`
`proving by a preponderance of the evidence that the claimed invention would have
`
`been obvious…. To satisfy its burden of proving obviousness, a petitioner cannot
`
`employ mere conclusory statements. The petitioner must instead articulate specific
`
`reasoning, based on evidence of record, to support the legal conclusion of
`
`obviousness.” (citation omitted)); Shopkick Inc. v. Novitaz, Inc., IPR2015-00279,
`
`Paper 7 at 29-30 (May 29, 2015) (“It is Petitioner’s responsibility ‘to explain
`
`specific evidence that support its arguments’” and “conclusory labels do not
`
`substitute for a fact-based analysis . . . establishing what is being modified and …
`
`why it would have been obvious to a person of ordinary skill to make the
`
`modification.” (citations omitted)). In view of Petitioners’ failure to provide
`
`articulated reasoning with some rational underpinning correlating Yalkowsky’s
`
`ideal solubility to rapamycin’s water solubility, Petitioners cannot establish that
`
`one of ordinary skill would have relied on Yalkowsky. Apotex Inc. v. Wyeth LLC,
`
`IPR2015-00873, Paper 8 at 11-13 (September 16, 2015) (denying institution
`
`where, inter alia, Petitioner and its declarant failed to explain with objective
`
`evidence and analysis why one of ordinary skill would correlate a prior art
`
`disclosure to the problem at issue).
`
`9
`
`
`
`

`
`
`
`The sole declarant to discuss the relationship between Yalkowsky’s ideal
`
`solubility teachings and rapamycin’s water solubility is Patent Owner’s expert
`
`Professor Alexander M. Klibanov (Ex. 2401).11 As described in more detail below
`
`and in Professor’s Klibanov’s declaration, fundamental solubility principles show
`
`that a rapamycin-in-water solution is not an ideal solution. As a result, Professor
`
`Klibanov concludes that one of ordinary skill would not have considered
`
`Yalkowsky’s teachings applicable here.
`
`There can be no genuine dispute of material fact that Yalkowsky is directed
`
`to ideal solubility, and specifically, its relationship to entropy of fusion. This is
`
`evident from the Yalkowsky abstract, which refers to estimating the “ideal
`
`solubility” of certain types of molecules. Ex. 1007 (Yalkowsky) at 108; Ex. 2401
`
`(Klibanov Decl.) ¶ 14. Additionally, Yalkowsky’s first paragraph provides
`
`background information on means for calculating ideal solubility (Ex. 1007 at
`
`108), and the very formula that Petitioners and their experts rely on (see, e.g.,
`
`Jorgensen Decl. ¶ 79; Baldwin Decl. ¶ 82) is expressly stated to relate to estimating
`
`
`
`
`
`11 Patent Owner did not submit any expert declaration in connection with its
`
`preliminary response in IPR2016-00084, because as of the due date for that
`
`response, Patent Office regulations precluded a Patent Owner from submitting
`
`expert testimony at the preliminary response stage.
`
`10
`
`
`
`

`
`
`
`entropy of fusion for ideal solutions (Ex. 1007 at 111). Ex. 2401 (Klibanov Decl.)
`
`¶ 17. Water solubility is not mentioned anywhere in Yalkowsky. Ex. 1007; Ex.
`
`2401 (Klibanov Decl.) ¶ 17.
`
`Petitioners ignore this critical aspect of Yalkowsky. Neither their Petitions
`
`nor expert declarations mention the term “ideal solubility” let alone explain its
`
`relevance to the issue here—rapamycin’s water solubility. As Petitioners have not
`
`explained why Yalkowsky’s ideal solubility teachings are relevant to improving
`
`rapamycin’s water solubility and Yalkowsky itself does not explain why it is
`
`relevant to such non-ideal solubility (Ex. 2401 (Klibanov Decl.) ¶ 17), Petitioners
`
`have failed to establish why one of ordinary skill would have relied upon
`
`Yalkowsky in connection with rapamycin’s water solubility, as they are required to
`
`do. Moreover, as explained below, there can be no genuine issue of material fact
`
`that a rapamycin-water solution is not an ideal solution. Accordingly, there is no
`
`evidence that one of ordinary skill would have been motivated to consider
`
`Yalkowsky, let alone combine Yalkowsky with any of the other references in
`
`Grounds A, B and C.
`
`As Professor Klibanov explains, 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 solution. Ex. 2401 (Klibanov Decl.) ¶ 18; Ex.
`
`2403 at 957-958. Ideal solubility concerns the solubility of a solute in an ideal
`
`11
`
`
`
`

`
`
`
`solvent for that solute. Ex. 2401 (Klibanov Decl.) ¶ 18. Consistent with the
`
`classical solubility principle that “like dissolves like,” when a solute and a solvent
`
`have nearly identical physicochemical properties (in particular, polarity and
`
`hydrophobicity), a solution of that solute and solvent will be nearly ideal.12 Id. at
`
`¶ 19.
`
`In contrast, a non-ideal solution is one that results when a solute and solvent
`
`have dissimilar physicochemical properties. Ex. 2401 (Klibanov Decl.) ¶ 18; Ex.
`
`2404 (Hildebrand) at 285 (“It 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.”).
`
`One of ordinary skill would apply these basic solubility principles to
`
`rapamycin (the solute) and water (the solvent) and reach only one conclusion:
`
`rapamycin and water have very different physicochemical properties (i.e.,
`
`
`
`
`
`12 Said another way, in an ideal solution, the attractive forces between the solute
`
`molecules are equivalent to the attractive forces between the solvent molecules.
`
`Ex. 2401 (Klibanov Decl.) ¶ 18; Ex. 2403 at 556 (defining an “ideal solution” as
`
`“[a] solution which exhibits no change of internal energy on mixing and complete
`
`uniformity of cohesive forces.” (emphasis added)).
`
`12
`
`
`
`

`
`
`
`hydrophobicity and polarity), and accordingly, a rapamycin-in-water solution is not
`
`an ideal solution. Ex. 2401 (Klibanov Decl.) ¶ 19.
`
`This conclusion is supported by Petitioners’ own declarants who
`
`characterize rapamycin as “a large molecule with relatively few hydrophilic
`
`moieties and with large hydrophobic [i.e., ‘water-hating’] regions.” Jorgensen
`
`Decl. ¶ 139; Baldwin Decl. ¶ 143. In contrast, water is hydrophilic (i.e., “water-
`
`loving”). Ex. 2401 (Klibanov Decl.) ¶ 20. Moreover, a person of ordinary skill
`
`comparing the chemical structures of rapamycin (see above on page 6) and water
`
`(H2O) would understand that rapamycin is only slightly polar, while water is
`
`highly polar. Ex. 2401 (Klibanov Decl.) ¶¶ 18-19. In view of the physicochemical
`
`differences between rapamycin and water, a solution of rapamycin in water cannot
`
`be an ideal solution or even close to it. Id. at ¶ 18.
`
`Indeed, if water was an ideal solvent for rapamycin, rapamycin would not
`
`have “poor solubility” in water, as Petitioners and their declarants have asserted.13
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`Because Yalkowsky’s ideal solubility relates to the solubility of solutes in
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`like solvents, Yalkowsky is not applicable to the non-ideal solubility of unlike
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`13 Jorgensen Decl. ¶¶ 75-76, 138-140; see also Baldwin Decl. ¶¶ 78-79, 142-144;
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`Breckenridge Pet. I at 15, 24-25, 40-41; Breckenridge Pet. II at 20, 28-29, 43-44;
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`Par Pet. at 20, 27-29, 42-43; Roxane Pet. at 18, 26-28, 43-45.
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`13
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`solutes and solvents, such as rapamycin with its allegedly “poor solubility in
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`water” and “large hydrophobic regions” and water, which is the ultimate
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`hydrophilic solvent. Ex. 2401 (Klibanov Decl.) ¶¶ 20-21.
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`Accordingly, Petitioners’ Grounds A, B and C each suffer from a fatal flaw,
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`namely, the failure to explain how or why one of ordinary skill would be motivated
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`to consider and combine Yalkowsky with any of the other references cited in their
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`grounds. Institution on Grounds A, B and C should be denied for this reason
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`alone.
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`B.
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`Petitioners’ Conclusory And Unsupported Assertions Cannot
`Remedy The Deficiencies In Their Analysis Or Give Rise To A
`Genuine Issue Of Material Fact
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`Petitioners cannot overcome the critical failure in their analysis by pointing
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`to Dr. Jorgensen’s and Dr. Baldwin’s conclusory assertion that Yalkowsky applies
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`to “all solvent systems.” See Jorgensen Decl. ¶ 78; Baldwin Decl. ¶ 81. “Expert
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`testimony that does not disclose the underlying facts or data on which the opinion
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`is based is entitled to little or no weight [at the pre-institution stage]. 37 C.F.R.
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`§ 42.65(a).” Kinetic Techs., Inc. v. Skyworks Solns., Inc., IPR2014-00529, Paper 8
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`at 14-15 (September 23, 2014) (denying institution where the expert’s declaration
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`“[did] not provide any factual basis for its assertions”); Wowza Media Sys., LLC v.
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`Adobe Sys., Inc., IPR2013-00054, Paper 16 at 5 (July 13, 2013) (declining to credit
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`expert testimony where the testimony did not explain part of the obviousness
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`14
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`analysis); Apotex Inc., IPR2015-00873, Paper 8 at 11-13 (finding unpersuasive
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`expert opinions that were not supported by sufficient objective evidence or
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`analysis). Therefore, because Dr. Jorgensen’s and Dr. Baldwin’s assertions are
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`unsupported, they are entitled to little or no weight and are insufficient to carry
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`Petitioners’ burden. Moreover, these assertions are inconsistent with the language
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`of Yalkowsky itself, which indisputably concerns ideal solubility and does not
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`include anywhere a reference to water solubility. Ex. 2401 (Klibanov Decl.) ¶¶ 14,
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`17. Accordingly, Petitioners’ declarants’ testimony cannot give rise to a genuine
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`issue of material fact. Kimberly-Clark Worldwide, Inc. v. First Quality Baby
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`Prods., LLC., 900 F. Supp.2d 903, 910 (E.D. Wis. 2012), aff’d, 579 Fed. Appx.
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`996 (Fed. Cir. 2014) (“An expert cannot be used to manufacture an issue of fact as
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`to what the prior art teaches when that prior art is clear on its face.”).
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`Petitioners also cannot overcome their failure to establish Yalkowsky’s
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`relevance by pointing to the Bell, Ballauff or Stern references that Drs. Jorgensen
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`and Baldwin cite as evidence that Yalkowsky’s teachings would be understood to
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`apply to “improve solubility of heterocyclic molecules” or to “improve solubility
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`of a macrocyclic molecule.” Jorgensen Decl. ¶ 78; Baldwin Decl. ¶ 81. Tellingly,
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`Drs. Jorgensen and Baldwin use only the general term “solubility” when discussing
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`these examples, and never state that they concern water solubility. Nor do Drs.
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`Jorgensen and Baldwin discuss the solvents at issue in any of those papers or
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`15
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`explain how they would be relevant to rapamycin’s water solubility. In fact, as
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`Professor Klibanov explains, none of Bell, Ballauff or Stern concerns the solubility
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`of a hydrophobic molecule in a hydrophilic solvent (e.g., water). Ex. 2401
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`(Klibanov Decl.) ¶ 22. To the contrary: each of these papers concerns only
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`hydrophobic molecules and their solubility in hydrophobic organic solvents. Id.
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`As a result, one of ordinary skill would not rely on any of these references for the
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`same reasons they would not rely on Yalkowsky. Id.
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`As Professor Klibanov’s testimony at this stage is limited to explaining
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`issues that were not discussed by Petitioners’ declarants—apart from the
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`conclusory and unsupported statements noted above—Professor Klibanov’s
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`testimony cannot give rise to a genuine issue of material fact under 37 C.F.R.
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`§ 42.108(c). Even if the Board were to find that Professor Klibanov’s testimony
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`overlaps in general subject matter with that of the Petitioners’ declarants, as the
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`commentary to rule 42.108 explains, “[t]he mere existence … of dueling expert
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`testimony does not necessarily raise a genuine issue of material fact.” 81 Fed. Reg.
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`18750 at 18756 (April 1, 2016) (internal quotations and citation omitted).
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`Petitioners’ declarants’ conclusory assertions cannot give rise to a genuine issue of
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`material fact. Phillips Petroleum Co. v. Huntsman Polymers Corp., 157 F.3d 866,
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`876 (Fed. Cir. 1998) (concluding that a party “fail[ed] to raise a genuine issue of
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`material fact precluding summary judgment” in part because it offered expert
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`16
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`opinions that were “wholly conclusory, devoid of facts upon which the affiant[s’]
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`conclusions, as experts, were reached” (internal quotations omitted)); see also 81
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`Fed. Reg. at 18756 (noting overlap between rule 108 and the Federal Circuit’s
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`“material fact” analysis in the context of summary judgment).
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`IV. Petitioners Fail To Explain Why Lemke Would Have Motivated One Of
`Ordinary Skill To Synthesize Everolimus Or To Have Reasonably
`Expected Everolimus To Be More Water Soluble Than Rapamycin
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`A.
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`Petitioners Ignore And Mischaracterize The Differences
`Between Rapamycin’s And Everolimus’ C40 Groups
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`When discussing the Lemke reference, Petitioners ignore and
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`mischaracterize the fundamental and indisputable chemical similarities and
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`differences between the C40 groups of rapamycin and everolimus. By way of
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`background, the chemical structures of rapamycin and everolimus are shown
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`below, focusing on their respective C40 positions.
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`At their C40 carbons, rapamycin has a hydroxyl (i.e., alcohol) (HO-) group and
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`everolimus has a 2-hydroxyethyl ether (HOCH2CH2O-) group. As both
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`compounds have a single alcohol (HO-) functionality (shown in blue) as part of
`
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`17
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`their C40 substituents, they do not differ in this respect. That is, everolimus does
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`not have any additional hydroxyl/alcohol (HO-) functional groups compared to
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`rapamycin. Rather, the atoms that differ between the two compounds’ C40
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`substituents are indicated above in red—everolimus has an ether oxygen (-O-)
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`functional group and two methylene (-CH2-) groups, whereas rapamycin does not.
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`Throughout their Petitions, Petitioners ignore and misrepresent these
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`indisputable facts, and instead suggest (without explanation) that everolimus has an
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`additional hydroxyl/alcohol (HO-) group as compared to rapamycin. This is
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`plainly incorrect as is apparent from the structures shown above.
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`B.
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`Petitioners Offer No Argument Or Evidence To Explain Why One
`Of Ordinary Skill Would Have Added An Ether And Two
`Carbons To Rapamycin To Increase Its Water Solubility
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`Petitioners rely on Lemke’s Table 16-1 to narrow the field of possible
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`functional groups to add at the C40 position. In particular, Drs. Jorgensen and
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`Baldwin state that Table 16-1 “provides guidance as to how substituents would be
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`expected to impact the solubility of a chemical compound” and sets forth “the
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`estimated solubilizing effect of various functional groups.” Jorgensen Decl. ¶ 82;
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`Baldwin Decl. ¶ 85. Drs. Jorgensen and Baldwin go on to provide a specific
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`example of how one of ordinary skill would understand the information in Table
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`16-1 by noting that, “[f]or example, hydroxyl (alcohol) groups have the potential to
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`18
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`solubilize 3 to 4 carbons (as shown highlighted below). (Id. [Ex. 1007] at 116.)”
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`Jorgensen Decl. ¶ 82; Baldwin Decl. ¶ 85.
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` Based on their analysis of the data presented in Table 16-1, Petitioners
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`state that “Lemke describes the functional groups with the largest solubilizing
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`potential as alcohol, phenol, amine, carboxylic acid, ester, and amide.” Jorgensen
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`Decl. ¶ 83; Baldwin Decl. ¶ 86. See also Jorgensen Decl. ¶ 148, which includes a
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`highlighted version of Lemke’s Table 16-1, reproduced below.
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`
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`Petitioners then eliminate some of these groups to arrive at a short-list of
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`functional groups that they say one of ordinary skill would be motivated to add to
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`rapamycin at its C40 position: hydroxyl, amino, or carboxylate groups.14 Notably,
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`14 Breckenridge Pet. I at 32-33, 46;