On behalf of: Par Pharmaceutical, Inc. et al.
`
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`
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`Entered: December 5, 2016
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`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 No. 5,665,772
`_______________________
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`
`PETITIONERS’ REPLY
`
`
`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.
`
`
`
`

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`Case IPR2016-00084
`U.S. Patent No. 5,665,772
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`The Claimed Compounds and Methods of Using Them as
`Immunosuppressants Would Have Been Obvious .......................................... 3
`
`A. Novartis Impermissibly Requires Petitioners to Identify a
`Single Lead Compound ......................................................................... 3
`The Prior Art Explicitly Identifies the Need to Improve
`Rapamycin’s Solubility ......................................................................... 5
`1.
`A POSA would have recognized the benefits of
`improving rapamycin’s solubility ............................................... 5
`A POSA would not have limited rapamycin
`modifications to making prodrugs or salts .................................. 6
`Rapamycin’s C40 Hydroxyl Would Have Been the Preferred
`Position for Modification ...................................................................... 8
`D. Novartis Fails to Address the Teachings of the Prior Art as a
`Whole .................................................................................................... 9
`Lemke and Yalkowsky together teach adding flexible
`1.
`bonds with polar groups to improve solubility ......................... 10
`Yalkowsky teaches that additional flexible bonds would
`have been reasonably expected to improve rapamycin’s
`water solubility .......................................................................... 12
`Yalkowsky is analogous art ...................................................... 15
`A POSA would not have preferred Novartis’s alternate
`modifications ............................................................................. 16
`Novartis Impermissibly Requires a POSA Be Motivated by
`Unknown Properties ............................................................................ 17
`Novartis Impermissibly Requires a Guarantee of Success ................. 19
`
`2.
`
`2.
`
`3.
`4.
`
`B.
`
`C.
`
`E.
`
`F.
`
`III. Novartis Has Not Established Sufficient Secondary Indicia to
`Overcome the Strong Showing of Obviousness ............................................ 20
`
`A.
`
`Everolimus Does Not Have Any Unexpected Results Compared
`to Rapamycin ....................................................................................... 20
`1.
`Everolimus does not have any difference in antitumor
`activity compared to rapamycin ................................................ 21
`Co-administration with cyclosporine is not a difference
`between everolimus and rapamycin .......................................... 25
`
`2.
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`Case IPR2016-00084
`U.S. Patent No. 5,665,772
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`3.
`
`Everolimus’s different half-life would not have been
`unexpected ................................................................................ 25
`Everolimus Did Not Satisfy Any Long-Felt But Unmet Needs ......... 26
`Novartis Fails to Provide Evidence of Commercial Success .............. 27
`
`B.
`C.
`
`IV. Conclusion ..................................................................................................... 28
`
`
`
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`Case IPR2016-00084
`U.S. Patent No. 5,665,772
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`
`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) .......................................................................... 21
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .................................................................... passim
`
`Brown & Williamson Tobacco Corp. v. Phillip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 27
`
`Daiichi Sankyo Co. v. Matrix Labs.,
`619 F.3d 1346 (Fed. Cir. 2010) ............................................................................ 3
`
`Geo M. Martin Co. v. Alliance Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 27
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) ..................................................................... 15, 18
`
`In re Freeman,
`474 F.2d 1318 (C.C.P.A. 1973) ................................................................... 21, 25
`
`In re Wilder,
`563 F.2d 457 (C.C.P.A. 1977) ............................................................................ 23
`
`Janssen Pharm. N.V. v. Mylan Pharm., Inc.,
`456 F. Supp. 2d 644 (D.N.J. 2006) ....................................................................... 7
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ............................................................................ 4
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ................................................................. 2, 8, 21
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ................................................................... 19, 23
`
`iii
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`Sanofi-Synthelabo v. Apotex Inc.,
`492 F. Supp. 2d 353 (S.D.N.Y. 2007),
`aff’d, 550 F.3d 1075 (Fed. Cir. 2008) ................................................................. 22
`
`Tec Air, Inc. v. Denso Mfg. Mich. Inc.,
`192 F.3d 1353 (Fed. Cir. 1999) .......................................................................... 27
`
`
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`I.
`
`INTRODUCTION
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`Claims 1-3 and 10 of the ’772 patent claim nothing more than compounds
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`with minor deviations from the structure of rapamycin. Claims 8 and 9 merely
`
`claim the use of those derivatives based on rapamycin’s well-known activity.
`
`Neither these compounds nor their activity was surprising. The prior art explicitly
`
`suggested modifying rapamycin to improve its water solubility. The prior art
`
`taught that derivatives modified at the C40 hydroxyl with short flexible chains
`
`containing polar groups would have reasonably been expected to improve water
`
`solubility while retaining immunosuppressant activity. Novartis has identified no
`
`persuasive evidence that the minor deviation in everolimus’s structure would result
`
`in any unexpected differences in properties compared to rapamycin.
`
`Novartis instead responds with legally irrelevant and technically incorrect
`
`distractions. Novartis first argues that rapamycin would not have been a lead
`
`compound because a POSA would allegedly have selected other known
`
`immunosuppressants over rapamycin. This argument does not withstand scrutiny.
`
`Novartis cannot reasonably dispute that references prominently and explicitly
`
`discussed rapamycin as a promising candidate for modification. Further, multiple
`
`researchers had selected rapamycin for modification by 1992, making it a “natural
`
`choice for further development efforts.” Bristol-Myers Squibb v. Teva Pharm.
`
`USA, 752 F.3d 967, 973 (Fed. Cir. 2014) (“BMS”).
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`Novartis next argues that a POSA would not have been motivated to
`
`improve rapamycin’s admittedly poor water solubility, letting formulators deal
`
`with the problem, or, if so motivated, would have only made prodrugs or salts.
`
`The prior art, however, taught rapamycin has poor water solubility and
`
`recommended making derivatives to improve rapamycin’s solubility. Novartis
`
`cannot dispute that making derivatives to address solubility was a “suitable option
`
`from which the prior art did not teach away.” Par Pharm. v. TWi Pharm., 773
`
`F.3d 1186, 1197-98 (Fed. Cir. 2014).
`
`Further, Novartis argues that a POSA could have made a myriad of other
`
`modifications at other positions because the prior art showed that they, too,
`
`resulted in derivatives with immunosuppressant activity. Novartis’s scattershot
`
`argument is self-contradictory. Novartis effectively suggests that too many such
`
`modifications would be expected to retain activity, while simultaneously asserting
`
`that a POSA would not have a reasonable expectation of obtaining an active
`
`derivative with a straightforward conservative modification. Novartis simply fails
`
`to squarely address the prior art as a whole. Instead, Novartis divides the analysis
`
`between experts, with one looking at activity and another looking at solubility. In
`
`so doing, Novartis provides no persuasive basis to find that the path identified by
`
`Dr. Jorgensen would not have been “a suitable option,” resulting in the claimed
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`compound. Id.
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`Finally, Novartis alleges everolimus has a host of properties purportedly
`
`demonstrating its non-obviousness over rapamycin. Novartis does not, and cannot,
`
`show that any of everolimus’s properties are meaningfully or unexpectedly
`
`different from those of rapamycin. In fact, everolimus’s activity stems directly
`
`from its similarity to rapamycin—its inhibition of mammalian Target Of
`
`Rapamycin (mTOR)—further confirming the obviousness of everolimus. Novartis
`
`cannot overcome the strong evidence that its derivative would have been obvious
`
`to a POSA.
`
`II. THE CLAIMED COMPOUNDS AND METHODS OF USING THEM
`AS IMMUNOSUPPRESSANTS WOULD HAVE BEEN OBVIOUS
`A. Novartis Impermissibly Requires Petitioners to Identify a Single
`Lead Compound
`
`In response to Petitioners’ evidence demonstrating that a POSA would select
`
`(and were selecting) rapamycin as a lead compound, Novartis argues that
`
`Petitioners failed to show that rapamycin was the single most promising lead
`
`compound. (POR 47-50.) That is not the law. Daiichi Sankyo v. Matrix Labs.,
`
`619 F.3d 1346, 1354 (Fed. Cir. 2010) (“[T]he lead compound analysis must, in
`
`keeping with KSR, not rigidly focus on the selection of a single, best lead
`
`compound.”).
`
`The lead compound analysis is guided by the compound’s pertinent
`
`properties and, “[g]enerally, a skilled artisan would be attracted to the most potent
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`compounds.” Otsuka Pharm. v. Sandoz, 678 F.3d 1280, 1294 (Fed. Cir. 2012). As
`
`Morris recognized, rapamycin is “the most potent xenobiotic immunosuppressant
`
`described,” “greater than FK506 and much greater than CsA.” (Ex. 1005 at 55.)
`
`Novartis contends that a POSA would not select a compound for
`
`modification unless it had clinical data, FDA approval, and a completely described
`
`biological mechanism. (POR 48-49.) A POSA would not have such stringent
`
`requirements. (Ex. 1118 ¶¶17-23.) Indeed, Novartis’s medicinal chemistry expert
`
`Dr. Roush testified that his projects only had “rodent testing.” (Ex. 1115, Roush
`
`Tr. 16:25-17:11.) If a POSA were limited to working with FDA-approved
`
`compounds, new drug compounds would rarely, if ever, be synthesized. In reality,
`
`researchers regularly selected rapamycin for modifications before the ’772 patent.
`
`(Ex. 1003 ¶¶89-100; Ex. 2093 ¶¶63-83.)
`
`Thus, a POSA would have identified rapamycin as a lead compound because
`
`of its potency and the excitement and interest it generated. (Ex. 1003 ¶¶132-137,
`
`Ex. 1118 ¶17.) Indeed, Morris reported that “[p]rogress in rapamycin (RPM)
`
`research has been rapid and is poised to accelerate even more dramatically.” (Ex.
`
`1005 at 39.) In fact, “‘medicinal chemists during the relevant time frame were
`
`actually treating and using [rapamycin] as a lead compound’ in the search for new
`
`[immunosuppressants] at the time.” BMS, 752 F.3d at 974; Ex. 2093 ¶¶63-83; Ex.
`
`1005 at 39.
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`B.
`
`The Prior Art Explicitly Identifies the Need to Improve Rapamy-
`cin’s Solubility
`1.
`
`A POSA would have recognized the benefits of improving
`rapamycin’s solubility
`
`Novartis argues that a POSA would not have been motivated to improve
`
`rapamycin’s water solubility because it was “soluble enough” and Morris did not
`
`classify it as “problematic” or “insufficient.” (POR 51.) This does not mean that a
`
`POSA would not seek to improve rapamycin’s admittedly poor solubility. BMS,
`
`752 F.3d at 974 (lead compounds are commonly modified to obtain “better”
`
`properties); Ex. 1118 ¶27-28.
`
`First, that rapamycin was just soluble to be used as a drug does not rule out
`
`obtaining significant benefits from improving its “minimal” solubility. (Ex. 1118
`
`¶27; Ex. 1005 at 46.) A POSA would have recognized that even modest
`
`improvements in rapamycin’s poor solubility would have practical advantages.
`
`(Ex. 1118 ¶¶25-26, 29; Ex. 2092 at 167:2-168:3; Ex. 1003 ¶76.) Morris taught that
`
`“[i]mproved absorption probably accounts for the improved oral bioavailability of
`
`[rapamycin] administered in solution compared with its preparation in suspension,”
`
`and that its lower bioavailability compared to FK506 and CsA “may be caused by
`
`its … less efficient absorption.” (Ex. 1005 at 55.)
`
`Dr. Klibanov asserts, without support, that the ’772 patent’s statement that
`
`“rapamycin is highly insoluble, making it difficult to formulate in stable galenic
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`compositions” is “based on [the patentees’] own work.” (Ex. 2092 ¶150.) Nothing
`
`supports Dr. Klibanov’s assertion that the ’772 patentees discovered rapamycin’s
`
`poor solubility. Rather, the clear admission in the background of the invention
`
`squarely corroborates Dr. Jorgensen’s testimony and the prior art’s recognition of
`
`rapamycin’s poor solubility. (Ex. 1003 ¶¶75-76; Ex. 1118 ¶25.) In fact, “[f]urther
`
`development of rapamycin was stopped due to solubility problems and toxicity
`
`associated with the cremophor used in the experimental formulations.” (Ex. 1034
`
`at 116.) Due to this solubility problem, the prior art recommended that a “[m]ajor
`
`emphasis [be] placed on the development of new analogs of rapamycin.” (Id.
`
`(emphasis added).)
`
`A POSA—a medicinal chemist—would have sought to address the source of
`
`the problem—the compound itself—and chemically modified rapamycin. As the
`
`prior art demonstrated, relying on formulation solutions could be ineffective or
`
`introduce other problems. (Ex. 1118 ¶¶26, 32-35; Ex. 1034 at 116 (rapamycin
`
`formulation led to “toxicity”).) A POSA would have considered resorting to
`
`formulation techniques to be a failure. (Ex. 1118 ¶¶32-35.)
`
`2.
`
`A POSA would not have limited rapamycin modifications to mak-
`ing prodrugs or salts
`
`Novartis attempts to short-circuit the POSA’s analysis of possible alternative
`
`modifications by suggesting that a POSA would have made only prodrugs and
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`water-soluble salts. (POR 53-55.)
`
`While prodrugs and salts are legitimate avenues for research, each poses
`
`particular challenges of their own, such that neither route would be preferred to the
`
`straightforward derivatives identified by Dr. Jorgensen. For example, prodrugs
`
`require metabolic conversion into the active ingredient in vivo, which create the
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`potential for significant inter- and intra-subject variability, end for interaction with
`
`enzyme inhibitors. (Ex. 1118 ¶¶37-39.) Salts generally require ionization to
`
`solubilize, creating well-known permeability issues. (Id. ¶¶42-43.) The prior art,
`
`including Dr. Klibanov’s cited references, specifically identified these and other
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`limitations for prodrugs and salts, including difficulty in predicting effect of
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`enzymes, inter-species variability, formation of dimers, intramolecular ionic
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`interactions decreasing dissolution, toxicity of counter-ions, and decreased
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`absorption of ionized species. (Id. ¶¶38-43; Ex. 1003 ¶83; see also Ex. 1115,
`
`Roush Tr. 9-16 (recounting problems posed with testing prodrugs).)
`
`Novartis relies on Janssen Pharm. v. Mylan Pharm., 456 F. Supp. 2d 644
`
`(D.N.J. 2006). (POR 54-55.) Whether a POSA would make a given modification
`
`is question of fact, and the facts in Janssen are not the facts here. The Janssen
`
`court rejected the proposed modifications to pirenperone to extend its duration of
`
`action because it would be less risky and uncertain to produce an extended release
`
`formulation. 456 F. Supp. 2d at 666-67. But here, Petitioners demonstrated that
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`the prior art as a whole would have led POSA to start by making small
`
`modifications at the C40 hydroxyl with a reasonable expectation of arriving at a
`
`derivative with improved solubility and retaining immunosuppressant activity.
`
`(Pet. 40-51; Ex. 1118 ¶44.) The law “does not require that the motivation be the
`
`best option, only that it be a suitable option from which the prior art did not teach
`
`away.” Par, 773 F. 3d at 1197-98. Making derivatives would have been (and was)
`
`a suitable option.
`
`C. Rapamycin’s C40 Hydroxyl Would Have Been the Preferred Posi-
`tion for Modification
`
`Novartis argues that “Par’s failure to consider any [other] positions (apart
`
`from C28) reflects its failure to perform a proper analysis of the prior art as a
`
`whole.” (POR 55-56.) However, Petitioners’ analyzed rapamycin’s entire
`
`structure to identify where a POSA would consider the most promising location.
`
`(Pet. 18-23.) The prior art teaches that the C40 hydroxyl would have been a
`
`POSA’s first choice for modifications, because (1) hydroxyl groups are the easiest
`
`to modify (Pet. 29-30, 32, 44; Ex. 1003 ¶142); (2) compared to the other
`
`hydroxyls, C40 was on the periphery of binding to FKBP12 and not implicated in
`
`binding to the then-unknown effector target (Pet. 29-32; Ex. 1003 ¶¶101-112, 121-
`
`123), and (3) others successfully modified rapamycin at the C40 hydroxyl and
`
`retained activity (Pet. 34-45; Ex. 1003 ¶¶57, 93-100).
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`Novartis contends modifications at other positions were possible. (POR 41;
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`Ex. 2092 ¶39; Ex. 2093 ¶¶105-113.) But Novartis does not (and cannot credibly)
`
`argue that a POSA would have started at those other locations because they would
`
`not have been seen as more likely to result in an active rapamycin derivative than
`
`C40. (Ex. 1118 ¶¶51-58.) In fact, one prior art rapamycin derivative modified at
`
`C40 had greater activity than the C28 derivative modified in the same way. (Id.
`
`¶53.) As Dr. Roush’s prior art survey demonstrates, significantly more rapamycin
`
`derivatives modified at the C40 hydroxyl retained immunosuppressant activity than
`
`those modified at any other position. (Compare Ex. 2093 ¶¶63-83 and ¶¶207-216.)
`
`And, contrary to Novartis’s suggestion, a POSA would not have preferred
`
`modifingy the C40 carbon (as opposed to the easily-modified C40 hydroxyl)
`
`because it would complicate synthesis and alter the stereochemistry of the
`
`molecule, making those modification more likely to interfere with activity. (Ex.
`
`1118 ¶¶64-70.) In reality, medicinal chemists at the time were modifying
`
`rapamycin at the C40 hydroxyl to obtain active derivatives. See BMS, 752 F.3d at
`
`974.
`
`D. Novartis Fails to Address the Teachings of the Prior Art as a
`Whole
`
`Refusing to confront the asserted combination of teachings, Novartis and its
`
`experts instead separately argue Lemke and Yalkowsky, ignoring both the problem
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`a POSA would have faced and the relevant prior art combination. As such,
`
`Novartis does not directly respond to Petitioners’ showing that the combination of
`
`prior art would have motivated a POSA to improve rapamycin’s solubility by
`
`modifying it at the C40 hydroxyl with flexible side chains containing polar groups.
`
`1.
`
`Lemke and Yalkowsky together teach adding flexible bonds with
`polar groups to improve solubility
`
`Citing the entry for ether on Lemke’s Table 16-1, Novartis argues that
`
`inserting an ethyleneoxy group would provide a “net zero effect.” (POR 11.)
`
`Novartis simply fails to address the combined teaching of Lemke and Yalkowsky.
`
`Lemke and Yalkowsky together taught that adding flexible side chains (to
`
`increase internal entropy) containing polar groups (to increase hydrophilicity) is
`
`likely to improve solubility. (E.g., Pet. 44-48.) Yalkowsky taught that the entropic
`
`effect of extending the side chain with flexible derivatives would create a powerful
`
`potential benefit to solubility. (Ex. 1118 ¶¶82-102.) Lemke teaches that extending
`
`the chain by replacing the C40 hydroxyl group to create a 2-hydroxylethoxy would
`
`not detract from the entropic benefit conferred by the additional flexible bonds.
`
`(Ex. 2092 ¶45 (stating this group would “have a net zero effect”).) Thus, a POSA
`
`would look to modify the C40 hydroxyl with a flexible side chain containing a
`
`group with water-solubilizing potential, e.g., an alcohol (hydroxyl), an amine, or a
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`carboxylic acid.2 (Ex. 1003 ¶¶146-153.) Novartis does not address this argument
`
`and combination in its response.
`
`Applying Lemke in isolation, Dr. Klibanov proposes nine modifications that
`
`a POSA would have expected “to have a beneficial impact on rapamycin’s water
`
`solubility,” because they have “an ionizable functional group.” (Ex. 2092 ¶55.)
`
`But the vast majority of Lemke’s groups do not ionize at physiological pH, and Dr.
`
`Klibanov does not cite any support showing why a POSA would ignore ten of the
`
`twelve groups included in Lemke’s table as having water-solubilizing potential.
`
`(Ex. 1118 ¶¶74-78.) Novartis provides no evidence that a POSA would disregard
`
`the noted water solubilizing potential of hydroxyl groups when, in fact, Lemke
`
`explicitly identifies hydroxyl groups as having the most water-solubilizing
`
`potential. (Ex. 1008 at 116.)
`
`
`2 Dr. Klibanov agrees that Lemke taught that rapamycin’s solubility could be im-
`
`proved by adding “nitrogen- and oxygen-containing groups,” including the amine
`
`and carboxylic acid modifications identified in the Petition. (Ex. 2092 ¶¶55, 60.)
`
`Contrary to Novartis’s insinuations, this is not a new argument raised during cross-
`
`examination. (Pet. 7, 44-48; Ex. 1003 ¶88 (flexible side chains with polar
`
`groups.); Ex. 1118 ¶¶47 & n.2, 76 & n.4.)
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`2.
`
`Yalkowsky teaches that additional flexible bonds would have been
`reasonably expected to improve rapamycin’s water solubility
`
`Novartis argues
`
`that Yalkowsky’s
`
`teachings do not apply because
`
`everolimus is not a “long chain” derivative of a “rigid” molecule. (POR 19-25.)
`
`However, Novartis fails to take rapamycin’s entire structure into account and
`
`improperly limits how a POSA would understand the impact of increased entropy
`
`on a chemical’s dissolution.
`
`Novartis does not dispute that Yalkowsky teaches that flexible side chains of
`
`longer than 6 atoms would be expected to increase a compound’s entropy of fusion
`
`upon melting. (See Ex. 2092 ¶124.) Novartis instead argues that the side chain on
`
`everolimus is shorter, arbitrarily limiting its analysis to the cyclohexyl group as the
`
`“relevant fragment” (id. ¶¶31, 99; Ex. 1118 ¶85):
`
`
`Yalkowsky taught, and Novartis does not dispute, that each added flexible
`
`bond in a chain containing more than 6 atoms would be expected to increase the
`
`entropy of fusion. (Id. ¶¶88-90.) As Novartis acknowledges (POR 19), rapamycin
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`is not a rigid molecule,3 but rather has significant flexibility (Ex. 1118 ¶¶86-87):
`
`
`
`A POSA would have looked at the entire molecule and understood that the
`
`flexible chain of rapamycin is far longer than 6 atoms, and that additional flexible
`
`bonds would increase entropy and favor dissolution. Indeed, the flexible chain
`
`3 Dr. Klibanov argues that Yalkowsky’s teachings apply only to compounds with
`
`benzene rings. (Ex. 2092 ¶¶105-108.) The teaching of the impact on increased en-
`
`tropy is not so limited, as illustrated in Yalkowsky’s Figure 2. (Ex. 1118 ¶91.)
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`extends at least back to the macrolide ring, if not further based on rapamycin’s
`
`conformation when bound to FKBP12 (id.):
`
`
`
`A POSA would have considered everolimus’s entire structure and
`
`understood that the addition of the 2-hydroxyethyl group at the C40 hydroxyl of
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`rapamycin would increase the flexibility of rapamycin with additional flexible
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`bonds. These flexible bonds would have been reasonably expected to increase the
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`internal entropy of fusion as taught by Yalkowsky and favorably influence
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`everolimus’s dissolution. (Id. ¶¶88-90; Ex. 1007 at 108 (“there is a regular
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`increase in ΔSf with increasing chain length”).)
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`Yalkowsky is analogous art
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`3.
`Novartis also contends that Yalkowsky can be ignored because it is not
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`analogous art. (POR 17-19.) A reference, though, is “analogous art” if it is
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`“within the field of the inventor’s endeavor” or “is reasonably pertinent to the
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`particular problem with which the inventor was involved.” In re Dillon, 919 F.2d
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`688, 694 (Fed. Cir. 1990). Yalkowsky is both. The ’772 patent is in the field of
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`medicinal chemistry and is seeking to improve solubility. (Ex. 1001 at 1:35-40.)
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`Dr. Yalkowsky was then (and is now) widely known to medicinal chemists as an
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`expert in solubility and his article is in the field of chemistry and directed to
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`solubility. (Ex. 1118 ¶13.)
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`That Yalkowsky passingly referred to ideal solubility does not bear on
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`determining whether it is analogous art or limit the applicability of its teachings to
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`the problem at hand. (POR 17-19.) Yalkowsky is entitled “Estimation of
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`Entropies of Fusion of Organic Compounds” and described the increased
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`conformations adopted by flexible chains upon dissolution.4 (Ex. 1118 ¶82; Ex.
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`1007 at 108, 109 & Fig. 2 (emphasis added).) This favorable effect is independent
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`of the solvent and merely reflects the conformations of the solute—and thus is not
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`4 Novartis incorrectly alleges Dr. Jorgensen did previously not rely on Yalkow-
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`sky’s Figure 2. (POR 23-24; Ex. 1118 ¶82 n.5.)
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`limited to ideal solutions. (Ex. 1118 ¶82.) Moreover, ideal solubility is premised
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`on basic thermodynamic concepts that apply to all systems, much like the ideal gas
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`law, and a POSA would have understood the same qualitative effects apply in real
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`and ideal systems. (Id. ¶¶13, 92-99.) Although a POSA would not have been
`
`interested in quantitatively calculating ideal solubility, a POSA would be very
`
`interested in the qualitative impact of entropy on solubility. (Id. ¶¶100-102.) A
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`POSA would have understood that increasing internal entropy had been shown to
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`increase calculations of ideal solubility and result in increased actual measured
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`solubility. (Id. ¶¶96-99.)
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`4.
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`A POSA would not have preferred Novartis’s alternate modifica-
`tions
`Novartis proposes a host of alternate modifications that a POSA could have
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`considered.5 However, because Novartis isolates its experts from the totality of the
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`problem set before a POSA, Novartis cannot establish that a POSA would have
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`preferred any of these modifications over the clear path set out in the Petitions.
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`As Dr. Roush testified in district court, “without guidance of what that
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`problem is that needs to be addressed and solved, it is really impossible to say”
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`5 Several of Dr. Klibanov’s suggested modification would be unstable or physio-
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`logically impossible that a POSA would not have preferred over those suggested in
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`the Petition. (Ex. 1118 ¶¶71-73, 76.)
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`what modifications a POSA would consider. (Ex. 1116, Roush Trial Tr. 726:16-
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`727:1.) Here, Novartis tasked Dr. Roush to address activity but he leaves Dr.
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`Klibanov to “address[] the water solubility aspects.” (Ex. 2093 ¶84 n.3.) And
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`Novartis tasked Dr. Klibanov to address solubility, but he does not address the
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`impact on activity. (Ex. 2092 ¶¶33-121 (never mentioning activity).) Thus, “it is
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`really impossible” for either expert to say what modifications a POSA would
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`consider when taking both activity and solubility into account. In contrast, Dr.
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`Jorgensen correctly analyzed the problem and the art as a whole. (Ex. 1118 ¶¶47-
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`50.)
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`E. Novartis Impermissibly Requires a POSA Be Motivated by Un-
`known Properties
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`Novartis argues that the Petition did not demonstrate that a POSA would
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`have reasonably expected to obtain a rapamycin derivative (1) with a half-life of 30
`
`hours, (2) that could be co-administered with cyclosporine, or (3) that would obtain
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`FDA-approval in six separate antitumor indications. (POR 56-60.)
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`Novartis (and its experts) confuse the reasonable expectation of success
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`portion of the motivation to combine analysis with the secondary consideration of
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`unexpected results.6 (Ex. 1115, Roush Tr. 33-35 (admitting he does not understand
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`6 Novartis argues that a POSA would not reasonably expect everolimus to have an-
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`titumor activity because the mechanism of rapamycin’s immunosuppressant activi-
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`the difference); Ex. 1035, Burris Dep. Tr. 19:19-24 (admitting he did not consider
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`motivation).)
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`When determining whether a POSA would have been motivated to modify
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`the prior art, the reasonable expectation of success “is measured ‘as of the date of
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`the invention,’” and any “additional unexpected properties … [do] not upset an
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`already established motivation to modify a prior art compound based on the
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`expected properties of the resulting compound.” BMS, 752 F.3d at 976. Thus,
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`“the expected properties of a claimed compound may be sufficient to lead to a
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`reasonable expectation of success in modifying a prior art compound.” Id., citing
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`Dillon, 919 F.2d at 697. Here, a POSA would have reasonably expected to
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`improve
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`rapamycin’s
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`solubility while
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`retaining
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`its
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`activity
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`as
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`an
`
`
`ty was then suggested to be different from its antitumor activity and immunosup-
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`pressants were reported to increase malignancy. (POR 59-60.) Yet Novartis’s cit-
`
`ed evidence does not support that a POSA would have expected these activities to
`
`result from different mechanisms. (Ex. 1119 ¶¶33-36.) Indeed, rapamycin’s im-
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`munosuppressant and antitumor activity stems from its inhibition of mTOR. (Id.
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`¶¶101-106.) Further, rapamycin was known in 1992 to have both immunosuppres-
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`sant and antitumor activity, and prior art patents identified C40 rapamycin deriva-
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`tives as having antitumor activity. (Id. ¶¶32-33, 43.)
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`immunosuppressant and in preventing allograft rejection. (Ex. 1003 ¶¶136, 145,
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`156; Ex. 1118 ¶¶103-110.)
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`F. Novartis Impermissibly Requires a Guarantee of Success
`Novartis also argues that a POSA would not have reasonably expected a
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`rapamycin derivative modified at C40 to retain immunosuppressive activity
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`because of a few prior art examples with weak or inconclusive activity. (POR 42-
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`47; Ex. 2093 ¶¶115-130.) At best this demonstrates there is no guarantee that
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`rapamycin derivative would retain all of rapamycin’s potency. That is not the
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`standard. Rather, “the expectation of succ