Paper No. __
`Date Filed: January 31, 2017
`
`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 DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`
`
`
`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.
`
`
`Date Filed: January 31, 2017
`
`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 DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`
`
`
`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.
`
`
`
`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 IPR2016-00084
`
`U.S. Patent No. 5,665,772
`
`PATENT OWNER’S DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`February 2, 2017
`
`1
`
`
`
`Structural Similarities And Differences
`Between Rapamycin And Everolimus
`Paper 27 at 7-8
`
`Ex. 2092 ¶¶ 30-32, 35, 43; Ex. 2091 at 126:16-127:5
`
`2
`
`
`
`Lemke Does Not Reasonably Suggest That An Ethyleneoxy
`Group Would Increase Rapamycin’s Water Solubility
`Paper 27 at 7-9
`
`Ex. 1008 at 116; see also Ex. 2092 ¶¶ 30-32; Ex. 2091 at 126:24-127:5
`
`3
`
`
`
`Lemke Does Not Reasonably Suggest That An Ethyleneoxy
`Group Would Increase Rapamycin’s Water Solubility
`Paper 27 at 9-11
`
`Ex. 1008 at 116; see also Ex. 2092 ¶¶ 43, 45
`
`4
`
`
`
`Lemke Does Not Reasonably Suggest That An Ethyleneoxy
`Group Would Increase Rapamycin’s Water Solubility
`Paper 27 at 11-12
`
`Ex. 1008 at 119; see also Ex. 2092 ¶¶ 43, 46
`
`5
`
`
`
`Water Solubility Predictions Must Consider
`Changes In Both Enthalpy And Entropy
`Paper 27 at 25; Paper 55 at 1
`
`ΔG
`Free Energy
`Change
`
`=
`
`ΔH
`
`–
`
`T
`
`x
`
`ΔS
`
`Enthalpy Change
`
`Temperature
`
`Entropy Change
`
`Ex. 2091 at 43:18-44:3, 46:23-47:15; Ex. 2222 at 113:19-115:6; Paper 46 at 16; Ex. 1118 ¶ 95
`
`6
`
`
`
`Yalkowsky Concerns Estimating Ideal Solubility Of
`Rigid Molecules And Their Long-Chain Derivatives
`Paper 27 at 17-18
`
`Yalkowsky (Abstract):
`“The entropy of fusion of many drugs and molecules of intermediate
`size can be estimated in the following manner: (1) for rigid molecules,
`ΔSf ≃ 13.5 eu; (2) for long chain derivatives of such molecules, ΔSf ≃
`13.5 eu [+] 2.5(n – 5) eu, where n is the number of flexible links in the
`chain. In most cases, these simple rules will provide an estimate of
`ΔSf which is sufficiently accurate to obtain reasonable estimates of
`ideal solubility.”
`
`Ex. 1007 at 108; see also Ex. 2092 ¶¶ 76-79
`
`7
`
`
`
`Rapamycin In Water Is Not An Ideal Solution
`
`Paper 27 at 17-19
`
`Dr. Jorgensen:
`“Q. So a solution of rapamycin in water would not be an ideal
`solution?
`“A. Correct.”
`
`Dr. Jorgensen:
`“Q. Do you agree that the Yalkowsky 1979 reference never
`expressly discusses water solubility?
`“A. That’s correct.”
`
`Ex. 2091 at 23:2-4, 47:24-48:3; see also Ex. 2092 ¶¶ 81-86
`
`8
`
`
`
`Yalkowsky Is Not Analogous Art
`
`Paper 27 at 17-19
`
`Dr. Jorgensen:
`“A medicinal chemist wouldn’t know these entropy of fusion
`equations. They wouldn’t know the article. They would
`understand the concept of Figure 2, but this is not an article --
`Industrial Engineering Chemistry Fundamentals -- that a
`medicinal chemist would have, you know, looked at.”
`
`Ex. 2091 at 45:11-24; see also Ex. 2092 ¶¶ 76-79, 81-86
`
`9
`
`
`
`Changes In Enthalpy Are Not Reasonably Predictable
`
`Paper 27 at 25
`
`Dr. Jorgensen:
`“The problem in computing solubility is there’s both an
`enthalpy and an entropy part. And the enthalpy part isn’t
`easily predictable.”
`
`Ex. 2091 at 43:18-25; see also Ex. 2092 ¶¶ 117-118
`
`10
`
`
`
`Yalkowsky Does Not Discuss Enthalpy
`
`Paper 27 at 17-18, 25; Paper 55 at 2-3
`
`Dr. Jorgensen:
`“Q. So Yalkowsky 1979 is not stating that entropy of fusion can
`be used to predict water solubility?
`“A. Yalkowsky -- that is correct. . . . This is only addressing
`the entropy change here. And that’s all I was addressing on
`the flexible side chain issue. So it’s a component of predicting it.
`“Q. But it’s not sufficient?
`“A. It’s not the whole ballgame.”
`
`Dr. Jorgensen:
`“Q. Does Yalkowsky discuss the impact of adding flexible
`groups on enthalpy?
`“A. Enthalpy, no. . . . Yalkowsky focused here on entropy
`issues.”
`
`Ex. 2091 at 47:3-15; Ex. 2222 at 120:4-9; see also Ex. 2092 ¶ 117
`
`11
`
`
`
`A Chemical Modification May Increase
`Entropy But Decrease Water Solubility
`Paper 27 at 17-18, 25-26; Paper 55 at 1-2
`
`Dr. Jorgensen:
`“Q. . . . Is it possible to have an increase in entropy and a
`decrease in water solubility . . . [a]s a consequence of making
`a given chemical modification?
`“A. I said any combination is possible. So you can have an
`increase in entropy and a decrease or an increase in enthalpy
`and vice versa. So they’re not directly coupled. So any
`combination of signs with delta H and delta S are possible.”
`
`Ex. 2222 at 121:22-122:10; see also Ex. 2092 ¶ 117
`
`12
`
`
`
`A Chemical Modification May Increase
`Entropy But Decrease Water Solubility
`Paper 27 at 17-18, 25-26
`
`Dr. Jorgensen:
`“Q. Would one of ordinary skill have understood, based on
`Yalkowsky, that the more rotatable bonds you add, the greater
`the increase in water solubility?
`“A. That statement, as made by you, would be incorrect. . . .
`So it isn’t sufficient to just add rotatable bonds. If it were,
`then you could just add alkyl groups and solubility would
`increase, and that’s not the case. . . .”
`
`Ex. 2091 at 57:3-58:15; see also Ex. 2092 ¶ 117
`
`13
`
`
`
`Yalkowsky 1972 Shows That Water Solubility
`May Decrease With An Increase In Entropy
`Paper 55 at 4-6; see also Paper 27 at 25-26
`
`Ex. 2219 at 853 (Fig. 2); Ex. 2222 at 133:7-134:11
`
`14
`
`
`
`Petitioners’ Argument Relies On Yalkowsky’s
`Equation 6 To Predict Solubility Changes
`Paper 27 at 20-21
`
`Petition:
`“Yalkowsky teaches that each added rotatable bond is worth
`approximately 2.5 eu (cal/mol-K), which translates to a favorable
`contribution of (298 x 2.5 x 0.001) = 0.745 kcal/mol to the free
`energy of fusion. Based on fundamental thermodynamics of
`equilibrium (ΔG = -2.3RT log K), each 1.3 kcal/mol provides a
`factor of 10 change in an equilibrium process such as solubility.”
`
`Yalkowsky’s Equation 6: “ΔSf = 13.5 + 2.5(n – 5) eu”
`
`Paper 2 at 33; Ex. 1007 at 111; see also Ex. 2092 ¶ 97; Ex. 1003 ¶ 79
`
`15
`
`
`
`Yalkowsky Defines Long Chains As n > 5
`
`Paper 27 at 20-22
`
`Yalkowsky:
`“This is in agreement with our observation that short chains
`(n ≤ 5), which are configurationally constrained by the rigid
`portion of the molecule, do not contribute appreciably to
`ΔSint. . . . For longer chains we can estimate the contribution to
`internal entropy by adding 2.5 (n – 5) eu, where n is the total
`number of chain atoms (exclusive of protons).”
`
`Ex. 1007 at 111; see also Ex. 2092 ¶¶ 96-97
`
`16
`
`
`
`Yalkowsky’s Figure 2 Only
`Applies To Long-Chain Derivatives
`Paper 27 at 23-25
`
`Yalkowsky:
`“For purposes of visualization, the melting process can be
`divided into four independent subprocesses: . . . (4) internal—
`the change from the uniform conformation of such molecules in
`the liquid. (This process is not applicable to rigid molecules and
`thus to most drugs. It does become important, however, for
`long-chain molecules.) . . . The first three process are
`illustrated schematically in Figure 1 and the fourth in Figure 2.”
`
`Ex. 1007 at 109; see also Ex. 2092 ¶¶ 114-115
`
`17
`
`
`
`Everolimus Is Not A Long-Chain
`Derivative Of Rapamycin
`Paper 27 at 20-23
`
`Dr. Klibanov:
`
`
`
`
`“Because this C40 substituent has only four chain atoms (two
`carbons and two oxygens) exclusive of protons (i.e., n is ‘less
`than five’), it does not constitute a ‘long chain’ under
`Yalkowsky’s definition.”
`
`Ex. 2092 ¶¶ 97-99
`
`18
`
`
`
`Dr. Jorgensen Refused To Provide
`An n Value For Yalkowsky’s Equation 6
`Paper 27 at 22 & n.4
`
`Dr. Jorgensen:
`“Q. If one of ordinary skill wanted to apply Yalkowsky 1979’s
`Equation 6 to everolimus, what N value would he or she use?
`“A. First of all, a person of ordinary skill wouldn’t be
`applying Equation 6. What they would be applying is the
`concept, so they just wouldn’t be thinking that way. So I’m not
`going to conjecture on what a person of ordinary skill
`would be doing with Equation 6, because they wouldn’t be
`interested in the details of Equation 6.”
`
`Ex. 2091 at 84:19-85:5
`
`19
`
`
`
`Stella Discloses Rapamycin Prodrugs That
`Were More Water Soluble Than Rapamycin
`Paper 27 at 39-40
`
`Dr. Jorgensen:
`“Q. [Stella’s] water soluble prodrugs had significantly higher
`water solubility than rapamycin did?
`“A. Yes.”
`
`Dr. Jorgensen:
`“Q. [The water solubility of the compound of Stella, Example 3
`is] significantly more water soluble than rapamycin?
`“A. Yes. More than a thousand fold.”
`
`Ex. 2091 at 212:3-6, 214:21-215:3; see also Ex. 1010 at 3:1-6:10; Ex. 2092 ¶¶ 162-163; Ex. 2093 ¶ 93
`
`20
`
`
`
`Lemke Teaches That Salts Can
`Greatly Increase Water Solubility
`Paper 27 at 13, 54
`
`Lemke:
`“In many instances the carboxylic acid or amine functional
`group is added to organic molecules with the specific purpose
`of promoting water solubility . . . .”
`
`Lemke:
`“[Amine and carboxylic acid] groups have a potentiating
`effect on solubility, both groups can form salts that, if capable of
`dissociation, will greatly increase water solubility.”
`
`Ex. 2045 at 43, 64; see also Ex. 2092 ¶¶ 51, 171; Ex. 2093 ¶ 97
`
`21
`
`
`
`The Prior Art Includes Large C40
`Derivatives With Immunosuppressive Activity
`Paper 27 at 32-35
`
`Dr. Partridge (District Court Litigation):
`“And [workers at American Home Products] made large
`changes in C40 and maintained the immunosuppressive
`activity.”
`
`Ex. 2107 at 217:22-218:17; see also Ex. 2093 ¶ 63
`
`22
`
`
`
`The Prior Art Includes Large C40
`Derivatives With Immunosuppressive Activity
`Paper 27 at 33-35
`
`Ex. 2118, Example 2
`
`Ex. 2075, Example 1
`
`Ex. 2121, Example 3
`
`Ex. 2121, Example 13
`
`Ex. 2119, Example 6
`
`Ex. 2136, Example 9
`
`Ex. 2136, Example 6
`
`Ex. 2136, Example 12
`
`Ex. 2093 ¶¶ 63-79; Ex. 2075; Ex. 2118; Ex. 2119; Ex. 2121; Ex. 2136
`
`23
`
`
`
`Petitioners Have Not Met Their
`Burden For Selecting A Lead Compound
`Paper 27 at 47-48
`
`“In [chemical compound] cases our analysis focuses on those
`proposed lead compounds that the alleged infringer has
`attempted to prove, by clear and convincing evidence, that the
`skilled artisan would have had a reason to select from the
`panoply of known compounds in the prior art.”
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280, 1291-92 (Fed. Cir. 2012) (emphasis added)
`
`24
`
`
`
`Rapamycin’s Water Solubility Was
`Sufficient For Use As An Immunosuppressant
`Paper 27 at 51
`
`Dr. Partridge:
`“Q. . . . You would agree that as of October 1992, rapamycin
`was sufficiently water soluble to be used as an
`immunosuppressant drug; is that correct?
`“A. It was apparently water soluble, but it was water soluble
`enough, yes.”
`
`Ex. 2107 at 228:24-229:11; see also Ex. 2092 ¶ 151
`
`25
`
`
`
`There Was No Reasonable Expectation Of
`Retaining Rapamycin’s Immunosuppressive Activity
`Paper 27 at 44-45
`
`Dr. Jorgensen:
`“It’s not clear what’s going to happen with the efficacy when you
`make changes. . . . So there would be probably concern about
`the efficacy going down for any kind of change to the structure
`of rapamycin.”
`
`Dr. Jorgensen:
`“Q. What skin graft assay result would one of ordinary skill in the
`art have expected to maintain with everolimus?
`“A. . . . So what would happen with everolimus would be
`unclear. . . .”
`
`Ex. 2091 at 205:6-206:6, 254:19-255:25; see also Ex. 2093 ¶¶ 116-118
`
`26
`
`
`
`There Was No Reasonable Expectation Of Increasing
`Rapamycin’s Bioavailability By Increasing Water Solubility
`Paper 27 at 51-52
`
`Morris:
`“The lower oral bioavailability of RPM [rapamycin]
`administered PO could be caused by degradation of the RPM
`before absorption, poor absorption, or a significant first-pass
`effect leading to efficient conversion of RPM by the liver into
`metabolites . . . .”
`
`Ex. 1005 at 47; see also Ex. 2092 ¶ 152
`
`27
`
`
`
`The ’772 Patent Specification Is Not Prior Art
`
`Paper 27 at 52 n.6; Paper 54 at 3-4
`
`Ex. 2120 at 1:34-40; see also Ex. 2092 ¶ 150
`
`28
`
`
`
`There Was No Reasonable Expectation Of
`Obtaining Everolimus’s Anti-Tumor Activity
`Paper 27 at 59-60; Paper 56 at 1
`
`Dr. Ratain (District Court Litigation):
`“Q. Okay. And so if you don’t know where the pharmacophore
`[for anti-tumor activity] is, you can’t form a reasonable
`expectation of similar activity and similar toxicity related to the
`mechanism?
`“A. That’s right.”
`
`Dr. Ratain (Inter Partes Review):
`“[M]y opinions relate only to secondary considerations.”
`
`Ex. 2152 at 320:25-321:5; Ex. 2223 at 11:15-24; see also Ex. 2094 ¶¶ 85-97
`
`29
`
`
`
`Hughes Does Not Provide A Reasonable Expectation
`Of Success Of Retaining Immunosuppressive Activity
`Paper 27 at 43-44
`
`Hughes:
`“The results of the LAF standard pharmacological test procedure
`demonstrates that the compound of Example 2 suppressed T-cell
`proliferation, and is therefore useful as an immunosuppressive
`agent. Based on the results of the in vitro and in vivo standard
`pharmacological test procedures, it was unclear whether the
`compound of Example 1 had immunosuppressive activity.”
`
`Ex. 1009 at 4:14-20; see also Ex. 2093 ¶¶ 116, 119-122
`
`30
`
`
`
`Hughes Does Not Provide A Reasonable Expectation
`Of Success Of Treating Transplant Rejection
`Paper 27 at 43, 69-70
`
`Hughes Patent Examiner:
`“[O]ne of ordinary skill in the art would see that 6.5 ± 0.5 [i.e.,
`the skin graft value for the untreated control] falls within the
`error range of 7.5 ± 1.2 [i.e., the skin graft value for the
`compound of Example 1] thus are not different.”
`
`Ex. 1009 at 4:4-25; Ex. 2129 at 59; see also Ex. 2093 ¶¶ 123-126
`
`31
`
`
`
`Hughes Does Not Provide A Reasonable Expectation
`Of Success Of Treating Transplant Rejection
`Paper 27 at 43, 69-70
`
`Hughes Patent Examiner:
`“These data of the new compounds are in line with the normal
`rejection time, being less than Rapamycin, are insufficient
`evidence that these compounds will provide the ‘treatment’
`of transplant rejection in currently available form.”
`
`Hughes Cancelled Application Claim 5:
`“5. A method a treating transplant rejection, host v. graft
`disease, autoimmune disease, and diseases of inflammation in
`a mammal by administering an effective amount of a compound
`having the [claimed structure].”
`
`Ex. 2142 at 15, 26-28; see also Ex. 2093 ¶¶ 123-126, 232-233
`
`32
`
`
`
`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing Patent Owner’s Demonstrative
`
`Exhibits For Oral Hearing was served on January 31, 2017, by causing it to
`
`be sent by email to counsel for Petitioners at the following email addresses:
`
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`
`Daniel G. Brown (daniel.brown@lw.com)
`
`Robert Steinberg (bob.steinberg@lw.com)
`
`Brenda L. Danek (Brenda.danek@lw.com)
`
`
`
`Jonathan M. Strang (jonathan.strang@lw.com)
`
`Matthew L. Fedowitz (mfedowitz@merchantgould.com)
`
`B. Jefferson Boggs (jboggs@merchantgould.com)
`
`Daniel R. Evans (devans@merchantgould.com)
`
`Keith A. Zullow (kzullow@goodwinlaw.com)
`
`Marta Delsignore (mdelsignore@goodwinprocter.com)
`
`
`
`Dated: January 31, 2017
`
`
`
`
`
`
`
`
`
`1
`
`
`
`
`
`/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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