`Date Filed: December 20, 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.,
`BRECKENRIDGE PHARMACEUTICAL, INC. AND
`ROXANE LABORATORIES, INC.,
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`Patent Owner
`
`
`
`Case IPR2016-000841
`U.S. Patent 5,665,772
`
`
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS ON
`CROSS-EXAMINATION OF WILLIAM L. JORGENSEN, PH.D
`
`
`
`
`1 Breckenridge Pharmaceutical, Inc. was joined as a party to this proceeding via a
`Motion for Joinder in IPR2016-01023; Roxane Laboratories, Inc. was joined as a
`party via a Motion for Joinder in IPR2016-01102.
`
`
`
`
`
`
`
`I.
`
`Yalkowsky Would Not Have Motivated A POSA To Modify
`Rapamycin To Arrive At Everolimus, Nor Provided A Reasonable
`Expectation That Everolimus Would Have Increased Water Solubility
`
`At Ex. 2222, page 113, line 19 to page 115, line 6, Dr. Jorgensen testified
`
`that that the free energy change (ΔG) for a process such as dissolution is dependent
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`upon the change in entropy (ΔS), enthalpy (ΔH) and temperature (T) as reflected in
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`the thermodynamic formula ΔG=ΔH-TΔS, and a chemical change that results in a
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`more negative value for ΔG will favor dissolution. This testimony is relevant to
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`Petitioners’ reliance on Yalkowsky’s entropy teachings and assertion that “flexible
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`bonds would have been reasonably expected to increase the internal entropy of
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`fusion as taught by Yalkowsky and favorably influence everolimus’s dissolution.
`
`([Ex. 1118] ¶¶88-90; Ex. 1007 at 108 (‘there is a regular increase in ΔSf with
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`increasing chain length’).)” Paper 46 (“Reply”) 14. This testimony is relevant
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`because it indicates that when considering the change in free energy of dissolution
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`(ΔG), and whether a given chemical change will increase solubility, it is not
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`sufficient to consider only the change in entropy (ΔS), as enthalpy (ΔH) must also
`
`be considered.
`
`At Ex. 2222, page 120, line 13 to page 122, line 10, Dr. Jorgensen testified
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`that chemically modifying a compound may result in an increase in entropy but a
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`decrease in water solubility. This testimony is relevant to Petitioners’ assertion
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`that “increasing internal entropy had been shown to increase calculations of ideal
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`
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`
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`solubility and result in increased actual measured solubility.” Reply 16. This
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`testimony is relevant because it contradicts Petitioners’ suggestion that an increase
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`in internal entropy will necessarily lead to an increase in water solubility, and
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`instead shows that an increase in internal entropy can lead to a decrease in water
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`solubility. See also Ex. 2091, Tr. 47:15-48:22 (discussing interplay between
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`entropic and enthalpic effects).
`
`At Ex. 2222, page 120, lines 4 to 9 and page 116, lines 14 to 25, Dr.
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`Jorgensen admitted that Yalkowsky does not discuss the impact of adding flexible
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`groups on enthalpy, and agreed that in “an ideal solution, the focus would be only
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`entropy of solution if you’re looking at the free energy change” because “the
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`enthalpy change in mixing is zero.” This testimony is relevant to Petitioners’
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`reliance on Yalkowsky, and assertion that Yalkowsky’s teachings about the effect
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`of entropy on dissolution are not limited to ideal solutions. Reply 15-16. This
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`testimony is relevant because it shows that while an increase in entropy may result
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`in an increase in ideal solubility (because the change in enthalpy, ΔH, is zero in an
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`ideal solution), the same is not true in a non-ideal solution because enthalpy must
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`also be considered.
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`At Ex. 2222, page 117, line 4 to page 118, line 16, Dr. Jorgensen testified
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`that the process described in Yalkowsky’s Figure 2 concerns entropy, and does not
`
`concern enthalpy. This testimony is relevant to Petitioners’ assertion that Figure 2
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`
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`2
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`
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`is not limited to ideal solutions. Reply 15-16; Ex. 1118 ¶ 82. This testimony is
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`relevant because it confirms that Yalkowsky’s Figure 2 does not account for a
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`change in enthalpy upon dissolution, and enthalpy is a factor that a person of
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`ordinary skill in the art (“POSA”) would consider when evaluating solubility in a
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`non-ideal solution (see supra).
`
`At Ex. 2222, page 120, lines 10 to 12, Dr. Jorgensen testified that the effect
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`of adding a flexible chain on enthalpy is not independent of the solvent (i.e., it is
`
`solvent-dependent). This testimony is relevant to Petitioners’ assertion that the
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`“favorable effect [on entropy of a flexible chain upon dissolution] is independent
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`of the solvent.” Reply 15-16; Ex. 1118 ¶ 82. This testimony is relevant because it
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`shows that the impact of adding a flexible chain is solvent-dependent where the
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`solution is non-ideal, because enthalpy must also be considered.
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`At Ex. 2222, page 115, line 7 to page 116, line 3, Dr. Jorgensen testified
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`(consistent with Petitioners’ counsel’s objection), that enthalpy of solution was not
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`an issue discussed in his supplemental declaration, and that he did not cite any
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`references that suggest a more polar compound would have a more negative
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`enthalpy of solution. This testimony is relevant because it goes to the weight and
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`credibility of Dr. Jorgensen’s testimony about water solubility and his assertion
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`that more polar compounds would have a more negative enthalpy of solution. Ex.
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`2222, Tr. 115:7-21.
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`3
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`At Ex. 2222, page 124, line 18 to page 127, line 13, Dr. Jorgensen testified
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`that that the trend discussed in paragraphs 97-99 of his supplemental declaration
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`(Ex. 1118), that solubility of alkyl p-aminobenzoates increased with increasing
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`chain length, was based on calculated ideal solubilities and solubility in methanol,
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`ethanol and 1-propanol, not in water; Dr. Jorgensen further testified that the trend
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`would be different in water. This testimony is relevant to Petitioners’ assertion
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`that “ideal solubility is premised on basic thermodynamic concepts that apply to all
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`systems . . . and a POSA would have understood the same qualitative effects apply
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`in real and ideal systems. ([Ex. 1118] ¶¶13, 92-99.)” Reply 16. This testimony is
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`relevant because, as Dr. Jorgensen testified, the “qualitative effect” on solubility of
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`increasing chain length will vary depending on the solvent.
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`At Ex. 2222, page 133, line 7 to page 134, line 11, Dr. Jorgensen agreed that
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`Yalkowsky 1972 (Ex. 2219) examined the water solubility of alkyl p-
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`aminobenzoates (the same compounds discussed in Yalkowsky (Ex. 1007) Table
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`III, Schwartz (Ex. 1117), and Ex. 1118 ¶¶ 97-99 (see Ex. 2222, Tr. 130:19-
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`131:19)), and reported in Figure 2 that as hydrocarbon chain length increased (and
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`therefore entropy increased), water solubility decreased, which trend is the
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`opposite of that reported in Table II of Schwartz in methanol, ethanol, or 1-
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`propanol, or as calculated using ideal solubility calculations. This testimony is
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`relevant to Petitioners’ assertion that “increasing internal entropy had been shown
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`
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`4
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`
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`to increase calculations of ideal solubility and result in increased actual measured
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`solubility.” Reply 16 (citing Dr. Jorgensen’s statement (Ex. 1118 ¶ 99) that “the
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`same trends [as reported in Schwartz (Ex. 1117) Table II] can be seen in the ideal
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`solubilities as in the measured solubilities—as alkyl side chain length increases,
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`solubility increases in each of the three solvents. ([Ex. 1117, Table II].) Thus, a
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`POSA would have understood that increasing alkyl side chains positively
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`influences solubility in real solutions and this impact is not limited to ideal
`
`solutions.”). This testimony is relevant because it confirms that a chemical change
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`that increases entropy, and results in an increase in ideal solubility or solubility in a
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`given organic solvent, may result in a decrease in aqueous solubility (i.e., the
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`opposite trend), contrary to Petitioners’ suggestion that adding flexible chains
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`would be expected to increase solubility in all solvents.
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`At Ex. 2222, page 128, line 6 to page 129, line 17, Dr. Jorgensen agreed that
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`Schwartz (Ex. 1117) at 252 indicates that “as you increase the length of a
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`hydrocarbon side chain, there is decreased aqueous solubility,” which is what a
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`POSA would expect. At Ex. 2222, page 134, line 20 to page 135, line 11, Dr.
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`Jorgensen further agreed that Yalkowsky 1972 (Ex. 2219) at 854 states that for
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`methyl, ethyl, propyl and butyl esters, there is a 2.24 fold decrease in water
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`solubility per methylene unit and for longer alkyl p-aminobenzoates, there is a 4.22
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`fold decrease per methylene unit. This testimony is relevant to Petitioners’
`
`
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`5
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`
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`assertion that “Yalkowsky taught that the entropic effect of extending the side
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`chain with flexible derivatives would create a powerful potential benefit to
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`solubility,” and that “ideal solubility is premised on basic thermodynamic concepts
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`that apply to all systems . . . and a POSA would have understood the same
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`qualitative effects apply in real and ideal systems.” Reply 10, 16. This testimony
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`is relevant because it shows that Petitioners’ reliance on entropy and ideal
`
`solutions does not account for all relevant factors at play in non-ideal solutions;
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`despite the addition of a flexible hydrocarbon side chain, and associated increase in
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`entropy, increasing the length of a hydrocarbon side chain would be expected to
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`decrease aqueous solubility.
`
`At Ex. 2222, page 69, lines 16 to 24, Dr. Jorgensen testified that adding
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`aliphatic carbons would be expected to diminish solubility. At Ex. 2222, page 127,
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`line 14 to page 128, line 5, Dr. Jorgensen further testified that adding methylene
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`groups (-CH2-) would be expected to increase entropy, but these groups are
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`hydrophobic and could decrease solubility. This testimony is relevant for the same
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`reasons as set forth in above, i.e., Petitioners’ focus on entropy alone ignores
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`enthalpy, which is an important factor impacting solubility in non-ideal solutions.
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`At Ex. 2222, page 69, line 25 to page 71, line 17 and page 74, line 8 to page
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`75, line 15, Dr. Jorgensen testified that Lemke’s chapter, which is specifically
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`directed to predicting the water solubility of organic functional groups (Ex. 1008),
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`
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`6
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`
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`nowhere (i) teaches that adding flexible chains will increase water solubility, (ii)
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`discusses entropy, or (iii) discusses the concepts in Yalkowsky (Ex. 1007). This
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`testimony is relevant because it goes to the weight and credibility of Petitioners’
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`assertions that a POSA would have applied Yalkowsky’s statements about how
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`flexible chains affect entropy and ideal solubility, to the non-ideal solution of
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`rapamycin in water, or that a POSA would combine Yalkowsky with Lemke to
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`predict water solubility of organic compounds. Reply 10, 15-16.
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`II.
`
`Petitioners Have Not Met Their Burden
`Of Establishing That A POSA Would Select
`Rapamycin As A Lead Compound Over Other Alternatives
`
`At Ex. 2222, page 5, line 14 to page 6, line 2, Dr. Jorgensen agreed that “[a]s
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`of October 1992, [medicinal chemists were] making derivatives of
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`immunosuppressants other than rapamycin” and testified that “if they were
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`working with other compounds, the assumption would be that they are viewing
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`some of these other compounds as their lead compound, and they’re making
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`derivatives of those compounds.” This testimony is relevant to Petitioners’
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`assertion that rapamycin would be a lead compound because “researchers regularly
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`selected rapamycin for modification.” Reply 3-4. This testimony is relevant
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`because it shows that medicinal chemists were using immunosuppressants other
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`than rapamycin “as their lead compound.”
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`At Ex. 2222, page 9, line 14 to page 16, line 7, Dr. Jorgensen testified that
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`7
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`
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`the Hughes (Ex. 1009) and Schiehser (Ex. 1011) patents were assigned to
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`American Home Products, and that he had not considered whether any of the other
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`medicinal chemists working on rapamycin were also affiliated with American
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`Home Products, nor had he looked at the file history for the Stella ‘803 patent (Ex.
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`2218 at 20-21), in which the inventors appointed an American Home Products
`
`attorney to prosecute their application. See also Ex. 2222, Tr. 104:20-105:12.
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`This testimony is relevant to Petitioners’ suggestion that numerous medicinal
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`chemists had selected rapamycin as a lead compound as of October 1992. Reply 4.
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`This testimony is relevant because it contradicts the suggestion that there was
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`widespread interest in making chemical derivatives of rapamycin.
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`At Ex. 2222, page 16, line 16 to page 17, line 5, Dr. Jorgensen agreed that
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`based on the information presented in Dr. Roush’s declaration (Ex. 2093 ¶¶ 161-
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`164) a POSA “would have thought that rapamycin was toxic in monkeys and
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`baboons.” This testimony is relevant to Petitioners’ assertion that rapamycin
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`would be selected as a lead compound. Reply 4. This testimony is relevant
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`because a proper legal analysis requires comparing all of rapamycin’s properties,
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`not just potency, to those of the other known immunosuppressants (see Reply 3-4)
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`prior to identifying a lead compound.
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`At Ex. 2222, page 19, line 23 to page 20, line 18, Dr. Jorgensen testified that
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`he doubts that in October 1992 the cause of rapamycin’s toxicity was understood,
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`8
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`and he had no knowledge of whether rapamycin’s toxicity was related to its
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`mechanism for immunosuppressive activity. This testimony is relevant to
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`Petitioners’ assertion that rapamycin would be selected as a lead compound. Reply
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`4. This testimony is relevant because the absence of information about the cause
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`of rapamycin’s toxicity is a factor that a POSA would have considered prior to
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`selecting a lead compound, and one that would have dissuaded a POSA from
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`selecting rapamycin as a lead compound.
`
`III. Petitioners Have Not Cited Any Prior Art Teaching That
`Rapamycin’s Water Solubility Led To Formulation Problems
`For Immunosuppressive Uses Such That A POSA Would
`Have Been Motivated To Chemically Modify Rapamycin
`
`At Ex. 2222, page 77, line 10 to page 81, line 18, page 90, line 5 to page 92,
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`line 9, and page 98, lines 6 to 11, Dr. Jorgensen identified Fiebig (Ex. 1034) and
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`Morris (Ex. 1005) as the only references that expressly discussed formulation
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`problems with rapamycin, but agreed that Fiebig concerns only antitumor uses (not
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`immunosuppressive uses) and formulations for injection (not oral administration),
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`and Morris does not report any difficulty in preparing formulations of rapamycin.2
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`2 Dr. Jorgensen also testified that Stella (Ex. 1010) does not expressly discuss
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`rapamycin formulation problems (Ex. 2222, Tr. 79:2-8), and concerns antitumor
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`uses and injectable administration, not immunosuppressive uses or oral
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`administration (id., Tr. 112:23-113:15).
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`9
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`This testimony is relevant to Petitioners’ assertion that the prior art taught that
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`rapamycin was difficult to formulate in stable galenic compositions. Reply 5-6.
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`This testimony is relevant because Petitioners have argued here that the POSA was
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`seeking an immunosuppressant with a sufficient level of oral bioavailability—not
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`an antitumor agent for injection,3 yet Petitioners have not identified any prior art
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`that indicates that there were formulation difficulties that would have provided a
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`motivation to improve rapamycin’s water solubility for immunosuppressant uses.
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`At Ex. 2222, page 85, line 3 to page 86, line 25, Dr. Jorgensen agreed that
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`rapamycin was moving forward in development as an immunosuppressant prior to
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`October 1992, as reflected by the filing of an investigational new drug application
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`(IND), the development of a rapamycin formulation, and approval to proceed with
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`initial human testing using that formulation. This testimony is relevant to
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`Petitioners’ assertions that “[rapamycin’s] development was hindered by poor
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`solubility” (Ex. 1118 ¶ 111), that poor solubility may preclude preclinical testing
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`(id. ¶ 32), and that a POSA would have been motivated to chemically modify
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`rapamycin rather than address any water solubility concerns through formulation
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`solutions (Reply 6). This testimony is relevant because the submission of an IND
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`for immunosuppression demonstrates that rapamycin was moving forward in
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`3 Dr. Ratain testified that as of October 1992, a POSA would not have been
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`motivated to pursue oral antitumor drugs (Ex. 2223, Tr. 216:6-21).
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`10
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`development and its alleged water solubility issues presumably were being
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`addressed through formulation techniques, or did not require addressing for
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`immunosuppressive uses.
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`At Ex. 2222, page 89, line 5 to page 90, line 13, Dr. Jorgensen testified that
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`he has not “specifically looked . . . into formulations of rapamycin” and “was not
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`focusing on formulation issues.” At page 96, lines 13 to 16, Dr. Jorgensen further
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`testified “formulation was not [his] assignment here.” This testimony is relevant to
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`Petitioners’ reliance on Dr. Jorgensen to assert that a POSA would not consider
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`formulation techniques to address rapamycin’s alleged water solubility concerns.
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`Reply 6 (citing Ex. 1118 ¶ 32). This testimony is relevant because without
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`considering the potential of formulation approaches to address rapamycin’s water
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`solubility, Dr. Jorgensen’s opinion that a POSA would have chosen to address
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`water solubility by chemical modification instead of formulations is entitled to
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`little weight. Ex. 1118 ¶ 32.
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`At Ex. 2222, page 90, line 14 to page 92, line 9 and page 92, line 13 to page
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`93, line 7, Dr. Jorgensen testified that Fiebig (Ex. 1034) tested various compounds
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`for antitumor activity in human tumor xenografts using in vitro rapamycin doses of
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`100 mg/kg/day, and does not disclose testing for transplant rejection activity. This
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`testimony is relevant to Petitioners’ assertion that Fiebig suggests that development
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`of rapamycin was stopped due to solubility problems. Reply 6. This testimony is
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`11
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`relevant because the development discussed in Fiebig relates to antitumor activity
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`at doses of 100 mg/kg/day, whereas Dr. Jorgensen testified that here a POSA’s
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`primary focus was on immunosuppression (Ex. 2222, Tr. 4:21-5:2), and
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`characterized an in vitro dose for immunosuppression of 7 mg/kg/week as a “high
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`dose” (id., Tr. 17:22-18:4, 19:16-22; Ex. 1118 ¶ 20; Ex. 1005 at 59-60).
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`At Ex. 2222, page 93, lines 15 to 19, Dr. Jorgensen testified that Fiebig (Ex.
`
`1034) reports that rapamycin development was stopped “due to solubility problems
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`and toxicity associated with the Cremophor used in the experimental formulation.”
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`At Ex. 2222, page 95, line 23 to page 97, line 3, Dr. Jorgensen further testified that
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`“[o]f course there are . . . other things that are used to solubilize hydrophobic
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`compounds include[ing] cyclodextrins,” as well as others. This testimony is
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`relevant to Petitioners’ assertion that “resorting to formulation techniques [would]
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`be a failure.” Reply 6; Ex. 1118 ¶¶ 32-35. This testimony is relevant because it
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`demonstrates that Petitioners’ reliance on a single instance of toxicity associated
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`with Cremophor, where no information is provided about the formulations tested
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`(see Ex. 2222, Tr. 97:4-98:5; Ex. 1034 at 116), including the concentrations of
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`rapamycin or Cremophor used, does not support the conclusion that all formulation
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`solutions would be ineffective, especially when Dr. Jorgensen admitted that he had
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`not looked into formulation issues.
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`At Ex. 2222, page 100, line 19 to page 101, line 19, Dr. Jorgensen testified
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`12
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`that “by formulation . . . poorly water-soluble compounds have been developed to
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`FDA-approved drugs” and formulation is one approach that can be used to
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`improve the bioavailability of poorly water-soluble compounds. This testimony is
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`relevant to Petitioners’ assertion that “relying on formulation solutions could be
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`ineffective or introduce other problems.” Reply 6. This testimony is relevant
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`because it shows that others had used formulation solutions to develop poorly
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`water-soluble compounds for therapeutic use, which is consistent with Dr.
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`Jorgensen’s prior testimony that when he was, for example, working on water
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`solubility problems with the drug Celebrex, “the intrinsic bioavailability was about
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`20 percent and then through formulation they were able to get it up to 45 percent,
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`and declared Victory.” Ex. 2019, Tr. 167:2-14; Ex. 2092 ¶ 160.
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`At Ex. 2222, page 102, lines 6 to 14, Dr. Jorgensen testified that “normally,
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`formulation shouldn’t be changing the mechanism of action of a compound.” This
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`testimony is relevant to Petitioners’ assertion that a POSA would seek to address
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`rapamycin’s allegedly poor water solubility while retaining rapamycin’s
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`immunosuppressive activity. Reply 1, 6. This testimony is relevant to that
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`motivation because formulation solutions could be used to increase rapamycin’s
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`rate of dissolution without altering its mechanism of action.
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`At Ex. 2222, page 105, line 13 to page 106, line 18, Dr. Jorgensen identified
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`Stella as the only reference “that sticks out in [his] mind that” discloses rapamycin
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`13
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`derivatives with better water solubility than rapamycin and further testified that
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`Stella’s rapamycin derivatives are prodrugs, including prodrugs with water
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`soluble-salts. This testimony is relevant to Petitioners’ assertion that a POSA
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`would not have preferred to prepare prodrugs or salts over the other derivatives
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`identified by Dr. Jorgensen. Reply 6-8; Ex. 1118 ¶¶ 39, 45. This testimony is
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`relevant because the only prior art rapamycin derivatives Petitioners identified with
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`improved water solubility were prodrugs and/or water-soluble salts.
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`IV. Petitioners Have Not Identified Any Prior Art Disclosing
`Alkylation Reactions At Rapamycin’s C40 Position
`
`At Ex. 2222, page 33, lines 2 to 25, Dr. Jorgensen testified that he could not
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`identify any references that disclose alkylation reactions to rapamycin’s hydroxyl
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`groups. This testimony is relevant to the weight and credibility of Dr. Jorgensen’s
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`suggestion that alkylation reactions of rapamycin were well-known and could be
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`used to modify rapamycin. Ex. 1118 ¶ 70.
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`V. A POSA Would Not Have Reasonably Expected That
`Everolimus Would Retain Rapamycin’s Immunosuppressive Activity
`
`At Ex. 2222, page 25, line 18 to page 28, line 2, Dr. Jorgensen testified that
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`the compound of Example 1 in the Kao ’447 patent (Ex. 2075) was tested in the
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`skin graft assay, whereas the compound of Example 3 was not, and “you generally
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`would test your best compounds in animal study. And compounds that you felt
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`were less promising, you would not test necessarily, is what appears that has
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`14
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`happened in [the Kao ’447 patent].” This testimony is relevant to Dr. Jorgensen’s
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`reasonable expectation of success opinions based on the biological data presented
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`in Hughes (Ex. 1009) for compounds of Examples 1 and 2. Ex. 1118 ¶ 23. This
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`testimony is relevant because only the compound of Hughes Example 1 was tested
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`in the skin graft assay, and that compound did not display immunosuppressive
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`activity (Paper 27, Patent Owner Response at 43; Ex. 2093 ¶¶ 120-125; Ex. 1009 at
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`4:4-10); the compound of Hughes Example 2, which was not tested in the skin
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`graft assay, would have been considered less promising according to Dr.
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`Jorgensen.
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`At Ex. 2222, page 55, line 2 to page 56, line 4, Dr. Jorgensen testified that
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`there is no clear way for a POSA to identify whether any given compound meets
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`his goal of retaining immunosuppressive activity, because he does not have any
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`specific goal or “clear cutoff.” This testimony is relevant to Petitioners’ assertion
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`that a POSA would have reasonably expected rapamycin derivatives to retain
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`immunosuppressive activity. Reply 18-19; Ex. 1118 ¶¶ 107-108. This testimony
`
`is relevant because without knowing what specific goal the POSA here was
`
`seeking to achieve, Petitioners cannot establish a reasonable expectation of
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`successfully achieving that goal.
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`15
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`Dated: December 20, 2016
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`Respectfully submitted,
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`
`
`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
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`16
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`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing Patent Owner’s Motion for
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`Observations on Cross-Examination of William L. Jorgensen, Ph.D. was served on
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`December 20, 2016 by causing it to be sent by email to counsel for Petitioners at
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`the following email addresses:
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`Daniel G. Brown (dan.brown@lw.com)
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`Robert Steinberg (bob.steinberg@lw.com)
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`Brenda L. Danek (Brenda.danek@lw.com)
`
`
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`Jonathan M. Strang (jonathan.strang@lw.com)
`
`Matthew L. Fedowitz (mfedowitz@merchantgould.com)
`
`B. Jefferson Boggs (jboggs@merchantgould.com)
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`Daniel R. Evans (devans@merchantgould.com)
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`Keith A. Zullow (kzullow@goodwinlaw.com)
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`Marta Delsignore (mdelsignore@goodwinprocter.com)
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`Dated: December 20, 2016
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`17
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`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100