`Trials@uspto.gov Paper 73
`571-272-7822
`
`Entered: January 11, 2018
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`Before LORA M. GREEN, CHRISTOPHER L. CRUMBLEY, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`CRUMBLEY, Administrative Patent Judge.
`
`
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`BRECKENRIDGE PHARMACEUTICAL, INC., AND
`ROXANE LABORATORIES, INC.,
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`_____________
`
`Case IPR2016-000841
`Patent 5,665,772
`____________
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`
`
`
`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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`I. INTRODUCTION
`In this inter partes review trial, instituted pursuant to 35 U.S.C. § 314,
`Petitioners Par Pharmaceutical, Inc., Breckenridge Pharmaceutical, Inc., and
`Roxane Laboratories, Inc. (collectively, “Par”) challenge the patentability of
`claims 1–3 and 8–10 of U.S. Patent No. 5,665,772 (“the ’772 patent,”
`Ex. 1001), owned by Novartis AG.
`We have jurisdiction under 35 U.S.C. § 6(b). This Final Written
`Decision, issued pursuant to 35 U.S.C. § 318(a), addresses issues and
`arguments raised during trial. For the reasons discussed below, we
`determine that Par has not proven, by a preponderance of the evidence, that
`claims 1–3 and 8–10 of the ’772 patent are unpatentable.
`
`A. Procedural History
`
`On October 26, 2015, Par requested an inter partes review of claims
`1–3 and 8–10 of the ’772 patent. Paper 2, “Pet.” Novartis filed a Patent
`Owner Preliminary Response. Paper 7. In a Decision on Institution of Inter
`Partes Review (Paper 8, “Dec. on Inst.”), we instituted trial as to claims 1–3
`and 8–10 on the following grounds of unpatentability:
`
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`1. Whether claims 1–3 and 10 are unpatentable under 35 U.S.C.
`§ 103(a) as having been obvious over Morris,2 Van Duyne,3
`Rossmann,4 Yalkowski,5 and Lemke6; and
`2. Whether claims 8 and 9 are unpatentable under 35 U.S.C. § 103(a)
`as having been obvious over Morris, Van Duyne, Rossmann,
`Yalkowski, Lemke, and Hughes.7
`Dec. on Inst. 18.
`Novartis filed a Request for Rehearing of our decision to institute trial
`(Paper 10), which we denied (Paper 21).
`Breckenridge filed a Petition and Motion for Joinder in IPR2016-
`01023, and Roxane filed a Petition and Motion for Joinder in IPR2016-
`01102. We granted Breckenridge’s Motion and granted-in-part Roxane’s
`Motion, and joined Breckenridge and Roxane as parties to this proceeding.
`Paper 37. We denied-in-part Roxane’s Motion to the extent it sought to add
`
`
`2 Randall Ellis Morris, Rapamycins: Antifungal, Antitumor,
`Antiproliferative, and Immunosuppressive Macrolides, 6 TRANSPLANTATION
`REVIEWS 39-87 (1992) (Ex. 1005).
`3 Gregory D. Van Duyne et al., Atomic Structure of the Rapamycin Human
`Immunophilin FKBP-12 Complex, 113 J. AM. CHEM. SOC’Y 7433–35 (1991)
`(Ex. 1006).
`4 Michael G. Rossmann et al., Three-Dimensional Coordinates from
`Stereodiagrams of Molecular Structures, B36 ACTA CRYST. 819–823 (1980)
`(Ex. 1024).
`5 Samuel H. Yalkowsky, Estimation of Entropies of Fusion of Organic
`Compounds, 18 INDUS. ENG’G CHEM. FUNDAM. 108–11 (1979) (Ex. 1007).
`6 Thomas L. Lemke, Chapter 16: Predicting Water Solubility, REVIEW OF
`ORGANIC FUNCTIONAL GROUPS 113–21 (2d ed. 1988) (Ex. 1008).
`7 U.S. Patent No. 5,233,036 to Hughes (Aug. 3, 1993) (Ex. 1009).
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`claim 7 of the ’772 patent to the instituted trial, and also denied Par’s Motion
`for Joinder in IPR2016-01059 and Breckenridge’s Motion for Joinder in
`IPR2016-01103, both of which sought joinder of claim 7. Id. Par,
`Breckenridge, and Roxane filed requests for rehearing of these denials.
`IPR2016-01059, Paper 20; IPR2016-01102, Paper 19; IPR2016-01103,
`Paper 19. As set forth in a Decision entered today in the related cases, these
`requests for rehearing are moot in view of our determination herein that
`claim 1 has not been proven unpatentable.
`Novartis filed a Patent Owner Response (Paper 27, “PO Resp.”), and
`Par filed a Reply (Paper 46, “Pet. Reply”).
`Par supported its Petition with the Declaration of William L.
`Jorgensen, Ph.D. Ex. 1003. Novartis took cross-examination testimony of
`Dr. Jorgensen via deposition and submitted the transcript of that deposition.
`Ex. 2091.
`With its Response, Novartis submitted three declarations: the
`Declaration of Alexander M. Klibanov (Ex. 2092); the Declaration of
`William R. Roush, Ph.D. (Ex. 2093); and the Declaration of Howard A.
`Burris, III, M.D. (Ex. 2095). Par cross-examined Novartis’s experts via
`deposition, and submitted the transcripts. Exs. 1114 (Klibanov), 1115
`(Roush), 1035 (Burris).
`With its Reply, Par submitted a Supplemental Declaration of
`Dr. Jorgensen (Ex. 1118), and submitted the declaration testimony of a
`second witness, Mark J. Ratain, M.D. (Ex. 1119). Novartis took cross-
`examination testimony via deposition of Drs. Jorgensen and Ratain, and
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`submitted the transcripts to the Board. Exs. 2222 (Jorgensen), 2223
`(Ratain).
`Novartis filed separate Observations on the Cross-Examination of
`Drs. Jorgensen and Ratain (Papers 55, 57), and Par filed Responses to the
`Observations (Papers 58, 59).8 As authorized by the Board, Novartis also
`filed an Identification of Portions of Petitioner’s Reply that allegedly exceed
`the proper scope of reply (Paper 63), and Par filed a Response to that list
`(Paper 65).
`Novartis filed a Motion to Exclude various exhibits and papers
`submitted by Par (Paper 54, “Mot.”), to which Par filed an Opposition
`(Paper 60) and Novartis filed a Reply (Paper 62).
`Oral hearing was requested by both parties (Papers 51, 52), and
`argument before the Board was held February 2, 2017. A transcript of the
`oral hearing is included in the record. Paper 71, “Tr.”9 Both parties filed
`
`
`8 In its responses to Novartis’ Observations, Par contends that by filing two,
`15-page observations, Novartis has exceeded the Board’s page limits. Paper
`60, 2–3. We agree that our Scheduling Order only authorized a single filing
`of observations; thus, Novartis exceeded the page limit by 15 pages.
`Furthermore, as Par argues, Novartis’ Observations are impermissibly
`argumentative because they characterize the witnesses’ testimony rather than
`simply setting forth the testimony itself. Per our Trial Practice Guide,
`excessively long or argumentative observations may be refused entry. See
`77 Fed. Reg. 48,756, 48,768. In view of Novartis’ failure to comply with
`our rules, we have not considered the Observations in reaching our
`conclusions in this Decision.
`9 With the authorization of the Board, Novartis filed an Unopposed Notice of
`Transcription Error (Paper 72) regarding an alleged error on page 48 of the
`transcript.
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`with the Board demonstrative exhibits that were used during the oral hearing
`(Papers 68, 70), but in view of the parties’ numerous objections to the
`exhibits (Papers 67, 69) and the fact that demonstratives are not evidence,
`the Board will expunge the demonstrative exhibits from the record.
`
`B. The ’772 Patent
`
`The ’772 patent, titled “O-alkylated Rapamycin Derivatives and Their
`Use, Particularly as Immunosuppressants,” issued September 9, 1997, from
`U.S. Patent Application No. 08/416,673, filed on September 24, 1993.
`Ex. 1001, (54), (45), (21), (22). The patent is directed to derivatives of
`rapamycin, which are said to have pharmaceutical utility, particularly as
`immunosuppressants. Ex. 1001, Abstract.
`Rapamycin is a known immunosuppressant having the following
`chemical structure:
`
`
`Id. at 1:15. The ’772 patent discloses various derivatives of rapamycin, in
`particular alkylated derivatives having substitutions at the 9, 26, 28, 39, or
`40 carbon. Id. at 1:50–2:19 (Formula I). Of these derivatives, the “preferred
`novel compounds” are the 40-O-substituted rapamycins. Id. at 2:55–56.
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`According to the ’772 patent, the disclosed rapamycin derivatives are
`particularly useful for treatment and prevention of a range of conditions,
`including: organ or tissue transplant rejection; autoimmune disease and
`inflammatory conditions; asthma; multi-drug resistance; tumors; fungal
`infections; inflammation; infection; and overdoses of other
`immunosuppressants. Id. at 3:22–4:10. The preferred 40-O-substituted
`derivatives are said to be highly immunosuppressive and are particularly
`useful in treating transplant rejection or autoimmune disease. Id. at 4:21–25.
`
`C. Illustrative Claim
`
`Of the challenged claims, claim 1 is independent, and is reproduced
`
`below:
`
`1. A compound of the formula:
`
`wherein R1 is hydroxy(C1–6)alkyl or
`hydroxy(C1–3)alkoxy(C1–3)alkyl.
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`Ex. 1001, 21:13–22:2.10
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`Claim 10 depends from claim 1 and is directed to a particular
`derivative of rapamycin, 40-O-(3-hydroxyethyl)-rapamycin, commonly
`called everolimus.
`
`II. ANALYSIS
`
`A. Claim Construction
`
`For purposes of our Decision on Institution, we noted that neither
`
`party asked that we construe any term used in the challenged claims, and we
`agreed that no terms required an express construction. Dec. on Inst. 7.
`During the instituted trial, neither party disagreed with this assessment, and
`we again see no need to provide an express construction for any of the terms
`in the challenged claims.
`
`B. Par’s Theory of the Case
`
`Par contends that claims 1–3 and 10 are unpatentable under 35 U.S.C.
`
`§ 103(a), as their subject matter would have been obvious over the combined
`disclosures of Morris, Van Duyne, Rossmann, Yalkowski, and Lemke. Pet.
`40–48. Par explains how the combined references teach the subject matter
`of each challenged claim and asserts that a person of ordinary skill in the art
`would have had reason to combine or modify the references. Id. Par also
`relies upon the Declaration of Dr. William Jorgensen (Ex. 1003) to support
`its positions.
`
`
`10 The chemical formula of claim 1 was corrected in a Certificate of
`Correction dated February 9, 2016.
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`In our Decision on Institution, we summarized the cited prior art and
`
`then Par’s theory of the case, which is based on a lead compound analysis.
`For completeness, we repeat those summaries below.
`
`1. Summary of the Prior Art
`Morris is a review of the research into rapamycin, “written relatively
`early in the research life of [rapamycin].” Ex. 1005, 41. Rapamycin is said
`to be “particularly intriguing because it inhibits the activation of immune
`cells by unique, relatively selective, and extremely potent and highly
`effective mechanisms.” Id. at 39. Morris reports that while water soluble
`prodrugs of rapamycin have been synthesized, rapamycin itself is only
`minimally soluble in water, at 20 µg/mL. Id. at 46. Furthermore, Morris
`states that the toxicity of rapamycin is “not known,” but that mice and rats
`appear to be very resistant to acute toxic effects of the drug. Id. at 49. Large
`animals were found to be more susceptible to toxic effects. Id. at 50–51.
`Nevertheless, Morris concludes that rapamycin and other new
`immunosuppressants “enable combination immunosuppressive therapy to
`reach new levels of sophistication” and “offer the hope that rejection can be
`prevented and treated more effectively and safely than ever before.” Id. at
`82.
`
`Van Duyne is a study of the atomic structure of the complex of
`rapamycin and FKBP-12, the immunophilin to which rapamycin binds.
`Ex. 1006, 7433. Van Duyne contains a stereodiagram of the alpha-carbon
`structure of the rapamycin/FKBP-12 complex, and discloses that rapamycin
`binds in a cavity in the FKBP-12 protein. Id. at 7433–34. The interface is
`said to involve atoms from rapamycin’s pyranose ring through the C28
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`hydroxyl, but also involves two additional hydrogen bonds, one being at the
`C40 hydroxyl. Id. at 7434. Van Duyne states that coordinates of the bound
`rapamycin complex are available from its authors, and will be deposited in
`the Brookhaven Protein Databank. Id.
`Rossmann discloses a method of deriving three-dimensional
`coordinates from stereodiagrams of molecular architecture. Ex. 1024, 819.
`Rossmann notes that many publications provide stereodiagrams of proteins
`and nucleic acids, but do not provide coordinates for the structure which
`would permit quantitative use of the published structural data. Id.
`Yalkowski discusses the estimation of the entropy of fusion for drugs
`and molecules of intermediate size. Ex. 1007, 108. Longer chains are said
`to contribute to internal entropy by 2.5 (n – 5) eu, where n is the number of
`atoms in the chain. Id. at 111. Dr. Jorgensen testifies that this means 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.”
`Ex. 1003 ¶ 79.
`
`Lemke provides a summary of the solubilizing potential of various
`functional groups in Table 16–1. Ex. 1008, 115–16. For example, in a
`polyfunctional molecule, an alcohol group is said to have the potential to
`solubilize 3–4 carbons, while an amine group may solubilize 3 carbons. Id.
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`2. Par’s Lead Compound Analysis
`To support its contention of obviousness, Par sets forth a “lead
`compound analysis” explaining how a person of ordinary skill in the art
`would have modified rapamycin to arrive at everolimus, the compound
`recited in claim 10 of the ’772 patent. Pet. 40. A lead compound analysis
`follows a two-part inquiry. First, we “determine[] whether a chemist of
`ordinary skill would have selected the asserted prior art compounds as lead
`compounds, or starting points, for further development efforts.” Otsuka
`Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). A
`compound may be considered a candidate “lead compound” if it is “most
`promising to modify in order to improve upon its . . . activity,” or “a natural
`choice for further development efforts.” Takeda Chem. Indus., Ltd. v.
`Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007); Altana
`Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009).
`The question of whether a person of ordinary skill in the art would have
`selected a compound as a lead compound is “guided by evidence of the
`compound’s pertinent properties.” Otsuka, 678 F.3d at 1292.
`Once it is determined that a person of ordinary skill in the art would
`have selected a particular lead compound, the second part of the analysis
`asks whether the artisan would have had reason to modify the lead
`compound to make the claimed compound, with a reasonable expectation of
`success. Id.
`Par’s proposed lead compound analysis may be summarized as
`follows. First, Par contends that a person of ordinary skill in the art would
`have selected rapamycin as a lead compound for developing improved
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`immunosuppressants. Pet. 26. As support, Par cites Morris’ disclosure of
`rapamycin’s “potent immunosuppressant activities,” as well as its
`description of rapamycin as “particularly intriguing.” Id. (citing Ex. 1005,
`39–42). Dr. Jorgensen testifies in support of this contention, also citing Van
`Duyne’s disclosure of the structure of rapamycin bound to FKBP-12,
`opining that this would have given the person of ordinary skill in the art
`further reason to select rapamycin as lead compound. Ex. 1003 ¶¶ 132–137.
`Par notes, however, that rapamycin was known to have low solubility,
`and that this would have been understood to limit the bioavailability of the
`drug. Pet. 41 (citing Ex. 1005, 46; Ex. 1003 ¶¶ 138–140). Par contends that
`a person of ordinary skill in the art would have had reason to modify
`rapamycin’s solubility to increase its bioavailability. Id. at 41–42.
`Having selected rapamycin as a lead compound that might benefit
`from modification, Par alleges a person of ordinary skill in the art would
`have turned to Van Duyne’s disclosure of the structure of rapamycin bound
`to the FKBP-12 protein, to understand the interaction of the drug with its
`known biological targets. Id. at 42. Dr. Jorgensen testifies that the skilled
`artisan would have first looked to rapamycin’s hydroxyl groups located at
`C10, C28, and C40 as potential sites for substitution. Ex. 1003 ¶ 142. Van
`Duyne allegedly discloses that rapamycin’s C40 carbon is located on the
`periphery of the binding with FKBP-12, whereas C10 and C28 are part of
`the binding domain. Id. ¶¶ 143–144; Ex. 1006, 7434.
`Par contends the skilled artisan would have used the method of
`Rossmann to convert Van Duyne’s stereograms into the alpha-carbon
`structural coordinates of the rapamycin/FKBP-12 complex, which would
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`have further confirmed the potential of C40 as a site for substitution. Pet.
`43–44. Dr. Jorgensen goes further, stating that the coordinates of the full
`structure of the rapamycin/FKBP-12 complex could have been obtained by
`contacting the authors of Van Duyne, and a person of ordinary skill in the art
`could have constructed a full three-dimensional model of the complex using
`known computer models. Ex. 1003 ¶¶ 113–14. From these models,
`Dr. Jorgensen concludes, the skilled artisan would have confirmed the
`suitability of C40 as a potential site for substitution. Id. ¶¶ 115–20.
`
`Finally, Par argues that a person of ordinary skill in the art would
`have looked to Yalkowski and Lemke to determine which substitutions to
`make at C40, and would have ultimately decided to attempt introduction of a
`flexible side chain containing an alcohol, amine, or carboxylic acid group.
`Pet. 44–47. Dr. Jorgensen testifies that small substituents would have been
`attempted first, therefore, the skilled artisan would have selected three initial
`candidates: the 2-hydroxyethoxy group (OCH2CH2OH), the 2-aminoethoxy
`group (OCH2CH2NH2), and the carboxymethoxy group (OCH2COOH).
`Ex. 1003 ¶¶ 150–53. Par notes that rapamycin modified to include a 2-
`hydroxyethoxy group at C40 is the particular derivative claimed in claim 10,
`40-O-(2-hydroxyethyl)-rapamycin (everolimus). Pet. 48. Because this
`compound falls within the scope of claims 1–3 as well, Par asserts that this
`lead compound analysis demonstrates the obviousness of claims 1–3 and 10.
`Id.
`
`3. The Level of Ordinary Skill in the Art
`Par contends, supported by the testimony of Dr. Jorgensen, that a
`person of ordinary skill in the art at the time of the invention would
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`generally have a Ph.D. in organic chemistry or medicinal chemistry or
`physical chemistry or a related field, or a Masters or Bachelor degree in
`chemistry or a related field and at least three years’ experience in drug
`discovery and design. Pet. 16 (citing Ex. 1003 ¶ 45). Novartis’ experts,
`with insubstantial exceptions, agree with Dr. Jorgensen’s recitation.
`Ex. 2092 ¶ 22 (Klibanov); Ex. 2093 ¶¶ 47–48 (Roush). We adopt the level
`of skill recited by the parties for purposes of our analysis herein.
`
`C. The Parties’ Factual Disputes
`
`During the instituted trial, the parties disputed facts relevant to almost
`
`every stage of Par’s proposed lead compound analysis. We resolve these
`factual disputes below, before turning to the question of obviousness.
`
`1. Selection of Rapamycin as Lead Compound
`Novartis first challenges Par’s contention that a person of ordinary
`skill in the art would have selected rapamycin as a lead compound for
`developing improved immunosuppressants. PO Resp. 47–50. Novartis
`argues that, as evidenced by the totality of the prior art, as of October 1992
`there were a number of known, promising immunosuppressants. Id. at 48
`(citing Ex. 2001, 61 (cyclosporin A), Ex. 1012, 283 (tacrolimus), Ex. 2023,
`517–18 (mycophenolate mofetil)). Some of these other compounds were
`reported to have effectiveness without major adverse effects, whereas
`rapamycin was known to be toxic. Id. Novartis argues that Par failed to
`provide any advantageous properties of rapamycin that would have led to its
`selection over these other compounds, other than its hindsight-based
`similarity to the claimed compound everolimus. Id. at 49–50.
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`Par responds that the law does not require it to identify the single most
`promising lead compound. Pet. Reply 3 (citing Daiichi Sankyo v. Matrix
`Labs., 619 F.3d 1346, 1354 (Fed. Cir. 2010)). Rather, rapamycin would
`have been among the group of lead compounds that a person of ordinary
`skill would have targeted for investigation, Par argues, because of
`rapamycin’s known potency. Id. at 4. As evidence supporting this selection,
`Par notes that rapamycin’s potency was known to be “greater than FK506
`[tacrolimus] and much greater than CsA [cyclosporin A].” Id. (quoting
`Ex. 1005, 55). Citing the testimony of Novartis’ expert Dr. Roush, Par also
`observes that researchers in the field were actually studying modifications to
`rapamycin during the relevant timeframe, further evidencing its potential as
`a lead compound. Id. (citing Ex. 2092 ¶¶ 63–83).
`Upon review of the record, we find that the evidence supports Par’s
`contention that a person of ordinary skill in the art would have recognized
`the potency of rapamycin and its potential for development of new
`immunosuppressant. Indeed, this known potency is recognized in the ’772
`patent’s discussion of the prior art, stating that the “known macrolide
`antibiotic” rapamycin “is an extremely potent immunosuppressant.”
`Ex. 1001, 1:10–35. We also find it relevant that others in the field were
`working to modify rapamycin, as Novartis’ expert acknowledged. Ex. 2029
`¶¶ 63–83; see also Ex. 1005 (describing rapamycin as “particularly
`intriguing”). The fact that other immunosuppressants have other beneficial
`characteristics such as lower toxicity does not convince us that a person of
`ordinary skill in the art would only investigate those compounds, ruling out
`rapamycin entirely.
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`That said, it is relevant to the lead compound analysis that rapamycin
`was only one of several known immunosuppressants, each of which had
`relative strengths and weaknesses. We find that a skilled researcher would
`have investigated rapamycin as a lead compound, but not to the exclusion of
`these other immunosuppressants.
`
`2. Rationale to Modify Rapamycin to Increase Solubility
`Having selected rapamycin as a lead compound, Par next contends
`that a person of ordinary skill in the art would have had reason to modify
`rapamycin in order to increase its solubility, and thus its bioavailability as a
`drug. Pet. 41–42. As support for this contention, Par observes that Morris
`reported rapamycin as being “only minimally soluble in water.” Ex. 1005,
`46. Dr. Jorgensen, Par’s expert, testifies that because “[a]queous solubility
`of a molecule influences its absorption in animals,” a skilled artisan would
`have recognized that improving the solubility of a poorly soluble drug would
`increase its bioavailability. Ex. 1003 ¶ 140. In turn, Dr. Jorgensen testifies,
`this increased bioavailability would allow lower doses of the drug to be
`administered, and allow the drug to be administered via oral administration.
`Id.
`
`Novartis contends that a person of ordinary skill in the art in 1992
`would not have had reason to attempt to increase rapamycin’s solubility. PO
`Resp. 51–52. According to Novartis, the prior art does not reflect any belief
`that rapamycin’s water solubility was problematically low, or that its
`bioavailability needed to be increased. Id. Novartis also cites the trial
`testimony of Dr. Partridge, Par’s expert in a copending District Court
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`action11 involving the ’772 patent, who agreed that as of October 1992
`rapamycin was “water soluble enough” to be used as an immunosuppressant
`and that it was not necessary to modify rapamycin for its
`immunosuppressant activity “to be realized.” Ex. 2107, 228:24–229:11.
`Alternatively, even if there existed a reason to increase the solubility
`of rapamycin in October 1992, Novartis argues, a person of ordinary skill in
`the art had other known ways of increasing solubility other than modifying
`the molecule itself. PO Resp. 53–55. For example, known techniques for
`improving water solubility at the time included formulation approaches such
`as reduced particle size or surfactants, the creation of prodrugs, and water-
`soluble salts. Id. (citing Ex. 2092 ¶¶ 157–159 (formulation), ¶¶ 161–170
`(prodrugs), ¶¶ 171–173 (water-soluble salts)). Novartis argues that each of
`these techniques would have been preferred over synthesizing a new
`derivative of rapamycin, because they would have had a better chance at
`maintaining the drug’s activity and would have been seen as “safer” than the
`“risky and uncertain” derivatives approach. Id. (quoting Janssen Pharm.
`N.V. v. Mylan Pharms., Inc., 456 F. Supp. 2d 644, 666–67 (D.N.J. 2006)).
`Par responds to Novartis’ first argument by noting that the insolubility
`of rapamycin was a recognized problem in the art (Pet. Reply 6 (citing
`Ex. 1034, 116), and that even if it were not explicitly recognized, a person of
`ordinary skill in the art would have understood the benefits of increased
`
`11 Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 14-1289-RGA (D.
`Del.). Trial was consolidated with Novartis Pharm. Corp. et al. v.
`Breckenridge Pharm., Inc., No. 14-1043-RGA (D. Del.) and Novartis
`Pharm. Corp. et al. v. Roxane Labs., Inc., No. 14-1196-RGA (D. Del.), and
`held on August 29–September 1, 2016.
`17
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`bioavailability that could be achieved through increased solubility. Id. at 5
`(citing Ex. 1118 ¶¶ 25–26). Furthermore, Par contends, the fact that
`rapamycin was “soluble enough” to be used as an immunosuppressant does
`not mean that a person of ordinary skill in the art would not have tried to
`increase that solubility. Id.
`To Novartis’ second argument, Par responds that other approaches to
`increasing solubility, “while legitimate avenues for research, [] pose
`particular challenges of their own.” Id. at 7. For example, Par notes that
`formulation approaches carried risks such as increased toxicity (id. at 6
`(citing Ex. 1034, 116)), while prodrugs require metabolic conversion and
`create the potential for inter- and intra-subject variability (id. at 7).
`We agree with Par on both counts. The record supports the
`conclusion that a person of ordinary skill in the art would have had reason to
`increase the solubility of the “minimally soluble” rapamycin, and one
`possible strategy to do so would be to create a derivative of the compound.
`For example, the Stella12 patent recognized that “there is a need in the art for
`a rapamycin derivative or prodrug which is relatively soluble in water so as
`to form a safe and injectable solution and which is as effective as rapamycin
`in the treatment of tumors.” Ex. 1010, 1:25–30. Par is correct in noting that
`a method selected to address a known problem need not be “the best option,
`only . . . 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). The fact
`that a derivative approach is “risky and uncertain,” and had known
`
`
`12 U.S. Patent No. 4,650,803 to Stella et al. (Mar. 17, 1987) (Ex. 1010).
`18
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`disadvantages such as potential reduction in immunosuppressant activity, is
`not sufficient to convince us that the art taught away from such approaches.
`Rather, the record supports the conclusion that all experimental approaches
`had potential benefits and drawbacks; indeed, this is inherent in the pursuit
`of scientific study. Alternative approaches, such as prodrugs or water-
`soluble salts, were not so clearly better than derivative synthesis that a
`person of ordinary skill in the art would have ruled out the latter.13 By the
`same token, however, we note that the derivatives approach was not clearly
`better than the alternatives Novartis raises; it was merely one of many
`possible approaches. This is certainly relevant to the obviousness analysis,
`which will be discussed below.
`
`3. Reasonable Expectation of Success in Making the Modification
`Next, Novartis contends that even if a person of ordinary skill in the
`art in October 1992 would have had reason to modify rapamycin, there
`would have been no reasonable expectation of success in doing so. “The
`reasonable expectation of success requirement refers to the likelihood of
`success in combining references to meet the limitations of the claimed
`invention.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d
`1359, 1367 (Fed. Cir. 2016). Novartis argues that there must also be a
`“reasonable expectation of success in achieving the actual combination of
`properties that the claimed compound possesses.” PO. Resp. 56 (emphasis
`
`
`13 At oral argument, Novartis’ counsel conceded that, “certainly[,] one of
`ordinary skill would consider making derivatives as one particular option.”
`Tr. 64:1–3.
`
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`in original). Because the record does not support the conclusion that a
`person of ordinary skill in the art would have expected “everolimus’ unique
`combination of properties, including immunosuppressant and antitumor
`activity,” Novartis contends the obviousness ground must fail. Id. at 56–60.
`Alternatively, even if our analysis is more narrowly focused on the
`solubility of the compound, Novartis argues there would have been no
`reasonable expectation of success. Id. at 29–30. According to Novartis, Par
`does not identify the degree of improved solubility or bioavailability that
`would have been considered a “success.” Id. at 30–31
`Par responds first by asserting that the law does not require that a
`person of skill in the art anticipate all properties of the claimed compound to
`have a reasonable expectation of success. Pet. Reply 17. Novartis’
`argument, Par contends, confuses the reasonable expectation of success with
`the secondary consideration of unexpected results. Id. at 17–18 (citing
`Bristol-Myers Squibb v. Teva Pharm. USA, 752 F.3d 967, 976 (Fed. Cir.
`2014).
`Par is correct; the law does not require that a person of ordinary skill
`have a reasonable expectation of success in achieving a compound with all
`the properties of the claimed compound. Rather, as the Federal Circuit
`noted, it is the limitations of the claims themselves that define the reasonable
`expectation of success. See Intelligent Bio-Sys., 821 F.3d at 1367 (referring
`to the “likelihood of success in combining references to meet the limitations
`of the claimed invention” (emphasis added)). Put differently, “one must
`have a motivation to combine accompanied by a reasonable expectation of
`achieving what is claimed in the patent-at-issue.” Id.
`
`
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`The cases cited by Novartis do not compel a contrary result. In re
`Rosuvastatin, 703 F.3d 511 (Fed. Cir. 2012), noted that at trial, the plaintiffs
`had “argued that the prior art provided no suggestion of rosuvastatin’s
`unexpectedly superior properties,” but the Federal Circuit did not rely on
`this argument as a basis for affirming the trial court’s conclusion of
`nonobviousness. Id. at 517–518. The Federal Circuit in Yamanouchi
`Pharm. Co. v. Danbury Pharmacal,
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