Petitioner’s Demonstratives
`
`Par Pharmaceuticals, Inc., Roxane
`Laboratories, Inc., and Breckenridge
`Pharmaceutical, Inc.,
`Petitioners
`v.
`Novartis AG,
`Patent Owner
`IPR2016-00084, IPR2016-01023, IPR2016-01102
`U.S. Patent No. 5,665,772
`
`Oral Argument
`February 2, 2017
`
`1
`
`
`
`Par Pharmaceuticals, Inc., Roxane
`Laboratories, Inc., and Breckenridge
`Pharmaceutical, Inc.,
`Petitioners
`v.
`Novartis AG,
`Patent Owner
`IPR2016-00084, IPR2016-01023, IPR2016-01102
`U.S. Patent No. 5,665,772
`
`Oral Argument
`February 2, 2017
`
`1
`
`
`
`Petitioner’s Demonstratives
`’772 Patent Claims Rapamycin Derivatives and Their Use as
`Immunosuppressants
`
`Rapamycin
`
`40-O-(2-hydroxyethyl)
`
`Ex. 1001; Pet. 11-13
`
`2
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`HO
`
`O
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`
`Instituted Grounds
`
`• Ground 1: Claims 1-3 and 10 are obvious in view of Morris, Van
`Duyne, Rossmann, Lemke, and Yalkowsky
`
`• Claims recite C40 rapamycin derivatives
`
`
`• Ground 2: Claims 8 and 9 are obvious in view of Morris, Van
`Duyne, Rossmann, Lemke, Yalkowsky, and Hughes
`
`
`• Claims recite methods of immunosuppression and preventing
`allograft rejection
`
`
`
`Ex. 1001; Pet. 11-13
`
`3
`
`
`
`Petitioner’s Demonstratives
`
`I. Rapamycin Would Have Been A Lead Compound
`
`II. A POSA Would Have Been Motivated to Improve
`
`Solubility
`
`III. A POSA Would Have Modified Rapamycin at C40
`
`Hydroxyl Using Known Techniques
`
`IV. Purported Deficiencies Raised by Novartis
`
`V. Secondary Considerations Do Not Outweigh the
`
`Other Evidence of Obviousness
`
`4
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin Would Have Been a Lead Compound
`
`•
`
`• Well-known drug with exciting and potent immunosuppressant activity
`
`Pet. 6, 16-17, 26, 41-42; Jorgensen Decl. ¶¶ 72-74, 133; Morris (1992) at 39-43, 52-64
`IND filed, “poised to accelerate,” “particularly intriguing”(Morris (1992) at 39)
`
`Pet. 6, 16-17, 26, 41-42; Jorgensen Decl. ¶¶ 74, 133
`• Hughes (1992) and Schiehser (1991) made derivatives with
`immunosuppressant activity
`Pet. 18; Jorgensen Decl. ¶¶ 89, 133, 136
`
`5
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`
`I. Rapamycin Would Have Been A Lead Compound
`
`II. A POSA Would Have Been Motivated to Improve
`
`Solubility
`
`III. A POSA Would Have Modified Rapamycin at C40
`
`Hydroxyl Using Known Techniques
`
`IV. Purported Deficiencies Raised by Novartis
`
`V. Secondary Considerations Do Not Outweigh the
`
`Other Evidence of Obviousness
`
`
`6
`
`
`
`Petitioner’s Demonstratives
`A POSA Would Be Motivated to Improve Solubility and Retain
`Immunosuppressant Activity
`
`Pet. 17, 26, 41-42; Jorgensen Decl. ¶¶ 75-76; Morris at 46
`
`• Prior art reported rapamycin was “minimally soluble” in water (20
`µg/ml) (Morris (1992) at 46)
`
`
`• Stella (1986) modified rapamycin at C28 and C40 hydroxyls to
`improve its solubility
`Pet. 18, 41-42; Jorgensen Decl. ¶¶ 90-92, 100, 140; Stella at 1:48-67, 3:56, 5:8, 6:9
`
`• Dr. Jorgensen: known benefits to improving solubility are
`improved bioavailability, better formulation, lower dosage
`Pet. 17, 41-42; Jorgensen Decl. ¶¶ 75-76, 140; Reply 5; Morris at 55; Jorgensen Supp. Decl. ¶¶ 25-27, 29;
`
`Jorgensen Dep. Tr. 167:2-168:3
`
`• ’772 Patent admits that solubility limited rapamycin as a
`pharmaceutical (Ex. 1001 at 1:36-40)
`Pet. 6, 41-42; Jorgensen Decl. ¶¶ 75, 138; Reply 5-6; Jorgensen Supp. Decl. ¶ 25
`
`7
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin Derivatives Retained Immunosuppressant Activity
`
`• Derivatives at C40 hydroxyl retained immunosuppressant activity
`Pet. 7, 18, 34-35, 44; Jorgensen Decl. ¶¶ 89, 93-100, 136
`
`• Ex. 1009 Hughes (1992)
`• Ex. 1011 Schiehser (1991)
`
`• Dr. Roush’s examples:
`• Ex. 2136 Failli (1992) (9 derivatives)
`• Ex. 2118 Failli (1991) (1 derivative)
`• Ex. 2119 Failli (1992) (2 derivatives)
`• Ex. 2075 Kao (1992) (1 derivative)
`• Ex. 2121 Caufield (1991) (6 derivatives)
`• Ex. 2122 Failli (1992) (3 derivatives)
`
`Reply 9, 19; POR 33-36; Roush Decl. ¶¶ 66-78; Jorgensen Supp. Decl. ¶¶ 103-104;
`
`8
`
`
`
`Petitioner’s Demonstratives
`
`I. Rapamycin Would Have Been A Lead Compound
`
`II. A POSA Would Have Been Motivated to Improve
`
`Solubility
`
`III. A POSA Would Have Modified Rapamycin at C40
`
`Hydroxyl Using Known Techniques
`
`IV. Purported Deficiencies Raised by Novartis
`
`V. Secondary Considerations Do Not Outweigh the
`
`Other Evidence of Obviousness
`
`
`9
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Initially Would Have Focused on Rapamycin’s Hydroxyls
`
`• Dr. Jorgensen testified that hydroxyls are synthetically easy to
`modify without disrupting stereochemistry, making them initial
`targets for modification
`Pet. 7, 18, 44, 46; Jorgensen Decl. ¶¶ 57, 142; Reply 8-9; Jorgensen Supp. Decl. ¶¶ 64-70
`
`10
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`
`C10 Hydroxyl Is in the Binding Pocket of FKBP12
`
`From Roush
`Decl. ¶ 201
`
`• C10 hydroxyl well-buried at the FKBP12 binding interface with
`“confirm[ed] . . . binding role[]” (Van Duyne (1991) at 7434)
`Pet. 20-21, 28; Jorgensen Decl. ¶¶ 111-112, 116-117, 143
`
`11
`
`
`
`Petitioner’s Demonstratives
`
`C28 Hydroxyl Interacts with FKBP12 and Is in Effector Domain
`
`Effector
`Domain
`
`Schreiber (1991) at 286, Fig. 5(B)
`
`• Schreiber (1991) showed C28 hydroxyl near effector domain
`Pet. 21-22; Jorgensen Decl. ¶¶ 121-122, 143; Schreiber at 286
`
`
`• Van Duyne (1991) described C28 hydroxyl at the “protein-ligand interface” with
`FKBP12
`
`Pet. 27-28, 30-31; Jorgensen Decl. ¶¶ 104, 112, 143; Van Duyne at 7434
`
`12
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`
`C40 Hydroxyl Would Have Been the Initial Focus for Modification
`
`• Van Duyne (1991) showed C40 hydroxyl on the periphery of FKBP12 binding
`
`Pet. 21, 29-31; Jorgensen Decl. ¶¶ 112, 143-144; Van Duyne at 7434
`• Schreiber (1991) showed C40 hydroxyl not near effector domain
`Pet. 22; Jorgensen Decl. ¶¶ 121-123; Schreiber at 286
`
`• Hughes (1992) and Schiehser (1991) reported C40 hydroxyl derivatives had
`Pet. 7, 18, 34-35, 44; Jorgensen Decl. ¶¶ 89, 93-100, 136
`immunosuppressant activity
`
`13
`
`HO
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`
`Known Techniques to Improve Solubility
`
`• Each additional flexible side chain contributes to more favorable
`entropy, providing a driving force for dissolution
`Pet. 23, 32-33, 45; Jorgensen Decl. ¶¶ 78-79, 146-147; Yalkowsky at 109, Figure 2; Jorgensen Supp. Decl. ¶ 82 n.5
`
`14
`
`
`
`Petitioner’s Demonstratives
`
`Known Techniques to Improve Solubility
`
`• Solubilizing substituents (e.g., nitrogen and oxygen containing
`groups) affect water solubility
`Pet. 23-24, 33-34, 45-46; Jorgensen Decl. ¶¶ 80-84, 148-149; Lemke at 116
`
`15
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Would Have First Used Hydroxyl, Amine, & Carboxylic Acid
`
`• Focus on groups with
`largest potential
`Pet. 45-46; Jorgensen Decl. ¶ 83
`
`Hydroxyl
`
`Phenol
`
`Amine
`
`Carboxylic
`Acid
`
`Ester
`
`Size, disrupt
`binding
`
`Hydrolyze,
`Unstable
`
`Amide
`
`Hydrolyze,
`Unstable
`Pet. 45-46; Jorgensen Decl. ¶¶ 83, 148-152; Lemke at 116
`
`16
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Would Have Started With Small Modifications First
`
`• Classic drug design strategy: start small and build up
`
`Pet. 44-45; Jorgensen Decl. ¶ 150
`• Rapamycin’s biological mechanism was not fully known
`
`• Rapamycin is large for a drug candidate
`
`Pet. 44-45; Jorgensen Decl. ¶ 150
`• Smallest stable modifications with flexible bonds containing
`hydroxyl, amine, and carboxylic acid:
`
`
`Pet. 44-45; Jorgensen Decl. ¶¶ 123, 151
`
`Pet. 46-47; Jorgensen Decl. ¶¶ 152-153
`
`17
`
`
`
`
`
`Rapamycin-C40OH Rapamycin-C40OR
`
` R
`
` = -CH2CH2OH -CH2CH2NH2
`
`
`
`
`-CH2COOH
`
`
`
`Petitioner’s Demonstratives
`
`I. Rapamycin Would Have Been A Lead Compound
`
`II. A POSA Would Have Been Motivated to Improve
`
`Solubility
`
`III. A POSA Would Have Modified Rapamycin at C40
`
`Hydroxyl Using Known Techniques
`
`IV. Purported Deficiencies Raised by Novartis
`
`V. Secondary Considerations Do Not Outweigh the
`
`Other Evidence of Obviousness
`
`
`18
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`19
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin Was a Lead Compound
`
`•
`
`[T]he lead compound analysis must, in keeping with KSR, not
`rigidly focus on the selection of a single, best lead
`compound.
`
`Daiichi Sankyo v. Matrix Labs., 619 F.3d 1346, 1354 (Fed. Cir. 2010)
`
`Novartis: “Many other immunosuppressants were known.” (POR 48)
`
`Board correctly noted that there need not be a single lead
`compound (Paper 8, Institution Decision at 13-14)
`
`
`
`
`
`
`• Morris (1992) establishes rapamycin was a “natural choice for
`further development efforts,” BMS, 752 F.3d at 973
`
`Reply 3-4
`
`Reply 1
`
`20
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin Was a Lead Compound
`
`• A POSA would not require clinical data or complete
`mechanism—scientists already selecting rapamycin as a lead
`
`Reply 3-4; Jorgensen Supp. Decl. ¶¶ 17-19, 21; Jorgensen Decl. ¶¶ 89-100; Roush Decl. ¶¶ 63-83
`
`
`
`
`
`Rapamycin more potent immunosuppressant than CsA or FK506
`Reply 3-4; Morris (1992) at 55
`
`[M]edicinal chemists during the relevant time frame were
`actually treating and using [the compound] as a lead
`compound.
`
`BMS v. Teva, 752 F.3d 967, 974 (Fed. Cir. 2014)
`
`•
`
`Generally, a skilled artisan would be attracted to the most
`potent compounds.
`
`
`
`Otsuka Pharm. v. Sandoz Inc., 678 F.3d 1280, 1294 (Fed. Cir. 2012)
`
`Reply 3-4; Ex. 1005 at 39, 55; Ex. 1118 ¶¶ 17-23, 89-100; Ex. 2093 ¶¶ 63-83; Ex. 1003 ¶¶ 132-137; Ex. 1009; Ex. 1010; Ex. 1011
`
`21
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`22
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin’s Poor Solubility Was Known
`
`Novartis: Rapamycin was “soluble enough” (POR 51)
`
`• Morris (1992) identified rapamycin as having “minimal” solubility
`
`
`• Dr. Jorgensen: medicinal chemists would seek to improve
`solubility because modest improvements have practical
`advantages
`increased bioavailability
`•
`easier formulation
`•
`lower dosages
`•
`Pet. 17, 41-42; Jorgensen Decl. ¶¶ 75-76, 140; Reply 5; Jorgensen Supp. Decl. ¶¶ 25-27, 29; Jorgensen Dep. Tr.
`167:2-168:3; Morris at 55
`
`Reply 5; Jorgensen Supp. Decl. ¶¶ 27-28
`
`
`
`
`23
`
`
`
`Petitioner’s Demonstratives
`
`Rapamycin’s Poor Solubility Was Known
`
`Novartis/Dr. Klibanov: ’772 patentees discovered rapamycin’s poor
`solubility and formulation issues (POR 52 n.6, Klibanov Decl. ¶ 150)
`
`• Only fair reading of ’772 patent is admission of known poor
`solubility and formulation issues
`
`
`•
`
`“[R]apamycin is highly insoluble, making it difficult to
`formulate in stable galenic compositions.”
`
`Ex. 1001 1:39-40
`
`
`Prior art identified formulation problems due to rapamycin’s
`poor water solubility
`
`Reply 5-6; Jorgensen Supp. Decl. ¶ 25; Jorgensen Decl. ¶¶ 75-76
`
`
`
`“Further development of rapamycin was stopped due to
`solubility problems and toxicity associated with the
`cremophor used in the experimental formulations.”
`
`
`
`
`Ex. 1034 Fiebig (1991) at 116
`
`24
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`25
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Would Have Synthesized Rapamycin Derivatives
`
`Novartis: POSA would have used formulation techniques or only
`made prodrugs or salts (POR 53-55)
`
`• A POSA is a medicinal chemist—not a formulator
`Pet. 16; Jorgensen Decl. ¶¶ 44-48; Reply 6; Jorgensen Supp. Decl. ¶ 32
`
`• A medicinal chemist would seek to address the source of the
`problem, the compound itself
`
`• A medicinal chemist would consider resorting to formulation
`techniques a failure
`
`Reply 6; Jorgensen Supp. Decl. ¶ 33
`
`
`
`Reply 6; Jorgensen Supp. Decl. ¶ 35
`
`The law “does not require that the motivation be the best
`option, only that it be a suitable option.”
`Par v. TWi, 773 F.3d 1186, 1197-98 (Fed. Cir. 2014)
`
`26
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Would Have Synthesized Rapamycin Derivatives
`
`•
`
`•
`
`Prior art explicitly recommended making derivatives:
`“[M]ajor emphasis placed on the development of new
`analogs of rapamycin.” (Ex. 1034 Fiebig (1991) at 116)
`
`
`Prodrugs and salts have limitations and challenges
`
`
`
`Reply 6
`
`•
`•
`•
`
`inter- and intra-species variability
`ionic interactions could stabilize crystal and reduce solubility
`reduced bioavailability
`
`Reply 6-8; Jorgensen Supp. Decl. ¶¶ 37-43; Jorgensen Decl. ¶ 83
`
`27
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`28
`
`
`
`Petitioner’s Demonstratives
`A POSA Would Have Had a Reasonable Expectation of Success Tied
`to the Relevant Motivation
`
`[E]xpected properties of a claimed compound may be
`sufficient to lead to a reasonable expectation of success in
`modifying a prior art compound . . . . [A]dditional unexpected
`properties . . . [do] not upset an already established
`motivation to modify a prior art compound based on the
`expected properties of the resulting compound.
`BMS, 752 F.3d at 976
`
`Reply 17-19
`
`29
`
`
`
`Petitioner’s Demonstratives
`
`Motivation: Immunosuppressant with Increased Solubility
`
`Novartis: No reasonable expectation of achieving compound with
`FDA-approved antitumor indications, specific half-life, and ability to
`co-administer with CsA (POR 56-60)
`
`• Novartis conflates “reasonable expectation of success” and
`“unexpected results”
`
`Reply 17-18
`
`
`
`•
`
`Reasonable expectation relates to POSA’s motivation
`
`• Unexpected results are a secondary consideration
`
`• Novartis’s expert did not apply the correct standard:
`Q. Dr. Roush, do you know the difference between objective
`indicia and reasonable expectation of success?
`A. I guess I don’t.
`
`Reply 17-18; Ex. 1115 Roush Dep. Tr. 34:24-35:5
`
`30
`
`
`
`Petitioner’s Demonstratives
`
`Motivation: Immunosuppressant with Increased Solubility
`
`•
`
`Novartis: No reasonable expectation of achieving compound with
`FDA-approved antitumor indications, specific half-life, and ability to
`co-administer with CsA (POR 56-60)
`
`Petition: A POSA would have been motivated to improve
`rapamycin’s solubility while maintaining immunosuppressant
`activity (Pet. 16-19, 26-27, 41-44)
`
`In forming reasonable expectation opinions, Novartis’s expert did
`not take a POSA’s motivation into account
`Reply 17-18
`
`•
`
`
`
`Q. You didn’t consider a motivation in coming to your
`conclusions on whether or not a person of ordinary skill in
`the art would have had a reasonable expectation of success?
`A. Correct.
`
`
`Ex. 1035 Burris Dep. Tr. 19:19-24
`
`31
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`32
`
`
`
`Petitioner’s Demonstratives
`
`Lemke and Yalkowsky Combined Teachings
`
`Novartis: “Ethyleneoxy” group would not increase solubility (POR 11)
`
`Lemke in combination with Yalkowsky teaches flexible side
`chains with solubilizing groups improve solubility
`Pet. 44-48; Reply 10-11; Jorgensen Decl. ¶¶ 146-153; Board Inst. Decision at 15
`
` •
`
`Novartis:
`+ 2 carbons – 2 carbons =
`net zero solubilizing effect
`Reply 10-11; Klibanov Decl. ¶ 45
`
`33
`
`
`
`Petitioner’s Demonstratives
`
`Yalkowsky Teaches Added Flexible Bonds Increase Entropy
`
`Novartis: Everolimus is not a “long-chain derivative” (POR 20-25)
`
`• Undisputed that rapamycin is not a rigid molecule
`
`• Undisputed that Yalkowsky teaches favorable impact on internal
`entropy for side chains greater than 6 atoms
`
`
`Reply 12; Klibanov Decl. ¶ 124
`
`Reply 12; POR 19
`
`Novartis’s “Relevant Fragment”
`
`Klibanov Decl. ¶¶ 30, 99
`
`Reply 12-14; Jorgensen Supp. Decl. ¶¶ 13, 85-90
`
`34
`
`HO
`
`O
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`O
`
`N
`
`O
`
`10
`
`O
`
`O
`
`OH
`O
`
`O
`
`
`
`Petitioner’s Demonstratives
`Combination of Lemke and Yalkowsky Show Expectation of
`Improved Solubility
`
`• Dr. Jorgensen: “Yalkowsky teaches that each added rotatable bond is worth
`approximately 2.5 eu (cal/mol-K), which translates to a favorable contribution
`of . . . 0.745 kcal/mol to the free energy of fusion. Based on fundamental
`thermodynamics of equilibrium . . . , each 1.3 kcal/mol provides a factor of 10
`change in an equilibrium process such as solubility.”
`Jorgensen Decl. ¶ 79
`
`• Novartis admits Lemke teaches an “ethyleneoxy” group would have “net zero”
`impact on solubility due to hydrophilicity (π value) POR 11; Klibanov Decl. ¶¶ 45-46 & n.5
`
`↑ favorable entropy + 0 effect on hydrophilicity ↑ solubility
`Reply 10-11
`
`35
`
`
`
`Petitioner’s Demonstratives
`
`Lemke Does Not Limit Solubilizing Groups to Salt-Forming Groups
`
`Novartis: POSA would only use ionizing groups (POR 12-13)
`
`10 of the 12 functional groups do not ionize
`Reply 11; Jorgensen Supp. Decl. ¶¶ 74-78
`
` •
`
`36
`
`
`
`Petitioner’s Demonstratives
`
`Yalkowsky’s Teachings on Internal Entropy Apply to Rapamycin
`
`Novartis: Yalkowsky is limited to ideal solubility (POR 17-19)
`
`Like the ideal gas law, ideal solubility is a model to understand
`real systems
`
` •
`
`Reply 15-16; Jorgensen Supp. Decl. ¶¶ 13, 92-99
`• Dr. Klibanov: assumptions for ideal systems “never happen”
`and are used to further understanding of real systems (Ex.
`1114 Klibanov Dep. Tr. at 42:11-44:8)
`
`Increase in internal entropy leads to increase in solubility in
`examples of nonideal solutions (Ex. 1117 Schwartz at 254,
`Table II, Table III)
`
`
`
`•
`
`Reply 16; Jorgensen Supp. Decl. ¶¶ 96-99
`
`37
`
`
`
`Petitioner’s Demonstratives
`
`Yalkowsky’s Teachings on Internal Entropy Apply to Rapamycin
`
`Novartis: Yalkowsky is limited to ideal solubility (POR 17-19)
`
`Yalkowsky teaches internal entropy
`
`Reply 15-16; Jorgensen Supp. Decl. ¶ 82
`
`Internal entropy is property of solute, independent of solvent
`Reply 15-16; Jorgensen Supp. Decl. ¶ 82
`
` •
`
`•
`
`38
`
`
`
`Petitioner’s Demonstratives
`
`Novartis’s Arguments Are Legally or Scientifically Incorrect
`
`1. Rapamycin as a lead compound
`
`2. Rapamycin solubility
`
`3. Approach to address rapamycin solubility
`
`4. Motivation to modify rapamycin
`
`5. Teachings of Lemke combined with Yalkowsky
`
`6. Reasonable expectation of success
`
`
`
`39
`
`
`
`Petitioner’s Demonstratives
`
`C40 Rapamycin Derivatives Retained Immunosuppressant Activity
`
`Novartis: Immunosuppressant activity of C40 rapamycin derivatives
`“unpredictable,” so no reasonable expectation of obtaining active
`derivative (POR 42-45)
`
`• Most reported C40 rapamycin derivatives had
`immunosuppressant activity (Hughes (1992), Scheihser (1991),
`Roush Decl. ¶¶ 63-79, citing exhibits)
`
`Few examples with weak or inconclusive activity would not
`undermine reasonable expectation of immunosuppressant
`activity
`
`
`•
`
`Reply 19-20
`
`Reply 19-20; Jorgensen Supp. Decl. ¶¶ 103-108
`
`40
`
`
`
`Petitioner’s Demonstratives
`
`A POSA Would Reasonably Expect to Improve Solubility
`
`Novartis: A POSA would not reasonably expect improved solubility
`because ethyleneoxy group did not increase water solubility in two
`examples (POR 27-28)
`
`
`
`•
`
`Stella (1985): rapamycin derivatives with 2500-fold increased
`water solubility using flexible side chains containing polar groups
`Reply 19-20; Jorgensen Supp. Decl. ¶ 15
`
`
`
`
`• Dr. Klibanov’s examples are irrelevant—no internal entropic
`advantage of mixing a liquid in a liquid
`Reply 19-20; Jorgensen Supp. Decl. ¶¶ 109-110
`
`
`41
`
`
`
`Petitioner’s Demonstratives
`
`I. Rapamycin Would Have Been A Lead Compound
`
`II. A POSA Would Have Been Motivated to Improve
`
`Solubility
`
`III. A POSA Would Have Modified Rapamycin at C40
`
`Hydroxyl Using Known Techniques
`
`IV. Purported Deficiencies Raised by Novartis
`
`V. Secondary Considerations Do Not Outweigh the
`
`Other Evidence of Obviousness
`
`42
`
`
`
`Petitioner’s Demonstratives
`
`Novartis Fails to Establish Any Secondary Consideration
`
`1. Everolimus does not have any unexpected results compared to
`rapamycin
`
`2. Everolimus did not satisfy any long-felt but unmet need
`
`3. Novartis did not establish that everolimus is a commercial
`success
`
`43
`
`
`
`Petitioner’s Demonstratives
`
`Everolimus Is Not Unexpectedly Different From Rapamycin
`
`Unexpected results requires both that
`
`(1) there is an actual difference in properties from the
`closest prior art and
`(2) the difference would have been unexpected to a POSA
`in 1992
`In re Freeman, 474 F.2d 1318, 1324 (C.C.P.A. 1973); BMS, 752 F.3d at 977
`
`•
`
`•
`
`•
`
`Reply 20-21
`Everolimus does not have different antitumor activity from
`rapamycin
`
`Everolimus does not have different cyclosporine
`pharmacokinetics
`
`Everolimus’s different half-life would not be unexpected
`Reply 25-26
`
`
`Reply 21-25
`
`Reply 25
`
`44
`
`
`
`Petitioner’s Demonstratives
`
`Novartis Fails to Compare Properties of Everolimus and Rapamycin
`
`• Novartis relies on FDA approval but does not identify any direct
`comparison of everolimus to the actual properties of rapamycin
`
`Reply 21-25
`
`To determine whether a given compound is obvious compared to the prior
`
`art compound, any and all properties of those compounds must be
`
`considered, even where the prior art has not disclosed the relevant
`
`properties of the prior art.
`Sanofi-Synthelabo v. Apotex, 492 F. Supp. 2d 353, 390 (S.D.N.Y. 2007)
`
`
`
`45
`
`
`
`Petitioner’s Demonstratives
`
`No Difference in Antitumor Activity
`
`• When properties compared, no difference between compounds
`
`Reply 22-23; Ratain Decl. ¶¶ 62-100
`• Regulatory approval status is not a property of the compound
`Reply 22; Ratain Decl. ¶¶ 51-55, 95
`• Reflects pharmaceutical industrial support and strategy
`
`
`
`
`
`• Can vary from country to country
`
`
`• Rapamycin has clinical activity in each of the approved tumor
`indications
`Reply 22-23; Ratain Decl. ¶¶ 62-100
`
`
`
`• Breast cancer (E.g., Ex. 2178, Ex. 2177)
`• Renal cell carcinoma (Ex. 2173, Ex. 1087)
`• NETs (Ex. 1088, Ex. 2163)
`• SEGA (Ex. 1098, Ex. 1099)
`• Renal angiomyolipoma (Ex. 1093)
`
`Ratain Decl. ¶¶ 64-75
`
`Ratain Decl. ¶¶ 83-87
`
`Ratain Decl. ¶¶ 76-82
`
`Ratain Decl. ¶¶ 96-100
`
`Ratain Decl. ¶¶ 88-95
`
`46
`
`
`
`Petitioner’s Demonstratives
`
`Breast Cancer
`
`
`
`No Difference in Antitumor Activity
`
`• Novartis’s expert: rapamycin breast cancer activity “impressive”
`
`
`
`• Clinical results broadly cited as demonstrating rapamycin’s activity
`in breast cancer
`
`Renal Cell Carcinoma
`
`Reply 23-24; Ratain Decl. ¶¶ 67, 70-71; Burris Dep. Tr. at 114:6-12
`
`
`• Rapamycin, as active metabolite of temsirolimus, approved by
`FDA with broader indication and as first-line therapy
`Reply 24-25; Ratain Decl. ¶¶ 85-87; Ex. 1087
`
`
`
`
`NETs
`
`
`
`• Activity of rapamycin in NETs compares favorably to reported
`activity that supported everolimus’s FDA-approval
`Reply 24; Ratain Decl. ¶¶ 79-82
`
`47
`
`
`
`Petitioner’s Demonstratives
`
`The Similar Activity of Rapamycin and Everolimus Is Not Surprising
`
`Reply 23; Ratain Decl. ¶¶ 101-108; Ex. 1120 at Fig. 1
`
`48
`
`
`
`Petitioner’s Demonstratives
`
`No Difference in Cyclosporine Pharmacokinetics
`
`• Cyclosporine interferes with metabolism of everolimus and
`rapamycin, leading to increase in plasma concentrations
`
`Reply 25; Ratain Decl. ¶ 46
`• Two methods to address increase in mTOR inhibitor levels
`Reply 25; Ratain Decl. ¶ 46
`
`
`1. Separate the dose of cyclosporine and mTOR inhibitor
`
`
`2. Reduce the dose of cyclosporine and mTOR inhibitor
`
`
`
`• No evidence that rapamycin and everolimus interact differently
`with cyclosporine
`
`Reply 25; Ratain Decl. ¶ 46
`
`49
`
`
`
`Petitioner’s Demonstratives
`
`No Unexpected Difference in Half-Life
`
`• No evidence that difference in half-life would be unexpected
`Reply 25-26
`
`• Actual difference in properties is not enough—difference must be
`unexpected
`
`• As of 1992, derivatives frequently reported to have different half-
`lives from parent compound
`
`• Longer half-lives considered to be clinically beneficial to reduce
`frequency of dosing and improve patient compliance
`Reply 25-26; Ratain Decl. ¶¶ 49-50
`
`Reply 25-26; Ratain Decl. ¶ 47
`
`Reply 25-26
`
`50
`
`
`
`Petitioner’s Demonstratives
`
`Novartis Fails to Establish Any Secondary Consideration
`
`1. Everolimus does not have any unexpected results compared to
`rapamycin
`
`2. Everolimus did not satisfy any long-felt but unmet need
`
`3. Novartis did not establish that everolimus is a commercial
`success
`
`51
`
`
`
`Petitioner’s Demonstratives
`
`Everolimus Did Not Satisfy Any Unmet Needs
`
`Rapamycin met need first
`
`
`
`
`
`• Rapamycin active in breast and renal cell cancer
`Reply 26; Ratain Decl. ¶¶ 64-75, 83-87, 109-110
`• Rapamycin approved and available for use in patients before
`everolimus
`
`
`Reply 26; Ratain Decl. ¶ 109
`
`Need was not satisfied
`
`
`
`• Need remains for breast and renal cell cancer treatments
`
`
`
`• Other treatments explicitly have been shown to be superior to
`everolimus
`
`Reply 26-27; Ratain Decl. ¶ 111
`
`52
`
`
`
`Petitioner’s Demonstratives
`
`Novartis Fails to Establish Any Secondary Consideration
`
`1. Everolimus does not have any unexpected results compared to
`rapamycin
`
`2. Everolimus did not satisfy any long-felt but unmet need
`
`3. Novartis did not establish that everolimus is a commercial
`success
`
`53
`
`
`
`Petitioner’s Demonstratives
`
`No Evidence Establishing Commercial Success
`
`• Gross sales, without more, do not establish commercial success
`Reply 27
`
`
`
`
`• No market or economic analysis performed
`
`
`
`• No evidence sales due to properties of everolimus and not FDA-
`approval
`
`
`Reply 27; Burris Dep. Tr. 135:12-137:3
`
`Reply 27-28; Ex. 2055; Ex. 2051
`
`• Rapamycin FDA-approved for immunosuppression
`
`• Does not cite Zortress sales for immunosuppression
`
`54
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), I certify that on this 31st day of January,
`
`2017, a
`
`true and correct copy of
`
`the
`
`foregoing PETITIONERS’
`
`DEMONSTRATIVES was served by electronic mail on Patent Owner’s lead and
`
`backup counsel at the following email address:
`
`Nicholas N. Kallas (Reg. No. 31,530)
`Peter J. Waibel (Reg. No. 43,228)
`Christina Schwarz (pro hac vice)
`Charlotte Jacobsen (pro hac vice)
`Susanne L. Flanders (pro hac vice)
`Jared L. Stringham (pro hac vice)
`Fitzpatrick, Cella, Harper & Scinto
`1290 Avenue of the Americas
`New York, NY 10104-3800
`ZortressAfinitorIPR@fchs.com
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`By: /Daniel G. Brown/
`
`Daniel G. Brown (Reg. No. 54,005)
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`212-906-1200; 212-751-4864 (Fax)
`
`Counsel for Petitioner
`Par Pharmaceutical, Inc.
`
`
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`
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